CN105198682A - Preparation method of substituted biphenyl - Google Patents
Preparation method of substituted biphenyl Download PDFInfo
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- CN105198682A CN105198682A CN201510587066.XA CN201510587066A CN105198682A CN 105198682 A CN105198682 A CN 105198682A CN 201510587066 A CN201510587066 A CN 201510587066A CN 105198682 A CN105198682 A CN 105198682A
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Abstract
The invention discloses a preparation method of substituted biphenyl. The preparation method includes the steps that under the anhydrous condition, a compound 2 and a compound 3 are subjected to a coupled reaction in solvent in the presence of Ni salt and ZnX3X4, and then substituted biphenyl is obtained, wherein Ni salt is one or more of NiX5X6(PPh3)2, NiX7X8(dppp), NiX9X10(dppf), NiX11X12(dppe) and acetylacetone nickel, the temperature of the coupled reaction is 0-30 DEG C, and ZnX3X4 is mixed with the compound 3 before the compound 2 is mixed with the compound 3. According to the method, reaction conditions are mild, the process is simple, operation is safe, requirements for equipment are low, aftertreatment is simple, pollution to the environment is small, industrial production is easy, the usage quantity of zinc halides is small, the cost is low, the yield is high, and the product purity is high.
Description
Technical field
The present invention relates to a kind of preparation method of substituted biphenyl.
Background technology
4-cyanobiphenyl class is a kind of important liquid crystal material intermediate, is widely used in the fields such as medicine, agricultural chemicals, spices and dyestuff.Traditional synthetic method makes the reasons such as atom utilization is low, material toxicity is large, step is long, environmental pollution is heavy, the three wastes are many, high to equipment requirements, yield is low because of regioselectivity, causes industrial production cost to increase.
The method of the 4-of report synthesis both at home and abroad cyanobiphenyl is the most frequently used at present:
1, biphenyl method one: this method take biphenyl as raw material, reacts with bromine, obtains 4-bromo biphenyl, then is obtained by reacting product with cupric cyanide or cuprous cyanide; Reaction formula is as follows:
2, biphenyl method two: this method take biphenyl as raw material, under the catalyst action of aluminum chloride, reacts with mauguinite, obtains target product.Reaction formula is as follows:
3, biphenyl method three (CN101357896A): this method take biphenyl as raw material, under the catalyst action of aluminum chloride, with trichoroacetic chloride generation F-K reaction, then with ammonia gas react, generate biphenyl acid amides, finally use sulfur oxychloride dehydration to obtain target product;
4, suzuki coupling method: this method take chlorobenzene as raw material, is prepared into chlorobenzene Grignard reagent, reacting with trimethyl borate, obtains phenylo boric acid, last with suzuki coupling is carried out to 6-chlorophenyl nitrile, obtain target product, this method is the method that current bibliographical information is maximum.Reaction formula is as follows:
The deficiency of above-mentioned reaction is: method 1, uses bromine, high volatility, and toxicity is large, not easily shipping storage, and simultaneous reactions can produce isomers, causes product purity low; Meanwhile, cuprous cyanide belongs to highly toxic product, and transport is taken all exists great potential safety hazard, therefore is not suitable for suitability for industrialized production; Method 2, mauguinite belongs to hypertoxic gas, and trace sucks and human body can be caused rapidly dead, leaks environmental hazard very big, therefore high to equipment requirements in reaction process, is therefore not suitable for suitability for industrialized production; Method 3, this synthetic method reaction scheme is long, and what pair gram acylations generation was a large amount of contains aluminium salt waste water, big for environment pollution, and use a large amount of sulfur oxychloride, serious to equipment corrosion, big for environment pollution, therefore cause industrial production cost high, be unfavorable for large-scale industrial production; Method 4, this method syntheti c route is long, and intermediate phenylo boric acid is expensive, and the Pd class catalyzer price that suzuki coupling uses is very expensive, therefore causes final finished price very not possess competitive power, does not possess the condition that commercialization is gone into operation.Four suitability for industrialized production are all difficult to carry out.
In addition, US6153810A also reports, under the existence of two (triphenylphosphine) nickelous chloride, by in the N-Methyl pyrrolidone solution of the tetrahydrofuran solution of p-methylphenyl zinc chloride instillation o-chloro benzonitrile, carry out linked reaction, 2-methyl-4 can be obtained '-cyanobiphenyl, yield 95.9%.
In sum, this area needs that a kind of reaction conditions is gentle, technique simple badly, operational safety, low for equipment requirements, aftertreatment is simple, environmental pollution is little, be easy to suitability for industrialized production, the preparation method of zinc halide consumption is low, cost is low, yield is high, product purity is high substituted biphenyl.
Summary of the invention
Technical problem to be solved by this invention is preparation method's severe reaction conditions in order to overcome existing substituted biphenyl, technique is loaded down with trivial details, operational hazards, high to equipment requirements, aftertreatment is loaded down with trivial details, contaminate environment, be not easy to the shortcomings such as suitability for industrialized production, cost is high, product purity is low, and providing a kind of preparation method of substituted biphenyl, the method reaction conditions is gentle, technique simple, operational safety, low for equipment requirements, aftertreatment is simple, environmental pollution is little, be easy to suitability for industrialized production, zinc halide consumption is low, cost is low, yield is high, product purity is high.
The invention provides a kind of preparation method of substituted biphenyl, it comprises the steps: in anhydrous conditions, in a solvent, at Ni salt and ZnX
3x
4existence under, compound 2 and compound 3 are carried out linked reaction, obtain substituted biphenyl; Described Ni salt is NiX
5x
6(PPh
3)
2, NiX
7x
8(dppp), NiX
9x
10(dppf), NiX
11x
12(dppe) one or more and in acetylacetonate nickel; The temperature of described linked reaction is 0 ~ 30 DEG C;
Before the mixing of described compound 2 and described compound 3, described ZnX
3x
4mix with described compound 3;
Wherein, X
1, X
2, X
3, X
4, X
5, X
6, X
7, X
8, X
9, X
10, X
11and X
12be chlorine atom, bromine atoms or atomic iodine independently; Described
only represent-an X
2replace;
N is 0 or 1;
Work as X
1for the chlorine atomic time, R
1, R
2, R
3, R
4and R
5be hydrogen atom, fluorine atom, substituted or unsubstituted C independently
1~ C
4alkyl or substituted or unsubstituted C
1~ C
4alkoxyl group, described " substituted or unsubstituted C
1~ C
4alkyl " and " substituted or unsubstituted C
1~ C
4alkoxyl group " described in be substituted by replace by one or more fluorine atom; Or, R
1, R
2, R
3, R
4and R
5in arbitrary be chlorine atom, the rest is hydrogen atom;
Work as X
1during for bromine atoms, R
1, R
2, R
3, R
4and R
5be hydrogen atom, fluorine atom, chlorine atom, substituted or unsubstituted C independently
1~ C
4alkyl or substituted or unsubstituted C
1~ C
4alkoxyl group, described " substituted or unsubstituted C
1~ C
4alkyl " and " substituted or unsubstituted C
1~ C
4alkoxyl group " described in be substituted by replace by one or more fluorine atom; Or, R
1, R
2, R
3, R
4and R
5in arbitrary be bromine atoms, the rest is hydrogen atom;
Work as X
1during for atomic iodine, R
1, R
2, R
3, R
4and R
5be hydrogen atom, fluorine atom, chlorine atom, bromine atoms, substituted or unsubstituted C independently
1~ C
4alkyl or substituted or unsubstituted C
1~ C
4alkoxyl group, described " substituted or unsubstituted C
1~ C
4alkyl " and " substituted or unsubstituted C
1~ C
4alkoxyl group " described in be substituted by replace by one or more fluorine atom; Or, R
1, R
2, R
3, R
4and R
5in arbitrary be atomic iodine, the rest is hydrogen atom;
R
6for cyano group or amino.
In the preparation method of described compound 1, described
represent an only-R
6replace.
In the preparation method of described compound 1, described NiX
5x
6(PPh
3)
2in PPh
3for triphenylphosphine.
In the preparation method of described compound 1, described NiX
7x
8(dppp) dppp in is two (diphenylphosphine) propane of 1,3-.
In the preparation method of described compound 1, described NiX
9x
10(dppf) dppf in is 1,1 '-bis-(diphenylphosphine) ferrocene.
In the preparation method of described compound 1, described NiX
11x
12(dppe) dppe in is two (diphenylphosphine) ethane of 1,2-.
In the preparation method of described compound 1, the Ni in described Ni salt is nickelous.
In the preparation method of described compound 1, preferably, described Ni salt is NiX
5x
6(PPh
3)
2, NiX
7x
8(dppp), NiX
9x
10(dppf), NiX
11x
12or acetylacetonate nickel (dppe).
In the preparation method of described compound 1, preferably, described X
1, X
2, X
3, X
4, X
5, X
6, X
7, X
8, X
9, X
10, X
11and X
12be chlorine atom.
In the preparation method of described compound 1, described X
2with described R
6for ortho position, a position or contraposition; When n is 1, described F (i.e. fluorine atom) and described R
6for ortho position, a position or contraposition, it is preferably contraposition.
In the preparation method of described compound 1, described C
1~ C
4alkyl can be the C of this area routine
1~ C
4alkyl is preferably methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl.
In the preparation method of described compound 1, described C
1~ C
4alkoxyl group can be the C of this area routine
1~ C
4alkoxyl group is preferably methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy or tert.-butoxy.
In the preparation method of described compound 1, the anhydrous condition of routine when described anhydrous condition is this area use Grignard reagent, the technique means by this area routine realizes; Described technique means is preferably for using shielding gas protection; Described shielding gas can be the conventional shielding gas of such reaction of this area, is preferably nitrogen and/or rare gas element; Described rare gas element can be the rare gas element of this area routine, is preferably one or more in helium, neon, argon gas, Krypton, xenon and radon gas.
In the preparation method of described compound 1, described linked reaction is preferably also carried out under anaerobic, the oxygen free condition of routine when described oxygen free condition is this area use Grignard reagent, and the technique means by this area routine realizes; Described technique means is preferably above-mentioned use shielding gas protection.
In the preparation method of described compound 1, described linked reaction is preferably also being carried out without under carbon dioxide conditions, described without carbon dioxide conditions be this area use Grignard reagent time routine without carbon dioxide conditions, the technique means by this area routine realizes; Described technique means is preferably above-mentioned use shielding gas protection.
In the preparation method of described compound 1, described compound 2 can be that described compound 2 is added described compound 3 with the blending means of described compound 3, also can be that described compound 3 is added described compound 2; Preferably, described compound 2 is that described compound 2 is added described compound 3 with the blending means of described compound 3; Described adding can for dripping.
In the preparation method of described compound 1, before described adding, described solvent can mix with described compound 2 and/or described compound 3; Preferably, described solvent is divided into solvent orange 2 A and solvent B two portions, and described solvent orange 2 A mixes with described compound 2, and described solvent B mixes with described compound 3.
In the preparation method of described compound 1, before described adding, described Ni salt can mix with described compound 2 and/or described compound 3; Preferably, described Ni salt mixes with described compound 3.
In the preparation method of described compound 1, the above-mentioned time added can be such reaction of this area conventional time, stablize controlled temperature of reaction and be as the criterion to obtain and (be preferably, that is reacted by such controls temperature of reaction from heat release, and this is that those skilled in the art can rule of thumb determine); Such as, when the volume of reactor is 0.5 ~ 2L (such as 1L), the ratio of the molar weight of the described time added and described compound 3 is preferably 3 ~ 8h/mol, such as 5.5h/mol.
In the preparation method of described compound 1, described solvent can be the conventional solvent of such reaction, be preferably ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, butyl ether, ethyl isobutyl ether, methyl tertiary butyl ether, N-Methyl pyrrolidone, N, one or more in dinethylformamide and methyl-sulphoxide are more preferably tetrahydrofuran (THF).
In the preparation method of described compound 1, described solvent orange 2 A can be the conventional solvent of such reaction, be preferably ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, butyl ether, ethyl isobutyl ether, methyl tertiary butyl ether, N-Methyl pyrrolidone, N, one or more in dinethylformamide and methyl-sulphoxide are more preferably tetrahydrofuran (THF).
In the preparation method of described compound 1, described solvent B can be the conventional solvent of such reaction, be preferably ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, butyl ether, ethyl isobutyl ether, methyl tertiary butyl ether, N-Methyl pyrrolidone, N, one or more in dinethylformamide and methyl-sulphoxide are more preferably tetrahydrofuran (THF).
In the preparation method of described compound 1, the quality mol ratio of described solvent and described compound 3 can be such and reacts conventional quality mol ratio, the present invention particularly preferably: 900 ~ 2300g/mol, such as 1000 ~ 1120g/mol.
The quality mol ratio of described solvent orange 2 A and described compound 3 can be such and reacts conventional quality mol ratio, the present invention particularly preferably: 600 ~ 1800g/mol, such as 710 ~ 1430g/mol, more such as 1210 ~ 1300g/mol; The quality mol ratio of described solvent B and described compound 3 can be such and reacts conventional quality mol ratio, the present invention particularly preferably: 300 ~ 500g/mol, such as 350 ~ 410g/mol.
In the preparation method of described compound 1, the mol ratio of described Ni salt and described compound 3 can be such and reacts conventional mol ratio, is preferably 0.0005 ~ 0.005, such as 0.001 ~ 0.0015.
In the preparation method of described compound 1, described ZnX
3x
41 (such as 1.0 ~ 1.5) can be more than or equal to the mol ratio of described compound 3; Also can be less than 1, be preferably 0.005 ~ 0.05, such as 0.007 ~ 0.01.
In view of the ZnX of technical grade
3x
4easy deliquescence water suction, thus have larger impact to Grignard reagent.Therefore, described ZnX
3x
4be preferably anhydrous ZnX
3x
4; But, described ZnX
3x
4also can be moisture ZnX
3x
4, be as the criterion not affect Grignard reagent, this is that those skilled in the art can rule of thumb determine, such as, as described ZnX
3x
4when being 0.005 ~ 0.05 with the mol ratio of described compound 3, moisture ZnX can be used
3x
4(be generally the ZnX of technical grade
3x
4).It should be noted that, although moisture ZnX
3x
4when consumption is less, those skilled in the art can think several without impact on Grignard reagent, but, use less ZnX
3x
4still can reach higher yield, be that those skilled in the art are at all unimaginable, this embodies creativeness of the present invention.
In the preparation method of described compound 1, the mol ratio of described compound 2 and described compound 3 can be the conventional mol ratio of such reaction, is preferably 1.1 ~ 2.0, such as 1.4 ~ 1.6, more such as 1.5.
In the preparation method of described compound 1, the temperature of described linked reaction preferably 10 DEG C ~ 15 DEG C.
In the preparation method of described compound 1, the process of described linked reaction can adopt the routine monitoring method (such as TLC, HPLC or NMR) in this area to monitor, for reaction end when generally no longer reacting with compound 3, reaction times is preferably 1h ~ 15h, such as 4h ~ 5h.
The preparation method of described compound 1 also can comprise the preparation method of compound 2, the preparation method of described compound 2 can be the preparation method of this area routine, preferably, it comprises the steps: in anhydrous conditions, in a solvent, magnesium and compound 4 are carried out grignard reaction, obtains described compound 2;
In the preparation method of described compound 2, described anhydrous condition is the anhydrous condition of this area grignard reaction routine, and the technique means by this area routine realizes; Described technique means is preferably for using shielding gas protection; Described shielding gas can be the conventional shielding gas of such reaction of this area, is preferably nitrogen and/or rare gas element; Described rare gas element can be the rare gas element of this area routine, is preferably one or more in helium, neon, argon gas, Krypton, xenon and radon gas.
In the preparation method of described compound 2, described grignard reaction preferably also carries out under anaerobic, and described oxygen free condition is the oxygen free condition of this area grignard reaction routine, and the technique means by this area routine realizes; Described technique means is preferably above-mentioned use shielding gas protection.
In the preparation method of described compound 2, described grignard reaction is preferably also carrying out without under carbon dioxide conditions, described without carbon dioxide conditions be this area grignard reaction routine without carbon dioxide conditions, the technique means by this area routine realizes; Described technique means is preferably above-mentioned use shielding gas protection.
In the preparation method of described compound 2, described solvent can be the conventional solvent of such reaction, be preferably ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, butyl ether, ethyl isobutyl ether, methyl tertiary butyl ether, N-Methyl pyrrolidone, N, one or more in dinethylformamide and methyl-sulphoxide are more preferably tetrahydrofuran (THF).
In the preparation method of described compound 2, the mass ratio of described solvent and described compound 4 can be such and reacts conventional mass ratio, is preferably 2 ~ 6, such as 3 ~ 4.
In the preparation method of described compound 2, described magnesium is preferably magnesium chips.
In the preparation method of described compound 2, the mol ratio of described magnesium and described compound 4 can be such and reacts conventional mol ratio, is preferably 1.0 ~ 2.0, such as 1.1 ~ 1.2.
In the preparation method of described compound 2, the temperature of described grignard reaction can be the conventional temperature of such reaction of this area, is preferably 20 DEG C ~ 70 DEG C, such as 40 DEG C ~ 50 DEG C, more such as 45 DEG C.
In the preparation method of described compound 2, the process of described grignard reaction can adopt the routine monitoring method (such as TLC, HPLC or NMR) in this area to monitor, for reaction end when generally no longer reacting with compound 4, reaction times is preferably 2h ~ 15h, such as 4h ~ 5h.
Linked reaction described in the reaction solution of described grignard reaction can directly drop into as the mixture of " described solvent orange 2 A and described compound 2 " in above-mentioned linked reaction.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is:
(1) the method reaction conditions is gentle, technique simple, operational safety, low for equipment requirements, aftertreatment is simple, environmental pollution is little, be easy to suitability for industrialized production, zinc halide consumption is low, cost is low, yield is high, product purity is high;
(2) the method can adopt trace Zn X
3x
4make catalyzer, significantly reduce ZnX
3x
4consumption, cost-saving, the three wastes reduce; Meanwhile, also greatly reduce the hydrolysis ratio of Grignard reagent, improve reaction yield; And, because the organic zinc of intermediate reduces and the change of order of addition(of ingredients), make reaction system not thickness, tetrahydrofuran (THF) consumption greatly reduce, significantly reduce costs, be easy to suitability for industrialized production.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
If no special instructions, the zinc chloride used in the embodiment of the present invention is technical grade zinc chloride, and it is because of deliquescence, containing a certain amount of water.
The preparation of embodiment 14-cyanobiphenyl
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
In 1L reaction flask; add 283.32g tetrahydrofuran (THF); 22.18g (0.924mol) magnesium chips, adds 94.44g (0.84mol) chlorobenzene, 94.44g tetrahydrofuran (THF) in addition funnel; after adding; instill a small amount of chlorobenzene and enter reaction flask, open and stir, after question response causes; system is warming up to 45 ~ 50 DEG C; open and drip remaining chlorobenzene solution, keep temperature of reaction system between 45 ~ 50 DEG C, after dropwising; reaction insulation 5h; sampling, detect raw material reaction complete, reaction flask is cooled to 20 ~ 25 DEG C; under nitrogen protection, preserve stand-by.Yield 95%.
The preparation of step 24-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 0.73g (0.00532mol) zinc chloride, 0.35g (0.000532mol) two (triphenylphosphine) nickelous chloride, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the phenyl-magnesium-chloride Grignard reagent of step 1 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drip and finish, insulation 4h, sampling detection reaction is complete, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, for 4-cyanobiphenyl, solid is weighed to obtain 88.9g, yield 93.4% (in 6-chlorophenyl nitrile), purity (GC) >=99.0%.
Embodiment 2
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
With embodiment 1.
The preparation of step 24-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 120g (0.88mol) Zinc Chloride Anhydrous, 0.35g (0.000532mol) two (triphenylphosphine) nickelous chloride, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the phenyl-magnesium-chloride Grignard reagent of step 1 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drip and finish, insulation 4h, sampling detection reaction is complete, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, for 4-cyanobiphenyl, solid is weighed to obtain 87.9g, yield 92.4% (in 6-chlorophenyl nitrile), purity (GC) >=99.0%.
The present embodiment can be known by inference in conjunction with other embodiments: as long as before the mixing of compound 2 and described compound 3, described ZnX
3x
4mix with described compound 3, no matter ZnX
3x
4equivalent, the problem that the thickness of comparative example 2 and yield decline can be avoided.
The preparation of embodiment 34-cyanobiphenyl
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
With embodiment 1.
The preparation of step 24-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 0.73g (0.00532mol) zinc chloride, 0.29g (0.000532mol) (dppp) NiCl
2, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the phenyl-magnesium-chloride Grignard reagent of step 1 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drip and finish, insulation 4h, sampling detection reaction is complete, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, for 4-cyanobiphenyl, solid is weighed to obtain 88.4g, yield 92.9% (in 6-chlorophenyl nitrile), purity (GC)>=99.0%.
The preparation of embodiment 44-phenylaniline
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
With embodiment 1.
The preparation of step 24-phenylaniline
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 67.87g (0.532mol) p-Chlorobenzoic acid amide, 0.73g (0.00532mol) zinc chloride, 0.29g (0.000532mol) (dppp) NiCl
2, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the phenyl-magnesium-chloride Grignard reagent of step 1 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drip and finish, insulation 4h, sampling detection reaction is complete, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, for 4-phenylaniline, solid is weighed to obtain 81.6g, yield 90.6% (in p-Chlorobenzoic acid amide), purity (GC)>=99.0%.
The preparation of embodiment 54-cyanobiphenyl
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
With embodiment 1.
The preparation of step 24-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 0.73g (0.00532mol) zinc chloride, 0.36g (0.000532mol) (dppf) NiCl
2, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the phenyl-magnesium-chloride Grignard reagent of step 1 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drip and finish, insulation 4h, sampling detection reaction is complete, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, for 4-cyanobiphenyl, solid is weighed to obtain 89.4g, yield 93.9% (in 6-chlorophenyl nitrile), purity (GC)>=99.0%.
The preparation of embodiment 64-cyanobiphenyl
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
With embodiment 1.
The preparation of step 24-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 0.73g (0.00532mol) zinc chloride, 0.28g (0.000532mol) (dppe) NiCl
2, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the phenyl-magnesium-chloride Grignard reagent of step 1 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drip and finish, insulation 4h, sampling detection reaction is complete, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, for 4-cyanobiphenyl, solid is weighed to obtain 88.6g, yield 92.1% (in 6-chlorophenyl nitrile), purity (GC)>=99.0%.
The preparation of embodiment 74-cyanobiphenyl
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
With embodiment 1.
The preparation of step 24-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 0.73g (0.00532mol) zinc chloride, 0.14g (0.000532mol) acetylacetonate nickel, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the phenyl-magnesium-chloride Grignard reagent of step 1 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drip and finish, insulation 4h, sampling detection reaction is complete, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, for 4-cyanobiphenyl, solid is weighed to obtain 86.7g, yield 90.1% (in 6-chlorophenyl nitrile), purity (GC) >=99.0%.
The preparation of embodiment 84-cyanobiphenyl
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
With embodiment 1.
The preparation of step 24-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 0.37g (0.00266mol) zinc chloride, 0.35g (0.000532mol) two (triphenylphosphine) nickelous chloride, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the phenyl-magnesium-chloride Grignard reagent of step 1 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drip and finish, insulation 4h, sampling detection reaction is complete, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, for 4-cyanobiphenyl, solid is weighed to obtain 89.2g, yield 93.7% (in 6-chlorophenyl nitrile), purity (GC) >=99.0%.
The preparation of embodiment 94 '-chloro-4-cyanobiphenyl
The preparation of step 14-chlorophenylmagnesium bromide Grignard reagent
In 1L reaction flask; add 482.46g tetrahydrofuran (THF); 22.18g (0.924mol) magnesium chips; in addition funnel, add 160.82g (0.84mol) to bromochlorophene, 160.82g tetrahydrofuran (THF), after adding; instillation enters reaction flask to bromochlorophene on a small quantity; open and stir, system is warming up to 20 ~ 25 DEG C after causing by question response; open dropping remaining to bromochlorophene solution; keep temperature of reaction system between 20 ~ 25 DEG C, after dropwising, reaction insulation 5h; sampling; detection raw material reaction is complete, under nitrogen protection, preserves stand-by.Yield 95%.
Step 24 ' preparation of-chloro-4-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 0.73g (0.00532mol) zinc chloride, 0.35g (0.000532mol) two (triphenylphosphine) nickelous chloride, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the 4-chlorophenylmagnesium bromide Grignard reagent of step 1 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drip and finish, insulation 4h, sampling detection reaction is complete, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, it is 4 '-chloro-4-cyanobiphenyl, solid is weighed to obtain 108.9g, yield 95.1% (in 6-chlorophenyl nitrile), purity (GC) >=99.0%.
The preparation of embodiment 104 '-bromo-4-cyanobiphenyl
The preparation of step 14-bromophenyl magnesium iodide Grignard reagent
In 2L reaction flask; add 712.91g tetrahydrofuran (THF); 22.18g (0.924mol) magnesium chips; in addition funnel, add 237.64g (0.84mol) to bromo-iodobenzene, 237.64g tetrahydrofuran (THF), after adding; instillation enters reaction flask to bromo-iodobenzene on a small quantity; open and stir, system is cooled to-15 ~ 10 DEG C after causing by question response; open dropping remaining to bromo-iodobenzene solution; keep temperature of reaction system between-15 ~ 10 DEG C, after dropwising, reaction insulation 5h; sampling; detection raw material reaction is complete, and under nitrogen protection ,-15 ~ 10 DEG C of preservations are stand-by.Yield 95%.
Step 24 ' preparation of-bromo-4-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 0.73g (0.00532mol) zinc chloride, 0.35g (0.000532mol) two (triphenylphosphine) nickelous chloride, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the 4-bromophenyl magnesium iodide Grignard reagent of step 1 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drip and finish, insulation 4h, sampling detection reaction is complete, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, it is 4 '-bromo-4-cyanobiphenyl, solid is weighed to obtain 132.1g, yield 96.2% (in 6-chlorophenyl nitrile), purity (GC) >=99.0%.
The preparation of embodiment 114 '-chloro-2-phenylaniline
The preparation of step 14-chlorophenylmagnesium bromide Grignard reagent
In 1L reaction flask; add 482.46g tetrahydrofuran (THF); 22.18g (0.924mol) magnesium chips; in addition funnel, add 160.82g (0.84mol) to bromochlorophene, 160.82g tetrahydrofuran (THF), after adding; instillation enters reaction flask to bromochlorophene on a small quantity; open and stir, system is warming up to 20 ~ 25 DEG C after causing by question response; open dropping remaining to bromochlorophene solution; keep temperature of reaction system between 20 ~ 25 DEG C, after dropwising, reaction insulation 5h; sampling; detection raw material reaction is complete, under nitrogen protection, preserves stand-by.Yield 95%.
Step 24 ' preparation of-chloro-2-phenylaniline
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 67.87g (0.532mol) Ortho-Chloro aniline, 0.73g (0.00532mol) zinc chloride, 0.29g (0.000532mol) (dppp) NiCl
2, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the 4-chlorophenylmagnesium bromide Grignard reagent of step 1 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drip and finish, insulation 4h, sampling detection reaction is complete, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, it is 4 '-chloro-2-phenylaniline, solid is weighed to obtain 98.9g, yield 91.6% (in Ortho-Chloro aniline), purity (GC)>=99.0%.
Embodiment 123 ', the preparation of the fluoro-2-phenylaniline of 4 '-two chloro-5-
Step 13, the preparation of 4-dichlorophenyl magnesium bromide Grignard reagent
In 1L reaction flask, add 569.27g tetrahydrofuran (THF), 22.18g (0.924mol) magnesium chips, 189.76g (0.84mol) 3 is added in addition funnel, 4-dichloro-bromobenzene, 189.76g tetrahydrofuran (THF), after adding, instill a small amount of 3, 4-dichloro-bromobenzene enters reaction flask, open and stir, after question response causes, system is warming up to 20 ~ 25 DEG C, open and drip remaining 3, 4-dichloro-bromobenzene solution, keep temperature of reaction system between 20 ~ 25 DEG C, after dropwising, reaction insulation 5h, sampling, detection raw material reaction is complete, under nitrogen protection, preserve stand-by.Yield 95%.
Step 23 ', the preparation of the fluoro-2-phenylaniline of 4 '-two chloro-5-
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, the chloro-4-fluoroaniline of 77.43g (0.532mol) 2-, 0.73g (0.00532mol) zinc chloride, 0.29g (0.000532mol) (dppp) NiCl
2, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip 3 of step 1 generation, 4-dichlorophenyl magnesium bromide Grignard reagent is in system, keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drip and finish, insulation 4h, sampling detection reaction is complete, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, be 3 ', the fluoro-2-phenylaniline of 4 '-two chloro-5-, solid is weighed to obtain 123.4g, yield 90.6% (in the chloro-4-fluoroaniline of 2-), purity (GC)>=99.0%.
The preparation of embodiment 134-cyanobiphenyl
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
With embodiment 1.
The preparation of step 24-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 0.73g (0.00532mol) zinc chloride, 0.35g (0.000532mol) two (triphenylphosphine) nickelous chloride, open and stir, reaction system is cooled to 0 ~ 5 DEG C, drip the phenyl-magnesium-chloride Grignard reagent of step 1 generation in system, keep temperature 0 ~ 5 DEG C, time for adding is 3 hours, drip and finish, insulation 5h, sampling detection reaction is complete, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, for 4-cyanobiphenyl, solid is weighed to obtain 90.4g, yield 94.8% (in 6-chlorophenyl nitrile), purity (GC) >=99.0%.
The preparation of embodiment 144-cyanobiphenyl
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
With embodiment 1.
The preparation of step 24-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 0.73g (0.00532mol) zinc chloride, 0.35g (0.000532mol) two (triphenylphosphine) nickelous chloride, open and stir, reaction system is cooled to 25 ~ 30 DEG C, drip the phenyl-magnesium-chloride Grignard reagent of step 1 generation in system, keep temperature 25 ~ 30 DEG C, time for adding is 5 hours, drip and finish, insulation 5h, sampling detection reaction is complete, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, for 4-cyanobiphenyl, solid is weighed to obtain 88.2g, yield 92.5% (in 6-chlorophenyl nitrile), purity (GC) >=99.0%.
The preparation of embodiment 154-cyanobiphenyl
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
With embodiment 1.
The preparation of step 24-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 3.65g (0.0266mol) zinc chloride, 0.35g (0.000532mol) two (triphenylphosphine) nickelous chloride, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the phenyl-magnesium-chloride Grignard reagent of step 1 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 5 hours, drip and finish, insulation 5h, sampling detection reaction is complete, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, for 4-cyanobiphenyl, solid is weighed to obtain 87.9g, yield 92.2% (in 6-chlorophenyl nitrile), purity (GC) >=99.0%.
Comparative example 1 first prepares organic zinc reagent
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
With embodiment 1.
The preparation of step 2 tetraphenylphosphonium chloride zincon
In another 1L tetra-mouthfuls of reaction flasks, add 480g tetrahydrofuran (THF), add 120g (0.88mol) zinc chloride; Grignard reagent dropwise step 1 prepared, in reaction system, keeps temperature 25 ~ 30 DEG C, after dropwising; insulated and stirred 3 hours, nitrogen protection is stand-by.
The preparation of step 34-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 0.35g (0.000532mol) two (triphenylphosphine) nickelous chloride, opens and stirs, reaction system is cooled to 10 ~ 15 DEG C, drip the tetraphenylphosphonium chloride zincon of step 2 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drips and finishes, insulation 4h, sampling detects, to 6-chlorophenyl nitrile residue 15%, and benzene residue 17%, extend the reaction times to 10h, reaction is no longer carried out; Dropped to by dilute hydrochloric acid in reaction solution, cancellation is reacted, and stirs 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, is warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, is cooled to 20 ~ 25 DEG C, obtaining white flaky solid, is 4-cyanobiphenyl, and solid is weighed to obtain 61.9g, yield 65.0% (in 6-chlorophenyl nitrile), purity (GC)≤70.0%.
It should be noted that, although zinc chloride-tetrahydrofuran solution moisture that US6153810A uses is low, price is very expensive, is difficult to industrialization and widely applies, be only only applicable to the micro-reaction in laboratory.Therefore, contriver attempts using the mixing solutions of zinc chloride and tetrahydrofuran (THF) to substitute in this comparative example, but find that yield is lower, by analysis, contriver thinks that major cause is that used technical grade zinc chloride is because of water suction deliquescence, containing certain moisture, thus cause Grignard reagent to be hydrolyzed, the benzene detected can be proved.Therefore, above-mentioned technique needs extra drying step to remove the moisture in technical grade zinc chloride.
Comparative example 2 first prepares organic zinc reagent
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
With embodiment 1.
The preparation of step 2 tetraphenylphosphonium chloride zincon
In another 1L tetra-mouthfuls of reaction flasks, add 120g (0.88mol) Zinc Chloride Anhydrous, Grignard reagent dropwise step 1 prepared is in reaction system, and keep temperature 25 ~ 30 DEG C, after dropwising, insulated and stirred 6 hours, nitrogen protection is stand-by.
The preparation of step 34-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 0.35g (0.000532mol) two (triphenylphosphine) nickelous chloride, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the tetraphenylphosphonium chloride zincon of step 2 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 5 hours, drip and finish, insulation 4h, sampling detects, to 6-chlorophenyl nitrile residue 5%, benzene residue 7%, 4-cyanobiphenyl accounts for 80%, extend the reaction times to 10h, reaction is no longer carried out, dropped to by dilute hydrochloric acid in reaction solution, cancellation is reacted, and stirs 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, is warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, is cooled to 20 ~ 25 DEG C, obtaining white flaky solid, is 4-cyanobiphenyl, and solid is weighed to obtain 73.3g, yield 77.0% (in 6-chlorophenyl nitrile), purity (GC) >=99.0%.
The quantity of solvent that US6153810A uses is very large, be unfavorable for controlling cost, therefore, contriver attempts the consumption reducing the solvent dissolving organic zinc, but find now system very thickness, solution poor fluidity, be sticky on bottle wall, very difficultly carry out lower step dropwise operation, time for adding extends and yield significantly reduces.
Comparative example 3 is without zinc chloride
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
In 1L reaction flask; add 283.32g tetrahydrofuran (THF); 22.18g (0.924mol) magnesium chips, adds 94.44g (0.84mol) chlorobenzene, 94.44g tetrahydrofuran (THF) in addition funnel; after adding; instill a small amount of chlorobenzene and enter reaction flask, open and stir, after question response causes; system is warming up to 45 ~ 50 DEG C; open and drip remaining chlorobenzene solution, keep temperature of reaction system between 45 ~ 50 DEG C, after dropwising; reaction insulation 5h; sampling, detect raw material reaction complete, reaction flask is cooled to 20 ~ 25 DEG C; under nitrogen protection, preserve stand-by.Yield 95%.
The preparation of step 24-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks; under nitrogen protection; add 219.54g tetrahydrofuran (THF) successively; 73.18g (0.532mol) is to 6-chlorophenyl nitrile; 0.35g (0.000532mol) two (triphenylphosphine) nickelous chloride, opens and stirs, reaction system is cooled to 10 ~ 15 DEG C; drip the phenyl-magnesium-chloride Grignard reagent of step 1 generation in system; keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drips and finishes; insulation 4h; sampling detects, and complete to 6-chlorophenyl nitrile reaction, 4-cyanobiphenyl accounts for 45%; 4-chlordiphenyl ketone (i.e. 4-chlorobenzophenone, by
hydrolysis obtains) account for 40%, benzene accounts for 7%, dropped to by dilute hydrochloric acid in reaction solution, cancellation is reacted, and stirs 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtaining white flaky solid, is 4-cyanobiphenyl, and solid is weighed to obtain 35.7g, yield 35.0% (in 6-chlorophenyl nitrile), purity (GC)≤45.0%.
The preparation of comparative example 44-cyanobiphenyl
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
With embodiment 1.
The preparation of step 24-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 0.73g (0.00532mol) zinc chloride, 0.35g (0.000532mol) two (triphenylphosphine) nickelous chloride, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the phenyl-magnesium-chloride Grignard reagent of step 1 generation in system, keep temperature 40 ~ 45 DEG C, time for adding is 3 hours, drip and finish, insulation 4h, sampling detects, 0% is accounted for 6-chlorophenyl nitrile, 4-cyanobiphenyl accounts for 35%, 4-chlordiphenyl ketone accounts for 40%, terphenyl ketone (namely
by
hydrolysis obtains) account for 15%, benzene accounts for 5%, reacts complete, is dropped to by dilute hydrochloric acid in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, is warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, is cooled to 20 ~ 25 DEG C, obtains white flaky solid, for 4-cyanobiphenyl, solid is weighed to obtain 109.9g, yield 40.4% (in 6-chlorophenyl nitrile), purity (GC)≤35.0%.
This comparative example shows, Grignard reagent is added dropwise to zinc chloride and in the solution of 6-chlorophenyl nitrile, after not only generating organic zinc reagent with zinc chloride, carry out linked reaction again with to 6-chlorophenyl nitrile, also directly Yu to 6-chlorophenyl nitrile, product 4-cyanobiphenyl can carry out cyano group addition reaction.Meanwhile, comparative example 3 also show Grignard reagent still can carry out addition reaction with cyano group at slightly low temperature.Thus, effect of the present invention cannot be expected when research and development---Grignard reagent optionally can first generate organic zinc, carry out linked reaction again, the place of also i.e. the invention.
Meanwhile, at such a temperature, as the cyano group in this example replaces with amino, amino also can react with Grignard reagent.
Comparative example 5 uses Manganous chloride tetrahydrate as catalyzer
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
With embodiment 1
The preparation of step 24-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 0.73g (0.00532mol) zinc chloride, 0.67g (0.00532mol) Manganese chloride anhydrous, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the phenyl-magnesium-chloride Grignard reagent of step 1 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drip and finish, insulation 4h, sampling detects, 30% is accounted for 6-chlorophenyl nitrile, 4-cyanobiphenyl accounts for 15%, 4-chlordiphenyl ketone accounts for 40%, benzene accounts for 10%, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, for 4-cyanobiphenyl, solid is weighed to obtain 78.1g, yield 16.4% (in 6-chlorophenyl nitrile), purity (GC)≤20.0%.
Comparative example 6 uses manganese powder as catalyzer
The preparation of step 1 phenyl-magnesium-chloride Grignard reagent
With embodiment 1
The preparation of step 24-cyanobiphenyl
In another 1L tetra-mouthfuls of reaction flasks, under nitrogen protection, add 219.54g tetrahydrofuran (THF) successively, 73.18g (0.532mol) is to 6-chlorophenyl nitrile, 0.73g (0.00532mol) zinc chloride, 0.29g (0.00532mol) manganese powder, open and stir, reaction system is cooled to 10 ~ 15 DEG C, drip the phenyl-magnesium-chloride Grignard reagent of step 1 generation in system, keep temperature 10 ~ 15 DEG C, time for adding is 3 hours, drip and finish, insulation 4h, sampling detects, 45% is accounted for 6-chlorophenyl nitrile, 4-cyanobiphenyl accounts for 5%, 4-chlordiphenyl ketone accounts for 20%, benzene accounts for 20%, dilute hydrochloric acid is dropped in reaction solution, cancellation is reacted, stir 10min, leave standstill, layering, organic layer 5% sodium chloride solution washs, stratification, organic layer adds gac, be warming up to backflow, filtered while hot, filtrate reduced in volume falls tetrahydrofuran (THF) to not going out, be cooled to 20 ~ 25 DEG C, obtain white flaky solid, for 4-cyanobiphenyl, solid is weighed to obtain 60.9g, yield 6.4% (in 6-chlorophenyl nitrile), purity (GC)≤10.0%.
Claims (10)
1. a preparation method for substituted biphenyl, is characterized in that, comprises the steps: in anhydrous conditions, in a solvent, at Ni salt and ZnX
3x
4existence under, compound 2 and compound 3 are carried out linked reaction, obtain substituted biphenyl; Described Ni salt is NiX
5x
6(PPh
3)
2, NiX
7x
8(dppp), NiX
9x
10(dppf), NiX
11x
12(dppe) one or more and in acetylacetonate nickel; The temperature of described linked reaction is 0 ~ 30 DEG C;
Before the mixing of described compound 2 and described compound 3, described ZnX
3x
4mix with described compound 3;
Wherein, X
1, X
2, X
3, X
4, X
5, X
6, X
7, X
8, X
9, X
10, X
11and X
12be chlorine atom, bromine atoms or atomic iodine independently;
N is 0 or 1;
Work as X
1for the chlorine atomic time, R
1, R
2, R
3, R
4and R
5be hydrogen atom, fluorine atom, substituted or unsubstituted C independently
1~ C
4alkyl or substituted or unsubstituted C
1~ C
4alkoxyl group, described " substituted or unsubstituted C
1~ C
4alkyl " and " substituted or unsubstituted C
1~ C
4alkoxyl group " described in be substituted by replace by one or more fluorine atom; Or, R
1, R
2, R
3, R
4and R
5in arbitrary be chlorine atom, the rest is hydrogen atom;
Work as X
1during for bromine atoms, R
1, R
2, R
3, R
4and R
5be hydrogen atom, fluorine atom, chlorine atom, substituted or unsubstituted C independently
1~ C
4alkyl or substituted or unsubstituted C
1~ C
4alkoxyl group, described " substituted or unsubstituted C
1~ C
4alkyl " and " substituted or unsubstituted C
1~ C
4alkoxyl group " described in be substituted by replace by one or more fluorine atom; Or, R
1, R
2, R
3, R
4and R
5in arbitrary be bromine atoms, the rest is hydrogen atom;
Work as X
1during for atomic iodine, R
1, R
2, R
3, R
4and R
5be hydrogen atom, fluorine atom, chlorine atom, bromine atoms, substituted or unsubstituted C independently
1~ C
4alkyl or substituted or unsubstituted C
1~ C
4alkoxyl group, described " substituted or unsubstituted C
1~ C
4alkyl " and " substituted or unsubstituted C
1~ C
4alkoxyl group " described in be substituted by replace by one or more fluorine atom; Or, R
1, R
2, R
3, R
4and R
5in arbitrary be atomic iodine, the rest is hydrogen atom;
R
6for cyano group or amino.
2. preparation method as claimed in claim 1, it is characterized in that, in the preparation method of described compound 1, described Ni salt is NiX
5x
6(PPh
3)
2, NiX
7x
8(dppp), NiX
9x
10(dppf), NiX
11x
12or acetylacetonate nickel (dppe);
And/or, described X
1, X
2, X
3, X
4, X
5, X
6, X
7, X
8, X
9, X
10, X
11and X
12be chlorine atom;
And/or, in the preparation method of described compound 1, described X
2with described R
6for ortho position, a position or contraposition;
And/or, in the preparation method of described compound 1, when n is 1, described F and described R
6for ortho position, a position or contraposition;
And/or, in the preparation method of described compound 1, described C
1~ C
4alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
And/or, in the preparation method of described compound 1, described C
1~ C
4alkoxyl group is methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy or tert.-butoxy.
3. preparation method as claimed in claim 1, is characterized in that, described compound 2 is that described compound 2 is added described compound 3 with the blending means of described compound 3, or, described compound 3 is added described compound 2.
4. preparation method as claimed in claim 3, it is characterized in that, described is incorporated as instillation;
And/or in the preparation method of described compound 1, before described adding, described solvent mixes with described compound 2 and/or described compound 3;
And/or in the preparation method of described compound 1, before described adding, described Ni salt mixes with described compound 2 and/or described compound 3;
And/or when the volume of reactor is 0.5 ~ 2L, the ratio of the molar weight of the described time added and described compound 3 is preferably 3 ~ 8h/mol.
5. preparation method as claimed in claim 4, it is characterized in that, in the preparation method of described compound 1, described solvent is divided into solvent orange 2 A and solvent B two portions, described solvent orange 2 A mixes with described compound 2, and described solvent B mixes with described compound 3.
6. preparation method as claimed in claim 5, it is characterized in that, in the preparation method of described compound 1, described solvent orange 2 A is in ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, butyl ether, ethyl isobutyl ether, methyl tertiary butyl ether, N-Methyl pyrrolidone, DMF and methyl-sulphoxide-kind or multiple;
And/or the quality mol ratio of described solvent orange 2 A and described compound 3 is 600 ~ 1800g/mol;
And/or, in the preparation method of described compound 1, described solvent B is one or more in ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, butyl ether, ethyl isobutyl ether, methyl tertiary butyl ether, N-Methyl pyrrolidone, DMF and methyl-sulphoxide;
And/or the quality mol ratio of described solvent B and described compound 3 is 300 ~ 500g/mol.
7. preparation method as claimed in claim 6, it is characterized in that, the quality mol ratio of described solvent orange 2 A and described compound 3 is 710 ~ 1430g/mol;
And/or the quality mol ratio of described solvent B and described compound 3 is 350 ~ 410g/mol.
8. preparation method as claimed in claim 1, is characterized in that, in the preparation method of described compound 1, described anhydrous condition realizes by using shielding gas protection;
And/or in the preparation method of described compound 1, described linked reaction is also carried out under anaerobic;
And/or in the preparation method of described compound 1, described linked reaction is also being carried out without under carbon dioxide conditions;
And/or, in the preparation method of described compound 1, described solvent is one or more in ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, butyl ether, ethyl isobutyl ether, methyl tertiary butyl ether, N-Methyl pyrrolidone, DMF and methyl-sulphoxide;
And/or in the preparation method of described compound 1, the quality mol ratio of described solvent and described compound 3 is 900 ~ 2300g/mol;
And/or in the preparation method of described compound 1, the mol ratio of described Ni salt and described compound 3 is 0.0005 ~ 0.005;
And/or, in the preparation method of described compound 1, described ZnX
3x
4be 1.0 ~ 1.5 or 0.005 ~ 0.05 with the mol ratio of described compound 3;
And/or in the preparation method of described compound 1, the mol ratio of described compound 2 and described compound 3 is 1.1 ~ 2.0;
And/or in the preparation method of described compound 1, the temperature of described linked reaction is 0 DEG C ~ 30 DEG C;
And/or in the preparation method of described compound 1, the time of described linked reaction is 1h ~ 15h.
9. preparation method as claimed in claim 8, it is characterized in that, described shielding gas is nitrogen and/or rare gas element;
And/or in the preparation method of described compound 1, described solvent is tetrahydrofuran (THF);
And/or in the preparation method of described compound 1, the quality mol ratio of described solvent and described compound 3 is 1000 ~ 1120g/mol;
And/or in the preparation method of described compound 1, the mol ratio of described Ni salt and described compound 3 is 0.001 ~ 0.0015;
And/or, in the preparation method of described compound 1, described ZnX
3x
4be 0.007 ~ 0.01 with the mol ratio of described compound 3;
And/or in the preparation method of described compound 1, the mol ratio of described compound 2 and described compound 3 is 1.4 ~ 1.6;
And/or in the preparation method of described compound 1, the temperature of described linked reaction is 10 DEG C ~ 15 DEG C;
And/or in the preparation method of described compound 1, the time of described linked reaction is 4h ~ 5h.
10. preparation method as claimed in claim 1, is characterized in that, also comprise the steps: in anhydrous conditions, in a solvent, magnesium and compound 4 are carried out grignard reaction, obtains described compound 2;
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| CN105753741A (en) * | 2016-04-26 | 2016-07-13 | 常州制药厂有限公司 | Method for preparing Sacubitril intermediate of anti-heart-failure medicine |
| CN106316745A (en) * | 2016-08-24 | 2017-01-11 | 苏州氟拓化工科技有限公司 | Preparing method of biphenyl compound |
| CN108276294A (en) * | 2018-03-12 | 2018-07-13 | 上海康鹏科技有限公司 | A kind of preparation method of fluorine-containing benzidine |
| CN113087592A (en) * | 2020-01-08 | 2021-07-09 | 浙江中欣氟材股份有限公司 | Synthetic method of 4,4' -dibromo octafluorobiphenyl |
| CN113087592B (en) * | 2020-01-08 | 2022-07-26 | 浙江中欣氟材股份有限公司 | Synthetic method of 4,4' -dibromo octafluoro biphenyl |
| CN111718279A (en) * | 2020-07-28 | 2020-09-29 | 山东盛华电子新材料有限公司 | Method and device for continuously producing sartanbiphenyl |
| CN111718279B (en) * | 2020-07-28 | 2023-04-07 | 山东盛华电子新材料有限公司 | Method and device for continuously producing sartanbiphenyl |
| US11827610B2 (en) | 2021-09-15 | 2023-11-28 | Enko Chem, Inc. | Protoporphyrinogen oxidase inhibitors |
| CN114685251A (en) * | 2022-04-25 | 2022-07-01 | 南京工业大学 | Direct cross-coupling reaction method of diaryl sulfoxide and aryl bromide |
| CN114685251B (en) * | 2022-04-25 | 2022-12-27 | 南京工业大学 | Direct cross-coupling reaction method of diaryl sulfoxide and aryl bromide |
| CN116554009A (en) * | 2023-03-29 | 2023-08-08 | 南京工业大学 | Electrophilic cross-coupling reaction method of aryl sulfone or heteroaryl sulfone and aryl bromide |
| CN116554009B (en) * | 2023-03-29 | 2024-05-28 | 南京工业大学 | Electrophilic cross-coupling reaction method of aryl sulfone or heteroaryl sulfone and aryl bromide |
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