CN105384677A - Method for synthesizing medical intermediate aryl substituted indole compound - Google Patents

Method for synthesizing medical intermediate aryl substituted indole compound Download PDF

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CN105384677A
CN105384677A CN201510741716.1A CN201510741716A CN105384677A CN 105384677 A CN105384677 A CN 105384677A CN 201510741716 A CN201510741716 A CN 201510741716A CN 105384677 A CN105384677 A CN 105384677A
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compound
formula
synthetic method
mol ratio
oxygenant
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CN105384677B (en
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张妍
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Nanjing Micro Structure Medicine Technology Co ltd
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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
    • C07D209/12—Radicals substituted by oxygen atoms
    • 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
    • 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

Abstract

The invention relates to a method for synthesizing a medical intermediate aryl substituted indole compound. The method includes the steps that in an organic solvent, a compound in the formula (I) and a compound in the formula (II) react for 6-10 hours at the temperature of 70-90 DEG C under the condition that a catalyst, an oxidizing agent, a ligand, 1,1,3,3-tetramethyldisiloxane (TMDS) and alkaline exist, the mixture is processed after the reaction is completed, and the compound in the formula (III) is obtained (please see the molecular formula of the compound in the specification), wherein R1 and R2 are independently selected from H or C1-C6 alkyl groups, R3 is selected from H, C1-C6 alkyl groups, C1-C6 phenyl groups, alkoxy or cyano group and X is halogen. According to the method, by selecting a proper substrate and adopting the catalyst, the oxidizing agent, the ligand, alkaline, the organic solvent, and a comprehensive reaction system composed of TMDS, a target product can be obtained at high yield, and the method has good application prospects and industrial production potentials in the technical field of medical intermediate synthesis.

Description

A kind of synthetic method of medicine intermediate aryl substituted indole compounds
Technical field
The present invention relates to a kind of synthetic method of heterogeneous ring compound, relate more particularly to a kind of synthetic method of aryl substituted indole compounds, belong to medicine intermediate synthesis field.
Background technology
At field of medicaments, Benzazole compounds is a kind of very important heterogeneous ring compound, and it is widely used at field of medicaments because having various biological activity, in many marketed drug, all contain indole structure.
Exactly because the so important effect of Benzazole compounds, the high-efficiency synthesis method of research and development Benzazole compounds is a very necessary problem for pharmaceuticals researcher.
Up to the present, numerous colleges and universities and research institution have developed the multiple synthetic method about Benzazole compounds, such as:
RobertJ.Phipps etc. (" Cu (II)-CatalyzedDirectandSite-SelectiveArylationofIndolesUnderM ildConditions ", J.Am.Chem.Soc., 2008,130,8172 – 8174) report the regioselectivity C-H reaction kinetic of a kind of Cu (II) catalysis, it can prepare the Benzazole compounds that C3 or C2 replaces, and reaction conditions is gentle, and its reaction formula is as follows:
SachinG.Modha etc. (" Atom-EconomicalTransformationofDiaryliodoniumSalts:Tande mC-HandN-HArylationofIndoles ", J.Am.Chem.Soc., 2015,137,1416-1419) report a kind of method adopting diaryl group iodized salt to carry out indoles substitution reaction, its reaction formula is as follows:
As mentioned above, in prior art, disclose the method for multiple synthesis of indole compounds, but these existing methods also exist many defects such as reaction yield is low, have impact on the widespread use in medicine intermediate synthesis field.
For these problems, the present inventor sums up and attempts in reading amount of literature data and basis, and means are auxiliary by experiment proves feasibility, and then proposes a kind of synthetic method that can be used as the aryl substituted indole compounds of medicine intermediate.This kind of method adopts novel combined reaction system, and the high yield of the Efficient Conversion and product that achieve reaction raw materials obtains, and possesses the potentiality of large-scale production, can meet the demand in medical synthesis field to a certain extent.
Summary of the invention
In order to overcome above-mentioned pointed defect of the prior art and the novel method for synthesizing seeking Benzazole compounds, present inventor has performed deep research and exploration, after having paid enough creative works, thus completing the present invention.
Specifically, technical scheme of the present invention and content relate to the synthetic method of aryl substituted indole compounds shown in a kind of following formula (III) that can be used as medicine intermediate, described method comprises: in organic solvent, in catalyzer, oxygenant, part, 1,1,3, under 3-tetramethyl disiloxane (TMDS) and alkali exist, following formula (I) compound and following formula (II) compound react 6-10 hour at 70-90 DEG C, through aftertreatment after reaction terminates, thus obtain described formula (III) compound
Wherein, R 1, R 2be selected from H or C independently of one another 1-C 6alkyl;
R 3be selected from H, C 1-C 6alkyl, C 1-C 6alkoxyl group, halogen or cyano group;
X is halogen.
In described synthetic method of the present invention, described C 1-C 6the implication of alkyl refers to the straight or branched alkyl with 1-6 carbon atom, such as can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl or n-hexyl etc. in non-limiting manner.
In described synthetic method of the present invention, described C 1-C 6the implication of alkoxyl group refers to the C with above-mentioned implication 1-C 6the group obtained after alkyl is connected with Sauerstoffatom.
In described synthetic method of the present invention, described halogen is haloid element, such as, can be F, Cl, Br or I.
In described synthetic method of the present invention, described catalyzer is Au (MeCN) SbF 6((acetonitrile) [(2-biphenyl) di-t-butyl phosphine] hexafluoro-antimonic acid gold (I)) or AuCl (PPh 3) any one in (triphenylphosphine gold trichloride), most preferably be Au (MeCN) SbF 6.
In described synthetic method of the present invention, described oxygenant is Cr 2cu 2o 5(copper chromite) and AgNTf 2the mixture of (No. CAS is 189114-61-2), wherein Cr 2cu 2o 5with AgNTf 2mol ratio be 4:1.
In described synthetic method of the present invention, described part is L1 or L2 of following formula:
Be preferably L1.
In described synthetic method of the present invention, described alkali is 1,4-diazabicylo [2.2.2] octane (DABCO), 1,8-diazabicylo 11 carbon-7-alkene (DBU), N, N'-dimethyl-ethylenediamine (DMEDA) or N, any one in N-diisopropylethylamine (DIPEA), most preferably is DABCO.
In described synthetic method of the present invention, described organic solvent is volume ratio is the Macrogol 200 (PEG-200) of 2:1 and the mixture of diethylene glycol monomethyl ether.
Wherein, the consumption of described organic solvent strict restriction, and those skilled in the art can carry out suitable selection according to practical situation and determine, such as its consumption size is carried out and aftertreatment to facilitate reaction, is no longer described in detail at this.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and formula (II) compound is 1:1.5-2.5, such as, can be 1:1.5,1:2 or 1:2.5.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and catalyzer is 1:0.04-0.08, such as, can be 1:0.04,1:0.06 or 1:0.08.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and oxygenant is 1:1-2, i.e. the mole dosage of described formula (I) compound and the Cr of the described oxygenant of formation 2cu 2o 5(copper chromite) and AgNTf 2the ratio of mole dosage sum be 1:1-2, such as can be 1:1,1:1.5 or 1:2.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and part is 1:0.05-0.1, such as, can be 1:0.05,1:0.07,1:0.09 or 1:0.1.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and 1,1,3,3-tetramethyl disiloxane (TMDS) is 1:0.1-0.2, such as, can be 1:0.1,1:0.15 or 1:0.2.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and alkali is 1:0.5-1.2, such as, can be 1:0.5,1:0.7,1:0.9,1:1.1 or 1:1.2.
In described synthetic method of the present invention, carry out aftertreatment after reaction terminates, this aftertreatment is specific as follows: after reaction terminates, filtered while hot, filtrate is naturally cooled to room temperature, and regulates pH to neutral, then fully to vibrate washing with deionized water, add extraction into ethyl acetate 2-3 time again, merge organic phase, concentrating under reduced pressure, enriched material is crossed silica gel column chromatography and is separated, rinse with the acetone-chloroform mixture of volume ratio 1:2, thus obtain described formula (III) compound.
In sum, the invention provides a kind of synthetic method of aryl substituted indole compounds, the method is selected by suitable substrate, and adopt unique catalyzer, oxygenant, part, alkali and organic solvent, and the combined reaction system of TMDS composition, thus high yield can obtain object product, have a good application prospect and industrial production potential in medicine intermediate synthesis technical field.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and object are only used for exemplifying the present invention; not any type of any restriction is formed to real protection scope of the present invention, more non-protection scope of the present invention is confined to this.
Embodiment 1
To in appropriate organic solvent (for volume ratio is the Macrogol 200 (PEG-200) of 2:1 and the mixture of diethylene glycol monomethyl ether), add 100mmol above formula (I) compound, 150mmol above formula (II) compound, 4mmol catalyst A u (MeCN) SbF 6, 100mmol oxygenant (is 80mmolCr 2cu 2o 5with 20mmolAgNTf 2mixture), 5mmol ligand L 1,10mmolTMDS and 50mmol alkali DABCO; Then stir and be warming up to 70 DEG C, and stirring reaction 10 hours at such a temperature;
After reaction terminates, filtered while hot, naturally cools to room temperature by filtrate, and regulates pH to neutral, then fully to vibrate washing with deionized water, add extraction into ethyl acetate 2-3 time again, merge organic phase, concentrating under reduced pressure, enriched material is crossed silica gel column chromatography and is separated, rinse with the acetone-chloroform mixture of volume ratio 1:2, thus obtain above formula (III) compound, productive rate is 96.2%.
1HNMR(CDCl 3,400MHz):δ7.98(dq,J＝7.3,0.8Hz,1H),7.69-7.61(m,3H),7.60-7.53(m,4H),7.45(s,1H),7.38(tt,J＝6.4,2.1Hz,1H),7.34-7.22(m,3H),7.10-7.03(m,3H),3.88(s,3H)。
Embodiment 2
To in appropriate organic solvent (for volume ratio is the Macrogol 200 (PEG-200) of 2:1 and the mixture of diethylene glycol monomethyl ether), add 100mmol above formula (I) compound, 200mmol above formula (II) compound, 6mmol catalyst A u (MeCN) SbF 6, 150mmol oxygenant (is 120mmolCr 2cu 2o 5with 30mmolAgNTf 2mixture), 7mmol ligand L 1,15mmolTMDS and 80mmol alkali DABCO; Then stir and be warming up to 80 DEG C, and stirring reaction 8 hours at such a temperature;
After reaction terminates, filtered while hot, naturally cools to room temperature by filtrate, and regulates pH to neutral, then fully to vibrate washing with deionized water, add extraction into ethyl acetate 2-3 time again, merge organic phase, concentrating under reduced pressure, enriched material is crossed silica gel column chromatography and is separated, rinse with the acetone-chloroform mixture of volume ratio 1:2, thus obtain above formula (III) compound, productive rate is 96.5%.
1HNMR(CDCl 3,400MHz):δ7.92-7.89(m,1H),7.55(s,5H),7.51(d,J＝4.3Hz,4H),7.47(s,1H),7.37(hept,J＝4.1Hz,1H),7.25(ddd,J＝14.0,7.5,6.1Hz,2H)。
Embodiment 3
To in appropriate organic solvent (for volume ratio is the Macrogol 200 (PEG-200) of 2:1 and the mixture of diethylene glycol monomethyl ether), add 100mmol above formula (I) compound, 250mmol above formula (II) compound, 8mmol catalyst A u (MeCN) SbF 6, 200mmol oxygenant (is 160mmolCr 2cu 2o 5with 40mmolAgNTf 2mixture), 10mmol ligand L 1,20mmolTMDS and 120mmol alkali DABCO; Then stir and be warming up to 90 DEG C, and stirring reaction 6 hours at such a temperature;
After reaction terminates, filtered while hot, naturally cools to room temperature by filtrate, and regulates pH to neutral, then fully to vibrate washing with deionized water, add extraction into ethyl acetate 2-3 time again, merge organic phase, concentrating under reduced pressure, enriched material is crossed silica gel column chromatography and is separated, rinse with the acetone-chloroform mixture of volume ratio 1:2, thus obtain above formula (III) compound, productive rate is 96.4%.
1HNMR(CDCl 3,400MHz):δ7.98-7.96(m,1H),7.84-7.80(m,2H),7.77-7.73(m,2H),7.61(d,J＝6.7Hz,2H),7.58-7.54(m,4H),7.45-7.41(m,1H),7.32(tt,J＝7.1,5.4Hz,2H)。
Embodiment 4
To in appropriate organic solvent (for volume ratio is the Macrogol 200 (PEG-200) of 2:1 and the mixture of diethylene glycol monomethyl ether), add 100mmol above formula (I) compound, 170mmol above formula (II) compound, 7mmol catalyst A u (MeCN) SbF 6, 120mmol oxygenant (is 96mmolCr 2cu 2o 5with 24mmolAgNTf 2mixture), 8mmol ligand L 1,17mmolTMDS and 100mmol alkali DABCO; Then stir and be warming up to 75 DEG C, and stirring reaction 9 hours at such a temperature;
After reaction terminates, filtered while hot, naturally cools to room temperature by filtrate, and regulates pH to neutral, then fully to vibrate washing with deionized water, add extraction into ethyl acetate 2-3 time again, merge organic phase, concentrating under reduced pressure, enriched material is crossed silica gel column chromatography and is separated, rinse with the acetone-chloroform mixture of volume ratio 1:2, thus obtain above formula (III) compound, productive rate is 95.9%.
1HNMR(CDCl 3,500MHz):δ7.72-7.68(m,1H),7.67-7.63(m,2H),7.45(d,J＝8.4Hz,1H),7.43-7.38(m,3H),7.32(d,J＝8.0Hz,2H),7.20-7.14(m,2H),7.12-7.08(m,1H),2.51(s,3H),2.45(s,3H)。
Embodiment 5-8
Remove catalyst A u (MeCN) SbF 6replace with AuCl (PPh 3) outward, other operation is all constant, thus repeats to implement embodiment 1-4, and obtain embodiment 5-8 in turn, its productive rate is
88.3-89.1％。As can be seen here, Au (MeCN) SbF 6there is best catalytic effect.
Embodiment 9-16
Embodiment 9-12: except oxygenant is replaced with the one-component Cr that consumption is the total consumption sum of original two kinds of components 2cu 2o 5outward, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 9-12 in turn.
Embodiment 13-16: except oxygenant is replaced with the one-component AgNTf that consumption is the total consumption sum of original two kinds of components 2outward, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 13-16 in turn.
The results are shown in following table 1.
Table 1
As can be seen here, when being used alone Cr 2cu 2o 5or AgNTf 2time, products collection efficiency all has obvious reduction, is especially used alone AgNTf 2time reduce more obvious.This demonstrate that to only have the mixture both simultaneously using as oxygenant, just can obtain products collection efficiency the most excellent.
Embodiment 17-24
Embodiment 17-20: except replacing with except L2 by ligand L 1, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 17-20 in turn.
Embodiment 21-24: except ligand L 1 being omitted, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 21-24 in turn.
The results are shown in following table 2.
Table 2
As can be seen here, ligand L 1 has best effect, is better than ligand L 2, although both structures are very similar, difference is only different at the connection carbon chain lengths of two phosphino-s.And when not using any part, then products collection efficiency has and reduces more significantly.
Embodiment 25-28
Remove 1,1, outside 3,3-tetramethyl disiloxane (TMDS) is omitted, other operation is all constant, thus repeat to implement embodiment 1-4, obtain embodiment 25-28 in turn, its products collection efficiency is 91.1-91.9%, as can be seen here, the existence of this TMDS deliberately significantly improves products collection efficiency, and this has important practical significance and the production advantage in large-scale commercial production.
Embodiment 29-40
Embodiment 29-32: except replacing with except DBU by alkali by DABCO, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 29-32 in turn.
Embodiment 33-36: except replacing with except DMEDA by alkali by DABCO, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 33-36 in turn.
Embodiment 37-40: except replacing with except DIPEA by alkali by DABCO, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 37-40 in turn.
The results are shown in following table 3.
Table 3
As can be seen here, for alkali, DABCO has best effect, and other alkali all causes productive rate to have obvious reduction.
Embodiment 41-48
Embodiment 41-44: except being replaced with by organic solvent except one-component PEG-200, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 41-44 in turn.
Embodiment 45-48: except being replaced with by organic solvent except one-component diethylene glycol monomethyl ether, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 45-48 in turn.
The results are shown in following table 4.
Table 4
As can be seen here, when using one-component as organic solvent, productive rate all has obvious reduction, when especially using diethylene glycol monomethyl ether as single solvent, reduces more obvious.
In sum, the invention provides a kind of synthetic method of aryl substituted indole compounds, the method is selected by suitable substrate, and adopt unique catalyzer, oxygenant, part, alkali and organic solvent, and the combined reaction system of TMDS composition, thus high yield can obtain object product, have a good application prospect and industrial production potential in medicine intermediate synthesis technical field.
Should be appreciated that the purposes of these embodiments is only not intended to for illustration of the present invention limit the scope of the invention.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various change, amendment and/or modification to the present invention, and these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.

Claims (10)

1. the synthetic method of aryl substituted indole compounds shown in a following formula (III), described method comprises: in organic solvent, in catalyzer, oxygenant, part, 1, under 1,3,3-tetramethyl disiloxane (TMDS) and alkali exist, following formula (I) compound and following formula (II) compound react 6-10 hour at 70-90 DEG C, through aftertreatment after reaction terminates, thus obtain described formula (III) compound
Wherein, R 1, R 2be selected from H or C independently of one another 1-C 6alkyl;
R 3be selected from H, C 1-C 6alkyl, C 1-C 6alkoxyl group, halogen or cyano group;
X is halogen.
2. synthetic method as claimed in claim 1, is characterized in that: described catalyzer is Au (MeCN) SbF 6((acetonitrile) [(2-biphenyl) di-t-butyl phosphine] hexafluoro-antimonic acid gold (I)) or AuCl (PPh 3) any one in (triphenylphosphine gold trichloride), most preferably be Au (MeCN) SbF 6.
3. synthetic method as claimed in claim 1 or 2, is characterized in that: described oxygenant is Cr 2cu 2o 5(copper chromite) and AgNTf 2mixture, wherein Cr 2cu 2o 5with AgNTf 2mol ratio be 4:1.
4. the synthetic method as described in any one of claim 1-3, is characterized in that: described part is L1 or L2 of following formula:
Be preferably L1.
5. the synthetic method as described in any one of claim 1-4, it is characterized in that: described alkali is 1,4-diazabicylo [2.2.2] octane (DABCO), 1,8-diazabicylo 11 carbon-7-alkene (DBU), N, N'-dimethyl-ethylenediamine (DMEDA) or N, any one in N-diisopropylethylamine (DIPEA), most preferably is DABCO.
6. the synthetic method as described in any one of claim 1-5, is characterized in that: the mol ratio of described formula (I) compound and formula (II) compound is 1:1.5-2.5.
7. the synthetic method as described in any one of claim 1-6, is characterized in that: the mol ratio of described formula (I) compound and catalyzer is 1:0.04-0.08.
8. the synthetic method as described in any one of claim 1-7, is characterized in that: the mol ratio of described formula (I) compound and oxygenant is 1:1-2.
9. the synthetic method as described in any one of claim 1-8, is characterized in that: the mol ratio of described formula (I) compound and part is 1:0.05-0.1.
10. the synthetic method as described in any one of claim 1-9, is characterized in that: the mol ratio of described formula (I) compound and 1,1,3,3-tetramethyl disiloxane (TMDS) is 1:0.1-0.2.
CN201510741716.1A 2015-11-04 2015-11-04 A kind of synthetic method of medicine intermediate aryl substituted indole class compound Expired - Fee Related CN105384677B (en)

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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MICHAEL C. WILLIS ET AL.: "2-(2-Haloalkenyl)-aryl Halides as Substrates for Palladium-Catalysed Tandem C-N Bond Formation: Efficient Synthesis of 1-Substituted Indoles", 《ADV.SYNTH.CATAL.》 *
RAJESH KANCHERLA ET AL.: "Divergent Reactivity in Palladium-Catalyzed Annulation with Diarylamines and α,β-Unsaturated Acids: Direct Access to Substituted 2-Quinolinones and Indoles", 《CHEM.EUR.J.》 *
UPENDRA SHARMA ET AL.: "Palladium-Catalyzed Annulation of Diarylamines with Olefins through C-H Activation: Direct Access to N-Arylindoles", 《ANGEW.CHEM.INT.ED.》 *

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