CN103664769A - Synthesis method of dipyridyl derivative or analogue - Google Patents
Synthesis method of dipyridyl derivative or analogue Download PDFInfo
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- CN103664769A CN103664769A CN201310717930.4A CN201310717930A CN103664769A CN 103664769 A CN103664769 A CN 103664769A CN 201310717930 A CN201310717930 A CN 201310717930A CN 103664769 A CN103664769 A CN 103664769A
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—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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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention relates to a synthesis method of a dipyridyl derivative or an analogue without adding a ligand. The method comprises the steps of mixing and heating 2-halogenated pyridine, its derivative or analogue, nickel salt, zinc powder or manganese powder and halide salt in a solvent to form a coupled product. The method has the advantages that the catalyst ligand is not required to be added; particularly, the high-toxic organic phosphine ligand is not required to be added; the catalyst nickel salt is low in price and small in use amount; and the method is easy and simple to operate, mild in condition, easy to amplify, especially suitable for industrial production, wide in application scope, high in yield, low in cost and environment-friendly.
Description
Technical field
The present invention relates to organic compound preparation and catalyze and synthesize field, being specifically related to a kind of method of dipyridyl derivatives and analogue.
Background technology
Dipyridyl and analogue are the very important nitrogenous type bitooth ligands of a class, have application [Hapke, M. extremely widely in coordination chemistry, analytical chemistry, supramolecular chemistry, nanochemistry etc.; Brandt, L.; L ü tzen, A.Chem.Soc.Rev.2008,37,2782]; In organic chemistry, Bipyridine compound is usually the good part of transition-metal catalysis catalyzer, many optical activity dipyridyls in asymmetric catalysis, occupy an important position again [Fletcher, N.C.J.Chem.Soc., Perkin Trans.12002,1831].Meanwhile, many Bipyridine compounds also occupy very important status in natural product chemistry.For example Caerulomycins and Collismycins series dipyridyl natural product, demonstrate good biological activity [Duan, X.F.; Ma, Z.Q.; Zhang, F.; Zhang, Z.B.J.Org.Chem.2009,74,939.].
Widespread use based on dipyridyl and analogue and important biological activity; existing many bibliographical informations the synthetic method of this compounds; wherein more typical and general method has two classes shown in following formula: transition metal-catalyzed linked reaction and reduced form linked reaction [Newkome, G.R.; Patri, A.K.; Holder, E.; Schubert, U.S.Eur.J.Org.Chem.2004,235]:
The advantage of method in aforesaid method (1) is both can be used for symmetric form product synthetic, also can be used for the synthetic of asymmetric product.But one is significantly limited to is metal reagent (M=Zn, SnR
3deng) preparation very difficult for this type of substrate, the synthetic of these compounds itself be one of a great problem in organic chemistry.Method (2) is although overcome difficulty prepared by above-mentioned metal reagent; but because people think that the dipyridyl that generates or analogue can complex catalysis metals (as Ni etc.) always; thereby make poisoning of catalyst and lose activity; therefore this type of reaction will add a large amount of catalytic metal Ni and part conventionally; even use the triphenylphosphine of equivalent nickel salt and four equivalents just can make to have reacted [Janiak, C.; Deblon, S.; Uehlin, S.Synthesis1999,959].This obvious preparation of compounds has for this reason brought great difficulty, and causes waste and the environmental pollution of reagent.In addition, existing method (2) overwhelming majority is only applicable to the preparation of symmetric form product.Two kinds of above-mentioned methods, are difficult to the metal reagent of preparation or have used a large amount of catalytic metals and part owing to having used, and make these methods generally stay in laboratory applications, are difficult to and even cannot be for industrial production.
Summary of the invention
The object of the invention is to overcome in prior art, three while preparing dipyridyl and analogue thereof large defect: (1) need to be used the metal reagent that be difficult to preparation; (2) need to add the defect of a large amount of metal catalyst/parts; (3) reductive coupling great majority are only applicable to symmetric form coupling; Thereby a kind of general autocatalysis type dipyridyl derivatives without additional part and the synthetic method of analogue are provided.
The method of the synthetic dipyridyl derivatives of the autocatalysis type without additional part of the present invention or analogue, described method comprises:
2-haloperidid and derivative or analogue, nickel salt, zinc powder or manganese powder, with halide salt, Hybrid Heating in solvent and obtain coupled product.
The reaction mechanism of method of the present invention is shown below:
Preferably, the 2-haloperidid derivative in described method comprises that a replacement, two replaces or polysubstituted 2-haloperidid, and substituting group is one or more in alkyl, alkoxyl group, phenyl, ketone group, ester group, cyano group, amide group or benzylalcohol base.
Preferably, described 2-haloperidid analogue comprises 2-halo pyridazine, 2-halogenated quinoline, 2-halo isoquinoline 99.9,2-halo quinoxaline and a replacement, two replacements or polysubstituted 2-halo pyridazine, 2-halogenated quinoline, 2-halo isoquinoline 99.9,2-halo quinoxaline, and substituting group is one or more in alkyl, alkoxyl group, phenyl, ketone group, ester group, cyano group, amide group or benzylalcohol base.
When described 2-haloperidid or derivatives thereof or its analogue comprise two kinds of different substrates, during such as RX, R ' X, can there are three kinds of linked reactions simultaneously, the i.e. linked reaction of two substrates self and the linked reaction between two substrates, for overcoming this problem, the amount that generally can control a kind of substrate is wherein excessive, and then makes reaction have good selectivity.Even when selecting two kinds of substrates of equivalent to react, and expectation obtains the product of coupling between substrate, although real reaction can produce the product of unwanted two kinds of substrates self coupling, but in system, also having coupled product between corresponding substrate produces, these products can obtain separation by subsequent disposal, although selectivity and productive rate with respect to substrate coupling of the same race have reduced, its product that is difficult to preparation for preparing traditional method provides a kind of new method.
Preferably, described 2-haloperidid or derivatives thereof or its analogue comprise two kinds of different substrates, and a kind of substrate is with respect to another kind of substrate excessive 50%.By wherein a kind of excessive interpolation of substrate, and then can realize the control to coupling reaction preference.
Preferably, in 2-haloperidid and derivative or analogue, halogen atom is chlorine, bromine and iodine.
Preferably, described nickel salt comprises six water and nickelous chloride, Dehydrated nickel chloride, any one or more of nickel acetate, nickelous bromide, acetylacetonate nickel.
Preferably, described solvent is dimethyl formamide, N,N-DIMETHYLACETAMIDE, methyl-2-pyrrolidone or acetonitrile.
Preferably, Heating temperature is 40～90 ℃.
In the present invention, autocatalysis type is prepared dipyridyl derivatives and analogue, by the breakthrough of reaction mechanism, radical change to catalyst system, catalyst levels and reaction conditions, thereby has obtained the production process route that a kind of implementation is strong.People generally believe dipyridyl and analogue can with catalytic metal complexing, thereby poison catalyzer, existing measure is the consumption that strengthens catalyzer, use the part of strong solvay-type as organophosphorus ligand, complexing with payment dipyridyl and analogue and catalytic metal, and the present invention is through well-designed, constantly sum up and exploration repeatedly, new mechanism and measures has been proposed, utilize this complexing to carry out catalyzed reaction, thereby broken through the restriction of current methods, fully phased out and used additional part, reduce to a great extent the consumption of catalyzer, make people generally believe that the synthetic of difficulty becomes gentle, selectivity is high, universal strong, thereby set up a kind of efficient, practical and compared with the preparation method of environmental protection.
Technology for present, the reduced form linked reaction of 2-halogen pyridine derivate is only suitable for symmetric form linked reaction in most cases, the present invention is by summing up and repeatedly explore through continuous, particularly repeatedly adjust condiment ratio, feeding mode, make technology provided by the present invention can be used in the cross-coupling of two kinds of different haloperidids or analogue completely, set up a kind of new easy and simple to handle, catalyzer feed intake little, without the asymmetric dipyridyl of preparation of additional part and the synthetic method of analogue.Applicant has successfully been applied to this method the single stage method of natural product CaerulomycinF and has synthesized.
The novel synthesis of dipyridyl provided by the invention and analogue, to take common and cheap nickel salt as catalytic metal, 2-haloperidid and analogue are under cheap inorganic halide salt and metal zinc or manganese powder effect, and one-step synthesis goes out target product, and it has advantages of as follows:
1) do not need to add additional part, the part such as high in price, large organic phosphine of toxicity.
2) consumption of catalytic metal can be low to moderate 2mol%.
3) simple to operate, and mild condition, be easy to amplify, be particularly suitable for suitability for industrialized production.
4) applied widely, yield is high, and cost is low.
Embodiment
Below in conjunction with embodiment, the present invention is carried out to further detailed description, but it is to be noted that the present invention is not only confined to following examples.
Embodiment 1,2,2'-dipyridyl-5,5'-dioctyl phthalate methyl esters synthetic
Six water nickelous chlorides (0.12g, 0.5mmol) add in 20mL DMF, add successively 2-pyridine bromide-5-methyl-formiate (2.16g, 10mmol), Lithium chloride (anhydrous) (0.43g, 10mmol) and zinc powder (0.78g, 12mmol).40 ℃ of system heating, add an iodine initiation reaction, are incubated subsequently 55-60 ℃ of reaction to reacting completely.In reaction mixture, add strong aqua to be neutralized to alkalescence, gained mixed solution dichloromethane extraction, organic layer, through dried over anhydrous sodium carbonate, reclaims solvent, and gained crude product obtains target product 2 through column chromatography purifying, 2'-dipyridyl-5,5'-dioctyl phthalate methyl esters, yield: 77%.
The product solid that is white in color, mp:260.6-261.9 ℃. ν
max(KBr)/cm
-11727.
1h NMR (400MHz, CDCl
3): δ 9.23 (s, 2H), 8.52 (s, 2H), 8.39 (s, 2H), 3.93 (s, 6H);
13c NMR (100MHz, CDCl
3): δ 165.6,158.3,150.6,138.1,122.5,121.3,52.5.
Embodiment 2,2,2'-quinoxaline synthetic
Six water nickelous chlorides (0.12g, 0.5mmol) add in 20mL DMF, add successively 2-chloro-quinoxaline (1.65g, 10mmol), Lithium chloride (anhydrous) (0.43g, 10mmol) and manganese powder (0.61g, 12mmol).40 ℃ of system heating, add an iodine initiation reaction, are incubated subsequently 55-60 ℃ of reaction to reacting completely.In reaction mixture, add strong aqua to be neutralized to alkalescence, gained mixed solution dichloromethane extraction, organic layer is through dried over anhydrous sodium carbonate, reclaim solvent, gained crude product obtains target product 2 through column chromatography purifying, 2'-dipyridyl-5,5'-dioctyl phthalate methyl esters, yield: 72%.
The product solid that is white in color, mp193-195 ℃.
1h NMR (400MHz, CDCl
3): δ 8.81 (d, J=8.6Hz, 2H), 8.28 (d, J=8.6Hz, 2H), 8.20 (d, J=8.3Hz, 2H), 7.83 (d, J=8.1Hz, 2H), 7.70 (t, J=7.2Hz, 2H), 7.52 (t, J=7.4Hz, 2H);
13c NMR (100MHz, CDCl
3): δ 150.0,146.5,136.8,130.2,127.7,127.1,126.8,122.4,121.6.
Embodiment 3,2,2'-dipyridyl-6,6'-dimethoxy nitrile synthetic
Six water nickelous chlorides (0.05g, 0.2mmol) add in 20mL DMF, add successively the chloro-6-cyanopyridine of 2-(1.39g, 10mmol), Lithium chloride (anhydrous) (0.65g, 15mmol) and zinc powder (0.56g, 11mmol).40 ℃ of system heating, add an iodine initiation reaction, are incubated subsequently 55-60 ℃ of reaction to reacting completely.In reaction mixture, add strong aqua to be neutralized to alkalescence, gained mixed solution dichloromethane extraction, organic layer, through dried over anhydrous sodium carbonate, reclaims solvent, and gained crude product obtains target product 2 through column chromatography purifying, 2'-dipyridyl-6,6'-dimethoxy nitrile, yield: 83%.
The product solid that is white in color, mp264.5-265.9 ℃. ν
max(KBr)/cm
-12236.
1h NMR (400MHz, CDCl
3): δ 8.73 (d, J=8.1Hz, 2H), 8.02 (t, J=7.8Hz, 2H), 7.78 (d, J=7.6Hz, 2H);
13c NMR (100MHz, CDCl
3): δ 155.6,138.4,133.4,129.0,124.6,117.0.
Embodiment 4,6-methoxyl group-2,2 '-dipyridyl synthetic
Six water nickelous chlorides (0.12g, 0.5mmol) add in 20mL DMF, add successively 2-bromopyridine (3.9g, 25mmol), the bromo-6-methoxypyridine of 2-(1.9g, 10mmol) Lithium chloride (anhydrous) (0.43g, 10mmol) and zinc powder (0.78g, 12mmol).40 ℃ of system heating, add an iodine initiation reaction, are incubated subsequently 55-60 ℃ of reaction to reacting completely.In reaction mixture, add strong aqua to be neutralized to alkalescence, gained mixed solution dichloromethane extraction, organic layer is through dried over anhydrous sodium carbonate, reclaim solvent, gained crude product obtains target product 2 through column chromatography purifying, 2'-dipyridyl-5,5'-dioctyl phthalate methyl esters, yield: 85%.
Product is colourless liquid;
1h NMR (400MHz, CDCl
3): δ 8.64 (s, 1H), 8.3 (d, J=8.0Hz, 1H), 8.02 (d, J=7.4Hz; 1H), 7.77 (m, 1H), 7.68 (t, J=8.0Hz, 1H), 7.25 (m; 1H), 6.77 (d, J=8.1Hz, 1H), 4.03 (s, 3H);
13c NMR (100MHz, CDCl
3): δ 163.5,156.0,153.3,149.0,139.4,136.9,123.5,121.1,113.8,111.1,53.2.
Embodiment 5,6-methoxyl group-2,2 '-dipyridyl synthetic
Six water nickelous chlorides (0.12g, 0.5mmol), Lithium chloride (anhydrous) (0.43g, 10mmol) and zinc powder (0.78g, 12mmol) add in 20mL DMF.2-chloropyridine (1.7g, 15mmol), the chloro-5-pyridyl-methanamine of 2-(1.43g, 10mmol) are mixed with to solution with 20mL DMF.When system heats 50 ℃, drip above-mentioned solution, while approximately dripping 5mL left and right, add an iodine initiation reaction, be incubated subsequently at 55-60 ℃, slowly drip above-mentioned solution, drip and approximately need 3 hours, after dropwising, in 60-70 ℃ of insulation reaction to reacting completely.In reaction mixture, add strong aqua to be neutralized to alkalescence, gained mixed solution dichloromethane extraction, organic layer, through dried over anhydrous sodium carbonate, reclaims solvent, and gained crude product obtains target product 2 through column chromatography purifying, 2'-dipyridyl-5-methylamine, yield: 71%.
Product is light yellow solid; Mp68-69 ℃.
1h NMR (400MHz, CDCl
3): δ 8.63 (s, 1H), 8.54 (s, 1H), 8.27 (dd, J=2.0Hz, J=8.0Hz, 2H), 7.78 (m, 2H), 7.30 (m, 1H), 4.70 (s, 2H), 3.53 (s, 2H);
13c NMR (100MHz, CDCl
3): δ 155.9,155.1,149.1,147.9,137.1,136.7,135.8,123.8,121.3,121.1,62.3.
Embodiment 6, natural product Caerulomycin F's is synthetic
Six water nickelous chlorides (0.12g, 0.5mmol), Lithium chloride (anhydrous) (0.43g, 10mmol) and zinc powder (0.78g, 12mmol) add in 20mL DMF.2-bromopyridine (3.2g, 20mmol), the bromo-4-methoxyl group-2-piconol of 6-(2.2g, 10mmol) are mixed with to solution with 20mL DMF.When system heats 50 ℃, drip above-mentioned solution, while approximately dripping 5mL left and right, add an iodine initiation reaction, be incubated subsequently at 55-60 ℃, slowly drip above-mentioned solution, drip and approximately need 3 hours, after dropwising, in 60-70 ℃ of insulation reaction to reacting completely.In reaction mixture, add strong aqua to be neutralized to alkalescence, gained mixed solution dichloromethane extraction, organic layer, through dried over anhydrous sodium carbonate, reclaims solvent, and gained crude product obtains target product Caerulomycin F, yield: 72% through column chromatography purifying.
Product is light yellow solid; Mp=63-64 ℃;
1h NMR (400MHz, CDCl
3): δ 8.67 (d, J=4.6Hz, 1H), 8.39 (d; J=8.0Hz, 1H), 7.89 (s, 1H); 7.88-7.79 (m, 1H), 7.33-7.30 (m, 1H); (6.77 d, J=2.0Hz, 1H); 4.77 (s, 2H), 4.14 (br s; 1H), 3.94 (s, 3H);
13c NMR (100MHz, CDCl
3): δ 167.3,160.9,156.5,155.5,148.9,136.9,123.9,121.3,106.6,105.3,64.3,55.3.
Claims (10)
1. a synthetic method for dipyridyl derivatives or analogue, comprising:
2-haloperidid and derivative or analogue, nickel salt, zinc powder or manganese powder, with halide salt, Hybrid Heating in solvent and obtain coupled product.
2. method according to claim 1, it is characterized in that, the derivative of described 2-haloperidid comprises that 2-haloperidid and replaces, two replacement or polysubstituted 2-haloperidids, and substituting group is one or more in alkyl, alkoxyl group, phenyl, ketone group, ester group, cyano group, amide group or benzylalcohol base.
3. method according to claim 1, it is characterized in that, described 2-haloperidid analogue comprises 2-halo pyridazine, 2-halogenated quinoline, 2-halo isoquinoline 99.9,2-halo quinoxaline and a replacement, two replacements or polysubstituted 2-halo pyridazine, 2-halogenated quinoline, 2-halo isoquinoline 99.9,2-halo quinoxaline, and substituting group is one or more in alkyl, alkoxyl group, phenyl, ketone group, ester group, cyano group, amide group or benzylalcohol base.
4. method according to claim 1 and 2, is characterized in that, in 2-haloperidid and derivative or analogue, halogen atom is chlorine, bromine and iodine.
5. method according to claim 1, is characterized in that, described nickel salt comprises Nickel dichloride hexahydrate, Dehydrated nickel chloride, any one or more of nickel acetate, nickelous bromide, acetylacetonate nickel.
6. method according to claim 1, is characterized in that, described halide salt comprises any one or more of lithium chloride, lithiumbromide, sodium-chlor, Sodium Bromide, magnesium chloride or magnesium bromide.
7. method according to claim 1, is characterized in that, described solvent is dimethyl formamide, N,N-DIMETHYLACETAMIDE, methyl-2-pyrrolidone or acetonitrile.
8. method according to claim 1, is characterized in that, Heating temperature is 40～90 ℃.
9. method according to claim 1, is characterized in that, the mol ratio of described 2-haloperidid and derivative or analogue, nickel salt, zinc powder or manganese powder and halide salt is 1:0.02:1.1:1.0～1:0.08:1.2:1.5.
10. method according to claim 1, is characterized in that, described 2-haloperidid and derivative or analogue comprise two kinds of different substrates, and a kind of substrate is with respect to another material excessive 50%.
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| CN112457239A (en) * | 2021-01-22 | 2021-03-09 | 九江善水科技股份有限公司 | Novel synthesis method of 2,2' -bipyridine |
| CN113402559A (en) * | 2021-06-15 | 2021-09-17 | 湖南大学 | Cyclic organic antimony compound and preparation method thereof |
| CN116003216A (en) * | 2023-01-17 | 2023-04-25 | 沈阳药科大学 | Preparation method of ibuprofen |
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