CN108264474B - A kind of synthetic method of tryptamines and its derivative - Google Patents
A kind of synthetic method of tryptamines and its derivative Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 15
- -1 anhydride compound Chemical class 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000006722 reduction reaction Methods 0.000 claims abstract description 17
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000012280 lithium aluminium hydride Substances 0.000 claims abstract description 12
- 230000009467 reduction Effects 0.000 claims abstract description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 10
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims abstract description 9
- 230000007062 hydrolysis Effects 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 238000006462 rearrangement reaction Methods 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 6
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims abstract description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002131 composite material Substances 0.000 claims abstract description 3
- 239000000543 intermediate Substances 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 3
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 claims description 2
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 2
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- MEFKFJOEVLUFAY-UHFFFAOYSA-N (2,2,2-trichloroacetyl) 2,2,2-trichloroacetate Chemical compound ClC(Cl)(Cl)C(=O)OC(=O)C(Cl)(Cl)Cl MEFKFJOEVLUFAY-UHFFFAOYSA-N 0.000 claims 1
- 229910001148 Al-Li alloy Inorganic materials 0.000 claims 1
- FCVHBUFELUXTLR-UHFFFAOYSA-N [Li].[AlH3] Chemical compound [Li].[AlH3] FCVHBUFELUXTLR-UHFFFAOYSA-N 0.000 claims 1
- 150000008065 acid anhydrides Chemical class 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 150000003457 sulfones Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- 150000002475 indoles Chemical class 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical compound C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 description 6
- 238000000926 separation method Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- DMCPFOBLJMLSNX-UHFFFAOYSA-N indole-3-acetonitrile Chemical compound C1=CC=C2C(CC#N)=CNC2=C1 DMCPFOBLJMLSNX-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 229910010084 LiAlH4 Inorganic materials 0.000 description 2
- CHIFTAQVXHNVRW-UHFFFAOYSA-N Nitrile-1H-Indole-3-carboxylic acid Natural products C1=CC=C2C(C#N)=CNC2=C1 CHIFTAQVXHNVRW-UHFFFAOYSA-N 0.000 description 2
- 229910002666 PdCl2 Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- XZRVKVCMOMBFJJ-UHFFFAOYSA-N acetonitrile methane Chemical compound C.CC#N XZRVKVCMOMBFJJ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- LJCNRYVRMXRIQR-UHFFFAOYSA-L potassium sodium tartrate Chemical compound [Na+].[K+].[O-]C(=O)C(O)C(O)C([O-])=O LJCNRYVRMXRIQR-UHFFFAOYSA-L 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- OZDNDGXASTWERN-CTNGQTDRSA-N Apovincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OC)N5C2=C1 OZDNDGXASTWERN-CTNGQTDRSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- XXRCUYVCPSWGCC-UHFFFAOYSA-N Ethyl pyruvate Chemical compound CCOC(=O)C(C)=O XXRCUYVCPSWGCC-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- DDNCQMVWWZOMLN-IRLDBZIGSA-N Vinpocetine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OCC)N5C2=C1 DDNCQMVWWZOMLN-IRLDBZIGSA-N 0.000 description 1
- WYTGDNHDOZPMIW-RCBQFDQVSA-N alstonine Chemical compound C1=CC2=C3C=CC=CC3=NC2=C2N1C[C@H]1[C@H](C)OC=C(C(=O)OC)[C@H]1C2 WYTGDNHDOZPMIW-RCBQFDQVSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 230000002460 anti-migrenic effect Effects 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 229950006936 apovincamine Drugs 0.000 description 1
- OZDNDGXASTWERN-UHFFFAOYSA-N apovincamine Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)C=C(C(=O)OC)N5C2=C1 OZDNDGXASTWERN-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940117360 ethyl pyruvate Drugs 0.000 description 1
- 229930005303 indole alkaloid Natural products 0.000 description 1
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- RPMXALUWKZHYOV-UHFFFAOYSA-N nitroethene Chemical group [O-][N+](=O)C=C RPMXALUWKZHYOV-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000004031 phenylhydrazines Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960003708 sumatriptan Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 description 1
- 229960000744 vinpocetine Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the synthetic methods of a kind of tryptamines and its derivative, include the following steps: (1) in the presence of anhydride compound, aryl sulfoxid es shown in structural formula (I) carry out rearrangement reaction, intermediate A shown in composite structure formula (III) with the nitrile compounds that alpha tin shown in structural formula (II) replaces；(2) under the action of magnesium powder and alkali, intermediate A obtains intermediate B shown in structure formula (IV) through basic hydrolysis；(3) in the tetrahydrofuran solution of intermediate B, triethylsilane, trim,ethylchlorosilane and palladium chloride is sequentially added and is reacted, obtain intermediate C shown in structure formula (V)；(4) under the action of lithium aluminium hydride reduction, reduction reaction occurs for intermediate C, obtains tryptamines shown in structure formula (VI) or derivatives thereof.The method of the present invention has reaction condition mild, and selectivity is good, and high income, product is easily separated, simple operation and other advantages.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to the synthetic method of a kind of tryptamines and its derivative.
Background technique
Tryptamines (Tryptamine), entitled 3- (the 2- amine ethyl) indoles of chemistry, tryptamines series derivates are critically important changes
Close object makes it have huge physiology, pharmacological property in terms of central nervous system due to the particularity of its structure.Tryptamines is derivative
Object has good result in terms of anti-migraine, and the drug listed includes sumatriptan, and Leeza is general smooth,
Triazolytryptamine etc..Furthermore for synthesis of indole Alkaloid pervone, vinpocetine etc., detailed process is tryptamines
Indoles tetracyclic is obtained with tryptamines and 3- ethyl -2- pyrans reactive ketone, then reacts to obtain Changchun with ethyl pyruvate active ester
Amine ethyl ester both obtains racemization Apovincamine acetoacetic ester with p-methyl benzenesulfonic acid dehydration, obtains single configuration Changchun with column chromatography for separation
Xi Ting, gross production rate 41% or so；Tryptamines is also a kind of important biochemical reagents simultaneously.
The method for synthesizing tryptamine derivatives is relatively more, specifically includes that (1) indoles is that raw material reacts to obtain through Wei Er David Smail
Then indole -3-formaldehyde reacts to obtain 3- (2- nitroethenyl group) indoles with nitromethane, most adds hydrogen or lithium aluminium hydride reduction through palladium charcoal afterwards
It is heated to reflux and restores to obtain 3- (2- amine ethyl) indoles；
(2) Michael addition reaction occurs for indole derivatives and nitroethylene derivative, obtains 3- (2- nitroethenyl group)
Indoles obtains tryptamines using reduction；
(3) tryptophan is through 265 DEG C of high temperature, N2Lower decarboxylation is protected to obtain tryptamines；
(4) tryptamines is obtained through multistep reaction using aniline and diethyl malonate as raw material；
(5) Fisher indoles method synthesizes: preparing tryptamines using substituted phenylhydrazines and the dimethylacetal condensation of 4- chlorobutyl；
(6) Mannich reaction occurs for indoles, formaldehyde and secondary amine, is passing through cyanogenation, finally reduction preparation.
Summary of the invention
In order to overcome defect existing in the prior art, the present invention provides the synthesis sides of a kind of tryptamines and its derivative
Method has reaction condition mild, and selectivity is good, and high income, product is easily separated, simple operation and other advantages.
The technical solution adopted by the invention is as follows:
The synthetic method of a kind of tryptamines and its derivative, includes the following steps:
(1) in the presence of anhydride compound, aryl sulfoxid es shown in structural formula (I) and alpha tin shown in structural formula (II)
Substituted nitrile compounds carry out rearrangement reaction, intermediate A shown in composite structure formula (III)；
(2) under the action of magnesium powder and alkali, intermediate A obtains intermediate B shown in structure formula (IV) through basic hydrolysis；
(3) in the tetrahydrofuran solution of intermediate B, triethylsilane, trim,ethylchlorosilane and palladium chloride are sequentially added
It is reacted, obtains intermediate C shown in structure formula (V)；
(4) under the action of lithium aluminium hydride reduction, intermediate C occur reduction reaction, obtain tryptamines shown in structure formula (VI) or
Tryptamine derivatives；
Wherein, R is selected from hydrogen or alkyl.
The synthetic route of tryptamines of the present invention is as follows:
The anhydride compound is trifluoroacetic anhydride, trifluoromethanesulfanhydride anhydride, methanesulfonic acid acid anhydride, p-toluenesulfonic anhydride, trichlorine
At least one of acetic anhydride, acetic anhydride, chloro difluoro acetic acid acid anhydride and glutaric anhydride.
In step (1), the molar ratio that adds of nitrile compounds and anhydride compound that aryl sulfoxid es, alpha tin replace is 1:
1.1~2:1.1~2.
In step (1), the temperature of rearrangement reaction is -80~0 DEG C, and the time of rearrangement reaction is 10min~15h.
In step (1), the rearrangement reaction carries out in a solvent, and solvent for use is acetonitrile or methylene chloride.
In step (2), the alkali is at least one of ammonium chloride, ammonium nitrate and ammonium sulfate.
In step (2), the molar ratio that adds of intermediate A, magnesium powder and alkali is 1:40~60:40~60.
In step (2), the temperature of hydrolysis is 30~60 DEG C, and the time of hydrolysis is 8~15h.
In step (2), the hydrolysis carries out in a solvent, and solvent for use is methanol, at least one in second alcohol and water
Kind.
In step (3), intermediate B, triethylsilane, trim,ethylchlorosilane and palladium chloride the molar ratio that adds be 1:1.5
~2.5:1~1.5:0.03~0.08.
In step (3), reaction temperature is 20~40 DEG C, and the reaction time is 2~5h.
In step (4), the molar ratio that adds of intermediate C and lithium aluminium hydride reduction is 1:3~5.
In step (4), the temperature of the reduction reaction is 20~40 DEG C, and the time of reduction reaction is 8~15h.
It in step (4), specifically includes: lithium aluminium hydride reduction is dissolved in ether, at -5~5 DEG C, under nitrogen protection, by aluminum hydride
The diethyl ether solution of lithium instills in the diethyl ether solution of intermediate C, and drop finishes, and 8~15h is reacted at 20~40 DEG C.
Compared with prior art, it has the following beneficial effects:
(1) reaction provides the tryptamine derivatives that conventional method is difficult to the branch synthesized substitution；
(2) reaction condition is mild；
(3) reaction selectivity is high；
(4) reaction raw materials are easy to get, and yield is higher.
Specific embodiment
Embodiment 1
(1)
(1) -40 DEG C, under nitrogen protection, in aryl sulfoxid es (1.67g, 5mmol) and α-tributyl tin acetonitrile (2.48g,
It is added dropwise trifluoroacetic anhydride (TFAA, 1.04mL, 0.75mmol), reacts in acetonitrile (MeCN, 25mL) solution 7.5mmol)
12h。
(2) it is gradually increased to room temperature after 20mL saturated sodium bicarbonate solution being added in reaction solution, uses dichloro after being spin-dried for acetonitrile
Methane (30mL × 3) extraction, concentration can obtain 1.5g product Intermediate through column chromatography for separation after organic phase is dried over anhydrous sodium sulfate
A, yield 84%, white solid.
Target product is characterized as below:
1H NMR(600MHz,CDCl3): δ 8.39 (d, J=8.6Hz, 1H), 7.82 (t, J=8.0Hz, 2H), 7.60 (d, J
=7.9Hz, 1H), 7.49-7.42 (m, 1H), 7.35 (t, J=7.5Hz, 1H), 7.21 (d, J=8.2Hz, 2H), 3.93 (s,
2H),2.48(s,3H),2.35(s,3H)。
13C NMR(151MHz,CDCl3):δ145.3,137.9,135.8,131.5,129.8,127.5,127.3,
126.8,124.2,119.9,119.0,116.9,115.6,21.7,21.4,14.3。
(2)
(1) 40 DEG C, under nitrogen protection, in the methanol of intermediate A (356mg, 1mmol) and magnesium powder (1.0g, 50mmol)
NH is slowly added into (MeOH, 25mL) solution4Cl (2.68g, 50mmol) is warming up to 50 DEG C of reactions after the generation of no bubble
12h。
(2) 20g silica white is added to be spin-dried for washing filtering with ethyl acetate after reaction solution, through column chromatography point after filtrate concentration
From 188mg product 2- methyl mercapto-indole -3-acetonitrile, yield 93%, white solid can be obtained.
Target product is characterized as below:
1H NMR(600MHz,CDCl3): δ 8.41 (s, 1H), 7.65 (d, J=7.9Hz, 1H), 7.34 (d, J=8.2Hz,
1H),7.30-7.24(m,1H),7.22-7.18(m,1H),3.96(s,2H),2.40(s,3H)。
13C NMR(151MHz,CDCl3):δ136.3,128.7,126.6,123.8,120.7,118.5,118.1,
111.2,109.1,20.0,13.7。
(3)
(1) room temperature, it is molten in 2- methyl mercapto-indole -3-acetonitrile (188mg, 0.93mmol) tetrahydrofuran under nitrogen protection
Triethylsilane (Et is sequentially added in liquid3SiH, 226mg, 1.95mmol), trim,ethylchlorosilane (TMSCl, 0.93mmol,
100mg), palladium chloride (PdCl2, 8.2mg) and reaction 3h.
(2) it is spin-dried for that 126mg product indole -3-acetonitrile, yield 87%, white solid can be obtained through column chromatography for separation.
Target product is characterized as below:
1H NMR(600MHz,CDCl3): δ 8.21 (s, 1H), 7.60 (d, J=7.9Hz, 1H), 7.41 (d, J=8.1Hz,
1H), 7.27 (dd, J=10.8,4.3Hz, 1H), 7.23 (d, J=1.2Hz, 1H), 7.20 (dd, J=7.8,7.2Hz, 1H),
3.85(s,2H)。
13C NMR(151MHz,CDCl3):δ136.4,126.1,123.0,122.9,120.4,118.3,118.2,
111.7,104.9,14.6。
(4)
(1) 0 DEG C, under nitrogen protection, in lithium aluminium hydride reduction (LiAlH4, 123mg, 3.24mmol) ether (Et2O, 2mL) it is molten
Ether (2mL) solution of indole -3-acetonitrile (126mg, 0.81mmol) is added dropwise in liquid, drop finishes, after being gradually brought to room temperature
React 12h.
At (2) 0 DEG C, saturation sodium tartrate potassium salt soln (5mL) is added in reaction solution, uses second after stirring 30min at room temperature
Acetoacetic ester (5mL × 5) extraction, organic phase is concentrated into after 1mL after being dried over anhydrous sodium sulfate topples over 30mL petroleum ether thereto,
It is filtered after -50 DEG C of freezing 30min up to white solid tryptamines, 97mg, yield 75%.
Target product is characterized as below:
1H NMR(600MHz,CDCl3): δ 8.45 (d, J=65.2Hz, 1H), 7.63 (d, J=7.9Hz, 1H), 7.41-
7.30 (m, 1H), 7.24-7.16 (m, 1H), 7.13 (t, J=7.4Hz, 1H), 7.02 (s, 1H), 3.05 (t, J=6.6Hz,
2H), 2.93 (t, J=6.6Hz, 2H), 1.40 (s, 2H).
13C NMR(151MHz,CDCl3):δ136.54,127.56,122.23,122.02,119.28,118.95,
113.66,111.29,42.41,29.55。
Embodiment 2
(1)
(1) -40 DEG C, under nitrogen protection, in aryl sulfoxid es (1.67g, 5mmol) and α-tributyl tin valeronitrile (2.79g,
7.5mmol), it is added dropwise trifluoroacetic anhydride (TFAA, 1.04mL, 0.75mmol), reacts in acetonitrile (MeCN, 25mL) solution
12h。
(2) it is gradually increased to room temperature after 20mL saturated sodium bicarbonate solution being added in reaction solution, uses dichloro after being spin-dried for acetonitrile
Methane (30mL × 3) extraction, concentration can obtain among 1.79g product through column chromatography for separation after organic phase is dried over anhydrous sodium sulfate
Body A, yield 90%.
Target product is characterized as below:
1H NMR(600MHz,CDCl3): δ 8.39 (d, J=8.5Hz, 1H), 7.75 (t, J=8.4Hz, 3H), 7.44 (m,
1H), 7.36-7.31 (m, 1H), 7.19 (d, J=8.1Hz, 2H), 4.44 (t, J=7.9Hz, 1H), 2.49 (s, 3H), 2.35
(s,3H),2.11-2.01(m,1H),1.79-1.69(m,1H),1.46-1.36(m,1H),1.31-1.20(m,1H),0.89
(t, J=7.4Hz, 3H).
13C NMR(151MHz,CDCl3):δ145.3,138.4,135.7,131.0,129.8,127.2,126.9,
126.6,125.0,124.2,120.1,119.6,116.0,35.6,28.5,21.7,21.7,20.6,13.4。
(2)
(1) 40 DEG C, under nitrogen protection, in the methanol of intermediate A (398mg, 1mmol) and magnesium powder (1.0g, 50mmol)
NH is slowly added into (MeOH, 25mL) solution4Cl (2.68g, 50mmol) is warming up to 50 DEG C of reactions after the generation of no bubble
12h。
(2) 20g silica white is added to be spin-dried for washing filtering with ethyl acetate after reaction solution, through column chromatography point after filtrate concentration
From 217mg product Intermediate B, yield 89%, colorless oil can be obtained.
Target product is characterized as below:
1H NMR(600MHz,CDCl3): δ 8.52 (s, 1H), 7.79 (d, J=8.0Hz, 1H), 7.34 (d, J=8.2Hz,
1H), 7.29-7.23 (m, 1H), 7.19 (t, J=7.5Hz, 1H), 4.36 (t, J=7.9Hz, 1H), 2.39 (s, 3H), 2.23-
2.13 (m, 1H), 1.94 (m, 1H), 1.60-1.51 (m, 1H), 1.50-1.41 (m, 1H), 0.98 (t, J=7.4Hz, 3H).
13C NMR(151MHz,CDCl3):δ136.7,128.0,125.6,123.5,121.2,120.4,119.0,
114.3,111.2,36.2,28.1,20.7,20.1,13.5。
(3)
(1) room temperature under nitrogen protection, sequentially adds in the tetrahydrofuran solution of intermediate B (227mg, 0.93mmol)
Triethylsilane (Et3SiH, 226mg, 1.95mmol), trim,ethylchlorosilane (TMSCl, 0.93mmol, 100mg), palladium chloride
(PdCl2, 8.2mg) and reaction 3h.
(2) it is spin-dried for that 153.5mg product Intermediate C, yield 83%, colorless oil can be obtained through column chromatography for separation.
Target product is characterized as below:
1H NMR(600MHz,CDCl3): δ 8.42 (s, 1H), 7.73 (d, J=7.9Hz, 1H), 7.42 (d, J=8.1Hz,
1H), 7.31 (t, J=7.5Hz, 1H), 7.25 (t, J=7.5Hz, 1H), 7.14 (d, J=2.4Hz, 1H), 4.11 (dd, J=
8.3,6.4Hz, 1H), 2.14-1.97 (m, 2H), 1.69-1.51 (m, 2H), 1.03 (t, J=7.4Hz, 3H).
13C NMR(151MHz,CDCl3):δ136.4,125.2,122.5,122.4,121.5,119.9,118.3,
111.8,110.2,35.8,28.5,20.4,13.4。
(4)
(1) 0 DEG C, under nitrogen protection, in lithium aluminium hydride reduction (LiAlH4, 123mg, 3.24mmol) ether (Et2O, 2mL) it is molten
Ether (2mL) solution of intermediate C (160mg, 0.81mmol) is added dropwise in liquid, drop finishes, reacts after being gradually brought to room temperature
12h。
At (2) 0 DEG C, saturation sodium tartrate potassium salt soln (5mL) is added in reaction solution, uses second after stirring 30min at room temperature
Acetoacetic ester (5mL × 5) extraction, organic phase is concentrated into after 1mL after being dried over anhydrous sodium sulfate topples over 30mL petroleum ether thereto,
It is filtered after -50 DEG C of freezing 30min up to 139mg tryptamine derivatives, yield 85%, colorless oil.
Target product is characterized as below:
1H NMR(600MHz,CDCl3): δ 8.65 (s, 1H), 7.65 (d, J=7.8Hz, 1H), 7.35 (d, J=8.0Hz,
1H), 7.19 (t, J=7.4Hz, 1H), 7.10 (t, J=7.4Hz, 1H), 6.97 (s, 1H), 3.03-2.90 (m, 3H), 1.77-
1.64 (m, 2H), 1.56 (s, 2H), 1.35-1.22 (m, 2H), 0.88 (t, J=7.3Hz, 3H).
13C NMR(151MHz,CDCl3):δ136.8,127.1,121.9 119.5,119.1,117.5,111.4,47.0,
40.6,35.6,20.9,14.3。
Claims (10)
1. the synthetic method of a kind of tryptamines and its derivative, which comprises the steps of:
(1) in the presence of anhydride compound, aryl sulfoxid es shown in structural formula (I) replace with alpha tin shown in structural formula (II)
Nitrile compounds carry out rearrangement reaction, intermediate A shown in composite structure formula (III)；
(2) under the action of magnesium powder and alkali, intermediate A obtains intermediate B shown in structure formula (IV) through basic hydrolysis；
(3) in the tetrahydrofuran solution of intermediate B, triethylsilane, trim,ethylchlorosilane and palladium chloride is sequentially added and is carried out
Reaction, obtains intermediate C shown in structure formula (V)；
(4) under the action of lithium aluminium hydride reduction, reduction reaction occurs for intermediate C, obtains tryptamines shown in structure formula (VI) or tryptamines
Derivative；
Wherein, R is selected from hydrogen or alkyl.
2. the synthetic method of tryptamines according to claim 1 and its derivative, which is characterized in that the anhydride compound
For trifluoroacetic anhydride, trifluoromethanesulfanhydride anhydride, methanesulfonic acid acid anhydride, p-toluenesulfonic anhydride, Trichloroacetic anhydride, acetic anhydride, a chlorine difluoro second
At least one of acid anhydrides and glutaric anhydride.
3. the synthetic method of tryptamines according to claim 1 and its derivative, which is characterized in that in step (1), aryl is sub-
The molar ratio of sulfone, the nitrile compounds that alpha tin replaces and anhydride compound is 1:1.1~2:1.1~2.
4. the synthetic method of tryptamines according to claim 1 and its derivative, which is characterized in that in step (1), reset anti-
The temperature answered is -80~0 DEG C, and the time of rearrangement reaction is 10min~15h.
5. the synthetic method of tryptamines according to claim 1 and its derivative, which is characterized in that in step (2), the alkali
For at least one of ammonium chloride, ammonium nitrate and ammonium sulfate.
6. the synthetic method of tryptamines according to claim 1 and its derivative, which is characterized in that in step (2), intermediate
A, magnesium powder and the molar ratio of alkali are 1:40~60:40~60.
7. the synthetic method of tryptamines according to claim 1 and its derivative, which is characterized in that in step (2), hydrolysis is anti-
The temperature answered is 30~60 DEG C, and the time of hydrolysis is 8~15h.
8. the synthetic method of tryptamines according to claim 1 and its derivative, which is characterized in that in step (3), intermediate
B, the molar ratio of triethylsilane, trim,ethylchlorosilane and palladium chloride is 1:1.5~2.5:1~1.5:0.03~0.08.
9. the synthetic method of tryptamines according to claim 1 and its derivative, which is characterized in that in step (4), intermediate
The molar ratio of C and lithium aluminium hydride reduction is 1:3~5.
10. the synthetic method of tryptamines according to claim 1 and its derivative, which is characterized in that in step (4), by hydrogen
Change aluminium lithium to be dissolved in ether, at -5~5 DEG C, under nitrogen protection, the ether that the diethyl ether solution of lithium aluminium hydride reduction is instilled intermediate C is molten
In liquid, drop finishes, and 8~15h is reacted at 20~40 DEG C.
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