CN105399627A - Synthetic method of 4'-bromomethylbiphenyl-2-carboxylate - Google Patents
Synthetic method of 4'-bromomethylbiphenyl-2-carboxylate Download PDFInfo
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- CN105399627A CN105399627A CN201510695292.XA CN201510695292A CN105399627A CN 105399627 A CN105399627 A CN 105399627A CN 201510695292 A CN201510695292 A CN 201510695292A CN 105399627 A CN105399627 A CN 105399627A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
Abstract
The invention discloses a synthetic method of 4'-bromomethylbiphenyl-2-carboxylate. The synthetic method comprises the following steps: 1, hydrolyzing 4'-methyl-2-cyanobiphenyl to obtain 4'-methyl-2-biphenyl formic acid; 2, esterifying 4'-methyl-2-biphenyl formic acid to obtain 4'-methyl-2-biphenyl formate; and 3, reacting 4'-methyl-2-biphenyl formate under the illumination of 15000-20000lx at 20-30DEG C for 4-6h to obtain 4'-bromomethylbiphenyl-2-carboxylate. The synthetic method of 4'-bromomethylbiphenyl-2-carboxylate allows 4'-bromomethylbiphenyl-2-carboxylate to be obtained after hydrolysis, esterification and bromination of 4'-methyl-2-cyanobiphenyl used as an initial material. The route of the method is short, so the problem of raw material waste caused by bromine removal and bromo group introduction is avoided; and a bromination reaction is an illumination reaction, so 4'-bromomethylbiphenyl-2-carboxylate can be directly used in telmisartan synthesis without purifying, thereby the cost is reduced.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, especially, relate to a kind of synthetic method of 4 '-bromomethylbiphenyl-2-carboxylicesters.
Background technology
Telmisartan is a kind of novel Altace Ramipril, is a kind of specific blood vessels Angiotensin Ⅱ acceptor (AT1 type) antagonist.Telmisartan Blood substitute angiotensinⅱreceptor is combined with AT1 receptor subtype (known angiotensinⅡ action site) high-affinity.Telmisartan is AT1 acceptor site without any position agonist effect, and telmisartan selectivity and AT1 receptors bind, this keying action is lasting.
The main synthetic line of current telmisartan is:
React with 4 '-bromomethylbiphenyl-2-carboxylicesters and n-propyl-4-methyl-6-(1-tolimidazole-2-base) benzoglyoxaline, generate telmisartan ester, then hydrolysis generates telmisartan, and recrystallization obtains finished product.
4 '-bromomethylbiphenyl-2-carboxylicesters is the important synthesis material of telmisartan as known from the above, and optimization and the improvement of its synthesis technique are significant.
Its route of synthesis technique of existing a kind of 4 '-bromomethylbiphenyl-2-carboxylicesters is as follows:
With 4 '-brooethyl-2-cyanobiphenyls for initiator, after esterification, hydrolysis, esterification, bromo, obtain product.This route is longer, adopts brooethyl cyanobiphenyl as starting material, sloughs bromine, go up bromine again, waste raw material, add production stage, increased the weight of environmental pollution in route.
Summary of the invention
The invention provides a kind of synthetic method of 4 '-bromomethylbiphenyl-2-carboxylicesters, long to solve existing synthetic route, pollute larger technical problem.
The technical solution used in the present invention is as follows:
A kind of synthetic method of 4 '-bromomethylbiphenyl-2-carboxylicesters, comprises the following steps:
The hydrolysis of a, 4 '-methyl-2-cyanobiphenyls obtains 4 '-methyl-2-formic acid biphenyl.
B, the esterification of 4 '-methyl-2-formic acid biphenyl obtain 4 '-methyl-2-manthanoate biphenyl.
C, 4 '-methyl-2-manthanoate biphenyl, under the illumination of 15000 ~ 20000lx, obtain 4 '-bromomethylbiphenyl-2-carboxylicesters for 4 ~ 6 hours in 20 ~ 30 DEG C of reactions.
Further, in step a, the aqueous solution of 4 '-methyl-2-cyanobiphenyls and sodium hydroxide is in the first solvent, and at 30 ~ 90 DEG C, reaction obtains 4 '-methyl-2-formic acid biphenyl for 8 ~ 12 hours.
Further, the mol ratio of 4 '-methyl-2-cyanobiphenyls, sodium hydroxide and water is 1:1.8 ~ 2.4:1.8 ~ 2.4, and the first solvent used is one or more in methyl alcohol, ethanol, Virahol, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF).
Further, in step b, 4 '-methyl-2-formic acid biphenyl is in the second solvent, and under the effect of dewatering agent and catalyzer, at 20 ~ 40 DEG C, reaction obtains 4 '-methyl-2-manthanoate biphenyl for 2 ~ 4 hours.
Further, the mol ratio of 4 '-methyl-2-formic acid biphenyl, dewatering agent, catalyzer and the second solvent is 1:1.0 ~ 1.6:0.02 ~ 0.05:2.0 ~ 3.0; Dewatering agent is dicyclohexylcarbodiimide, and catalyzer is DMAP, and the second solvent is the one in methyl alcohol, ethanol, Virahol, the trimethyl carbinol.
Further, in step c, 4 '-methyl-2-manthanoate biphenyl and N-bromo-succinimide bromination in the 3rd solvent obtains 4 '-bromomethylbiphenyl-2-carboxylicesters.
Further, the mol ratio of 4 '-methyl-2-manthanoate biphenyl, N-bromo-succinimide is 1:1.0 ~ 1.2, and the 3rd solvent is the one in methylene dichloride, acetonitrile, ethyl acetate.
Further, the organic phase washing obtained by illumination reaction is dry, removes solvent, adds methyl alcohol crystallization, the drying of gained crystal is obtained 4 '-bromomethylbiphenyl-2-carboxylicesters.
Further, organic layer by sodium sulfite solution, saturated aqueous common salt and water washing, adds desiccant dryness after washing successively, filters and extremely does at 40 ~ 50 DEG C of concentrated solvents.
Further, add methyl alcohol crystallization and the process of crystal drying be specially:
Add methyl alcohol and be cooled to-5 ~ 5 DEG C of crystallizatioies 4 ~ 6 hours, filter and obtain crystal, by crystal 30 ~ 40 DEG C of vacuum-dryings 6 ~ 8 hours, obtain 4 '-bromomethylbiphenyl-2-carboxylicesters.
The present invention has following beneficial effect: the synthetic method of above-mentioned 4 '-bromomethylbiphenyl-2-carboxylicesters, and with 4 '-methyl-2-cyanobiphenyls for starting material, after hydrolysis, esterification, bromination obtains 4 '-bromomethylbiphenyl-2-carboxylicesters.Route is shorter, avoids first debrominate and goes up the problem that bromine causes wastage of material again.Bromination reaction is illumination reaction simultaneously, and the by product in end product is little, without the refining synthesis being directly used in telmisartan, can reduce cost.
Except object described above, feature and advantage, the present invention also has other object, feature and advantage.Below with reference to figure, the present invention is further detailed explanation.
Accompanying drawing explanation
The accompanying drawing forming a application's part is used to provide a further understanding of the present invention, and schematic description and description of the present invention, for explaining the present invention, does not form inappropriate limitation of the present invention.In the accompanying drawings:
Fig. 1 is the schema of 4 '-bromomethylbiphenyl-2-carboxylicesters synthetic method of the preferred embodiment of the present invention.
Embodiment
Below in conjunction with accompanying drawing, embodiments of the invention are described in detail, but the multitude of different ways that the present invention can be defined by the claims and cover is implemented.
With reference to Fig. 1, the preferred embodiments of the present invention provide a kind of synthetic method of 4 '-bromomethylbiphenyl-2-carboxylicesters, comprise the following steps:
The hydrolysis of S100,4 '-methyl-2-cyanobiphenyls obtains 4 '-methyl-2-formic acid biphenyl.
S200, the esterification of 4 '-methyl-2-formic acid biphenyl obtain 4 '-methyl-2-manthanoate biphenyl.
S300,4 '-methyl-2-manthanoate biphenyl, under the illumination of 15000 ~ 20000lx, obtain 4 '-bromomethylbiphenyl-2-carboxylicesters for 4 ~ 6 hours in 20 ~ 30 DEG C of reactions.
Concrete reaction process is as follows:
4 '-methyl-2-cyanobiphenyls, as shown in chemical structural formula 2, obtains the 4 '-methyl-2-formic acid biphenyl as shown in chemical structural formula 3 through hydrolysis reaction.4 '-methyl-2-manthanoate the biphenyl as shown in chemical structural formula 4 is obtained after the esterification of 4 '-methyl-2-formic acid biphenyl.4 '-methyl-2-manthanoate biphenyl bromination obtains the product 4 '-bromomethylbiphenyl-2-carboxylicesters as shown in chemical structural formula 1.
Intensity of illumination lower than 15000lx then react be not easy cause, intensity of illumination more than 20000lx then react cause too fast, react more difficult control, side reaction is more.Temperature is on the low side then the reaction times longer, higher then impurity is more.Not exclusively, overlong time then by product is more in then reaction that reaction times is less than 4 hours.
The present invention has following beneficial effect: the synthetic method of above-mentioned 4 '-bromomethylbiphenyl-2-carboxylicesters, and with 4 '-methyl-2-cyanobiphenyls for starting material, after hydrolysis, esterification, bromination obtains 4 '-bromomethylbiphenyl-2-carboxylicesters.Route is shorter, avoids first debrominate and goes up the problem that bromine causes wastage of material again.Bromination reaction is illumination reaction simultaneously, and the by product in end product is little, without the refining synthesis being directly used in telmisartan, can reduce cost.
Further, in step a, the aqueous solution of 4 '-methyl-2-cyanobiphenyls and sodium hydroxide is in the first solvent, and at 30 ~ 90 DEG C, reaction obtains 4 '-methyl-2-formic acid biphenyl for 8 ~ 12 hours.Temperature of reaction is lower than 30 DEG C, then hydrolysis time is longer, is unfavorable for producing, and temperature obviously can not reduce the reaction times higher than 90 DEG C of warps, therefore temperature of reaction is selected between 30 ~ 90 DEG C.This one-step hydrolysis reaction simultaneously, the time lower than 8 hours then hydrolysis not exclusively, 12 little reactive groups constantly this completely, then extend the reaction times and can not bring significant change.
Temperature of reaction is preferably 80 DEG C; Reaction times is preferably 10 hours.After completion of the reaction, by reaction solution with about hydrochloric acid adjust pH to 2, crystallization, washing, filter, filter cake is washed to neutrality, dry, obtains 4 '-methyl-2-formic acid biphenyl.
Further, the mol ratio of 4 '-methyl-2-cyanobiphenyls, sodium hydroxide and water is 1:1.8 ~ 2.4:1.8 ~ 2.4, and the first solvent used is one or more in methyl alcohol, ethanol, Virahol, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF).Be preferably methyl alcohol.Be hydrolyzed under this molar ratio, can guarantee that raw material hydrolysis is relatively more thorough, can not produce more impurity, aftertreatment is also relatively simple simultaneously.
Further, in step b, 4 '-methyl-2-formic acid biphenyl is in the second solvent, and under the effect of dewatering agent and catalyzer, at 20 ~ 40 DEG C, reaction obtains 4 '-methyl-2-manthanoate biphenyl for 2 ~ 4 hours.Because dewatering agent used is dicyclohexylcarbodiimide (DCC), its advantage can be reacted exactly at a lower temperature, and the reaction times is shorter.Through test of many times, select this temperature and time as reaction conditions.
Temperature of reaction is preferably 25 DEG C; Reaction times is preferably 3 hours.After completion of the reaction, filter, add water crystallization, and filter, filter cake is washed to neutrality, dry, obtains 4 '-methyl-2-manthanoate biphenyl.
Further, the mol ratio of 4 '-methyl-2-formic acid biphenyl, dewatering agent, catalyzer, the second solvent is 1:1.0 ~ 1.6:0.02 ~ 0.05:2.0 ~ 5.0.Dewatering agent is dicyclohexylcarbodiimide (DCC), and catalyzer is DMAP (DMAP), and the second solvent is the one in methyl alcohol, ethanol, Virahol, the trimethyl carbinol.Dicyclohexylcarbodiimide (DCC) can quantitative reaction, does not therefore need to add too much, crosses and increases aftertreatment difficulty at most.DMAP (DMAP) is catalyzer, increases its consumption and can not significantly improve its speed of reaction.Therefore 0.03 mole is selected for its charging capacity.The mol ratio of four is preferably 1:1.2:0.03:2.0.Second solvent is preferably methyl alcohol.
Further, in step c, 4 '-methyl-2-manthanoate biphenyl and N-bromo-succinimide bromination in the 3rd solvent obtains 4 '-bromomethylbiphenyl-2-carboxylicesters.
Further, the mol ratio of 4 '-methyl-2-manthanoate biphenyl, N-bromo-succinimide is 1:1.0 ~ 1.2, and the 3rd solvent is the one in methylene dichloride, acetonitrile, ethyl acetate.N-bromo-succinimide is bromizating agent, crosses and cannot not react completely at least, crosses and can increase its dibromo replacement by product at most.
The two mol ratio is preferably 1:1.1.Preferred methylene dichloride.
Further, the organic phase washing obtained by illumination reaction is dry, removes solvent, adds methyl alcohol crystallization, the drying of gained crystal is obtained 4 '-bromomethylbiphenyl-2-carboxylicesters.
Further, organic layer by sodium sulfite solution, saturated aqueous common salt and water washing, adds desiccant dryness after washing successively, filters and extremely does at 40 ~ 50 DEG C of concentrated solvents.
Further, add methyl alcohol crystallization and the process of crystal drying be specially:
Add methyl alcohol and be cooled to-5 ~ 5 DEG C of crystallizatioies 4 ~ 6 hours, filter and obtain crystal, by crystal 30 ~ 40 DEG C of vacuum-dryings 6 ~ 8 hours, obtain 4 '-bromomethylbiphenyl-2-carboxylicesters.
Embodiment 1
1, the preparation of 4 '-methyl-2-formic acid biphenyl
4'-methyl-2-cyanobiphenyls 5.00kg is added in glass reaction still, methyl alcohol 10.00kg adds 2.07kg sodium hydroxide under stirring, the 0.94kg aqueous solution, be warming up to 80 DEG C, react 10 hours, TLC detects (developping agent=sherwood oil: ethyl acetate=1:1), reaction end is cooled to 40 DEG C, and stir 20 ~ 30 minutes, then add hydrochloric acid and adjust about pH=2, stir repetition measurement pH value after 30 minutes, unchanged, continue cooling, after being cooled to room temperature, fraction solids is had to separate out, continue stirring two hours, centrifugal, be washed to neutrality, product drying 10 ~ 12 hours, obtain product 5.30kg, yield 91.06%, fusing point 146 ~ 148 DEG C, purity 99.12%.
2, the preparation of 4 '-methyl-2-manthanoate biphenyl
5.30kg4 '-methyl-2-formic acid biphenyl, anhydrous methanol 10.60kg is added, 5.83kgDCC, 0.09kgDMAP in reactor, 25 DEG C are reacted 3 hours, and reaction terminates rear filtration, and filtrate proceeds to another reactor, add 50.00kg water, stirring and crystallizing, then centrifugal, be washed to neutrality, 40 DEG C of drying under reduced pressure obtain 5.54kg4 '-methyl-2-manthanoate biphenyl in 24 hours, fusing point 55 ~ 57 DEG C, yield 98.05%, purity 99.06%.
3, the preparation of 4 '-bromomethylbiphenyl-2-carboxylicesters
In reactor, add 5.54kg4 '-methyl-2-manthanoate biphenyl, methylene dichloride 27.70kg, 4.80kgNBS, under 18000lx illumination condition, 25 DEG C are reacted 5 hours.Reaction solution gradually becomes faint yellow by red-brown, add 10% sodium sulfite solution 20.00kg to wash once, use saturated aqueous common salt 20.00kg respectively again, water 20.00 washs organic layer, finally add anhydrous sodium sulfate drying organic layer, dry complete rear filtration also controls below 50 DEG C, to concentrate methylene dichloride to dry, then suction 5.50kg methyl alcohol, be cooled to rapidly 0 DEG C of stirring and crystallizing 5 hours, filter.Temperature control 35 DEG C of vacuum-dryings 8 hours, obtain 6.72kg4 '-bromomethylbiphenyl-2-carboxylicesters, yield is about 90%, purity 99.13%.
Embodiment 2
1, the preparation of 4 '-methyl-2-formic acid biphenyl
4'-methyl-2-cyanobiphenyls 5.00kg is added in glass reaction still, methyl alcohol 10.00kg adds 2.07kg sodium hydroxide under stirring, the 0.94kg aqueous solution, be warming up to 30 DEG C, react 8 hours, TLC detects (developping agent: sherwood oil: ethyl acetate=1:1), reaction end is cooled to 40 DEG C, and stir 20 ~ 30 minutes, then add hydrochloric acid and adjust about pH=2, stir repetition measurement pH value after 30 minutes, unchanged, continue cooling, after being cooled to room temperature, fraction solids is had to separate out, continue stirring two hours, centrifugal, be washed to neutrality, product drying 10 ~ 12 hours, obtain product 5.18kg, yield 89.00%, fusing point 146 ~ 148 DEG C, purity 99.02%.
2, the preparation of 4 '-methyl-2-manthanoate biphenyl
5.18kg4 '-methyl-2-formic acid biphenyl, dehydrated alcohol 10.36kg is added, 6.05kgDCC, 0.09kgDMAP in reactor, 20 DEG C are reacted 2 hours, and reaction terminates rear filtration, and filtrate proceeds to another reactor, add 50.00kg water, stirring and crystallizing, then centrifugal, be washed to neutrality, 40 DEG C of drying under reduced pressure obtain 5.03kg4 '-methyl-2-manthanoate biphenyl in 24 hours, fusing point 55 ~ 57 DEG C, yield 97.78%, purity 98.96%.
3, the preparation of 4 '-bromomethylbiphenyl-2-carboxylicesters
In reactor, add 5.73kg4 '-methyl-2-manthanoate biphenyl, methylene dichloride 28.65kg, 4.67kgNBS, under 15000lx illumination condition, 25 DEG C are reacted 4 hours.Reaction solution gradually becomes faint yellow by red-brown, add 10% sodium sulfite solution 20.00kg to wash once, use saturated aqueous common salt 20.00kg respectively again, water 20.00 washs organic layer, finally add anhydrous sodium sulfate drying organic layer, dry complete rear filtration also controls below 50 DEG C, to concentrate methylene dichloride to dry, then suction 5.70kg methyl alcohol, be cooled to rapidly-3 DEG C of stirring and crystallizing 5 hours, filter.Temperature control 30 DEG C of vacuum-dryings 6 hours, obtain 6.83kg4 '-bromomethylbiphenyl-2-carboxylicesters, yield is about 88.37%, purity 99.05%.
Embodiment 3
1, the preparation of 4 '-methyl-2-formic acid biphenyl
4'-methyl-2-cyanobiphenyls 5.00kg is added in glass reaction still, methyl alcohol 15.00kg adds 2.07kg sodium hydroxide under stirring, the 0.94kg aqueous solution, be warming up to 80 DEG C, react 10 hours, TLC detects (developping agent: sherwood oil: ethyl acetate=1:1), reaction end is cooled to 40 DEG C, and stir 20 ~ 30 minutes, then add hydrochloric acid and adjust about pH=2, stir repetition measurement pH value after 30 minutes, unchanged, continue cooling, after being cooled to room temperature, fraction solids is had to separate out, continue stirring two hours, centrifugal, be washed to neutrality, product drying 10 ~ 12 hours, obtain product 5.00kg, yield 85.91%, fusing point 146 ~ 148 DEG C, purity 98.85%.
2, the preparation of 4 '-methyl-2-manthanoate biphenyl
In reactor, add 5.00kg4 '-methyl-2-formic acid biphenyl, without water beetle 10.00kg, 5.03kgDCC, 0.08kgDMAP, 25 DEG C are reacted 3 hours, and reaction terminates rear filtration, and filtrate proceeds to another reactor, add 50.00kg water, stirring and crystallizing, then centrifugal, be washed to neutrality, 40 DEG C of drying under reduced pressure obtain 5.06kg4 '-methyl-2-manthanoate biphenyl in 24 hours, fusing point 55 ~ 57 DEG C, yield 94.36%, purity 99.10%
3, the preparation of 4 '-bromomethylbiphenyl-2-carboxylicesters
In reactor, add 5.06kg4 '-methyl-2-manthanoate biphenyl, methylene dichloride 25.30kg, 3.98kgNBS, under 18000lx illumination condition, 25 DEG C are reacted 5 hours.Reaction solution gradually becomes faint yellow by red-brown, add 10% sodium sulfite solution 20.00kg to wash once, use saturated aqueous common salt 20.00kg respectively again, water 20.00 washs organic layer, finally add anhydrous sodium sulfate drying organic layer, dry complete rear filtration also controls below 50 DEG C, to concentrate methylene dichloride to dry, then suction 5.00kg methyl alcohol, be cooled to rapidly-5 DEG C of stirring and crystallizing 5 hours, filter.Temperature control 35-40 DEG C vacuum-drying 8 hours, obtain 5.76kg4 '-bromomethylbiphenyl-2-carboxylicesters, yield is about 84.40%, purity 98.96%.
Embodiment 4
1, the preparation of 4 '-methyl-2-formic acid biphenyl
4'-methyl-2-cyanobiphenyls 5.00kg is added in glass reaction still, methyl alcohol 15.00kg adds 1.98kg sodium hydroxide under stirring, the 0.89kg aqueous solution, be warming up to 85 DEG C, react 11 hours, TLC detects (developping agent: sherwood oil: ethyl acetate=1:1), reaction end is cooled to 40 DEG C, and stir 20 ~ 30 minutes, then add hydrochloric acid and adjust about pH=2, stir repetition measurement pH value after 30 minutes, unchanged, continue cooling, after being cooled to room temperature, fraction solids is had to separate out, continue stirring two hours, centrifugal, be washed to neutrality, product drying 10 ~ 12 hours, obtain product 5.05kg, yield 86.83%, fusing point 146 ~ 148 DEG C, purity 98.65%.
2, the preparation of 4 '-methyl-2-manthanoate biphenyl
In reactor, add 5.00kg4 '-methyl-2-formic acid biphenyl, without water beetle 10.00kg, 4.85kgDCC, 0.06kgDMAP, 30 DEG C are reacted 3 hours, and reaction terminates rear filtration, and filtrate proceeds to another reactor, add 50.00kg water, stirring and crystallizing, then centrifugal, be washed to neutrality, 40 DEG C of drying under reduced pressure obtain 5.13kg4 '-methyl-2-manthanoate biphenyl in 24 hours, fusing point 55 ~ 57 DEG C, yield 96.42%, purity 99.10%
3, the preparation of 4 '-bromomethylbiphenyl-2-carboxylicesters
In reactor, add 5.00kg4 '-methyl-2-manthanoate biphenyl, methylene dichloride 25.30kg, 3.95kgNBS, under 18000lx illumination condition, 28 DEG C are reacted 5 hours.Reaction solution gradually becomes faint yellow by red-brown, add 10% sodium sulfite solution 20.00kg to wash once, use saturated aqueous common salt 20.00kg respectively again, water 20.00 washs organic layer, finally add anhydrous sodium sulfate drying organic layer, dry complete rear filtration also controls below 50 DEG C, to concentrate methylene dichloride to dry, then suction 5.00kg methyl alcohol, be cooled to rapidly 0 DEG C of stirring and crystallizing 4 hours, filter.Temperature control 38 DEG C of vacuum-dryings 7 hours, obtain 5.82kg4 '-bromomethylbiphenyl-2-carboxylicesters, yield is about 86.37%, purity 98.96%.
Embodiment 5
1, the preparation of 4 '-methyl-2-formic acid biphenyl
4'-methyl-2-cyanobiphenyls 5.00kg is added in glass reaction still, methyl alcohol 15.00kg adds 2.07kg sodium hydroxide under stirring, the 0.94kg aqueous solution, be warming up to 90 DEG C, react 12 hours, TLC detects (developping agent: sherwood oil: ethyl acetate=1:1), reaction end is cooled to 40 DEG C, and stir 20 ~ 30 minutes, then add hydrochloric acid and adjust about pH=2, stir repetition measurement pH value after 30 minutes, unchanged, continue cooling, after being cooled to room temperature, fraction solids is had to separate out, continue stirring two hours, centrifugal, be washed to neutrality, product drying 10 ~ 12 hours, obtain product 5.09kg, yield 87.46%, fusing point 146 ~ 148 DEG C, purity 98.85%.
2, the preparation of 4 '-methyl-2-manthanoate biphenyl
In reactor, add 5.00kg4 '-methyl-2-formic acid biphenyl, without water beetle 10.00kg, 5.03kgDCC, 0.08kgDMAP, 40 DEG C are reacted 4 hours, and reaction terminates rear filtration, and filtrate proceeds to another reactor, add 50.00kg water, stirring and crystallizing, then centrifugal, be washed to neutrality, 40 DEG C of drying under reduced pressure obtain 5.20kg4 '-methyl-2-manthanoate biphenyl in 24 hours, fusing point 55 ~ 57 DEG C, yield 97.51%, purity 99.12%
3, the preparation of 4 '-bromomethylbiphenyl-2-carboxylicesters
In reactor, add 5.00kg4 '-methyl-2-manthanoate biphenyl, methylene dichloride 25.30kg, 3.98kgNBS, under 20000lx illumination condition, 30 DEG C are reacted 6 hours.Reaction solution gradually becomes faint yellow by red-brown, add 10% sodium sulfite solution 20.00kg to wash once, use saturated aqueous common salt 20.00kg respectively again, water 20.00 washs organic layer, finally add anhydrous sodium sulfate drying organic layer, dry complete rear filtration also controls below 50 DEG C, to concentrate methylene dichloride to dry, then suction 5.00kg methyl alcohol, be cooled to rapidly 5 DEG C of stirring and crystallizing 6 hours, filter.Temperature control 40 DEG C of vacuum-dryings 8 hours, obtain 5.92kg4 '-bromomethylbiphenyl-2-carboxylicesters, yield is about 87.63%, purity 98.05%.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. a synthetic method for 4 '-bromomethylbiphenyl-2-carboxylicesters, is characterized in that, comprises the following steps:
The hydrolysis of a, 4 '-methyl-2-cyanobiphenyls obtains 4 '-methyl-2-formic acid biphenyl;
B, the esterification of 4 '-methyl-2-formic acid biphenyl obtain 4 '-methyl-2-manthanoate biphenyl;
C, 4 '-methyl-2-manthanoate biphenyl, under the illumination of 15000 ~ 20000lx, obtain 4 '-bromomethylbiphenyl-2-carboxylicesters for 4 ~ 6 hours in 20 ~ 30 DEG C of reactions.
2. the synthetic method of 4 '-bromomethylbiphenyl-2-carboxylicesters according to claim 1, it is characterized in that, in described step a, the aqueous solution of described 4 '-methyl-2-cyanobiphenyls and sodium hydroxide is in the first solvent, and at 30 ~ 90 DEG C, reaction obtains 4 '-methyl-2-formic acid biphenyl for 8 ~ 12 hours.
3. the synthetic method of 4 '-bromomethylbiphenyl-2-carboxylicesters according to claim 2, it is characterized in that, the mol ratio of described 4 '-methyl-2-cyanobiphenyls, sodium hydroxide and water is 1:1.8 ~ 2.4:1.8 ~ 2.4, first solvent used is one or more in methyl alcohol, ethanol, Virahol, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF).
4. the synthetic method of 4 '-bromomethylbiphenyl-2-carboxylicesters according to claim 1, it is characterized in that, in described step b, 4 '-methyl-2-formic acid biphenyl is in the second solvent, under the effect of dewatering agent and catalyzer, at 20 ~ 40 DEG C, reaction obtains 4 '-methyl-2-manthanoate biphenyl for 2 ~ 4 hours.
5. the synthetic method of 4 '-bromomethylbiphenyl-2-carboxylicesters according to claim 4, it is characterized in that, the mol ratio of described 4 '-methyl-2-formic acid biphenyl, described dewatering agent, described catalyzer and described second solvent is 1:1.0 ~ 1.6:0.02 ~ 0.05:2.0 ~ 3.0; Described dewatering agent is dicyclohexylcarbodiimide, and described catalyzer is DMAP, and described second solvent is the one in methyl alcohol, ethanol, Virahol, the trimethyl carbinol.
6. the synthetic method of 4 '-bromomethylbiphenyl-2-carboxylicesters according to claim 1, it is characterized in that, in described step c, described 4 '-methyl-2-manthanoate biphenyl and N-bromo-succinimide bromination in the 3rd solvent obtains 4 '-bromomethylbiphenyl-2-carboxylicesters.
7. the synthetic method of 4 '-bromomethylbiphenyl-2-carboxylicesters according to claim 6, it is characterized in that, the mol ratio of described 4 '-methyl-2-manthanoate biphenyl, described N-bromo-succinimide is 1:1.0 ~ 1.2, and described 3rd solvent is the one in methylene dichloride, acetonitrile, ethyl acetate.
8. the synthetic method of 4 '-bromomethylbiphenyl-2-carboxylicesters according to claim 1, it is characterized in that, the organic phase washing obtained by illumination reaction is dry, removes solvent, add methyl alcohol crystallization, the drying of gained crystal is obtained described 4 '-bromomethylbiphenyl-2-carboxylicesters.
9. the synthetic method of 4 '-bromomethylbiphenyl-2-carboxylicesters according to claim 8, it is characterized in that, described organic layer by sodium sulfite solution, saturated aqueous common salt and water washing, adds desiccant dryness after washing successively, filters and extremely does at 40 ~ 50 DEG C of concentrated solvents.
10. the synthetic method of 4 '-bromomethylbiphenyl-2-carboxylicesters according to claim 8, is characterized in that, adds methyl alcohol crystallization and the process of crystal drying is specially:
Add methyl alcohol and be cooled to-5 ~ 5 DEG C of crystallizatioies 4 ~ 6 hours, filter and obtain crystal, by described crystal 30 ~ 40 DEG C of vacuum-dryings 6 ~ 8 hours, obtain described 4 '-bromomethylbiphenyl-2-carboxylicesters.
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| CN113105327A (en) * | 2021-03-30 | 2021-07-13 | 湖北宇阳药业有限公司 | Synthetic method of 4-bromomethyl-2-methyl formate biphenyl |
| CN114436833A (en) * | 2021-12-27 | 2022-05-06 | 南京红太阳医药研究院有限公司 | Preparation method of telmisartan key intermediate 4' -methylbiphenyl-2-carboxylic ester |
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