CN103012201A - Synthetic method of 2-cyano-4'-methyl diphenyl - Google Patents
Synthetic method of 2-cyano-4'-methyl diphenyl Download PDFInfo
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- CN103012201A CN103012201A CN2012105055815A CN201210505581A CN103012201A CN 103012201 A CN103012201 A CN 103012201A CN 2012105055815 A CN2012105055815 A CN 2012105055815A CN 201210505581 A CN201210505581 A CN 201210505581A CN 103012201 A CN103012201 A CN 103012201A
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Abstract
The invention provides a synthetic method of 2-cyano-4'-methyl diphenyl as an antihypertensive drug intermediate. Under the catalysis function of a Pd complex catalyst, 2-bromobenzonitrile and parabromotoluene react in one step to prepare the 2-cyano-4'-methyl diphenyl with high purity. The synthetic method has the advantages of few reaction steps, easiness for control of reaction conditions, convenience for operation, low price of raw materials, easiness for acquisition, and the like.
Description
Technical field
The invention belongs to chemical field, particularly a kind of synthetic method of 2-Cyano-4 '-methylbiphenyl.
Background technology
The CAS accession number of 2-cyano group-4 '-methyl diphenyl is: 114772-53-1; English name: 4'-Methyl-2-cyanobiphenyl calls and is 4'-Methylbiphenyl-2-carbonitrile, 2-Cyano-4'-methylbiphenyl; Molecular structure is:
(trade(brand)name: sartanbiphenyl Sartanbiphenyl) is the key intermediate of husky smooth class antihypertensive drug (such as losartan, valsartan, eprosartan, Irb etc.) to the 2-Cyano-4 '-methylbiphenyl.Sartans have effect extensively, hypotensive effect significantly, the characteristics such as easy administration, side effect be little, along with large quantities of medicines in recent years come into the market, the market consumption of 2-Cyano-4 '-methylbiphenyl intermediate is growing, and the manufacturing technology of research 2-cyano group-4 '-methyl diphenyl seems particularly important.
At present, the method for synthetic 2-cyano group-4 '-methyl diphenyl is summarized shown in the following formula:
Route (1) utilizes the synthetic 2-Cyano-4 '-methylbiphenyl of Meyer reaction take o-methoxybenzoic acid as raw material, and synthetic route is long, total recovery is low, the industrialization cost high.Route (2), (4) are respectively with aryl phosphine title complex (the Herrmann WA of palladium, Brossmer C, Oefele K, etal. Palladacycles as structurally defined catalysts for the Heck olefination of chloro-and bromoarenes, Angew Chem Int Ed Engl. 1995,34 (17), be catalyzer with cuprous bromide 1844-1847), carry out the synthetic 2-cyano group-4 ' of grignard reaction-methyl diphenyl, grignard reaction is dangerous large, in the industrial application difficulty; And catalyzer is difficult to separate with product, can not reuse.Route (3) is take nickel, zinc or manganese complex (EP0566468) as catalyzer, and reaction preference is low, separating-purifying is difficult.The 4-methylphenylboronic acid of using in the route (5) needed-70 ℃ of lower synthesizing, and condition is harsh, has limited industrialization.Route (6) cost of material is cheap, but uses a large amount of manganese in the catalyzer, and aftertreatment is cumbersome.Route (7) is the domestic and international method of industrialized synthetic 2-cyano group-4 '-methyl diphenyl, and this method raw material is cheap, and catalyst structure is simple, operational condition is gentle, and yield is higher, but still it is many to exist by product, the principal product separation difficulty, the problem such as yield is unstable.
Summary of the invention
The objective of the invention is for the deficiencies in the prior art, a kind of chemical synthesis process of new 2-Cyano-4 '-methylbiphenyl is provided.
Synthetic method of the present invention is as follows:
A kind of synthetic method of 2-Cyano-4 '-methylbiphenyl comprises the following steps:
1) adjacent bromobenzyl nitrile is dissolved in organic solvent;
2) add catalyzer, be heated to 30～60 ℃ under stirring, and continue to stir 5～10min;
3) splash into para-bromo toluene, stir 2～4 h in 30～60 ℃;
4) be chilled to room temperature, add dilute hydrochloric acid and transfer to pH=6～7, tell organic layer,
5) water layer normal hexane extraction merges organic layer, and washing, drying, distillation, recrystallization get faint yellow needle-like crystal, are product 2-Cyano-4 '-methylbiphenyl.
Preferably, the described organic solvent of step 1) is selected from: one or more in tetrahydrofuran (THF), toluene, benzene, sherwood oil, hexanaphthene, pyridine, DMF, the N-Methyl pyrrolidone.Preferred, organic solvent is selected from: one or both in tetrahydrofuran (THF), toluene or the sherwood oil.Preferred, organic solvent is the mixture of tetrahydrofuran (THF) and toluene, tetrahydrofuran (THF): toluene=1:1～2, volume ratio.Solvent has a significant impact transformation efficiency, the selection rate of product, and the otherness of different solvents is very large.There are solvation effect or synergistic effect between solvent and the reactant.We find that unexpectedly organic solvent is the mixture of tetrahydrofuran (THF) and toluene, and when the volume ratio of tetrahydrofuran (THF) and toluene was 1:1, the selectivity of reaction was best.
In the step 1), the concentration of adjacent bromobenzyl nitrile is 0.5 ~ 2mol/L; The concentration of adjacent bromobenzyl nitrile is too low, and speed of response is slowed down; The concentration of adjacent bromobenzyl nitrile is too high, although the corresponding raising of speed of response meeting, the speed of reaction increase of side reaction is more, and the purity of product and the selectivity of reaction all reduce.
The described catalyzer of step 1) is the Pd composition catalyst, and its structural formula is:
Step 2) in, the add-on of catalyzer is: catalyzer: para-bromo toluene=0.01 ~ 0.05:1, mol ratio.Also there is impact in the adding of catalyzer to reaction opportunity, and catalyzer fully mixes with adjacent bromobenzyl nitrile first, then adds para-bromo toluene, and the productive rate of product and purity are all higher.If first adjacent bromobenzyl nitrile is mixed with para-bromo toluene, then add catalyzer, not only the productive rate of product is low, and impurity is more, and this may be that by product causes in the reaction.From the mechanism analysis, catalyzer elder generation and the complexing of adjacent bromobenzyl nitrile form associated complex or complex compound intermediate, then with para-bromo toluene generation linked reaction.
In the step 3), the mol ratio of para-bromo toluene and adjacent bromobenzyl nitrile is: para-bromo toluene: adjacent bromobenzyl nitrile=1:1.2 ~ 1:2; Para-bromo toluene slowly splashes in the solution, and time for adding is 0.5 ~ 1 hour.The proportioning of reactant, the order of addition(of ingredients) of reactant and time for adding are very important to reaction.Time for adding is too short, and productive rate is reduced; Order of addition(of ingredients) also has a significant effect to the productive rate of reaction.The proportioning of reactant has the greatest impact to productive rate, keeps adjacent bromobenzyl nitrile excessive in reaction process always, is conducive to the carrying out that reacts.
In the step 4), the concentration of described dilute hydrochloric acid is 1～2.5 mol/L.
The described recrystallization of step 5) uses the mixture of benzene and tetrahydrofuran (THF) as recrystallization solvent, and the ratio of benzene and tetrahydrofuran (THF) is 1:2, volume ratio.Recrystallization solvent is very large on purity and the yield impact of product, and the polarity of solvent, solvating ability and solvability are all influential to the effect of recrystallization.Adopt different solvents, the difficulty of the crystallisate that obtains is different, and some solvent such as sherwood oil, can't obtain the product of crystallization at all.Use the mixed solvent of toluene, tetrahydrofuran (THF) or toluene and tetrahydrofuran (THF), can obtain crystalline product.But when using tetrahydrofuran (THF) as recrystallization solvent, because the solubleness of product in tetrahydrofuran (THF) is very large, the loss of product is larger in the recrystallization process.We find at last, and during with the mixed solvent recrystallization of toluene and tetrahydrofuran (THF) 1:2 volume ratio, effect is best, and product purity is the highest.
Preferably, described reaction is at N
2Protection under carry out.
The present invention gets beneficial effect: the present invention adopts the method for direct catalysis bromo-derivative coupling, and single stage method is finished reaction, and output is high, and by product is few, and the catalyzer recycling has reduced reaction cost.Method of the present invention had both reduced reactions steps, had reduced again the generation of waste liquid.Operational path is simple, and is easy and simple to handle, and raw material cheaply is easy to get, and toxicity is less, adapts to the demand of market development.
Description of drawings
Fig. 1 is the infrared spectrum of 2-Cyano-4 '-methylbiphenyl.
Embodiment
The present invention will by following examples, be further described.The step that the present invention does not describe in detail all can adopt prior art.
Catalyzer of the present invention is according to the method preparation of patent application CN102671704A.
The synthetic method of 2-Cyano-4 '-methylbiphenyl comprises the following steps:
1) in the 500ml four-hole bottle, logical N
2Air in the displacement bottle, 3 times repeatedly, clean to air displacement till; Add successively adjacent bromobenzyl nitrile (50.96 g, 0.28mol) and 250ml tetrahydrofuran (THF);
2) add catalyzer 3mmol, be heated to 45 ℃ under stirring, and continue to stir 5min,
Described catalyzer is the Pd composition catalyst, and its structural formula is:
3) para-bromo toluene (37.5g, 0.22mol) slowly splashes in the solution, and time for adding is 0.5 ~ 1 hour.The mol ratio of para-bromo toluene and adjacent bromobenzyl nitrile is: para-bromo toluene: adjacent bromobenzyl nitrile=1:1.27; Stir 3h in 45 ℃;
The add-on of catalyzer is: catalyzer: para-bromo toluene=0.014:1, mol ratio.
4) be chilled to room temperature, the dilute hydrochloric acid that adds 1.5mol/L transfers to pH=6～7; Tell organic layer,
5) water layer extracts with normal hexane (150ml * 2), merges organic layer, and water (200ml * 2) is washed anhydrous Na
2SO
4Drying, 130～138 ℃/266Pa cut is collected in underpressure distillation, the volume ratio of benzene and tetrahydrofuran (THF) be the mixture of the benzene of 1:2 and tetrahydrofuran (THF) as recrystallization solvent, recrystallization gets faint yellow needle-like crystal, mp46～48 ℃.TLC checks and shows a bit.Product is the 2-Cyano-4 '-methylbiphenyl after testing.
Embodiment 2:
1) in the 500 ml four-hole bottles, logical N
2Air in the displacement bottle, 3 times repeatedly, clean to air displacement till; Add successively adjacent bromobenzyl nitrile (25. 48 g, 0. 14 mol) and 250ml tetrahydrofuran (THF);
2) add catalyzer 3mmol, be heated to 30 ℃ under stirring, and continue to stir 10min,
Described catalyzer is the Pd composition catalyst, and its structural formula is:
3) para-bromo toluene (17.1 g, 0. 1mol) slowly splashes in the solution, and time for adding is 0.5 ~ 1 hour.The mol ratio of para-bromo toluene and adjacent bromobenzyl nitrile is: para-bromo toluene: adjacent bromobenzyl nitrile=1:1.4; Stir 4 h in 30 ℃;
The add-on of catalyzer is: catalyzer: para-bromo toluene=0.03:1, mol ratio.
4) be chilled to room temperature, the dilute hydrochloric acid that adds 1mol/L transfers to pH=6～7; Tell organic layer;
5) water layer extracts with normal hexane (150ml * 2), merges organic layer, and water (200ml * 2) is washed anhydrous Na
2SO
4Drying, 130～138 ℃/266Pa cut is collected in underpressure distillation, the volume ratio of benzene and tetrahydrofuran (THF) be the mixture of the benzene of 1:2 and tetrahydrofuran (THF) as recrystallization solvent, recrystallization gets faint yellow needle-like crystal, mp46～48 ℃.TLC checks and shows a bit.Product is the 2-Cyano-4 '-methylbiphenyl after testing.
Embodiment 3:
1) in the 500 ml four-hole bottles, logical N
2Air in the displacement bottle, 3 times repeatedly, clean to air displacement till; Add successively adjacent bromobenzyl nitrile (81. 9 g, 0. 45 mol) and 250ml tetrahydrofuran (THF),
2) add catalyzer 12mmol, be heated to 60 ℃ under stirring, and continue to stir 8min,
Described catalyzer is the Pd composition catalyst, and its structural formula is:
3) para-bromo toluene (42.75 g, 0. 25 mol) slowly splashes in the solution, and time for adding is 0.5 ~ 1 hour.The mol ratio of para-bromo toluene and adjacent bromobenzyl nitrile is: para-bromo toluene: adjacent bromobenzyl nitrile=1:1.8; Stir 2 h in 60 ℃;
The add-on of catalyzer is: catalyzer: para-bromo toluene=0.048:1, mol ratio.
4) be chilled to room temperature, the dilute hydrochloric acid that adds 2.5mol/L transfers to pH=6～7; Tell organic layer;
5) water layer extracts with normal hexane (150ml * 2), merges organic layer, and water (200ml * 2) is washed anhydrous Na
2SO
4Drying, 130～138 ℃/266Pa cut is collected in underpressure distillation, the volume ratio of benzene and tetrahydrofuran (THF) be the mixture of the benzene of 1:2 and tetrahydrofuran (THF) as recrystallization solvent, recrystallization gets faint yellow needle-like crystal, 46～48 ℃ of mp.T LC checks and shows a bit.Product is the 2-Cyano-4 '-methylbiphenyl after testing.
Embodiment 4:
The other the same as in Example 1, difference are that organic solvent is different, and its transformation efficiency is as shown in the table:
Table 1 solvent is on the impact of product
| Organic solvent | Transformation efficiency | Selection rate | Product purity |
| Pyridine | 82 | 68 | 86.4 |
| N-Methyl pyrrolidone | 78 | 65 | 88.6 |
| Toluene | 84 | 86 | 99.2 |
| Tetrahydrofuran (THF) | 86 | 65 | 92.2 |
| Toluene, tetrahydrofuran compound (mixing of 1:1 volume ratio) | 92 | 89 | 99.7 |
| Benzene | 72 | 66 | 81.7 |
| Sherwood oil | 86 | 76 | 98.8 |
| Hexanaphthene | 34 | 26 | 84.6 |
| DMF | 68 | 72 | 82.8 |
Organic solvent has a significant impact transformation efficiency, the selection rate of product, and the otherness of different organic solvents is very large.There are solvation effect or synergistic effect between organic solvent and the reactant.When sherwood oil, tetrahydrofuran (THF) and toluene were made solvent, transformation efficiency and selectivity were all higher; When hexanaphthene was made solvent, transformation efficiency and selectivity were all lower.We find that unexpectedly organic solvent is the mixture of tetrahydrofuran (THF) and toluene, and when the volume ratio of tetrahydrofuran (THF) and toluene was 1:1, selectivity was best; Its transformation efficiency and selectivity are apparently higher than other solvent.
Claims (9)
1. the synthetic method of a 2 cyno 4 methyl biphenyl comprises the following steps:
1) adjacent bromobenzyl nitrile is dissolved in organic solvent;
2) add catalyzer, be heated to 30～60 ℃ under stirring, and continue to stir 5～10min;
3) splash into para-bromo toluene, stir 2～4 h in 30～60 ℃;
4) be chilled to room temperature, add dilute hydrochloric acid and transfer to pH=6～7, tell organic layer,
5) water layer normal hexane extraction merges organic layer, and washing, drying, distillation, recrystallization get faint yellow needle-like crystal, are the product 2 cyno 4 methyl biphenyl.
2. the synthetic method of 2 cyno 4 methyl biphenyl according to claim 1, it is characterized in that, the described organic solvent of step 1) is selected from: one or more in tetrahydrofuran (THF), toluene, benzene, sherwood oil, hexanaphthene, pyridine, DMF, the N-Methyl pyrrolidone; Preferably, organic solvent is selected from: one or both in tetrahydrofuran (THF), toluene or the sherwood oil; Preferred, organic solvent is the mixture of tetrahydrofuran (THF) and toluene, tetrahydrofuran (THF): toluene=1:1～2, volume ratio.
3. the synthetic method of 2 cyno 4 methyl biphenyl according to claim 1 is characterized in that, in the step 1), the concentration of adjacent bromobenzyl nitrile is 0.5 ~ 2mol/L.
4. the synthetic method of 2 cyno 4 methyl biphenyl according to claim 1 is characterized in that, the described catalyzer of step 1) is the Pd composition catalyst, and its structural formula is:
5. the synthetic method of 2 cyno 4 methyl biphenyl according to claim 1 is characterized in that step 2) in, the add-on of catalyzer is: catalyzer: para-bromo toluene=0.01 ~ 0.05:1, mol ratio.
6. the synthetic method of 2 cyno 4 methyl biphenyl according to claim 1 is characterized in that, in the step 3), the mol ratio of para-bromo toluene and adjacent bromobenzyl nitrile is: para-bromo toluene: adjacent bromobenzyl nitrile=1:1.2 ~ 1:2; Para-bromo toluene slowly splashes in the solution, and time for adding is 0.5 ~ 1 hour.
7. the synthetic method of 2 cyno 4 methyl biphenyl according to claim 1 is characterized in that, in the step 4), the concentration of described dilute hydrochloric acid is 1～2.5 mol/L.
8. the synthetic method of 2 cyno 4 methyl biphenyl according to claim 1 is characterized in that, the described recrystallization of step 5) uses the mixture of benzene and tetrahydrofuran (THF) as recrystallization solvent, and the volume ratio of benzene and tetrahydrofuran (THF) is 1:2.
9. the synthetic method of each described 2 cyno 4 methyl biphenyl is characterized in that according to claim 1～8, and described reaction is at N
2Protection under carry out.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108003058A (en) * | 2017-12-12 | 2018-05-08 | 淄博鑫泉医药技术服务有限公司 | The process for purification of sartanbiphenyl |
| CN108623497A (en) * | 2018-07-13 | 2018-10-09 | 上海新埠医药科技有限公司 | A kind of preparation method of 2- Cyano-4 '-methylbiphenyls |
| CN112661666A (en) * | 2020-12-24 | 2021-04-16 | 南京工业大学 | Process for catalytically synthesizing 2-cyano-4' -methyl biphenyl |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108003058A (en) * | 2017-12-12 | 2018-05-08 | 淄博鑫泉医药技术服务有限公司 | The process for purification of sartanbiphenyl |
| CN108623497A (en) * | 2018-07-13 | 2018-10-09 | 上海新埠医药科技有限公司 | A kind of preparation method of 2- Cyano-4 '-methylbiphenyls |
| CN108623497B (en) * | 2018-07-13 | 2021-07-30 | 上海启讯医药科技有限公司 | Preparation method of 2-cyano-4' -methyl biphenyl |
| CN112661666A (en) * | 2020-12-24 | 2021-04-16 | 南京工业大学 | Process for catalytically synthesizing 2-cyano-4' -methyl biphenyl |
| CN112661666B (en) * | 2020-12-24 | 2023-04-21 | 南京工业大学 | Process for catalytic synthesis of 2-cyano-4' -methyl biphenyl |
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