CN109776355A - The preparation method of smooth hypotensor important intermediate 2- cyano-the 4 '-bromomethylbiphenyl of one seed sand - Google Patents
The preparation method of smooth hypotensor important intermediate 2- cyano-the 4 '-bromomethylbiphenyl of one seed sand Download PDFInfo
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Abstract
The invention discloses the preparation methods of smooth hypotensor important intermediate 2- cyano-the 4 '-bromomethylbiphenyl of a seed sand, the method are as follows: using 2- Cyano-4 '-methylbiphenyl shown in Formulas I as raw material, using bromine as bromine source, hydrogen peroxide is as oxidant, under the action of radical initiator, it is uniformly mixed in organic solvent, obtain mixture, then water-stop is added in the mixture, under illumination condition, in 25 DEG C of -100 DEG C of reactions, after TLC detection raw material converts completely substantially, obtain 2- cyano -4 '-bromomethylbiphenyl shown in the post-treated obtained Formula II of reaction mixture；Method of the present invention is low in cost, mild condition, efficiently, it is high atom economy, environmentally friendly.
Description
(1) technical field
The present invention relates to a kind of safely cleaning, efficient, highly selective prepare 2- cyano -4 '-bromomethylbiphenyl method.
(2) background technique
Husky smooth hypotensor is since adverse reaction is few, tolerance is good, safety and compliance are high for it, while to the heart, kidney etc.
The advantages that damage of internal organs is smaller is widely used.When wherein Losartan, Valsartan, Irbesartan etc. are by city head
Between test, it is lasting.
Most important intermediate is exactly 2- cyano -4 '-bromomethylbiphenyl in husky smooth class bulk pharmaceutical chemicals synthetic route at present, it is
The parent nucleus of all sartans, importance is self-evident, has had lot of documents to report its synthetic route at present
Road.
Early in 2005, Sumitomo Chemical Co was just in patent CN102746193A " 4 '-bromomethyl -2- cyano of preparation
The method of biphenyl " in just report with 2,2 '-azos two (4- methoxyl group -2,4- methyl pentane nitrile), 2,2 '-azo, two isobutyl
Nitrile, 2,2 '-azos two (2- methylbutyronitrile), dibenzoyl peroxide, di-t-butyl peroxide are radical initiator, sodium bromate
As oxidant, the halogenated alkanes such as methylene chloride make solvent, allow 2- Cyano-4 '-methylbiphenyl that Benzylphosphonium Bromide occurs with bromine and react.
According to this method, the role transformation that the hydrogen bromide generated in bromination process as by-product can be passed through oxidant is bromine, from
And the problems such as avoiding hydrogen bromide to the inhibition of reaction and changing colour as caused by bromine
2012, Taining victory was up to Industrial Co., Ltd. in a kind of patent CN1628094A " system of 2- cyano -4- bromomethyl connection
Preparation Method " in report with tetrabutylammonium bromide or cetyl trimethylammonium bromide or benzyl triethyl ammonium bromide for catalysis
Agent, it is target product by 2- Cyano-4 '-methylbiphenyl bromination that using C5H6Br2N2O2 as bromating agent, tetrachloro-ethylene, which is solvent person,.
NaBrO/NaHSO system is used in J Org Chem publishes an article within Ishii etc. 1998, realize the choosing to benzyl
Selecting property bromination.
Mestres et al. has delivered article NaBr/H in Green Chem202/H+(molar ratio 2:l:2) oxybromination
System, under radiation of visible light or heated reflux condition, in CCI4In or without organic solvent realize the benzyl position bromine to toluene
Change.
Iskra et al. HBr/H202System, in 40w incandescent lamp or the brominated benzyl of 125W high voltage mercury lamp radiation Toluene
Bromine yield is greater than 80%.
The bromination reaction being related in above-mentioned patent or article requires to use similar benzoyl peroxide (BPO), azo
The radical initiators such as bis-isobutyronitrile (AIBN), and biggish ingredient proportion is needed during the reaction, generally in 5%-10%
Between.Initiator all remains in waste liquid after the completion of reaction, so that the post-processing of waste liquid is extremely difficult.Therefore development one
More environmentally friendly, efficient, highly selective 2- cyano-the 4 '-bromomethylbiphenyl method for preparing of kind has great importance
The technical solution adopted by the present invention is that:
A kind of 2- cyano -4 '-bromomethylbiphenyl preparation method as shown in Formula II, the method is specifically according to such as lower section
It is prepared by method:
Using 2- Cyano-4 '-methylbiphenyl shown in Formulas I as raw material, using bromine as bromine source, hydrogen peroxide as oxidant,
It under the action of radical initiator, is uniformly mixed in organic solvent, obtains mixture, be then added in the mixture
Water-stop reacts under illumination condition at 25 DEG C~100 DEG C, after TLC detection raw material converts completely substantially, obtains reaction mixing
2- cyano -4 '-bromomethylbiphenyl shown in the post-treated obtained Formula II of liquid；2- Cyano-4 '-methylbiphenyl shown in the Formulas I,
The ratio between amount of substance of bromine, hydrogen peroxide and radical initiator is 1:0.54~0.6:0.81~0.9:0.005；It is described from
It is N- hydroxyl substituted phthalimide or its analog by base initiator；The additional amount of the water is described in lucky energy sealing
Mixture subject to；
Further, the radical initiator is one of following: n-Hydroxyphthalimide (NHPI), N, N '-
Dihydroxy pyromellitic acid imines (NDHPI), N- hydroxysaccharine (NHS), N- acetyl group phthalimide
(NAPI) or 3- picolyl-n-Hydroxyphthalimide (Py-NHPI), preferably n-Hydroxyphthalimide
(NHPI)。
Further, the organic solvent is methylene chloride, acetonitrile or hexamethylene.
Further, the additional amount of the organic solvent is calculated as 3 with the quality of the 2- Cyano-4 '-methylbiphenyl
~6ml/g.
Further, the light source is preferably 8w LED lamp source.
Further, the processing method after the reaction mixture are as follows: after reaction, add in the reaction mixture of Xiang Suoshu
Sodium sulfite aqueous solution washes away remaining bromine and hydrogen peroxide, and water layer is extracted twice again with reaction dissolvent after static layering, is associated with
Machine phase after boiling off solvent, obtains target product 2- cyano -4 '-bromomethylbiphenyl with re crystallization from toluene.
Compared with prior art, the beneficial effects are mainly reflected as follows:
(1) bromine is converted by the hydrogen bromide that reaction generates using hydrogen peroxide, increases Atom economy.
(2) hydrogen peroxide simplifies subsequent processing, reduces cost as oxidant cleanliness without any pollution.
(3) selecting N- hydroxyl substituted phthalimide and the like is radical initiator, is reduced to catalyst
The demand of dosage improves the selectivity of reaction, reduces the pair generated by excessive bromination while reducing liquid waste processing difficulty
Product.
(4) method of the present invention is low in cost, mild condition, efficiently, it is high atom economy, environmentally friendly.
(4) Detailed description of the invention
Fig. 1 is the Liquid Chromatography data of embodiment 1；
Fig. 2 is the Liquid Chromatography data of standard sample.
(5) specific embodiment
The present invention is described further combined with specific embodiments below, but protection scope of the present invention is not limited in
This:
Example 1:
In a 250ml four-hole boiling flask, it is added 2- Cyano-4 '-methylbiphenyl 60g (0.311mol), N- hydroxyl neighbour's benzene
Dicarboximide 0.28g (0.00174mol), methylene chloride 180ml, 20mL water water seal, prevents the bromination generated in reaction process
Hydrogen escape causes feed stock conversion to decline, and is warming up to 40 DEG C, weighs bromine 27.84g (0.174mol) and leaks in 50mL constant pressure addition
In bucket, 8 watts of LED lamp source illumination, 1h is added dropwise.30% hydrogen peroxide of 29.58g (0.261mol), 1h drop are weighed after being added dropwise
Add complete, the reaction was continued.After TLC detection raw material converts completely substantially, add sodium sulfite aqueous solution that remaining bromine and dioxygen is quenched
Water.Water layer is extracted twice again with solvent after static layering, is merged organic phase, after boiling off solvent, is once obtained with re crystallization from toluene
Product 2- cyano -4 '-bromomethylbiphenyl 72.7g, purity 98.7%, yield 86%.
Example 2:
In a 250ml four-hole boiling flask, it is added 2- Cyano-4 '-methylbiphenyl 60g (0.311mol), N- hydroxyl neighbour's benzene
Dicarboximide 0.28g (0.00174mol), acetonitrile 180ml are warming up to 90 DEG C.Weigh bromine 27.84g (0.174mol) in
In 50mL constant pressure funnel, 8 watts of LED lamp source illumination, 1h is added dropwise.29.58g (0.261mol) is weighed after being added dropwise
30% hydrogen peroxide, 1h are added dropwise, and the reaction was continued.After TLC detection raw material converts completely substantially, sodium sulfite aqueous solution is added to be quenched
Remaining bromine and hydrogen peroxide.Acetonitrile and water mixed solution are extracted with a large amount of methylene chloride, reduces the loss of product.Merge organic
After boiling off solvent, product 2- cyano -4 '-bromomethylbiphenyl 71.5g is once obtained with re crystallization from toluene for phase, and purity 98.4% is received
Rate 84.5%.
Example 3:
In a 250ml four-hole boiling flask, it is added 2- Cyano-4 '-methylbiphenyl 60g (0.311mol), N- hydroxyl neighbour's benzene
Dicarboximide 0.28g (0.00174mol), hexamethylene 180ml, 20mL water water seal, is warming up to 90 DEG C.Weigh bromine 27.84g
(0.174mol) in 50mL constant pressure funnel, 8 watts of LED lamp source illumination, 1h is added dropwise.29.58g is weighed after being added dropwise
(0.261mol) 30% hydrogen peroxide, 1h are added dropwise, and the reaction was continued.After TLC detection raw material converts completely substantially, add sodium sulfite
Remaining bromine and hydrogen peroxide is quenched in aqueous solution, and reaction solution is cooled to 5 DEG C, and system has solid precipitation, and solid is directly obtained by filtration, and uses
Re crystallization from toluene once obtains product 2- cyano -4 '-bromomethylbiphenyl 72.3g, purity 98.6%, yield 85.5%.
Example 4
In a 250ml four-hole boiling flask, it is added 2- Cyano-4 '-methylbiphenyl 60g (0.311mol), N, N '-dihydroxy
Pyromellitic acid imines (NDHPI) 0.43g (0.00174mol), methylene chloride 180ml, 20mL water water seal, is warming up to 40 DEG C.It weighs
In 50mL constant pressure funnel, 8 watts of LED lamp source illumination, 1h is added dropwise bromine 27.84g (0.174mol).After being added dropwise
30% hydrogen peroxide of 29.58g (0.261mol) is weighed, 1h is added dropwise, and the reaction was continued.After TLC detection raw material converts completely substantially,
Add sodium sulfite aqueous solution that remaining bromine and hydrogen peroxide is quenched.Water layer is extracted twice again with solvent after static layering, is merged organic
After boiling off solvent, product 2- cyano -4 '-bromomethylbiphenyl 71.1g is once obtained with re crystallization from toluene for phase, and purity 98.7% is received
Rate 84%.
Example 5:
In a 250ml four-hole boiling flask, it is added 2- Cyano-4 '-methylbiphenyl 60g (0.311mol), N, N '-dihydroxy
Pyromellitic acid imines (NDHPI) 0.43g (0.00174mol), acetonitrile 180ml are warming up to 90 DEG C.Weigh bromine 27.84g
(0.174mol) in 50mL constant pressure funnel, 8 watts of LED lamp source illumination, 1h is added dropwise.29.58g is weighed after being added dropwise
(0.261mol) 30% hydrogen peroxide, 1h are added dropwise, and the reaction was continued.After TLC detection raw material converts completely substantially, add sodium sulfite
Remaining bromine and hydrogen peroxide is quenched in aqueous solution.Acetonitrile and water mixed solution are extracted with a large amount of methylene chloride, reduces the loss of product.
Merge organic phase, after boiling off solvent, product 2- cyano -4 '-bromomethylbiphenyl 70.3g, purity are once obtained with re crystallization from toluene
98.5%, yield 83%.
Example 6:
In a 250ml four-hole boiling flask, it is added 2- Cyano-4 '-methylbiphenyl 60g (0.311mol), N, N '-dihydroxy
Pyromellitic acid imines (NDHPI) 0.43g (0.00174mol), hexamethylene 180ml, 20mL water water seal, is warming up to 90 DEG C.Weigh bromine
In 50mL constant pressure funnel, 8 watts of LED lamp source illumination, 1h is added dropwise plain 27.84g (0.174mol).Claim after being added dropwise
30% hydrogen peroxide of 29.58g (0.261mol) is taken, 1h is added dropwise, and the reaction was continued.After TLC detection raw material converts completely substantially, add
Remaining bromine and hydrogen peroxide is quenched in sodium sulfite aqueous solution, and reaction solution is cooled to 5 DEG C, and system has solid precipitation, directly filters
To solid, product 2- cyano -4 '-bromomethylbiphenyl 70.5g, purity 98.6%, yield are once obtained with re crystallization from toluene
83.4%.
Example 7:
In a 250ml four-hole boiling flask, it is added 2- Cyano-4 '-methylbiphenyl 60g (0.311mol), N- hydroxyl neighbour's sulphur
Acyl saccharin (NHS) 0.88g (0.00174mol), methylene chloride 180ml, 20mL water water seal, is warming up to 40 DEG C.Weigh bromine
In 50mL constant pressure funnel, 8 watts of LED lamp source illumination, 1h is added dropwise plain 27.84g (0.174mol).Claim after being added dropwise
30% hydrogen peroxide of 29.58g (0.261mol) is taken, 1h is added dropwise, and the reaction was continued.After TLC detection raw material converts completely substantially, add
Remaining bromine and hydrogen peroxide is quenched in sodium sulfite aqueous solution.Water layer is extracted twice again with solvent after static layering, merges organic phase,
After boiling off solvent, product 2- cyano -4 '-bromomethylbiphenyl 63.4g, purity 98.1%, yield are once obtained with re crystallization from toluene
75%.
Example 8:
In a 250ml four-hole boiling flask, it is added 2- Cyano-4 '-methylbiphenyl 60g (0.311mol), N- hydroxyl neighbour's sulphur
Acyl saccharin (NHS) 0.88g (0.00174mol), acetonitrile 180ml are warming up to 90 DEG C.Weigh bromine 27.84g
(0.174mol) in 50mL constant pressure funnel, 8 watts of LED lamp source illumination, 1h is added dropwise.29.58g is weighed after being added dropwise
(0.261mol) 30% hydrogen peroxide, 1h are added dropwise, and the reaction was continued.After TLC detection raw material converts completely substantially, add sodium sulfite
Remaining bromine and hydrogen peroxide is quenched in aqueous solution.Acetonitrile and water mixed solution are extracted with a large amount of methylene chloride, reduces the loss of product.
Merge organic phase, after boiling off solvent, product 2- cyano -4 '-bromomethylbiphenyl 59.2g, purity are once obtained with re crystallization from toluene
98.3%, yield 70%.
Example 9:
In a 250ml four-hole boiling flask, it is added 2- cyano -4 ' methyl biphenyl 60g (0.311mol), N- hydroxyl neighbour's sulphonyl
Saccharin (NHS) 0.88g (0.00174mol), hexamethylene 180ml, 20mL water water seal, is warming up to 90 DEG C.Weigh bromine
In 50mL constant pressure funnel, 8 watts of LED lamp source illumination, 1h is added dropwise 27.84g (0.174mol).It is weighed after being added dropwise
30% hydrogen peroxide of 29.58g (0.261mol), 1h are added dropwise, and the reaction was continued.After TLC detection raw material converts completely substantially, add Asia
Remaining bromine and hydrogen peroxide is quenched in aqueous sodium persulfate solution, and reaction solution is cooled to 5 DEG C, and system has solid precipitation, is directly obtained by filtration
Solid once obtains product 2- cyano -4 '-bromomethylbiphenyl 60.9g, purity 98.5%, yield 72% with re crystallization from toluene.
Example 10:
It in a 250ml four-hole boiling flask, is added 2- Cyano-4 '-methylbiphenyl 60g (0.311mol), N- acetyl group is adjacent
Phthalimide (NAPI) 0.33g (0.00174mol), methylene chloride 180ml, 20mL water water seal, is warming up to 40 DEG C.It weighs
In 50mL constant pressure funnel, 8 watts of LED lamp source illumination, 1h is added dropwise bromine 27.84g (0.174mol).After being added dropwise
30% hydrogen peroxide of 29.58g (0.261mol) is weighed, 1h is added dropwise, and the reaction was continued.After TLC detection raw material converts completely substantially,
Add sodium sulfite aqueous solution that remaining bromine and hydrogen peroxide is quenched.Water layer is extracted twice again with solvent after static layering, is merged organic
After boiling off solvent, product 2- cyano -4 '-bromomethylbiphenyl 70.5g is once obtained with re crystallization from toluene for phase, and purity 98.1% is received
Rate 84%.
Example 11:
It in a 250ml four-hole boiling flask, is added 2- Cyano-4 '-methylbiphenyl 60g (0.311mol), N- acetyl group is adjacent
Phthalimide (NAPI) 0.33g (0.00174mol), acetonitrile 180ml are warming up to 90 DEG C.Weigh bromine 27.84g
(0.174mol) in 50mL constant pressure funnel, 8 watts of LED lamp source illumination, 1h is added dropwise.29.58g is weighed after being added dropwise
(0.261mol) 30% hydrogen peroxide, 1h are added dropwise, and the reaction was continued.After TLC detection raw material converts completely substantially, add sodium sulfite
Remaining bromine and hydrogen peroxide is quenched in aqueous solution.Acetonitrile and water mixed solution are extracted with a large amount of methylene chloride, reduces the loss of product.
Merge organic phase, after boiling off solvent, product 2- cyano -4 '-bromomethylbiphenyl 67.8g, purity are once obtained with re crystallization from toluene
98.3%, yield 80%.
Example 12:
It in a 250ml four-hole boiling flask, is added 2- Cyano-4 '-methylbiphenyl 60g (0.311mol), N- acetyl group is adjacent
Phthalimide (NAPI) 0.33g (0.00174mol), hexamethylene 180ml, 20mL water water seal, is warming up to 90 DEG C.Weigh bromine
In 50mL constant pressure funnel, 8 watts of LED lamp source illumination, 1h is added dropwise plain 27.84g (0.174mol).Claim after being added dropwise
30% hydrogen peroxide of 29.58g (0.261mol) is taken, 1h is added dropwise, and the reaction was continued.After TLC detection raw material converts completely substantially, add
Remaining bromine and hydrogen peroxide is quenched in sodium sulfite aqueous solution, and reaction solution is cooled to 5 DEG C, and system has solid precipitation, directly filters
To solid, product 2- cyano -4 '-bromomethylbiphenyl 70.2g, purity 98.5%, yield 83% are once obtained with re crystallization from toluene.
Example 13
In a 250ml four-hole boiling flask, it is added 2- Cyano-4 '-methylbiphenyl 60g (0.311mol), 3- picolyl-
N-Hydroxyphthalimide (Py-NHPI) 0.49g (0.00174mol), methylene chloride 180ml, 20mL water water seal, heating
To 40 DEG C.Bromine 27.84g (0.174mol) is weighed in 50mL constant pressure funnel, 8 watts of LED lamp source illumination, 1h is dripped
Finish.30% hydrogen peroxide of 29.58g (0.261mol) is weighed after being added dropwise, 1h is added dropwise, and the reaction was continued.TLC detects raw material base
After this conversion completely, add sodium sulfite aqueous solution that remaining bromine and hydrogen peroxide is quenched.Water layer is extracted again with solvent after static layering
Twice, merges organic phase, after boiling off solvent, product 2- cyano -4 '-bromomethylbiphenyl 71.4g is once obtained with re crystallization from toluene,
Purity 98.4%, yield 83%.
Example 14:
In a 250ml four-hole boiling flask, it is added 2- Cyano-4 '-methylbiphenyl 60g (0.311mol), 3- picolyl-
N-Hydroxyphthalimide (Py-NHPI) 0.49g (0.00174mol), acetonitrile 180ml are warming up to 90 DEG C.Weigh bromine
In 50mL constant pressure funnel, 8 watts of LED lamp source illumination, 1h is added dropwise 27.84g (0.174mol).It is weighed after being added dropwise
30% hydrogen peroxide of 29.58g (0.261mol), 1h are added dropwise, and the reaction was continued.After TLC detection raw material converts completely substantially, add Asia
Remaining bromine and hydrogen peroxide is quenched in aqueous sodium persulfate solution.Acetonitrile and water mixed solution are extracted with a large amount of methylene chloride, reduces product
Loss.Merge organic phase, after boiling off solvent, product 2- cyano -4 '-bromomethylbiphenyl is once obtained with re crystallization from toluene
70.6g, purity 98.3%, yield 82%.
Example 15:
In a 250ml four-hole boiling flask, it is added 2- Cyano-4 '-methylbiphenyl 60g (0.311mol), 3- picolyl-
N-Hydroxyphthalimide (Py-NHPI) 0.49g (0.00174mol), hexamethylene 180ml, 20mL water water seal, is warming up to
90℃.Bromine 27.84g (0.174mol) is weighed in 50mL constant pressure funnel, 8 watts of LED lamp source illumination, 1h is added dropwise.
30% hydrogen peroxide of 29.58g (0.261mol) is weighed after being added dropwise, 1h is added dropwise, and the reaction was continued.It is basic that TLC detects raw material
After conversion completely, add sodium sulfite aqueous solution that remaining bromine and hydrogen peroxide is quenched, reaction solution is cooled to 5 DEG C, and system has solid analysis
Out, solid is directly obtained by filtration, product 2- cyano -4 '-bromomethylbiphenyl 68.5g, purity are once obtained with re crystallization from toluene
98.8%, yield 80%.
Claims (8)
1. a kind of 2- cyano -4 '-bromomethylbiphenyl preparation method as shown in Formula II, it is characterised in that: the method is specific
It is prepared as follows:
Using 2- Cyano-4 '-methylbiphenyl shown in Formulas I as raw material, using bromine as bromine source, hydrogen peroxide is as oxidant, in freedom
It under the action of base initiator, is uniformly mixed obtains mixture in organic solvent, water-stop then is added in the mixture,
Under illumination condition, after 25 DEG C~100 DEG C reaction TLC detection raw materials convert completely substantially, reaction mixture is obtained after
It manages and 2- cyano -4 '-bromomethylbiphenyl shown in Formula II is made；It is 2- Cyano-4 '-methylbiphenyl, bromine shown in the Formulas I, double
The ratio between amount of substance of oxygen water and radical initiator is 1:0.54~0.6:0.81~0.9:0.005；The free radical draws
Sending out agent is N- hydroxyl substituted phthalimide or its analog；The additional amount of the water can seal the mixing with lucky
Subject to object；
2. the method as described in claim 1, it is characterised in that: the radical initiator is one of following: N- hydroxyl is adjacent
Phthalimide, N, N '-dihydroxy pyromellitic acid imines, N- hydroxysaccharine, N- acetyl group O-phthalic
Acid imide or 3- picolyl-n-Hydroxyphthalimide.
3. method according to claim 2, it is characterised in that: the radical initiator is one of following: N- hydroxyl is adjacent
Phthalimide.
4. the method as described in claim 1, it is characterised in that: the organic solvent is methylene chloride, acetonitrile or hexamethylene.
5. the method as described in claim 1, it is characterised in that: the additional amount of the organic solvent is with the 2- cyano-
The quality of 4 '-methyl biphenyls is calculated as 3~6ml/g.
6. the method as described in claim 1, it is characterised in that: the light source is 8w LED light.
7. the method as described in claim 1, it is characterised in that: the reaction time is 2~6h.
8. the method as described in claim 1, it is characterised in that: the processing method after the reaction mixture are as follows: reaction terminates
Afterwards, sodium sulfite aqueous solution is added to wash away remaining bromine and hydrogen peroxide in the reaction mixture of Xiang Suoshu, water layer is used after static layering
The organic solvent of the reaction process extracts twice again, merges organic phase, after boiling off solvent, obtains target with re crystallization from toluene
Product 2- cyano -4 '-bromomethylbiphenyl.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111302973A (en) * | 2020-03-26 | 2020-06-19 | 嘉兴学院 | Preparation method of normal-temperature brominated sartanbiphenyl based on bromine |
| 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 |
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| CN103265426A (en) * | 2013-04-08 | 2013-08-28 | 福建三泰生物医药有限公司 | Environment-friendly preparation method of 2 - (4 - Bromomethylphenyl) propionic acid based on two-phase free radical reaction |
| CN107935956A (en) * | 2017-10-25 | 2018-04-20 | 浙江工业大学 | A kind of pipelineization prepares the method and its reaction unit of the benzyl position bromomethyl biphenyl containing substituent |
| EP3318546A1 (en) * | 2016-11-08 | 2018-05-09 | Justus-Liebig-Universität Gießen | Process for the chlorination and iodination of compounds using n-hydroxyphthalimide |
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| EP0553879A2 (en) * | 1992-01-31 | 1993-08-04 | Takeda Chemical Industries, Ltd. | Process for producing 4-bromomethylbiphenyl compounds |
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| CN111302973A (en) * | 2020-03-26 | 2020-06-19 | 嘉兴学院 | Preparation method of normal-temperature brominated sartanbiphenyl based on bromine |
| 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 |
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Application publication date: 20190521 |