CN106831490B - A kind of synthetic method of 2- cyano-benzyl bromide and the like - Google Patents
A kind of synthetic method of 2- cyano-benzyl bromide and the like Download PDFInfo
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- CN106831490B CN106831490B CN201710048906.4A CN201710048906A CN106831490B CN 106831490 B CN106831490 B CN 106831490B CN 201710048906 A CN201710048906 A CN 201710048906A CN 106831490 B CN106831490 B CN 106831490B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a kind of synthetic method of 2- cyano-benzyl bromide and the like, step is to react using compound I as raw material with tert-butyl chloro-silicane, and the first solvent and acid binding agent is added, generates compound II；2）It is dissolved in the second solvent by compound II, adds palladium catalyst and cyanidization agent, carried out cyanogenation and generate compound III；3）Compound III is not necessarily to slough protecting group, is dissolved in third solvent, the bromination reaction directly under phosphorus tribromide effect, and compound IV is made.Present invention process route is simple, and product quality and yield are higher.
Description
Technical field
The invention belongs to pharmaceutical intermediate synthesis technical fields, and in particular to a kind of pharmaceutical intermediate 2- cyano-benzyl bromide and its
The synthetic method of analog.
Background technique
2- cyano-benzyl bromide is the intermediate fragments for treating the drug alogliptin benzoate of type II diabetes, in the existing country
In outer document report, most of be made through methyl hydrogen bromo-reaction, this method exists using 2- methyl cyanophenyl as raw material
Organic Process Research and Development,vol.2(1998),p.261-269；Chemistry-A
European Journal,v ol.8(2002),p.2000-2004；Journal of Organic Chemistry,vol.79
(2014),p.11592-11608；There is numerous reports in the documents such as WO2009/55437, but to be related to free radical anti-for this method
Mechanism is answered, inevitably there is dibromo substitution product impurity, it is difficult to separating-purifying, and influence product quality and yield.
Summary of the invention
The present invention relates to a kind of synthetic methods of 2- cyano-benzyl bromide and the like, and process route is simple, the quality of product
And high income.
To achieve the goals above, the present invention, which adopts the following technical solutions, is achieved：
For the technical problem that the existing reaction yield for synthesizing 2- cyano-benzyl bromide and the like is low, impurity content is high, mention
A kind of new synthetic method is supplied.Its reaction step is：
R is hydrogen H or deuterium D in formula.
Step is：1) it is dissolved in the first solvent, for raw material with guarantor with compound I (2- bromobenzyl alcohol or 2- bromobenzyl alcohol-d4)
Base tert-butyl chloro-silicane (TBSCl) reaction is protected, acid binding agent is added, 2-3h is reacted under 0-40 DEG C of reaction temperature, is generated
Compound II.
First solvent can be methylene chloride, chloroform or 1,2- dichloroethanes.The acid binding agent can be imidazoles, three
Ethamine or pyridine, preferably imidazoles.The molar ratio of compound I and TBSCl are 1:The molar ratio of 1-2, compound I and acid binding agent is
1:1.5-2。
2) compound II is dissolved in the second solvent, adds palladium catalyst, add cyanidization agent, carry out cyanogenation generation
Compound III, 80-150 DEG C of reaction temperature, preferably 100 DEG C；Reaction time is 2-12h, preferably 6h.
Second solvent can be dimethylformamide (DMF) or dimethyl sulfoxide (DMSO).The cyanating reagent is
Zn(CN)2Or CuCN.The palladium catalyst is Pd2(dba)3、PdCl2(PPh3)2、Pd(PPh3)4Or Pd (OAc)2, preferably Pd2
(dba)3.The ligand is dppf, dpppe, Xphos etc., preferably dppf.Palladium catalyst dosage is that the 1-5% of compound II rubs
That ratio；Ligand dosage is the 0.5-2.5% molar ratio of compound II；Cyanating reagent dosage is 1-1.5 times mole of compound II
Than.
3) compound III is dissolved in third solvent, without sloughing protecting group directly in phosphorus tribromide (PBr3) under effect
Bromination reaction is carried out, reaction temperature is 0-40 DEG C, reaction time 3-10h, and compound IV (2- bromomethyl benzonitrile or 2- cyanogen is made
Bromide benzyl-d4).Wherein third solvent is methylene chloride；Phosphorus tribromide dosage is the 1-3 times of molar ratio of compound III, preferably
1.4 times of molar ratios.
Compared with prior art, the advantages and positive effects of the present invention are：The synthetic method of 2- cyano-benzyl bromide of the invention,
Reaction condition is mild, and each step yield is higher, and there is no the difficult problems of isomery separation；Post-reaction treatment is simple, and raw material is easy to get.
Specific embodiment
The technical scheme of the present invention will be explained in further detail With reference to embodiment.
Embodiment 1
2- cyano-benzyl bromide is synthesized with following steps：
1) 2- bromobenzyl alcohol (I) 18.7g, methylene chloride 60mL, 8.2g imidazoles, stirring and dissolving, control are added in 250mL there-necked flask
Temperature processed at 20 DEG C hereinafter, slowly be added dropwise tert-butyl chloro-silicane 18g, add and 2-3h be stirred at room temperature, TLC display has reacted
Finish, is filtered to remove the imidazole hydrochloride of generation, filtrate is spin-dried for obtaining 30g compound II, the yield 98% of the step；
2) in 250mL there-necked flask, compound II 30g is added under nitrogen protection, is added solvent DMF (dimethylformamide)
50mL, zinc cyanide 6.8g, palladium catalyst Pd2(dba)30.9g, ligand dppf (1,1'- bis- (diphenylphosphine) ferrocene) 0.27g,
Catalysis auxiliary material zinc powder 3.0g is added, is warming up to 100 DEG C of heat preservation 6h, end of reaction is down to room temperature, filters out insoluble matter, filtrate
Middle addition 60mL water dilution, is extracted with the ethyl acetate of 100mL × 2, merges organic phase, saturated salt solution 60 × 2 washs, anhydrous
Sodium sulphate is dry, and revolving removes solvent, obtains compound III about 21g, the yield 85% of the step；
3) in 250mL there-necked flask, compound III 21g is added, tribromide is slowly added dropwise in methylene chloride about 100mL
Phosphorus 27.5g, drop finish, and are warming up to 40 DEG C of back flow reaction 6h, after the reaction was completed, 75mL water quenching are added dropwise and goes out, stand liquid separation, organic phase is used
5% sodium bicarbonate aqueous solution 50mL is washed once, and water 50mL is washed once, and organic addition anhydrous sodium sulfate is dry, is spin-dried for solvent and is obtained
Product 15.5g, the yield 92% of the step.
Embodiment 2
2- cyano-benzyl bromide is synthesized with following steps：
1) 2- bromobenzyl alcohol (I) 65g in 500mL there-necked flask, methylene chloride 200mL, 8.2g imidazoles, stirring and dissolving, control temperature
Degree at 20 DEG C hereinafter, slowly be added dropwise tert-butyl chloro-silicane 62.5g, add and 2.5h be stirred at room temperature, TLC display has reacted
Finish, is filtered to remove the imidazole hydrochloride of generation, filtrate is spin-dried for obtaining 100g compound II, the yield 96% of the step；
2) in 1000mL there-necked flask, compound II 100g is added under nitrogen protection, solvent DMF 200mL, zinc cyanide is added
48.5g, catalyst Pd2(dba)33.0g, ligand dppf 0.9g, zinc powder 10.0g, are warming up to 100 DEG C of heat preservation 8h, end of reaction,
It is down to room temperature, filters out insoluble matter, filtrate is added the dilution of 220mL water, is extracted with the ethyl acetate of 400mL × 2, merged organic
Phase, saturated salt solution 200 × 2 wash, and anhydrous sodium sulfate is dry, and revolving removes solvent, obtain compound III about 72.2g, the step
Rapid yield 84%；
3) in 500mL there-necked flask, compound III 70g, methylene chloride about 350mL is added, tribromide is slowly added dropwise
Phosphorus 94.6g, drop finish, and are warming up to 40 DEG C of back flow reaction 8h, after the reaction was completed, 200mL water quenching are added dropwise and goes out, stands liquid separation, organic phase
It is washed once with 5% sodium bicarbonate aqueous solution 100mL, water 150mL is washed once, and organic addition anhydrous sodium sulfate is dry, is spin-dried for molten
Agent obtains product 52.0g, the yield 93% of the step.
Embodiment 3
2- cyano-benzyl bromide-d4 is synthesized with following steps：
1) 2- bromobenzyl alcohol-d4 (I) 65g in 500mL there-necked flask, methylene chloride 200mL, 8.2g imidazoles, stirring and dissolving, control
Temperature at 20 DEG C hereinafter, slowly be added dropwise tert-butyl chloro-silicane 62.5g, add and 2.5h be stirred at room temperature, TLC display has reacted
Finish, is filtered to remove the imidazole hydrochloride of generation, filtrate is spin-dried for obtaining 99.0g compound II, the yield 95% of the step；
2) in 1000mL there-necked flask, compound II 99.0g is added under nitrogen protection, solvent DMF 200mL, zinc cyanide is added
48.5g, catalyst Pd2(dba)33.0g, ligand dppf 0.9g, zinc powder 10.0g, are warming up to 100 DEG C of heat preservation 7h, end of reaction,
It is down to room temperature, filters out insoluble matter, filtrate is added the dilution of 220mL water, is extracted with the ethyl acetate of 400mL × 2, merged organic
Phase, saturated salt solution 200 × 2 wash, and anhydrous sodium sulfate is dry, and revolving removes solvent, obtain compound III about 71.0g, the step
Rapid yield 83%.
3) in 500mL there-necked flask, compound III 70g is added, tribromide is slowly added dropwise in methylene chloride about 350mL
Phosphorus 94.6g, drop finish, and are warming up to 40 DEG C of back flow reaction 8h, after the reaction was completed, 200mL water quenching are added dropwise and goes out, stands liquid separation, organic phase
It is washed once with 5% sodium bicarbonate aqueous solution 100mL, water 150mL is washed once, and organic addition anhydrous sodium sulfate is dry, is spin-dried for molten
Agent obtains product 53.0g, the yield 93.5% of the step.
Above embodiments are only several in the several preferred embodiment of the present invention, it is noted that the present invention is not limited to
Above-described embodiment；It for those of ordinary skill in the art, still can be to technical solution documented by previous embodiment
It modifies or equivalent replacement of some of the technical features；And these modifications or substitutions, do not make relevant art side
The essence of case is detached from the spirit and scope of claimed technical solution of the invention.
Claims (4)
1. a kind of synthetic method of 2- cyano-benzyl bromide, which is characterized in that step is：
1) it using compound I as raw material, is dissolved in the first solvent, is reacted with protecting group tert-butyl chloro-silicane, addition is tied up
2-3h is reacted in sour agent under 0-40 DEG C of reaction temperature, generates compound II；
First solvent is methylene chloride, chloroform or 1,2- dichloroethanes, and the acid binding agent is imidazoles, triethylamine or pyridine,
The molar ratio of compound I and tert-butyl chloro-silicane is 1:The molar ratio of 1-2, compound I and acid binding agent is 1:1.5-2；
2) compound II is dissolved in the second solvent, adds palladium catalyst, add cyanidization agent, carried out cyanogenation and generate chemical combination
Object III, 80-150 DEG C of reaction temperature, reaction time 2-12h；
Second solvent is dimethylformamide or dimethyl sulfoxide, and the cyanating reagent is Zn (CN)2Or CuCN, the palladium
Catalyst is Pd2(dba)3、PdCl2(PPh3)2、Pd(PPh3)4Or Pd (OAc)2, palladium catalyst dosage is the 1-5% of compound II
Molar ratio, cyanating reagent dosage are the 1-1.5 times of molar ratio of compound II；
3) compound III is dissolved in third solvent, it is anti-directly to carry out bromination under phosphorus tribromide effect without sloughing protecting group
It answers, reaction temperature is 0-40 DEG C, reaction time 3-10h, and compound IV is made；
Third solvent is methylene chloride, and phosphorus tribromide dosage is the 1-3 times of molar ratio of compound III；
Reaction process is：
R is hydrogen H or deuterium D in formula.
2. the synthetic method of 2- cyano-benzyl bromide according to claim 1, which is characterized in that reaction temperature in the step 2)
100℃。
3. the synthetic method of 2- cyano-benzyl bromide according to claim 1 or 2, which is characterized in that reaction in the step 2)
Time is 6h.
4. the synthetic method of 2- cyano-benzyl bromide according to claim 1, which is characterized in that phosphorus tribromide in the step 3)
Dosage is 1.4 times of molar ratios of compound III.
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