CN104529895A - Synthetic method of nitrogen-containing heterocyclic compound - Google Patents
Synthetic method of nitrogen-containing heterocyclic compound Download PDFInfo
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- CN104529895A CN104529895A CN201410757741.4A CN201410757741A CN104529895A CN 104529895 A CN104529895 A CN 104529895A CN 201410757741 A CN201410757741 A CN 201410757741A CN 104529895 A CN104529895 A CN 104529895A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
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Abstract
The invention relates to a synthetic method of a nitrogen-containing heterocyclic compound. The method comprises the following step: in a solvent, reacting an aryl carbonyl compound with aryl trifluoroborate in the presence of a palladium catalyst, a nitrogen-containing ligand and an accelerator to further prepare the nitrogen-containing heterocyclic compound. The method is simple in reaction, simple and convenient to operate and high in yield, is a totally new synthetic method of a nitrogen-containing heterocyclic compound, provides a new synthetic route for preparation of the type of compound and has good scientific research value and industrialization potency.
Description
Technical field
The present invention relates to a kind of synthetic method containing heteroatoms fused ring compound, particularly a kind of synthetic method with the nitrogen-containing heterocycle compound of isoquinoline 99.9 skeleton, belongs to organic chemical synthesis field.
Background technology
Relating in vitochemical multiple embody rule field, especially in medicinal chemistry art, nitrogen-containing heterocycle compound is a kind of widely used medicine intermediate, or final active pharmaceutical compounds is also often containing nitrogen heterocyclic ring, exactly because nitrogen-containing heterocycle compound has potential biological activity and pharmaceutical use and is paid close attention to widely.
In miscellaneous nitrogen-containing heterocycle compound, isoquinoline 99.9 skeleton has important function and position, be synthesis multi-medicament important as precursors, fragment and/or intermediate, such as it is the important component part of antibacterials, by introducing isoquinoline 99.9 skeleton, gained medicine has the plurality of advantages such as antibacterial, antiviral, antitumor, antidepressant usually.
For isoquinoline compound and synthesis thereof, researcher has synthesized and various new isoquinoline compound and preparation method thereof, thus provide basic raw material for the synthesis of final medical compounds, such as, there are following isoquinoline compound and/or its synthetic method in prior art:
Disclose a kind of synthetic method of 7-bromo-isoquinoline in CN102875465A, become bromine method by diazotization, in non-aqueous solvent, obtain 7-bromo-isoquinoline through polystep reaction, concrete reaction process is as follows:
CN102627604A discloses two class isoquinilone derivatives and the application as cancer therapy drug thereof, and find that it has human cancer cell through research and suppress significantly and kill activity, described two class isoquinoline compound structural formulas are as follows:
WO2012086727A discloses a kind of isoquinoline 99.9-6-sulfone amide derivative, and this derivative can be used to treat glaucoma, Bulbi hypertonia and circulation system disease, and this derivant structure is as follows:
This derivative, by many synthetic routes, obtains through reacting up at least 4 steps.
WO2012026529A discloses a kind of novel synthesis of isoquinilone derivatives, and be included under at least one in nitrile solvents, amide solvent, sulfoxide type solvents and ureas solvent and alkali exists, formula III compound and formula II compound are obtained by reacting formula I:
WO2011162274A discloses a kind of isoquinilone derivatives, and it can be used as CRTH2 inhibitor, and structural formula is as follows:
This compound is obtained, the loaded down with trivial details and expensive reagents of reaction process by least 5 steps reactions.
WO2010027889A discloses a kind of method of substituted isoquinoline formula I, and described method comprises:
Under methyl alcohol and high price iodine oxygenant exist, with anhydrous acid process formula A compound, then products therefrom is used chlorizating agent process, thus obtains formula I, its Chinese style I and A structural formula of compound as follows:
CN101544636A discloses a kind of polyhalogenated isoquinoline formula I derivative and the synthetic method thereof with pharmaceutical activity, and described derivative grinds reacting by heating by II and III under condition of no solvent, then adds catalyzer and continues reaction and obtain:
As mentioned above, although disclose the multiple method preparing isoquinoline compound in prior art, but these methods or reactions steps various, or product yield is lower, or employ expensive reagent, still cannot meet at present for the extensive and easy requirement of the nitrogen-containing heterocycle compound preparation method containing isoquinoline 99.9 skeleton.Therefore for the exploration of the preparation method of the nitrogen-containing heterocycle compound containing isoquinoline 99.9 skeleton, an important development direction in this field current and focus is still.
Summary of the invention
In view of this, in order to solve as too low in yield, the many defects such as process is loaded down with trivial details, expensive reagents is rare that exist in above-mentioned prior art, the present inventor conducts in-depth research for the chemical synthesis process of the nitrogen-containing heterocycle compound containing isoquinoline 99.9 skeleton, after paying a large amount of creative work, thus complete the present invention.
At this, applicant is intended to illustrate, technical scheme of the present invention is in Zhejiang Province's Natural Science Fund In The Light (numbering: be accomplished under subsidy LY14B020009), express thanks at this.
The present invention relates to a kind of synthetic method of nitrogen-containing heterocycle compound, described method comprises in a solvent, under palladium catalyst, containing n-donor ligand and promotor exist, make that aryl carbonyl compound and aryl trifluoroborate react and a step has obtained isoquinoline compound.
Specifically, the invention provides the synthetic method of nitrogen-containing heterocycle compound shown in a kind of formula (I),
Described method comprises:
Under palladium catalyst, containing n-donor ligand and promotor exist, formula (II) compound and formula (III) compound react in reaction solvent, the nitrogen-containing heterocycle compound of production (I),
Wherein: R
1be selected from H, halogen, nitro, C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group or phenyl;
R
2be selected from H, halogen or C
1-C
6alkyl;
M is alkali metal;
Ar
1, Ar
2be phenyl independently of one another, with 1-5 substituent phenyl, naphthyl or with 1-5 substituent naphthyl;
Described substituting group is halogen, C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group or phenyl.
In described synthetic method of the present invention, described palladium catalyst is organic palladium or inorganic palladium compound.Such as can be palladium acetylacetonate (Pd (acac)
2), acid chloride, palladium trifluoroacetate, Palladous chloride, Na
2pdCl
4, Pd (NH
3)
4cl
2, Pd (PPh
3)
4, PdCl
2(dppf), dppePdCl
2, Na
2pdCl
2, PdCl
2(CH
3cN)
2, PdCl
2(PPh
3)
2, Pd (NH
3)
4cl
2, PdCl
2(cod) any one in or any multiple mixture.
Preferably, described palladium catalyst is selected from palladium acetylacetonate (Pd (acac)
2), any one in acid chloride, palladium trifluoroacetate, Palladous chloride or multiple mixture, most preferably be palladium acetylacetonate (Pd (acac)
2).
In described synthetic method of the present invention, described containing n-donor ligand is L1 or L2:
Wherein, X
1-X
8be selected from H or C independently of one another
1-C
6alkyl, Y
1-Y
4be selected from H, C independently of one another
1-C
6alkyl or phenyl.
Described containing n-donor ligand is preferably any one in following formula L-1 to L-4:
Described containing n-donor ligand most preferably is L-1, and namely 2,2 '-dipyridyl (being sometimes abbreviated as below " bpy ").
In described method of the present invention, 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 method of the present invention, C
1-C
6alkoxyl group refers to " C defined above
1-C
6alkyl " be connected with O atom after group.
In described method of the present invention, unless otherwise prescribed, the halogen in halogen or halo such as can be F, Cl, Br or I.
In described synthetic method of the present invention, M is alkali metal, such as, can be Li, Na or K.
In described method of the present invention, Ar
1or Ar
2be phenyl independently of one another, with 1-5 substituent phenyl, naphthyl or with 1-5 substituent naphthyl, phenyl or naphthyl wherein can replace by 1-5 substituting group (described substituting group definition as above), such as can be 1,2,3,4 or 5 substituting groups replace.
In described synthetic method of the present invention, described promotor is the monohydrate of trifluoroacetic acid (TFA), following formula (IV) compound or formula (IV) compound:
Wherein R is H, nitro or C
1-C
6alkyl.
Described promotor is preferably the monohydrate of formula (IV) compound or formula (IV) compound, the more preferably monohydrate of formula (IV) compound, further be preferably tosic acid or tosic acid monohydrate, most preferably be tosic acid monohydrate.
In described synthetic method of the present invention, described reaction solvent is water, benzene,toluene,xylene, chlorobenzene, 1,4-dioxane, 1,6-dioxane, tetrahydrofuran (THF) (THF), 2-methyltetrahydrofuran, N, one or more in dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), methylene dichloride, trichloromethane, tetracol phenixin, ethylene dichloride, normal hexane, ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol, butanols, amylalcohol, hexanol etc., most preferably are water.The consumption of reaction solvent is not particularly limited, and can select according to the common practise in organic synthesis field, such as, select to make to react the amount steadily can carrying out, be easy to control, or is convenient to the amount etc. of aftertreatment.
In described synthetic method of the present invention, described formula (II) compound is 1:1-3 with the mol ratio of (III) compound, this scope includes any sub-range scope wherein, also include any concrete point value wherein, exemplarily such as can be 1:1,1:1.2,1:1.4,1:1.6,1:1.8,1:2,1:2.2,1:2.4,1:2.6,1:2.8 or 1:3.
In described synthetic method of the present invention, the mole dosage of described palladium catalyst is the 2-10% of formula (II) compound mole dosage, such as, can be 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%.
In described synthetic method of the present invention, the mol ratio of described palladium catalyst and described containing n-donor ligand is 1:2-3, such as, can be 1:1.2,1:1.5,1:1.7,1:1.9,1:2,1:2.2,1:2.4,1:2.6,1:2.8 or 1:3.
In described synthetic method of the present invention, described formula (II) is 1:5-15 with the mol ratio of described promotor, such as, can be 1:5,1:7,1:9,1:10,1:12,1:14 or 1:15.
In described synthetic method of the present invention, temperature of reaction is 60-140 DEG C, such as can be 60 DEG C, 70 DEG C, 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C, 120 DEG C, 130 DEG C or 140 DEG C in non-limiting manner.
In described synthetic method of the present invention, reaction times, there is no particular limitation, such as by liquid chromatographic detection object product or raw material residual percentage and determine the suitable reaction times, it typically is 15-30 hour, is such as 15 hours, 17 hours, 19 hours, 21 hours, 23 hours, 25 hours, 27 hours, 29 hours or 30 hours in non-limiting manner.
In described synthetic method of the present invention, the aftertreatment after reaction terminates can be following method: after reaction terminates, by mixture impouring ethyl acetate, use saturated NaHCO in turn
3the aqueous solution and salt water washing, after aqueous layer with ethyl acetate extraction, merge organic layer (namely merge the organic layer after washing and extract the organic layer obtained), use anhydrous Na
2sO
4drying, negative pressure evaporation is except desolventizing, and residue is purified by flash column chromatography (n-hexane/ethyl acetate, both volume ratios are 1:1-3), obtains target product.
In described synthetic method of the present invention, exemplify as one is exemplary, Ar
1for phenyl, 3-tolyl, rubigan or naphthalene-2-base.
In described synthetic method of the present invention, exemplify as one is exemplary, Ar
2for phenyl, 3-tolyl, rubigan or naphthalene-2-base.
In described synthetic method of the present invention, exemplify as one is exemplary, R
2for H or ethyl.
Compared with prior art, the present invention by selecting type (II) and (III) compound as reaction substrate, using palladium compound as catalyzer, by the synergy of specific containing n-donor ligand promotor, one-step synthesis obtains nitrogen-containing heterocycle compound.Described method reaction is simple, easy and simple to handle, yield is high, and be a kind of brand-new synthetic method of nitrogen-containing heterocycle compound, the preparation for nitrogen-containing heterocycle compound provides new synthetic route.
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.
Wherein following group refers to following implication:
Me: methyl; Ph: phenyl.
The synthesis of embodiment 1:1,3-bis-tolyl isoquinoline 99.9
100ml water, 20mmol formula (II) compound (wherein Ar is added in reaction vessel
1for 3-tolyl), 20mmol formula (III) compound, 0.4mmol palladium acetylacetonate, 0.8mmol containing n-donor ligand L-1 and 100mmol tosic acid monohydrate, stir lower reactions 25 hours in 60 DEG C.After reaction terminates, by mixture impouring ethyl acetate, use saturated NaHCO in turn
3the aqueous solution and salt water washing, after aqueous layer with ethyl acetate extraction, merge organic layer (namely merge the organic layer after washing and extract the organic layer obtained), use anhydrous Na
2sO
4drying, negative pressure evaporation is except desolventizing, and residue is purified by flash column chromatography (n-hexane/ethyl acetate, both volume ratios are 1:1), obtains the target product into liquid.Productive rate is 71.9%, and purity is 98.7% (HPLC).
Nucleus magnetic resonance:
1hNMR (500MHz, CDCl
3) δ 8.11 (d, J=10Hz, 1H), 8.05 (d, J=10Hz, 2H), 7.98 (d, J=10Hz, 1H), 7.93 (d, J=5Hz, 1H), 7.68 (dd, J=10Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=10Hz, 1H), 7.43-7.52 (m, 2H) 7.39 (dd, J=5Hz, 1H), 7.33 (d, J=10Hz, 1H), 7.22 (d, J=10Hz, 1H), 2.49 (s, 3H), 2.46 (s, 3H).
Embodiment 2:1,3-bis-synthesis of rubigan isoquinoline 99.9
100ml water, 20mmol formula (II) compound (wherein Ar is added in reaction vessel
1for rubigan), 40mmol formula (III) compound, 1mmol palladium acetylacetonate, 2.5mmol containing n-donor ligand L-1 and 300mmol tosic acid monohydrate, stir lower reactions 15 hours in 80 DEG C.After reaction terminates, by mixture impouring ethyl acetate, use saturated NaHCO in turn
3the aqueous solution and salt water washing, after aqueous layer with ethyl acetate extraction, merge organic layer (namely merge the organic layer after washing and extract the organic layer obtained), use anhydrous Na
2sO
4drying, negative pressure evaporation is except desolventizing, and residue is purified by flash column chromatography (n-hexane/ethyl acetate, both volume ratios are 1:2), obtains the target product into solid.Productive rate is 92.4%, and purity is 98.7% (HPLC).
Fusing point: 150-151 DEG C;
Nucleus magnetic resonance:
1hNMR (500MHz, CDCl
3) δ 8.06-8.15 (m, 4H), 7.94 (d, J=10Hz, 1H), 7.69-7.75 (m, 3H), 7.53-7.56 (m, 3H), 7.46 (d, J=10Hz, 2H).
The synthesis of embodiment 3:1,3-dinaphthyl-2-base isoquinoline 99.9
100ml water, 20mmol formula (II) compound (wherein Ar is added in reaction vessel
1for naphthalene-2-base), 30mmol formula (III) compound, 1.5mmol palladium acetylacetonate, 3.5mmol containing n-donor ligand L-1 and 150mmol tosic acid monohydrate, stir lower reactions 20 hours in 120 DEG C.After reaction terminates, by mixture impouring ethyl acetate, use saturated NaHCO in turn
3the aqueous solution and salt water washing, after aqueous layer with ethyl acetate extraction, merge organic layer (namely merge the organic layer after washing and extract the organic layer obtained), use anhydrous Na
2sO
4drying, negative pressure evaporation is except desolventizing, and residue is purified by flash column chromatography (n-hexane/ethyl acetate, both volume ratios are 1:1), obtains the target product into solid.Productive rate is 62.7%, and purity is 98.2% (HPLC).
Fusing point: 119-121 DEG C;
Nucleus magnetic resonance:
1hNMR (500MHz, CDCl
3) δ 8.76 (s, 1H), 8.19-8.38 (m, 4H), 7.87-8.07 (m, 8H), 7.69-7.72 (m, 1H), 7.49-7.59 (m, 5H).
The synthesis of bromo-1, the 3-phenylbenzene isoquinoline 99.9 of embodiment 4:7-
100ml water, 20mmol formula (II) compound (wherein Ar is added in reaction vessel
1for phenyl), 40mmol formula (III) compound, 0.8mmol palladium acetylacetonate, 1.8mmol containing n-donor ligand L-1 and 200mmol tosic acid monohydrate, stir lower reactions 20 hours in 90 DEG C.After reaction terminates, by mixture impouring ethyl acetate, use saturated NaHCO in turn
3the aqueous solution and salt water washing, after aqueous layer with ethyl acetate extraction, merge organic layer (namely merge the organic layer after washing and extract the organic layer obtained), use anhydrous Na
2sO
4drying, negative pressure evaporation is except desolventizing, and residue is purified by flash column chromatography (n-hexane/ethyl acetate, both volume ratios are 1:2), obtains the target product into solid.Productive rate is 65.2%, and purity is 98.6% (HPLC).
Fusing point: 136-137 DEG C;
Nucleus magnetic resonance:
1hNMR (500MHz, CDCl
3) δ 8.18-8.26 (m, 3H), 8.01 (s, 1H), 7.71-7.79 (m, 4H), 7.47-7.58 (m, 5H), 7.39-7.42 (m, 1H).
The synthesis of embodiment 5:4-ethyl-1,3-phenylbenzene isoquinoline 99.9
100ml water, 20mmol formula (II) compound (wherein Ar is added in reaction vessel
1for phenyl), 45mmol formula (III) compound, 1mmol palladium acetylacetonate, 2.5mmol containing n-donor ligand L-1 and 150mmol tosic acid monohydrate, stir lower reactions 20 hours in 100 DEG C.After reaction terminates, by mixture impouring ethyl acetate, use saturated NaHCO in turn
3the aqueous solution and salt water washing, after aqueous layer with ethyl acetate extraction, merge organic layer (namely merge the organic layer after washing and extract the organic layer obtained), use anhydrous Na
2sO
4drying, negative pressure evaporation is except desolventizing, and residue is purified by flash column chromatography (n-hexane/ethyl acetate, both volume ratios are 1:3), obtains the target product into solid.Productive rate is 67.9%, and purity is 98.9% (HPLC).
Fusing point: 121-123 DEG C;
Nucleus magnetic resonance:
1hNMR (500MHz, CDCl
3) δ 8.12-8.16 (m, 2H), 7.70-7.76 (m, 3H), 7.58-7.59 (m, 2H), 7.43-7.54 (m, 6H), 7.37-7.40 (m, 1H), 3.10 (q, J=5.0Hz, 2H), (1.35 t, J=5.0Hz, 3H).
Can be found out by above-described embodiment 1-5, when adopting the compound system constructed by reaction substrate of the present invention, catalyzer, part and promotor, the nitrogen-containing heterocycle compound of isoquinoline 99.9 skeleton can be had accordingly by various types of aryl carbonyl compound and phenylboronate with higher yields and high purity.
Embodiment 6-11
All replace with except following palladium compound except by catalyst acetyl acetone palladium wherein, implement embodiment 6-11 respectively in the mode identical with embodiment 1-5, the productive rate of embodiment corresponding relation and corresponding nitrogen-containing heterocycle compound is as shown in the table.
As seen from the above table, when adopting acid chloride, palladium trifluoroacetate and Palladous chloride, the productive rate of corresponding product all has significant reduction, this demonstrate that palladium acetylacetonate has best catalytic performance and unique catalysis specificity.
Embodiment 12-21
All replace with except following palladium compound except by catalyst acetyl acetone palladium wherein, implement embodiment 12-21 respectively in the mode identical with embodiment 1-5, the productive rate of embodiment corresponding relation and corresponding diaryl isoquinoline compound is as shown in the table.
Note: "--" represents unreacted.
As seen from the above table, when adopting other palladium compound, react hardly.
Embodiment 22-33
Except when aqueous solvent wherein all to be replaced with as solvent in following table, implement embodiment 22-33 respectively in the mode identical with embodiment 1-5, the productive rate of embodiment corresponding relation and corresponding diaryl isoquinoline compound is as shown in the table.
As seen from the above table, when adopting other organic solvent, reaction also can be carried out, but productive rate has significant reduction, thus demonstrates in this organic reaction, and for organic solvent, the water for non-organic solvent has best solvent effect on the contrary.
Embodiment 34-44
Replace with except following part except by ligand L-1 wherein, implement embodiment 34-44 respectively in the mode identical with embodiment 1-5, the productive rate of embodiment corresponding relation and corresponding diaryl isoquinoline compound is as shown in the table.
Except when part being changed to following part, implement embodiment 40-44 respectively in the mode identical with embodiment 1-5 respectively:
Find that the productive rate of corresponding nitrogen-containing heterocycle compound is 24.9-37.5%.
As can be seen here, part of the present invention for reaction carry out smoothly obtaining with the high yield of product there is significant influence, wherein 2,2 '-dipyridyl has best synergy, even if there is 4 of identical precursor structure with it, 4 '-dimethylbipyridine or 5,5 '-dimethylbipyridine all can not obtain so identical reaction effect.
Embodiment 45-49
Replace with except following promotor except by tosic acid monohydrate wherein, implement embodiment 45-49 respectively in the mode identical with embodiment 1-5, the productive rate of embodiment corresponding relation and corresponding nitrogen-containing heterocycle compound is as shown in the table.
Embodiment 50-54
Except not using promotor, implement embodiment 50-54 respectively in the mode identical with embodiment 1-5, the productive rate of embodiment corresponding relation and corresponding nitrogen-containing heterocycle compound is as shown in the table.
Note: "--" represents and do not contain.
From embodiment 45-54, promotor has remarkably influenced for the productive rate of product, and wherein tosic acid monohydrate has best accelerating system effect, even if adopt tosic acid, its productive rate is also remarkable in tosic acid monohydrate.And when not using promotor, then products collection efficiency significantly reduces, even without research necessity and lose industrialized potentiality
In sum, can clearly be found out by above-mentioned all embodiments, when namely employing method of the present invention uses the palladium catalyst (especially palladium acetylacetonate) being selected from palladium, be selected from the containing n-donor ligand (especially L-1) of L-1 to L-4, and suitable solvent (especially water) and Suitable accelerators (especially tosic acid monohydrate) form complex reaction system time, the nitrogen-containing heterocycle compound with isoquinoline 99.9 skeleton can be obtained with high yield and high purity, it is a kind of brand-new synthetic method having very much prospects for commercial application, for the efficient quick synthesis of nitrogen-containing heterocycle compound provides brand-new synthetic route.
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. a synthetic method for nitrogen-containing heterocycle compound shown in formula (I),
Described method comprises:
Under palladium catalyst, containing n-donor ligand and promotor exist, formula (II) compound and formula (III) compound react in reaction solvent, the nitrogen-containing heterocycle compound of production (I),
Wherein: R
1be selected from H, halogen, nitro, C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group or phenyl;
R
2be selected from H, halogen or C
1-C
6alkyl;
M is alkali metal;
Ar
1, Ar
2be phenyl independently of one another, with 1-5 substituent phenyl, naphthyl or with 1-5 substituent naphthyl;
Described substituting group is halogen, C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group or phenyl.
2. synthetic method as claimed in claim 1, is characterized in that: described palladium catalyst is palladium acetylacetonate (Pd (acac)
2), acid chloride, palladium trifluoroacetate, Palladous chloride, Na
2pdCl
4, Pd (NH
3)
4cl
2, Pd (PPh
3)
4, PdCl
2(dppf), dppePdCl
2, Na
2pdCl
2, PdCl
2(CH
3cN)
2, PdCl
2(PPh
3)
2, Pd (NH
3)
4cl
2, PdCl
2(cod) any one in or any multiple mixture; Preferably, described palladium catalyst is selected from palladium acetylacetonate (Pd (acac)
2), any one in acid chloride, palladium trifluoroacetate, Palladous chloride or multiple mixture, most preferably be palladium acetylacetonate (Pd (acac)
2).
3. synthetic method as claimed in claim 1 or 2, is characterized in that: described containing n-donor ligand is L1 or L2:
Wherein, X
1-X
8be selected from H or C independently of one another
1-C
6alkyl, Y
1-Y
4be selected from H, C independently of one another
1-C
6alkyl or phenyl;
Be preferably any one in following formula L-1 to L-4:
Most preferably be L-1.
4. the synthetic method as described in any one of claim 1-3, is characterized in that: described promotor is the monohydrate of trifluoroacetic acid (TFA), following formula (IV) compound or formula (IV) compound:
Wherein R is H, nitro or C
1-C
6alkyl.
Be preferably the monohydrate of formula (IV) compound or formula (IV) compound, the more preferably monohydrate of formula (IV) compound, further be preferably tosic acid or tosic acid monohydrate, most preferably be tosic acid monohydrate.
5. the synthetic method as described in any one of claim 1-4, it is characterized in that: described reaction solvent is water, benzene,toluene,xylene, chlorobenzene, 1,4-dioxane, 1,6-dioxane, tetrahydrofuran (THF) (THF), 2-methyltetrahydrofuran, N, one or more in dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), methylene dichloride, trichloromethane, tetracol phenixin, ethylene dichloride, normal hexane, ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol, butanols, amylalcohol, hexanol etc., most preferably are water.
6. the synthetic method as described in any one of claim 1-5, is characterized in that: described formula (II) compound is 1:1-3 with the mol ratio of (III) compound.
7. the synthetic method as described in any one of claim 1-6, is characterized in that: the mole dosage of described palladium catalyst is the 2-10% of formula (II) compound mole dosage.
8. the synthetic method as described in any one of claim 1-7, is characterized in that: the mol ratio of described palladium catalyst and described containing n-donor ligand is 1:2-3.
9. the synthetic method as described in any one of claim 1-8, is characterized in that: described formula (II) is 1:5-15 with the mol ratio of described promotor.
10. synthetic method as claimed in claim 9, is characterized in that: temperature of reaction is 60-140 DEG C; Reaction times is 15-30 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410757741.4A CN104529895B (en) | 2014-12-11 | 2014-12-11 | Synthetic method of replacing nitrogen-containing heterocyclic compound |
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| CN106749020B (en) * | 2016-12-30 | 2019-11-01 | 河南师范大学 | A kind of synthetic method of 3- acyl group quinolines |
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