CN108264474B - A kind of synthetic method of tryptamines and its derivative - Google Patents

A kind of synthetic method of tryptamines and its derivative Download PDF

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CN108264474B
CN108264474B CN201810136678.0A CN201810136678A CN108264474B CN 108264474 B CN108264474 B CN 108264474B CN 201810136678 A CN201810136678 A CN 201810136678A CN 108264474 B CN108264474 B CN 108264474B
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tryptamines
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synthetic method
anhydride
structure formula
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CN108264474A (en
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李开笑
包王镇
严超
李泽阳
林丽慧
杨希
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Zhejiang Normal University CJNU
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    • 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

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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

A kind of synthetic method of tryptamines and its derivative
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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