CN108610275A - A kind of synthetic method of 3- (2- vinyls) indole derivatives - Google Patents
A kind of synthetic method of 3- (2- vinyls) indole derivatives Download PDFInfo
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- CN108610275A CN108610275A CN201611127615.6A CN201611127615A CN108610275A CN 108610275 A CN108610275 A CN 108610275A CN 201611127615 A CN201611127615 A CN 201611127615A CN 108610275 A CN108610275 A CN 108610275A
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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
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention discloses a kind of methods of 3 (2 vinyl) indole derivatives of synthesis.Reaction carries out continuous Friedel Crafts with 3 dimethylamino acrylonitrile as raw material using indole derivatives cheap and easy to get, with structure diversity and reacts/elimination reaction in presence of an acid, synthesizes 3 (2 vinyl) indole derivatives.Compared with 3 (2 vinyl) the indole derivatives synthetic methods reported, raw material of the present invention is cheap and easy to get, toxicity is low, easy to operate, synthetic reaction condition is mild and efficient.
Description
Technical field
The present invention relates to a kind of using indole derivatives cheap and easy to get, with structure diversity as raw material and 3- dimethylamino
Acrylonitrile carries out continuous Friedel-Crafts reactions/elimination reaction in presence of an acid, synthesizes 3- (2- vinyls) Yin
The method of diindyl derivative.Compared with 3- (2- vinyls) the indole derivatives synthetic method reported, raw material of the present invention
It is cheap and easy to get, toxicity is low, easy to operate, synthetic reaction condition is mild and efficient.
Background technology
3- alkenyl indole derivatives are a kind of important N- heterocyclic compounds, and the potential source biomolecule activity that they have has been subjected to
To the extensive concern of people.3- alkenyl indole derivatives act not only as antitumor, anti-inflammatory, antiviral equal drugs use, and
And still synthesize the important intermediate of other biologically active indole derivatives.Pfizer Inc's patent in 1993
(CN 1072679A) and 2006 Angeletti P. Ist Richerche Bio.'s patent (CN 1863528A) report a variety of tools
There are antiviral and anti-inflammatory activity 3- alkenyl indole derivatives.3- (2- vinyls) indole derivatives are as 3- alkenyl indoles
A member in derivative large family has important in medicine and chemical field.Tradition prepares 3- (2- vinyls) indoles and derives
The method of object is 1) 3- formyl indoles and cyan-acetic ester react under L-PROLINE effect
(Synth.Commun.2012,42,1746)；2) 3- formyl indoles are reacted with cyanogen methyl acid phosphate diethylester
(Bioorg.Med.Chem.lett.1999,9,221).However, since 3- formyl indoles derivative derives than corresponding indoles
Price lattice want high, and p diethylaminobenzoic acid esters toxicity of compound is larger, the above method and the economical and environmentally friendly theory of molecule
It disagrees, limits application.The present invention utilizes indole derivatives (2) and 3- dimethylamine cheap and easy to get, with structure diversity
Base acrylonitrile (3) reacts in acid condition, passes through R in regulation and control (2)1、R2、R3Substituent group has synthesized the 3- of serial different structure
(2- vinyls) indole derivatives (1).Reaction is with raw material is cheap and easy to get, toxicity is low, reaction condition is mild, wide adaptability
Etc. advantages.
Invention content
That the purpose of the present invention is to provide a kind of raw materials is cheap and easy to get, toxicity is low, reaction condition is mild, wide adaptability, energy
The method for simply and easily synthesizing 3- alkenyl indole derivatives.
To achieve the goals above, technical scheme is as follows：
Under mixed acid effect, indole derivatives (2) are with 3- dimethylamino acrylonitrile (3) in organic solvent by continuous
Friedel-Crafts reactions/elimination reaction generate 3- (2- vinyls) indole derivatives (1).(reaction equation 1)
Technical solution is characterized in that：
1. indole derivatives (2) are raw material, wherein：
Substituent R1、R2、R3For hydrogen, C1-C3Alkyl, aryl C6H5-aXa, benzyl CH2C6H5-aXa, naphthalene C10H7-bXbOr five
Membered heterocyclic compound C4H3-cXcY.Wherein X is aromatic ring, substituent group on naphthalene nucleus or five-ring heterocycles, can be halogen, nitro, cyanogen
Base, ester group, acyl group, C1-C3Alkyl or C1-C3Alkoxy；Y is oxygen atom or sulphur atom；A is the integer of 0-5, and b is the whole of 0-7
Number, c are the integer of 0-3.
2. reaction dissolvent is dichloromethane, dichloroethanes, chloroform, carbon tetrachloride, ether, tetrahydrofuran, 1,4- dioxies six
One or more kinds of organic solvents in ring and toluene；Wherein, reaction carries out effect in halogenated alkane solvents dichloroethanes
It is best.
3. the molar ratio of indole derivatives (2) and 3- dimethylamino acrylonitrile (3) is 1:1-3:1.Wherein, molar ratio 1:
Reaction effect is best when 1.
4. indole derivatives (2) react with 3- dimethylamino acrylonitrile (3) under acidic environment, needed in reaction
Acid is formic acid, acetic acid, monoxone, benzoic acid, p-methyl benzenesulfonic acid monohydrate, p-methyl benzenesulfonic acid, trifluoroacetic acid, methanesulfonic acid, three
The one or more being fluorinated in borate ether；Wherein reaction effect is carried out with p-methyl benzenesulfonic acid monohydrate/glacial acetic acid mixed acid
Fruit is best.
5. synthetic method described in accordance with the claim 3, it is characterised in that：During the reaction, one water of p-methyl benzenesulfonic acid
The optimum molar ratio for closing object and glacial acetic acid is 1:10.
6. during the reaction, 3- dimethylamino acrylonitrile (3) and the optimum molar ratio of toluenesulfonic acid monohydrate are 1:
2。
7. the reaction time is 1-24 hours.Wherein, optimum reacting time is 2-8 hours.
8. reaction temperature is 0-120 DEG C.Wherein, optimal reaction temperature is 60-80 DEG C.
The present invention has the following advantages：
1) raw material indole derivatives (2) have structure diversity.
2) indole derivatives (2) are easy to prepare, and it is cheap and easy to get to prepare raw material.
3) raw material 3- dimethylamino acrylonitrile (3) is easy to prepare, and prepares that raw material is cheap and easy to get, toxicity is low.
4) acid used in reacting, it is cheap and easy to get, toxicity is low.
5) 3- (2- vinyls) indole derivatives (1) synthetic reaction condition is mild, step is simple, product yield high.
In short, the present invention reacted by continuous Friedel-Crafts using the structure diversity of indole derivatives (2)/
Elimination reaction synthesizes 3- (2- vinyls) indole derivatives (1) of different type and structure, and raw material is cheap and easy to get, toxicity
Low, easy to operate, target product yield is high.
Description of the drawings
Fig. 1 is 3- (1- dimethylamino -2- cyano ethyls)-indole derivatives 1a nuclear magnetic resonance spectroscopies1H NMR(CDCl3)；
Fig. 2 is 3- (1- dimethylamino -2- cyano ethyls)-indole derivatives 1a carbon-13 nmr spectras13C{1H}NMR
(CDCl3)；
Specific implementation mode
In presence of an acid, indole derivatives (2) with 3- dimethylamino acrylonitrile (3) in organic solvent by continuous
Friedel-Crafts reactions/elimination reaction generates 3- (1- dimethylamino -2- cyano ethyls)-indole derivatives (1) (reaction equation
1)。
Detailed process is：By indole derivatives (2) (0.5mmol), 3- dimethylamino acrylonitrile (3) (0.5mmol), to first
Benzene sulfonic acid monohydrate (190mg, 1.0mmol), glacial acetic acid (600mg, 10.0mmol) and 2mL dichloroethanes stir 8 at 80 DEG C
Hour.Reaction solution is poured into separatory funnel after completion of the reaction, and 10mL saturated sodium bicarbonate aqueous solutions are added thereto, is shaken
It shakes, stand, oil-water separation phase, water phase dichloromethane extraction (2 × 5mL) separates organic phase.With anhydrous sulphur after organic phase merging
Sour sodium is dry, filters.Decompression is lower to remove Volatile Colstituent, then detaches (eluent is dichloromethane) with silica gel column chromatography, obtains
Target product (1).Target product is confirmed by nuclear magnetic resoance spectrum and high resolution mass spectrum measurement.
Contribute to further understand the present invention by following embodiments, but present disclosure is not limited to that.
Embodiment 1
In 10mL reaction bulbs, 1- methyl -2-phenylindone (2a) (104mg, 0.5mmol), 3- dimethylamine are sequentially added
Base acrylonitrile (3) (48mg, 0.5mmol), p-methyl benzenesulfonic acid monohydrate (190mg, 1.0mmol), glacial acetic acid (600mg,
10.0mmol) and 2mL solvent dichloroethanes, 8h is stirred to react at 80 DEG C.Reaction solution is poured into separatory funnel after completion of the reaction,
And 10mL saturated sodium bicarbonate aqueous solutions are added thereto, shaking is stood, oil-water separation phase, and water phase extracts (2 with dichloromethane
× 5mL), separate organic phase.It is organic mix after with anhydrous sodium sulfate is dry, filtering.Decompression is lower to remove Volatile Colstituent, then uses
Silica gel column chromatography detaches (eluent is dichloromethane), and it is target product (1a) (90mg, yield 70%) to obtain yellow solid.Mesh
Mark product is confirmed by nuclear magnetic resoance spectrum and high resolution mass spectrum measurement.(reaction equation 2)
Embodiment 2
Reaction step is with operation with embodiment 1, and difference from Example 1 is, the reaction time is for 24 hours.Stop reaction, warp
Post-processing obtains target product 1a (89mg, yield 69%).
Embodiment 3
Reaction step is with operation with embodiment 1, and difference from Example 1 is, reaction time 4h.Stop reaction, warp
Post-processing obtains target product 1a (44mg, yield 34%).
Embodiment 4
With operation with embodiment 1, difference from Example 1 is reaction step, and reaction temperature is 40 DEG C.Stop anti-
It answers, it is post-treated to obtain target product 1a (30mg, yield 23%).
Embodiment 5
With operation with embodiment 1, difference from Example 1 is reaction step, and p-methyl benzenesulfonic acid one is hydrated in reaction
The addition of object is 142mg (0.75mmol).Stop reaction, it is post-treated to obtain target product 1a (68mg, yield 53%).
Embodiment 6
With operation with embodiment 1, difference from Example 1 is reaction step, and p-methyl benzenesulfonic acid one is hydrated in reaction
The addition of object is 285mg (1.5mmol).Stop reaction, it is post-treated to obtain target product 1a (90mg, yield 70%).
Embodiment 7
Reaction step is with operation with embodiment 1, and difference from Example 1 is, the addition of glacial acetic acid is in reaction
300mg(5mmol).Stop reaction, it is post-treated to obtain target product 1a (81mg, yield 63%).
Embodiment 8
Reaction step is with operation with embodiment 1, and difference from Example 1 is, the addition of glacial acetic acid is in reaction
900mg(15mmol).Stop reaction, it is post-treated to obtain target product 1a (89mg, yield 69%).
Embodiment 9
With operation with embodiment 1, difference from Example 1 is reaction step, and reaction uses dimethyl sulfoxide (DMSO) conduct
Solvent.Stop reaction, it is post-treated to obtain target product 1a (23mg, yield 18%).
Embodiment 10
Reaction step is with operation with embodiment 1, and difference from Example 1 is, (R in indole derivatives 2b1=R2=
Me,R3=H).Stop reaction, it is post-treated to obtain target product 1b (75mg, yield 77%).
Typical compound characterize data
3- (1- dimethylamino -2- cyano ethyls)-indole derivatives 1a, white solid, 110-111 DEG C of fusing point.1H NMR
(400MHz,CDCl3) δ 7.82 (d, J=7.8Hz, 1H, 4-H of indolyl), 7.58 (m, 3H, aromatic CH), 7.39
(m, 6H, CH=CHCN and aromatic CH), 5.73 (d, J=16.6Hz, 1H, CH=CHCN), 3.64 (s, 3H, CH3)
.13C{1H}NMR(100MHz,CDCl3) δ 145.3 (Cq, C2of indolyl), 144.3 (CH=CHCN), 137.9,129.4,
125.0,and 110.2(Cq each),120.5(Cq,CN),130.8,129.6,128.8,123.4,122.2,120.1,and
110.4 (aromatic CH), 89.3 (CH=CHCN), 31.2 (CH3) molecular formula：C18H14N2；HRMS theoretical values：
258.1157；Measured value：258.1161.
Claims (9)
1. a kind of synthetic method of 3- (2- vinyls) indole derivatives, 3- (2- vinyls) indole derivatives (1)
Structural formula is as follows,
Substituent R1、R2、R3Respectively hydrogen, C1-C3Alkyl, aryl C6H5-aXa, benzyl CH2C6H5-aXa, naphthalene C10H7-bXbOr five yuan
Heterocyclic compound C4H3-cXcY；Wherein X is aromatic ring, substituent group on naphthalene nucleus or five-ring heterocycles, can be halogen, nitro, cyano,
Ester group, acyl group, C1-C3Alkyl or C1-C3Alkoxy；Y is oxygen atom or sulphur atom；A is the integer of 0-5, and b is the integer of 0-7, c
For the integer of 0-3；
It is characterized in that：With indole derivatives (2) be starting material, by with 3- dimethylamino acrylonitrile (3) in acidic environment
It is lower to carry out continuous Friedel-Crafts reactions/elimination reaction, generate 3- (2- vinyls) indole derivatives (1)；
Synthetic route as shown in following reaction equations,
2. synthetic method described in accordance with the claim 1, it is characterised in that：
Reaction dissolvent is organic solvent dichloromethane, dichloroethanes, chloroform, carbon tetrachloride, ether, tetrahydrofuran, 1,4- dioxies
One or two or more kinds in six rings and toluene；The acid needed in reaction be formic acid, acetic acid, monoxone, benzoic acid, to toluene sulphur
One or two or more kinds in sour monohydrate, p-methyl benzenesulfonic acid, trifluoroacetic acid, methanesulfonic acid, boron trifluoride ether；Indoles derives
The molar ratio of object (2) and acid is 1:1-1:20；Reaction time is 1-24 hours；Reaction temperature is 0-120 DEG C；It presses after reaction
Conventional isolation and purification method carries out product separation, obtains 3- (2- vinyls) indole derivatives (1).
3. synthetic method according to claim 2, it is characterised in that：Indole derivatives (2) and 3- dimethylamino acrylonitrile
(3) when reacting under acidic environment, the acid used is preferably the mixed acid of p-methyl benzenesulfonic acid monohydrate/glacial acetic acid.
4. synthetic method described in accordance with the claim 3, it is characterised in that：During the reaction, p-methyl benzenesulfonic acid monohydrate
Molar ratio with glacial acetic acid is 1:0.5-1:15.
5. synthetic method according to claim 2, it is characterised in that：During the reaction, 3- dimethylamino acrylonitrile (3)
Optimum molar ratio with acid is 1:2.
6. synthetic method according to claim 2, it is characterised in that：Indole derivatives (2) and 3- dimethylamino acrylonitrile
(3) when reacting, optimum molar ratio is 1:1；The molar concentration of indole derivatives (2) is 0.05-1.0M.
7. synthetic method according to claim 2, it is characterised in that：The molar concentration of indole derivatives (2) be 0.4M most
It is excellent.
8. synthetic method according to claim 2, it is characterised in that：Indole derivatives (2) and 3- dimethylamino acrylonitrile
(3) when reacting, optimum reacting time 1-24 hours.
9. synthetic method according to claim 2, it is characterised in that：Indole derivatives (2) and 3- dimethylamino acrylonitrile
(3) optimum temperature reacted is 0-80 DEG C.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111018771A (en) * | 2018-10-09 | 2020-04-17 | 中国科学院大连化学物理研究所 | Method for synthesizing 3- (2-cyanovinyl) indole derivative |
| CN111285791A (en) * | 2018-12-06 | 2020-06-16 | 中国科学院大连化学物理研究所 | 2- (1-dimethylamino-2-cyanoethyl) pyrrole derivative and synthesis method thereof |
| WO2021226161A1 (en) * | 2020-05-06 | 2021-11-11 | Biohaven Therapeutics Ltd. | Process for the preparation of verdiperstat |
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2016
- 2016-12-09 CN CN201611127615.6A patent/CN108610275A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111018771A (en) * | 2018-10-09 | 2020-04-17 | 中国科学院大连化学物理研究所 | Method for synthesizing 3- (2-cyanovinyl) indole derivative |
| CN111285791A (en) * | 2018-12-06 | 2020-06-16 | 中国科学院大连化学物理研究所 | 2- (1-dimethylamino-2-cyanoethyl) pyrrole derivative and synthesis method thereof |
| WO2021226161A1 (en) * | 2020-05-06 | 2021-11-11 | Biohaven Therapeutics Ltd. | Process for the preparation of verdiperstat |
| CN115551511A (en) * | 2020-05-06 | 2022-12-30 | 拜尔哈文制药股份有限公司 | Method for preparing Updispinostat |
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