CN108623497B - Preparation method of 2-cyano-4' -methyl biphenyl - Google Patents
Preparation method of 2-cyano-4' -methyl biphenyl Download PDFInfo
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- CN108623497B CN108623497B CN201810769122.5A CN201810769122A CN108623497B CN 108623497 B CN108623497 B CN 108623497B CN 201810769122 A CN201810769122 A CN 201810769122A CN 108623497 B CN108623497 B CN 108623497B
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- C07—ORGANIC CHEMISTRY
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- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- B01J31/2208—Oxygen, e.g. acetylacetonates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/003—Compounds containing elements of Groups 2 or 12 of the Periodic System without C-Metal linkages
Abstract
The invention discloses a preparation method of 2-cyano-4' -methyl biphenyl. The method comprises the following steps: mixing o-chlorobenzonitrile, a compound with a structure shown as a formula 1, a nickel catalyst with a structure shown as a formula 2 and p-methyl phenyl magnesium chloride, and performing cross coupling reaction to obtain the 2-cyano-4' -methyl biphenyl.
Description
Technical Field
The invention relates to intermediate preparation, in particular to a preparation method of 2-cyano-4' -methyl biphenyl.
Background
The sartan, angiotensin II receptor antagonist (AT antagonist) has the advantages of wide application, good curative effect, good tolerance and the like in the aspect of treating cardiovascular diseases, and is a very important novel cardiovascular disease treatment drug.
2-cyano-4' -methyl biphenyl (sartan biphenyl, OTBN) is a key intermediate for synthesizing most sartan drugs at present, and a plurality of sartan drugs such as valsartan, losartan and irbesartan can be derived through structural modification. Therefore, the synthesis method of sartanbiphenyl has great market demand and is concerned by academia and industry.
The synthesis process using o-anisic acid as a raw material is developed in the early stage, and although the raw material is relatively cheap and easily available, the synthesis process needs to be carried out in multiple steps, so that the cost is high, and the three wastes are more. At present, the method of transition metal catalysis is widely adopted in industry to synthesize the sartanbiphenyl. Specifically, there are several strategies:
1) suzuki coupling strategy
The transition metal catalyst used may be a complex of Ni or Pd, with reported yields of 85-97%. The coupling reaction has more steps, the synthesis method has greatly simplified route, high yield and less side reaction, and is easy to be amplified for production. The disadvantages are that the toluic acid is needed and the conditions for preparing the toluic acid are relatively harsh. The result with better yield needs to use palladium metal and ligand with higher cost, which brings certain cost pressure to the process. Meanwhile, the reaction needs to add extra equivalent of alkali, such as NaOH, K2CO3, K3PO4 and the like, and the work and cost of waste treatment are increased.
2) Negishi coupling strategy
P-toluene magnesium chloride reacts with ZnCl2 to obtain toluene zinc chloride, and the toluene zinc chloride is coupled with o-chlorobenzonitrile under the catalysis of a catalyst to obtain sartanbiphenyl. The metals used may be Pd and Ni, with reported yields of 57-92%. The method has the greatest advantage that the coupling is completed in one step without preparing an intermediate p-tolueneboronic acid. The disadvantages are that side reactions are more, the purification of the product is difficult to a certain degree, and various metals are used, so that inorganic salt mixing brings certain difficulty to the recovery and treatment of three wastes, and the environmental pollution is great.
3) Kumada coupling strategy
The p-methyl magnesium chloride and the o-chlorobenzonitrile are directly coupled, and the currently reported catalyst mainly comprises Mn salt, Co salt, Ni salt and the like, and the yield is 57-89%. The reaction does not need to prepare the p-tolueneboronic acid and add other equivalent salts, so the reaction is simple to operate, economic and efficient. However, because the Grignard is relatively too active, and the carbon-magnesium bond and the carbon-transition metal bond have large difference in energy level and are not beneficial to the transmetallization reaction, the reaction is generally difficult to control, the yield is low, the side reactions are more, and the required amount of the Grignard reagent is large. The current solution strategy is mainly to introduce some amide bond-containing solvents such as NMP, DMF, DMAC and the like to soften the nucleophilic reagent, and by the method, the reported yield can be improved to 70-84%. However, these auxiliary solvents not only increase the cost, but also cause environmental pollution due to the difficulty of recovery.
Therefore, the method for producing sartanbiphenyl by using the process technology has the advantages of convenient and easily obtained raw materials, simple operation and low cost, and meets the environment-friendly requirement.
Disclosure of Invention
The invention aims to provide a novel preparation method of 2-cyano-4' -methyl biphenyl.
The invention provides a preparation method of 2-cyano-4' -methyl biphenyl, which comprises the following steps:
mixing o-chlorobenzonitrile, a compound with a structure shown as a formula 1, a nickel catalyst with a structure shown as a formula 2 and p-methyl phenyl magnesium chloride, and performing cross coupling reaction to obtain 2-cyano-4' -methyl biphenyl;
wherein M is selected from hydrogen, magnesium, sodium, potassium, lithium, or R4N；
R is selected from hydrogen and C1-20Alkyl radical, C1-6Cycloalkyl radical, C2-20Alkenyl radical, C2-20Alkynyl, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, halo C1-6Cycloalkyl radical, C6-20Aryl, or C6-20A heteroaryl group;
x is selected from chlorine or bromine;
wherein, X2And X3Are respectively selected from chlorine, bromine, OAc or acac;
l is selected from triphenylphosphine, tricyclohexylphosphine, DPPF, triisopropylphosphine, tri-n-butylphosphine, dialkylhydroxyphosphine R2(OH) P, or trialkoxyphosphine (RO)3P；
R' is selected from hydrogen, C1-20Alkyl radical, C6-20Aryl, or C6-20A heteroaryl group.
In another preferred embodiment, R is C1-3An alkyl group; more preferably, R is methyl or ethyl.
In another preferred embodiment, the temperature of the cross-coupling reaction is 15-60 ℃; more preferably, the temperature of the cross-coupling reaction is 25-45 ℃.
In another preferred embodiment, the solvent used in the cross-coupling reaction is tetrahydrofuran, or a mixture of tetrahydrofuran and one or more of the following solvents: toluene, hexane, heptane, methylcyclohexane.
In another preferred example, the mixing is to drop p-methyl phenyl magnesium chloride into a system containing o-chlorobenzonitrile, a compound with a structure shown in formula 1 and a nickel catalyst with a structure shown in formula 2.
In another preferred embodiment, the amount of the compound with the structure shown in formula 1 is 3-15 mol% of the o-chlorobenzonitrile.
Therefore, the invention provides a new process technology which is convenient and easy to obtain raw materials, simple to operate and low in cost and meets the environment-friendly requirement for producing sartanbiphenyl.
Drawings
FIG. 1 is an infrared spectrum of methoxy zincdichlorozincate prepared in examples 1 and 2.
Detailed Description
The inventors have extensively studied and found that the cross-coupling synthesis of sartanbiphenyl can be successfully realized by adding a catalytic amount of hydroxy or alkoxy dichloro zincic acid. The cocatalyst is convenient and easy to obtain, the coupling process is stable and reliable, the impurities generated by the reaction are few, the product purity is high, the three wastes generated by the process can be greatly reduced, and the inorganic salt can be recycled.
The invention provides a preparation method of 2-cyano-4' -methyl biphenyl (sartanbiphenyl, OTBN):
the method comprises the step of using an oxy-dichloro zincic acid compound (formula 1) as a cocatalyst and a nickel catalyst (formula 2) to jointly catalyze the cross-coupling reaction of p-toluene magnesium halide and o-chlorobenzonitrile, so as to synthesize the 2-cyano-4' -methyl biphenyl (ottbn).
Specifically, the preparation method comprises the following steps: mixing o-chlorobenzonitrile, a compound shown in a formula 1, a nickel catalyst shown in a formula 2 and p-methyl phenyl magnesium chloride, and performing cross coupling reaction to obtain the 2-cyano-4' -methyl biphenyl.
In one embodiment of the present invention, the method is to add p-tolylmagnesium chloride dropwise to a system containing o-chlorobenzonitrile, a nickel catalyst represented by formula 2 and a co-catalyst represented by formula 1.
In one embodiment of the present invention, the compound of formula 1 is added in an amount of 3 to 15 mol%, for example, 3 to 10 mol%, 3 to 5 mol%, 5 to 15 mol%, 5 to 10 mol%, 8 to 15 mol%, 8 to 10 mol%, etc., based on the o-chlorobenzonitrile.
In one embodiment of the invention, the reaction temperature in the cross-coupling reaction is 15 to 60 ℃, preferably 25 to 45 ℃.
In one embodiment of the present invention, the solvent used in the cross-coupling reaction is THF (tetrahydrofuran), or a mixed solvent of THF and one or more solvents selected from toluene, hexane, heptane, methylcyclohexane, and the like.
The complex of the nickel catalyst shown in formula 2 may be prepared in advance, or the nickel salt and the desired ligand may be added to the reaction system in proportion, respectively, to produce the desired nickel catalyst on site.
In one embodiment of the present invention, the cocatalyst represented by formula 1 may be prepared in advance by, but not limited to, dropping an alcohol (preferably C) in an organic solution containing zinc dichloride1-3More preferably methanol, ethanol, etc.), and then stirring at room temperature after the addition is completed, and desolventizing to obtain the cocatalyst shown in formula 1 or directly using the cocatalyst shown in formula 1 for cross-coupling reaction without concentration.
In a comparative example of the present invention, the compound of formula 1 was not added, and as a result, the objective compound was not obtained. The invention improves the compatibility of the reaction by using the compound of formula 1, so that the reaction can be compatible with nitrile group, ester group, acyl group and the like.
In another embodiment of the present invention, the nickel salt and the desired ligand may also be added separately in proportions to the reaction system to produce the desired nickel catalyst in situ.
The amount of Grignard reagent used in the method of the invention is 1.05-1.20 equivalents, such as but not limited to 1.05-1.10 equivalents, 1.05-1.15 equivalents, 1.10-1.15 equivalents, etc.
The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.
The main advantages of the invention are:
1. the preparation method provided by the invention has the advantages of convenient and easily obtained raw materials, simple operation and low cost, and the process technology is suitable for environment-friendly requirements.
2. The present invention can crystallize to obtain magnesium chloride alone by concentrating and cooling the aqueous phase, while other processes in the prior art may have the by-products of mixed inorganic salts, such as zinc and magnesium salts, manganese and magnesium salts, and boric and magnesium salts.
3. The preparation method provided by the invention improves the compatibility of the reaction by using the compound shown in the formula I, for example, the reaction can be compatible with nitrile group, ester group, acyl group and the like.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified. The weight volume percentage units in the present invention are well known to those skilled in the art and refer to, for example, the weight of solute in a 100 ml solution. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The purity determination method of the 2-cyano-4' -methyl biphenyl prepared in the following examples is as follows:
1.1.1.1 diluents: methylene dichloride
1.1.1.2 blank solution: methylene dichloride
1.1.1.3N0131(MB) sample solution
Weighing 100mg of 2-cyano-4' -methyl biphenyl sample in a 10mL volumetric flask, adding a diluent solvent, fixing the volume to a scale, and mixing uniformly.
1.1.2 assay:
and after the system applicability meets the regulation, respectively taking the solutions, injecting the solutions into a liquid chromatograph, and recording a chromatogram.
Example 1
Preparation of Methoxydichloro zincic acid
Adding 500mL of THF and 30g of zinc dichloride into a 1L reaction kettle, dropwise adding 7.05g of methanol at 10.0-30.0 ℃, continuously stirring at room temperature for 1 hour after dropwise adding, and desolventizing to obtain a white solid which is taken as a cocatalyst of methoxy zinc dichloride. The yield was 100% (note: the cocatalyst could be used directly in the coupling reaction without concentration)
Example 2
Preparation of Methoxydichloro zincic acid
Adding 500mL of THF and 30g of zinc dichloride into a 1L reaction kettle, dropwise adding 3.97g of water at 10.0-30.0 ℃, continuously stirring at room temperature for 1 hour after dropwise adding, and desolventizing to obtain white solid which is taken as a cocatalyst oxy-dichloro zincic acid. (Note: the cocatalyst can also be used directly in the coupling reaction without concentration)
ATR(cm-1) 3479,2991,2967,2899,1454,1351,1249,1173,1014,914,864,755,692,579, see figure 1.
Example 3
Preparation of 2-cyano-4' -methylbiphenyl (sartanbiphenyl, OTBN)
1.0Kg of THF, 300g of o-chlorobenzonitrile, 22g of methoxydichlorozincic acid and 35g of bis (triphenylphosphine) nickel dichloride are placed in a 5L vessel, the stirring is switched on, the mixture is stirred for 15 minutes at room temperature, and the atmosphere is replaced by nitrogen for 3 times.
1160g of p-methylphenylmagnesium chloride THF solution (30 wt%) was added dropwise to the kettle under a nitrogen atmosphere, and the reaction solution became black. Controlling the temperature of the feed liquid in the kettle to be 28.0-32.0 ℃, finishing dropping for 3-4 hours, preserving the temperature and continuing to react for 30 minutes. The reaction was quenched by adding 500g of 2% diluted hydrochloric acid to the pot, the pH was 5 to 6, the mixture was stirred for 10 minutes, and the mixture was allowed to stand for separation, the lower aqueous layer was extracted with 100g of toluene, the lower aqueous layer was collected, and the organic layers were combined. And (3) decompressing and recovering the solvent, transferring the concentrated solution into a distillation device, starting to heat, slowly raising the temperature to 80.0-100.0 ℃ of the kettle material, slowly opening the vacuum, and keeping the vacuum degree to 0.06-0.095 MP. Opening a valve of a front-end distillate receiving tank, controlling the temperature of kettle materials to be 80.0-100.0 ℃, the top temperature to be 80.0-95.0 ℃, receiving the front-end distillate, wherein the obtained front-end distillate is mainly 4,4 '-dimethylbiphenyl by-products, opening a product discharging valve after the front-end distillate is finished, adjusting the heating control inner temperature to be 180.0-195.0 ℃, the vacuum degree to be 0.06-0.095MPa, the top temperature to be 160.0-170.0 ℃, receiving the product distillate, obtaining 379g of 2-cyano-4' -methylbiphenyl, and obtaining the yield of 90 percent and the purity of 99.8 percent.1HNMR(400MHz,CDCl3)δ:2.41(s,3H),7.20-7.40(m,2H),7.40-7.60(m,2H),7.60-7.70(m,1H),7.70-7.80(m,1H).
The aqueous phase was concentrated to 1/3 volumes, cooled to 0 degrees, and then filtered to give magnesium chloride as a solid with a purity of > 98%.
Example 4
In example 3, the intended compound, 2-cyano-4' -methylbiphenyl, was not obtained without using methoxydichlorozincate.
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the scope of the invention, which is defined by the claims appended hereto, and any other technical entity or method that is encompassed by the claims as broadly defined herein, or equivalent variations thereof, is contemplated as being encompassed by the claims.
Claims (5)
1. A method for preparing 2-cyano-4' -methylbiphenyl, comprising the steps of:
mixing o-chlorobenzonitrile, a compound with a structure shown as a formula 1, a nickel catalyst of bis (triphenylphosphine) nickel dichloride and p-methyl phenyl magnesium chloride, and performing cross coupling reaction to obtain 2-cyano-4' -methyl biphenyl; the dosage of the compound with the structure shown in the formula 1 is 3-15 mol% of o-chlorobenzonitrile;
wherein M is selected from hydrogen;
r is selected from hydrogen or methyl;
x is selected from chlorine or bromine.
2. The method of claim 1, wherein the cross-coupling reaction temperature is 15-60 ℃.
3. The method of claim 2, wherein the cross-coupling reaction temperature is from 25 ℃ to 45 ℃.
4. The method according to claim 1, wherein the solvent used in the cross-coupling reaction is tetrahydrofuran, or a mixture of tetrahydrofuran and one or more of the following solvents: toluene, hexane, heptane, methylcyclohexane.
5. The preparation method according to claim 1, wherein the mixing is performed by dropwise adding p-methylphenyl magnesium chloride into a system containing o-chlorobenzonitrile, the compound having the structure shown in formula 1 and a nickel catalyst bis (triphenylphosphine) nickel dichloride.
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| CN114733526A (en) * | 2022-04-25 | 2022-07-12 | 浙江天宇药业股份有限公司 | Nickel-loaded porous carbon material catalyst and preparation method and application thereof |
| CN115215813A (en) * | 2022-07-28 | 2022-10-21 | 江苏新瑞药业有限公司 | Method for controlling valsartan impurity |
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