CN105384677B - A kind of synthetic method of medicine intermediate aryl substituted indole class compound - Google Patents
A kind of synthetic method of medicine intermediate aryl substituted indole class compound Download PDFInfo
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- CN105384677B CN105384677B CN201510741716.1A CN201510741716A CN105384677B CN 105384677 B CN105384677 B CN 105384677B CN 201510741716 A CN201510741716 A CN 201510741716A CN 105384677 B CN105384677 B CN 105384677B
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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
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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
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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
Abstract
The present invention relates to a kind of synthetic method of aryl substituted indole class compound shown in lower formula (III), the described method includes：In organic solvent, in catalyst, oxidant, ligand, 1,1,3, in the presence of 3 tetramethyl disiloxanes (TMDS) and alkali, lower formula (I) compound and lower formula (II) compound reacted at 70 90 DEG C 6 10 it is small when, it is post-treated after reaction, so as to obtain the formula (III) compoundWherein, R1、R2It is each independently selected from H or C1‑C6Alkyl；R3Selected from H, C1‑C6Alkyl, C1‑C6Alkoxy, halogen or cyano group；X is halogen.This method is selected by suitable substrates, and using catalyst, oxidant, ligand, alkali and organic solvent, and the combined reaction system of TMDS compositions, purpose product can be obtained with high yield, had a good application prospect and industrial production potential in medicine intermediate synthesis technical field.
Description
Technical field
The present invention relates to a kind of synthetic method of heterocyclic compound, relates more particularly to a kind of aryl substituted indole class chemical combination
The synthetic method of thing, belongs to medicine intermediate synthesis field.
Background technology
In field of medicaments, Benzazole compounds are a kind of particularly important heterocyclic compounds, it is because having various biology
Activity and be widely used in field of medicaments, all contain indole structure in many marketed drugs.
Exactly because such important effect of Benzazole compounds, researches and develops the high-efficiency synthesis method pair of Benzazole compounds
It is a very necessary problem for pharmaceuticals researcher.
Up to the present, numerous colleges and universities and research institution have had been developed for a variety of synthesis in relation to Benzazole compounds
Method, such as：
(" Cu (II)-Catalyzed Direct and Site-Selective such as Robert J.Phipps
Arylation of Indoles Under Mild Conditions”,J.Am.Chem.Soc.,2008,130,8172–
8174) a kind of regioselectivity C-H reaction kinetics of Cu (II) catalysis are reported, it can prepare the indoles of C3 or C2 substitutions
Compound, and reaction condition is gentle, its reaction equation is as follows：
(" the Atom-Economical Transformation of Diaryliodonium such as Sachin G.Modha
Salts:Tandem C-H and N-H Arylation of Indoles”,J.Am.Chem.Soc.,2015,137,1416-
1419) a kind of method that indoles substitution reaction is carried out using diaryl group iodized salt is reported, its reaction equation is as follows：
As described above, the method for a variety of synthesis of indole class compounds is disclosed in the prior art, however, these existing sides
Method have impact on the extensive use in medicine intermediate synthesis field there is many defects such as reaction yield is low.
For these difficulties and problems, the present inventor read amount of literature data and on the basis of summarize with trial, and lead to
Cross laboratory facilities auxiliary and prove feasibility, and then propose a kind of aryl substituted indole class compound that can be used as medicine intermediate
Synthetic method.This kind of method uses novel combined reaction system, realizes the Efficient Conversion of reaction raw materials and the height of product
Yield obtains, and possesses the potentiality of large-scale production, can meet the needs of medical synthesis field to a certain extent.
The content of the invention
In order to overcome it is as indicated above in the prior art the defects of and seek the novel method for synthesizing of Benzazole compounds,
Present inventor has performed in-depth study and exploration, after enough creative works have been paid, so as to complete the present invention.
Specifically, technical scheme and content are related to a kind of lower formula (III) institute that can be used as medicine intermediate
Show the synthetic method of aryl substituted indole class compound, the described method includes：In organic solvent, in catalyst, oxidant, match somebody with somebody
Body, 1, in the presence of 1,3,3- tetramethyl disiloxane (TMDS) and alkali, lower formula (I) compound and lower formula (II) compound are in 70-
It is post-treated after reaction when reaction 6-10 is small at 90 DEG C, so that the formula (III) compound is obtained,
Wherein, R1、R2It is each independently selected from H or C1-C6Alkyl；
R3Selected from H, C1-C6Alkyl, C1-C6Alkoxy, halogen or cyano group；
X is halogen.
In the synthetic method of the present invention, the C1-C6The implication of alkyl refers to the straight chain with 1-6 carbon atom
Or branched alkyl, it may be, for example, methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, uncle in non-limiting manner
Butyl, n-pentyl, isopentyl or n-hexyl etc..
In the synthetic method of the present invention, the C1-C6The implication of alkoxy refers to the C with above-mentioned implication1-C6
The group that alkyl obtains after being connected with oxygen atom.
In the synthetic method of the present invention, the halogen is halogen, may be, for example, F, Cl, Br or I.
In the synthetic method of the present invention, the catalyst is Au (MeCN) SbF6((acetonitrile) [(2- biphenyl) two uncles
Butyl phosphine] hexafluoro-antimonic acid gold (I)) or AuCl (PPh3) any one in (triphenylphosphine chlorauride), it is most preferably Au
(MeCN)SbF6。
In the synthetic method of the present invention, the oxidant is Cr2Cu2O5(copper chromite) and AgNTf2(No. CAS
For 189114-61-2) mixture, wherein Cr2Cu2O5With AgNTf2Molar ratio be 4:1.
In the synthetic method of the present invention, the ligand is the L1 or L2 of following formula：
Preferably L1.
The present invention the synthetic method in, the alkali for Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane (DABCO), 1,
11 carbon -7- alkene (DBU) of 8- diazabicylos, N, N'- dimethyl-ethylenediamines (DMEDA) or N, N- diisopropylethylamine
(DIPEA) any one in, is most preferably DABCO.
In the synthetic method of the present invention, the organic solvent is that volume ratio is 2:1 polyethylene glycol 200 (PEG-
200) with the mixture of diethylene glycol monomethyl ether.
Wherein, the dosage of the organic solvent does not have stringent restriction, and those skilled in the art can be according to actual conditions
Carry out suitably selection and determine, such as its dosage size is no longer carried out detailed herein with facilitating reaction progress and post processing
Thin description.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and formula (II) compound is 1:
1.5-2.5 it may be, for example, 1:1.5、1:2 or 1:2.5.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and catalyst is 1:0.04-
0.08, it may be, for example, 1:0.04、1:0.06 or 1:0.08.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and oxidant is 1:1-2, i.e. institute
State Cr of the mole dosage of formula (I) compound with forming the oxidant2Cu2O5(copper chromite) and AgNTf2Mole dosage
The sum of ratio be 1:1-2, may be, for example, 1:1、1:1.5 or 1:2.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and ligand is 1:0.05-0.1, example
Such as can be 1:0.05、1:0.07、1:0.09 or 1:0.1.
In the synthetic method of the present invention, formula (I) compound and 1,1,3,3- tetramethyl disiloxane
(TMDS) molar ratio is 1:0.1-0.2, may be, for example, 1:0.1、1:0.15 or 1:0.2.
In the synthetic method of the present invention, the molar ratio of 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 the synthetic method of the present invention, post-processed after reaction, the post processing is specific as follows：Reaction knot
Shu Hou, is filtered while hot, by filtrate cooled to room temperature, and adjusts pH to neutrality, washing is then fully vibrated with deionized water,
Add ethyl acetate to extract 2-3 times, merge organic phase, be concentrated under reduced pressure, concentrate crosses silica gel column chromatography separation, with volume ratio 1:
2 acetone-chloroform mixture is rinsed, so as to obtain the formula (III) compound.
In conclusion the present invention provides a kind of synthetic method of aryl substituted indole class compound, this method passes through conjunction
Suitable substrate selection, and using unique catalyst, oxidant, ligand, alkali and organic solvent, and the synthesis of TMDS compositions
Reaction system, purpose product is obtained so as to high yield, before medicine intermediate synthesis technical field has good application
Scape and industrial production potential.
Embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and
Purpose is only used for enumerating the present invention, not forms any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action
Protection scope of the present invention is confined to this.
Embodiment 1
(it is 2 for volume ratio to appropriate organic solvent:1 polyethylene glycol 200 (PEG-200) and diethylene glycol monomethyl ether
Mixture) in, add formula (I) compound, the upper formula (II) compounds of 150mmol, 4mmol catalyst Au (MeCN) on 100mmol
SbF6, 100mmol oxidants are (for 80mmol Cr2Cu2O5With 20mmol AgNTf2Mixture), 5mmol ligand Ls 1,10mmol
TMDS and 50mmol alkali DABCO；Then stirring is warming up to 70 DEG C, and when stirring reaction 10 is small at such a temperature；
After reaction, filter while hot, by filtrate cooled to room temperature, and adjust pH to neutrality, then use deionization
Water fully vibrates washing, adds ethyl acetate and extracts 2-3 times, merges organic phase, be concentrated under reduced pressure, concentrate crosses silica gel column chromatography
Separation, with volume ratio 1:2 acetone-chloroform mixture is rinsed, so as to obtain formula (III) compound, yield is
96.2%.
1H NMR(CDCl3,400MHz):δ 7.98 (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
(it is 2 for volume ratio to appropriate organic solvent:1 polyethylene glycol 200 (PEG-200) and diethylene glycol monomethyl ether
Mixture) in, add formula (I) compound, the upper formula (II) compounds of 200mmol, 6mmol catalyst Au (MeCN) on 100mmol
SbF6, 150mmol oxidants are (for 120mmol Cr2Cu2O5With 30mmol AgNTf2Mixture), 7mmol ligand Ls 1,
15mmol TMDS and 80mmol alkali DABCO；Then stirring is warming up to 80 DEG C, and when stirring reaction 8 is small at such a temperature；
After reaction, filter while hot, by filtrate cooled to room temperature, and adjust pH to neutrality, then use deionization
Water fully vibrates washing, adds ethyl acetate and extracts 2-3 times, merges organic phase, be concentrated under reduced pressure, concentrate crosses silica gel column chromatography
Separation, with volume ratio 1:2 acetone-chloroform mixture is rinsed, so as to obtain formula (III) compound, yield is
96.5%.
1H NMR(CDCl3,400MHz):δ 7.92-7.89 (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
(it is 2 for volume ratio to appropriate organic solvent:1 polyethylene glycol 200 (PEG-200) and diethylene glycol monomethyl ether
Mixture) in, add formula (I) compound, the upper formula (II) compounds of 250mmol, 8mmol catalyst Au (MeCN) on 100mmol
SbF6, 200mmol oxidants are (for 160mmol Cr2Cu2O5With 40mmol AgNTf2Mixture), 10mmol ligand Ls 1,
20mmol TMDS and 120mmol alkali DABCO；Then stirring is warming up to 90 DEG C, and when stirring reaction 6 is small at such a temperature；
After reaction, filter while hot, by filtrate cooled to room temperature, and adjust pH to neutrality, then use deionization
Water fully vibrates washing, adds ethyl acetate and extracts 2-3 times, merges organic phase, be concentrated under reduced pressure, concentrate crosses silica gel column chromatography
Separation, with volume ratio 1:2 acetone-chloroform mixture is rinsed, so as to obtain formula (III) compound, yield is
96.4%.
1H NMR(CDCl3,400MHz):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
(it is 2 for volume ratio to appropriate organic solvent:1 polyethylene glycol 200 (PEG-200) and diethylene glycol monomethyl ether
Mixture) in, add formula (I) compound, the upper formula (II) compounds of 170mmol, 7mmol catalyst Au (MeCN) on 100mmol
SbF6, 120mmol oxidants are (for 96mmol Cr2Cu2O5With 24mmol AgNTf2Mixture), 8mmol ligand Ls 1,17mmol
TMDS and 100mmol alkali DABCO；Then stirring is warming up to 75 DEG C, and when stirring reaction 9 is small at such a temperature；
After reaction, filter while hot, by filtrate cooled to room temperature, and adjust pH to neutrality, then use deionization
Water fully vibrates washing, adds ethyl acetate and extracts 2-3 times, merges organic phase, be concentrated under reduced pressure, concentrate crosses silica gel column chromatography
Separation, with volume ratio 1:2 acetone-chloroform mixture is rinsed, so as to obtain formula (III) compound, yield is
95.9%.
1H NMR(CDCl3,500MHz):δ 7.72-7.68 (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
Except by catalyst Au (MeCN) SbF6Replace with AuCl (PPh3) outside, other operations are constant, so as to repeat to implement
Embodiment 1-4, sequentially obtains embodiment 5-8, its yield is
88.3-89.1%.It can be seen from the above that Au (MeCN) SbF6With best catalytic effect.
Embodiment 9-16
Embodiment 9-12：Except oxidant is replaced with one-component of the dosage for the sum of the total dosage of original two kinds of components
Cr2Cu2O5Outside, other operations are constant, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 9-12.
Embodiment 13-16：Except oxidant is replaced with one-component of the dosage for the sum of the total dosage of original two kinds of components
AgNTf2Outside, other operations are constant, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 13-16.
The result is shown in table 1 below.
Table 1
It can be seen from the above that as exclusive use Cr2Cu2O5Or AgNTf2When, products collection efficiency has obvious reduction, especially individually
Use AgNTf2When reduce become apparent.This demonstrate that both mixtures are only used to be obtained as oxidant at the same time
Products collection efficiency the most excellent.
Embodiment 17-24
Embodiment 17-20：In addition to ligand L 1 is replaced with L2, other operations are constant, so as to repeat to implement embodiment
1-4, sequentially obtains embodiment 17-20.
Embodiment 21-24：In addition to ligand L 1 is omitted, other operations are constant, so as to repeat to implement embodiment
1-4, sequentially obtains embodiment 21-24.
The result is shown in table 2 below.
Table 2
It can be seen from the above that ligand L 1 has best effect, it is better than ligand L 2, although both structures are very similar, area
It is only not different in the connection carbon chain lengths of two phosphino-s.And when without using any ligand, then products collection efficiency has more aobvious
The reduction of work.
Embodiment 25-28
Outer except 1,1,3,3- tetramethyl disiloxane (TMDS) is omitted, other operations are constant, so as to repeat real
Embodiment 1-4 has been applied, has sequentially obtained embodiment 25-28, its products collection efficiency is 91.1-91.9%, it can be seen that, the TMDS's deposits
Products collection efficiency is deliberately being significantly improved, this has important practical significance in large-scale industrial production and the production advantage.
Embodiment 29-40
Embodiment 29-32：In addition to alkali is replaced with DBU by DABCO, other operations are constant, so as to repeat to implement reality
A 1-4 is applied, sequentially obtains embodiment 29-32.
Embodiment 33-36：In addition to alkali is replaced with DMEDA by DABCO, other operations are constant, so as to repeat to implement
Embodiment 1-4, sequentially obtains embodiment 33-36.
Embodiment 37-40：In addition to alkali is replaced with DIPEA by DABCO, other operations are constant, so as to repeat to implement
Embodiment 1-4, sequentially obtains embodiment 37-40.
The result is shown in table 3 below.
Table 3
It can be seen from the above that for alkali, DABCO has best effect, and other alkali cause yield to have obvious reduction.
Embodiment 41-48
Embodiment 41-44：In addition to organic solvent is replaced with one-component PEG-200, other operations are constant, so that weight
Embodiment 1-4 is implemented again, sequentially obtains embodiment 41-44.
Embodiment 45-48：In addition to organic solvent is replaced with one-component diethylene glycol monomethyl ether, other operations are not
Become, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 45-48.
The result is shown in table 4 below.
Table 4
It can be seen from the above that when using one-component as organic solvent, yield has obvious reduction, especially with diethyl
When glycol monomethyl ether is as single solvent, reduction becomes apparent.
In conclusion the present invention provides a kind of synthetic method of aryl substituted indole class compound, this method passes through conjunction
Suitable substrate selection, and using unique catalyst, oxidant, ligand, alkali and organic solvent, and the synthesis of TMDS compositions
Reaction system, purpose product is obtained so as to high yield, before medicine intermediate synthesis technical field has good application
Scape and industrial production potential.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to the protection model of the limitation present invention
Enclose.In addition, it should also be understood that, after the technology contents of the present invention have been read, those skilled in the art can make the present invention each
Kind change, modification and/or variation, all these equivalent forms equally fall within the guarantor that the application the appended claims are limited
Within the scope of shield.
Claims (6)
1. the synthetic method of aryl substituted indole class compound shown in a kind of lower formula (III), the described method includes：In organic solvent
In, in the presence of catalyst, oxidant, ligand, 1,1,3,3- tetramethyl disiloxane and alkali, lower formula (I) compound and following formula
(II) compound reacted at 70-90 DEG C 6-10 it is small when, it is post-treated after reaction, so as to obtain the formula (III) chemical combination
Thing,
Wherein, R1、R2It is each independently selected from H or C1-C6Alkyl；
R3Selected from H, C1-C6Alkyl, C1-C6Alkoxy, halogen or cyano group；
X is halogen；
The catalyst is Au (MeCN) SbF6；
The oxidant is Cr2Cu2O5With AgNTf2Mixture, wherein Cr2Cu2O5With AgNTf2Molar ratio be 4:1；
The ligand is the L1 of following formula:
The alkali is 1,4- diazabicylos [2.2.2] octane；
The organic solvent is that volume ratio is 2:1 polyethylene glycol 200 and the mixture of diethylene glycol monomethyl ether.
2. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound is rubbed with formula (II) compound
You are than being 1:1.5-2.5.
3. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound and the molar ratio of catalyst are
1:0.04-0.08。
4. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound and the molar ratio of oxidant are
1:1-2。
5. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound and the molar ratio of ligand are 1:
0.05-0.1。
6. such as claim 1-5 any one of them synthetic methods, it is characterised in that：Formula (I) compound and 1,1,3,3-
The molar ratio of tetramethyl disiloxane is 1:0.1-0.2.
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Non-Patent Citations (3)
| Title |
|---|
| 2-(2-Haloalkenyl)-aryl Halides as Substrates for Palladium-Catalysed Tandem C-N Bond Formation: Efficient Synthesis of 1-Substituted Indoles;Michael C. Willis et al.;《Adv.Synth.Catal.》;20061231;第348卷;851-856 * |
| Divergent Reactivity in Palladium-Catalyzed Annulation with Diarylamines and α,β-Unsaturated Acids: Direct Access to Substituted 2-Quinolinones and Indoles;Rajesh Kancherla et al.;《Chem.Eur.J.》;20150504;第21卷;8723-8726 * |
| Palladium-Catalyzed Annulation of Diarylamines with Olefins through C-H Activation: Direct Access to N-Arylindoles;Upendra Sharma et al.;《Angew.Chem.Int.Ed.》;20140909;第53卷;11895-11899 * |
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