CN103012201B - Synthetic method of 2-cyano-4'-methyl diphenyl - Google Patents
Synthetic method of 2-cyano-4'-methyl diphenyl Download PDFInfo
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- CN103012201B CN103012201B CN201210505581.5A CN201210505581A CN103012201B CN 103012201 B CN103012201 B CN 103012201B CN 201210505581 A CN201210505581 A CN 201210505581A CN 103012201 B CN103012201 B CN 103012201B
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- 0 CC([C@@](CCC(C(c1ccccc1)c1ccccc1)*(C(C)C1)=C)C(C)=C1C(c1ccccc1)c1ccccc1)I Chemical compound CC([C@@](CCC(C(c1ccccc1)c1ccccc1)*(C(C)C1)=C)C(C)=C1C(c1ccccc1)c1ccccc1)I 0.000 description 1
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 as 4'-Methylbiphenyl-2-carbonitrile 2-Cyano-4'-methylbiphenyl; Molecular structure is:
2-Cyano-4 '-methylbiphenyl (trade(brand)name: sartanbiphenyl, Sartanbiphenyl) is the key intermediate of husky smooth class antihypertensive drug (as losartan, valsartan, eprosartan, Irb etc.).Sartans have effect extensively, hypotensive effect significantly, the feature 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 following formula:
Route (1), taking o-methoxybenzoic acid as raw material, utilizes the synthetic 2-Cyano-4 '-methylbiphenyl of Meyer reaction, and synthetic route is long, total recovery is low, industrialization cost is 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 1844-1847) catalyzer with cuprous bromide, carry out synthetic 2-cyano group-the 4 '-methyl diphenyl of grignard reaction, grignard reaction is dangerous large, in industrial application difficulty; And catalyzer is difficult to separate with product, can not reuse.Route (3) is taking the title complex (EP0566468) of nickel, zinc or manganese as catalyzer, and reaction preference is low, separating-purifying is difficult.The 4-methylphenylboronic acid of using in route (5) need synthesize at-70 DEG C, and condition harshness, has limited industrialization.Route (6) cost of material is cheap, but in catalyzer, uses a large amount of manganese, and aftertreatment is cumbersome.Route (7) is the method for industrialized synthetic 2-cyano group-4 '-methyl diphenyl both at home and abroad, and this method raw material is cheap, and catalyst structure is simple, operational condition gentleness, yield is higher, but still it is many to exist by product, principal product separation difficulty, the problem such as yield is unstable.
Summary of the invention
The object 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 synthetic method for 2-Cyano-4 '-methylbiphenyl, comprises the following steps:
1) adjacent bromobenzyl nitrile is dissolved in to organic solvent;
2) add catalyzer, under stirring, be heated to 30～60 DEG C, and continue to stir 5～10min;
3) splash into para-bromo toluene, stir 2～4 h in 30～60 DEG C;
4) be chilled to room temperature, add dilute hydrochloric acid to be adjusted to pH=6～7, separate organic layer,
5) water layer normal hexane extraction, merges organic layer, and washing, dry, distillation, recrystallization obtain faint yellow needle-like crystal, are product 2-Cyano-4 '-methylbiphenyl.
Preferably, the organic solvent described in step 1) is selected from: one or more in tetrahydrofuran (THF), toluene, benzene, sherwood oil, hexanaphthene, pyridine, DMF, N-Methyl pyrrolidone.Preferred, organic solvent is selected from: one or both in tetrahydrofuran (THF), toluene or sherwood oil.Preferred, organic solvent is the mixture of tetrahydrofuran (THF) and toluene, tetrahydrofuran (THF): toluene=1:1～2, volume ratio.Transformation efficiency, the selection rate of solvent to product has a significant impact, and the otherness of different solvents is very large.Between solvent and reactant, there is solvation effect or synergistic effect.We find unexpectedly, and organic solvent is the mixture of tetrahydrofuran (THF) and toluene, and when the volume ratio of tetrahydrofuran (THF) and toluene is 1:1, the selectivity of reaction is best.
In step 1), the concentration of adjacent bromobenzyl nitrile is 0.5 ~ 2mol/L; The concentration of adjacent bromobenzyl nitrile is too low, can make speed of response slow 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.
Catalyzer described in step 1) is Pd composition catalyst, and its structural formula is:
; Wherein,
dBCthe structure of Ph-is
; R is selected from the alkyl of 1～15 carbon; Preferred, R is methyl, ethyl, propyl group, diphenyl-methyl.The synthetic method of catalyzer adopts the method for CN102671704A.
Step 2) in, the add-on of catalyzer is: catalyzer: para-bromo toluene=0.01 ~ 0.05:1, mol ratio.Also there is impact to reaction in the opportunity that adds of catalyzer, catalyzer first fully mixes with adjacent bromobenzyl nitrile, 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 in reaction, by product causes.From the Analysis on Mechanism of reaction, 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 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 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, can make productive rate reduce; 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 of reaction.
In step 4), the concentration of described dilute hydrochloric acid is 1～2.5 mol/L.
Recrystallization described in 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.Purity and the yield impact of recrystallization solvent on product is very large, and polarity, solvating ability and the solvability of solvent have impact to the effect of recrystallization.Adopt different solvents, the difficulty difference of the crystallisate obtaining, some solvent as sherwood oil, cannot obtain the product of crystallization at all.The mixed solvent that uses toluene, tetrahydrofuran (THF) or toluene and tetrahydrofuran (THF), can obtain crystalline product.But while using tetrahydrofuran (THF) as recrystallization solvent, because the solubleness of product in tetrahydrofuran (THF) is very large, in recrystallization process, the loss of product is larger.We finally find, 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 obtains beneficial effect: the present invention adopts the method for direct catalysis bromo-derivative coupling, and single stage method completes reaction, and output is high, and by product is few, and 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, easy and simple to handle, and raw material is cheaply easy to get, and toxicity is less, adapts to the demand of market development.
Brief description of the 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.
embodiment 1
The synthetic method of 2-Cyano-4 '-methylbiphenyl, comprises the following steps:
1) in 500ml four-hole bottle, logical N
2air in 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, under stirring, be heated to 45 DEG C, and continue to stir 5min,
Described catalyzer is Pd composition catalyst, and its structural formula is:
; Wherein,
dBCthe structure of Ph-is
, R is diphenyl-methyl.
3) para-bromo toluene (37.5g, 0.22mol) slowly splashes in 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 DEG C;
The add-on of catalyzer is: catalyzer: para-bromo toluene=0.014:1, mol ratio.
4) be chilled to room temperature, add the dilute hydrochloric acid of 1.5mol/L to be adjusted to pH=6～7; Separate organic layer,
5) for water layer, normal hexane (150ml × 2) extracts, and merges organic layer, and water (200ml × 2) is washed, anhydrous Na
2sO
4dry, underpressure distillation, collects 130～138 DEG C/266Pa cut, and the benzene that the volume ratio of benzene and tetrahydrofuran (THF) is 1:2 and the mixture of tetrahydrofuran (THF) are as recrystallization solvent, and recrystallization obtains faint yellow needle-like crystal, mp46～48 DEG C.TLC checks and shows a bit.Product is 2-Cyano-4 '-methylbiphenyl after testing.
embodiment 2:
1) in 500 ml four-hole bottles, logical N
2air in 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, under stirring, be heated to 30 DEG C, and continue to stir 10min,
Described catalyzer is Pd composition catalyst, and its structural formula is:
; Wherein,
dBCthe structure of Ph-is,
r is propyl group.
3) para-bromo toluene (17.1 g, 0. 1mol) slowly splashes in 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 DEG C;
The add-on of catalyzer is: catalyzer: para-bromo toluene=0.03:1, mol ratio.
4) be chilled to room temperature, add the dilute hydrochloric acid of 1mol/L to be adjusted to pH=6～7; Separate organic layer;
5) for water layer, normal hexane (150ml × 2) extracts, and merges organic layer, and water (200ml × 2) is washed, anhydrous Na
2sO
4dry, underpressure distillation, collects 130～138 DEG C/266Pa cut, and the benzene that the volume ratio of benzene and tetrahydrofuran (THF) is 1:2 and the mixture of tetrahydrofuran (THF) are as recrystallization solvent, and recrystallization obtains faint yellow needle-like crystal, mp46～48 DEG C.TLC checks and shows a bit.Product is 2-Cyano-4 '-methylbiphenyl after testing.
embodiment 3:
1) in 500 ml four-hole bottles, logical N
2air in 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, under stirring, be heated to 60 DEG C, and continue to stir 8min,
Described catalyzer is Pd composition catalyst, and its structural formula is:
; Wherein,
dBCthe structure of Ph-is
, R is ethyl.
3) para-bromo toluene (42.75 g, 0. 25 mol) slowly splashes in 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 DEG C;
The add-on of catalyzer is: catalyzer: para-bromo toluene=0.048:1, mol ratio.
4) be chilled to room temperature, add the dilute hydrochloric acid of 2.5mol/L to be adjusted to pH=6～7; Separate organic layer;
5) for water layer, normal hexane (150ml × 2) extracts, and merges organic layer, and water (200ml × 2) is washed, anhydrous Na
2sO
4dry, underpressure distillation, collects 130～138 DEG C/266Pa cut, and the benzene that the volume ratio of benzene and tetrahydrofuran (THF) is 1:2 and the mixture of tetrahydrofuran (THF) are as recrystallization solvent, and recrystallization obtains faint yellow needle-like crystal, 46～48 DEG C of mp.T LC checks and shows a bit.Product is 2-Cyano-4 '-methylbiphenyl after testing.
embodiment 4:
The other the same as in Example 1, difference is organic solvent difference, its transformation efficiency is as shown in the table:
The impact of table 1 solvent on 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 |
Transformation efficiency, the selection rate of organic solvent to product has a significant impact, and the otherness of different organic solvents is very large.Between organic solvent and reactant, there is solvation effect or synergistic effect.When sherwood oil, tetrahydrofuran (THF) and toluene make solvent, transformation efficiency and selectivity are all higher; When hexanaphthene makees solvent, transformation efficiency and selectivity are all lower.We find unexpectedly, and organic solvent is the mixture of tetrahydrofuran (THF) and toluene, and when the volume ratio of tetrahydrofuran (THF) and toluene is 1:1, selectivity is best; Its transformation efficiency and selectivity are apparently higher than other solvent.
Claims (11)
1. a synthetic method for 2-Cyano-4 '-methylbiphenyl, comprises the following steps:
1) adjacent bromobenzyl nitrile is dissolved in to organic solvent;
2) add catalyzer, under stirring, be heated to 30～60 DEG C, and continue to stir 5～10min; Described catalyzer is Pd composition catalyst, and its structural formula is:
wherein,
dBCthe structure of Ph-is
r is selected from the alkyl of 1～15 carbon;
3) splash into para-bromo toluene, stir 2～4h in 30～60 DEG C;
4) be chilled to room temperature, add dilute hydrochloric acid to be adjusted to pH=6～7, separate organic layer,
5) water layer normal hexane extraction, merges organic layer, and washing, dry, distillation, recrystallization obtain faint yellow needle-like crystal, are product 2-Cyano-4 '-methylbiphenyl.
2. the synthetic method of 2-Cyano-4 '-methylbiphenyl according to claim 1, is characterized in that step 2) in, R is methyl, ethyl, propyl group or diphenyl-methyl.
3. the synthetic method of 2-Cyano-4 '-methylbiphenyl according to claim 1, it is characterized in that, organic solvent described in step 1) is selected from: one or more in tetrahydrofuran (THF), toluene, benzene, sherwood oil, hexanaphthene, pyridine, DMF, N-Methyl pyrrolidone.
4. the synthetic method of 2-Cyano-4 '-methylbiphenyl according to claim 3, is characterized in that, organic solvent is selected from: one or both in tetrahydrofuran (THF), toluene or sherwood oil.
5. the synthetic method of 2-Cyano-4 '-methylbiphenyl according to claim 1, is characterized in that, organic solvent is the mixture of tetrahydrofuran (THF) and toluene, tetrahydrofuran (THF): toluene=1:1～2, volume ratio.
6. the synthetic method of 2-Cyano-4 '-methylbiphenyl according to claim 1, is characterized in that, in step 1), the concentration of adjacent bromobenzyl nitrile is 0.5～2mol/L.
7. the synthetic method of 2-Cyano-4 '-methylbiphenyl 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.
8. the synthetic method of 2-Cyano-4 '-methylbiphenyl according to claim 1, is characterized in that, in 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 solution, and time for adding is 0.5～1 hour.
9. the synthetic method of 2-Cyano-4 '-methylbiphenyl according to claim 1, is characterized in that, in step 4), the concentration of described dilute hydrochloric acid is 1～2.5mol/L.
10. the synthetic method of 2-Cyano-4 '-methylbiphenyl according to claim 1, is characterized in that, the recrystallization described in 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.
11. according to the synthetic method of the 2-Cyano-4 '-methylbiphenyl described in claim 1～10 any one, it is characterized in that, described reaction is at N
2protection under carry out.
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| 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 |
| 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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| US5288895A (en) * | 1992-04-13 | 1994-02-22 | Elf Sanofi | Process for the preparation of a biphenyl derivative |
| CN102671704A (en) * | 2012-05-14 | 2012-09-19 | 山东轻工业学院 | Pd complex catalyst, preparation method and application thereof |
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|---|---|---|---|---|
| US5288895A (en) * | 1992-04-13 | 1994-02-22 | Elf Sanofi | Process for the preparation of a biphenyl derivative |
| CN102671704A (en) * | 2012-05-14 | 2012-09-19 | 山东轻工业学院 | Pd complex catalyst, preparation method and application thereof |
Non-Patent Citations (5)
| Title |
|---|
| 2-氰基-4’-甲基联苯的合成;魏开红;《化学与生物工程》;20041231(第3期);第39页1.2试验过程、2.2溶剂的选择 * |
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| 魏开红.2-氰基-4’-甲基联苯的合成.《化学与生物工程》.2004,(第3期),第39页1.2试验过程、2.2溶剂的选择. |
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