CN104892566A - Preparation method of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene - Google Patents
Preparation method of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene Download PDFInfo
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Abstract
The invention relates to a preparation method of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene, which comprises the following steps: carrying out coupling reaction on 2-bromothiophene and p-bromofluorobenzene to obtain 2-(4-fluorophenyl)thiophene; carrying out Friedel-Craft reaction on the 2-(4-fluorophenyl)thiophene and 2-methyl-5-bromobenzoic acid to obtain 5-bromo-2-methylphenyl-2-(4-fluorophenyl)thienyl ketone; and finally, carrying out reduction reaction on the 5-bromo-2-methylphenyl-2-(4-fluorophenyl)thienyl ketone to obtain the 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene. By using the cheap and accessible p-bromofluorobenzene and 2-methyl-5-bromobenzoic acid as the raw materials for synthesizing the canagliflozin intermediate, the product is easy for purification, and the method is simple to operate and has the advantages of low cost and environment friendliness.
Description
Technical field
The invention belongs to medicinal chemistry art, particularly relate to a kind of Ka Gelie clean intermediate 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene, specifically a kind of 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene preparation method.
Background technology
Ka Gelie has another name called Kan Gelie clean (Canagliflozin) only, commodity are called Invokana, chemistry (2S by name, 3R, 4R, 5S, 6R)-2-(3-((5-(4-fluorophenyl) thiophene-2-base) methyl)-4-methylphenyl)-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol, the mode excreted by kidney after breakdown of glucose can be reduced glucose level, have and take safety when clinical studies show Ka Gelie treats separately type ii diabetes only, better tolerance, have obvious fat-reducing effect and good glycemic control.
2-(5-bromo-2-methyl-benzyl)-5-(4-fluorophenyl) thiophene arranges clean important intermediate as Synthesis Card lattice not only directly can be prepared into another clean important source material 2-of Ka Gelie (the iodo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene as the clean synthesis material of Ka Gelie.
In existing preparation method, mostly first first be prepared into acid reagent by 2-bromothiophene and P-Bromofluorobenzene to be obtained by reacting 2-(4-fluorophenyl) thiophene through Suzuki again, also patent reports by P-Bromofluorobenzene be prepared into grignard reagent again with 2-bromothiophene with NiCl
2(dppe) catalyzer is made, through Kumada reaction preparation 2-(4-fluorophenyl) thiophene; Subsequently, carry out Friedel-Crafts reaction and obtain aromatic ketone; Reduction again through boron trifluoride diethyl etherate and triethyl silicon hydrogen obtains target product 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene.But aforesaid method is high cost all, be not easy to industrialization.
2-(4-fluorophenyl) the thiophene I synthetic route that patent documentation US2012160218 discloses is as follows:
Carry out Suzuki by the Phenylsulfonic acid reagent of P-Bromofluorobenzene and thiophene in above-mentioned patent documentation and be obtained by reacting 2-(4-fluorophenyl) thiophene, the synthesis yield of above-mentioned patent report is 92%.
2-(4-fluorophenyl) the thiophene I synthetic route that patent documentation US2010043682 discloses is as follows:
The grignard reagent of 2-bromothiophene and P-Bromofluorobenzene is passed through at Pd (OAC) in above-mentioned patent documentation
2or NiCl
2(dppe) 2-(4-fluorophenyl) thiophene is obtained by reacting by Kumada under doing the effect of catalyzer.
The synthetic route of 5-bromo-2-aminomethyl phenyl-2-(4-fluorophenyl) the thiophene ketone II that patent documentation US2012160218 discloses is as follows:
Carry out Friedel-Crafts reaction by the acyl chlorides reagent of 2-(4-fluorophenyl) thiophene and 2-methyl-5-bromo-benzoic acid and obtain the bromo-2-aminomethyl phenyl of 5--2-(4-fluorophenyl) thiophene ketone, yield only has 69%.
The synthetic route of 2-(5-bromo-2-methyl-benzyl)-5-(4-fluorophenyl) thiophene that patent documentation US2012160218 discloses is as follows:
This route carries out reduction by boron trifluoride diethyl etherate and triethyl silicon hydrogen to the bromo-2-aminomethyl phenyl of 5--2-(4-fluorophenyl) thiophene ketone and obtains target product, and yield is 70%, and the reductive agent comparative price used is expensive.
Patent documentation PCT Int.Appl., the method that the synthetic route of 2011079772 reports and patent documentation US2012160218 use is similar, is all to use boron trifluoride diethyl etherate and triethyl silicon hydrogen as reductive agent.
Summary of the invention
For above-mentioned technical problem of the prior art, the invention provides the preparation method of a kind of 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene, the preparation method of described this 2-(5-bromo-2-methyl-benzyl)-5-(4-fluorophenyl) thiophene solves the technical problem that preparation method's cost of the prior art is high, complex process, yield are low.
The invention provides the preparation method of a kind of 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene, comprise the steps:
1) 2-bromothiophene and P-Bromofluorobenzene obtain 2-(4-fluorophenyl) thiophene by linked reaction;
2) 2-(4-fluorophenyl) thiophene and 2-methyl-5-bromo-benzoic acid obtain the bromo-2-aminomethyl phenyl of 5--2-(4-fluorophenyl) thiophene ketone by Friedel-Crafts reaction;
3) 5-bromo-2-aminomethyl phenyl-2-(4-fluorophenyl) thiophene ketone obtains 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene through reduction reaction.
Further, in step 1) in, first prepare grignard reagent by P-Bromofluorobenzene, then by described Grignard reagent and 2-bromothiophene in transition metal-catalyzed lower reaction, obtain compound 2-(4-fluorophenyl) thiophene.
Further, in step 2) in, first prepare 2-methyl-5-bromo-benzoyl chloride by 2-methyl-5-bromo-benzoic acid, 2-methyl-5-bromo-benzoyl chloride and 2-(4-fluorophenyl) thiophene are carried out Friedel-Crafts reaction, obtain the bromo-2-aminomethyl phenyl of compound 5--2-(4-fluorophenyl) thiophene ketone.
Further, in step 3) in, described 5-bromo-2-aminomethyl phenyl-2-(4-fluorophenyl) thiophene ketone carries out reduction reaction and obtains target compound 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene.
Further, in step 1) in, temperature of reaction is 10 ~ 70 DEG C; Solvent is selected from one or more the combination in tetrahydrofuran (THF), ether, isopropyl ether, n-butyl ether, 2-methyltetrahydrofuran, toluene; The described reaction times is 5 ~ 24h, catalyzer is selected from cobaltous acetate, cobalt dichloride, two (methyl ethyl diketone) cobalt, tri acetylacetonato cobalt, acid chloride, palladium chloride, [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride, tetrakis triphenylphosphine palladium, two (methyl ethyl diketone) palladium, (1,5-cyclooctadiene) palladium chloride, nickelous acetate, nickelous chloride, two (triphenyl phosphorus) nickelous chloride one or more combination.The preferred tetrahydrofuran (THF) of described solvent.Described catalyzer is two (methyl ethyl diketone) palladium preferably.
Further, in step 1) in, temperature of reaction is 35 ~ 85 DEG C; Reaction times is 2 ~ 12h.
Further, in step 2) in, temperature of reaction is-30 ~ 50 DEG C, solvent is selected from one or more the combination in methylene dichloride, oil of mirbane, ethylene glycol, tetrahydrofuran (THF), methyl-sulphoxide, dimethylbenzene, the described reaction times is 2 ~ 24h, and catalyzer is selected from one or more the combination in zinc chloride, aluminum chloride, iron trichloride, titanium tetrachloride.The preferred methylene dichloride of solvent.The preferred aluminum chloride of catalyzer.
Further, in step 2) in, described acylating reagent is oxalyl chloride or sulfur oxychloride, and temperature of reaction is 15 ~ 45 DEG C; The described reaction times is 2 ~ 15h; Catalyzer is DMF.
Further, in step 3) in, solvent is selected from one or more the combination in tetrahydrofuran (THF), ether, isopropyl ether, n-butyl ether, 2-methyltetrahydrofuran, toluene, the described reaction times is 2 ~ 10h, goes back original reagent and is selected from one or more combination in aluminum chloride, tin tetrachloride, sodium borohydride, trifluoroacetic acid, boron trifluoride diethyl etherate, iron trichloride, Lithium Aluminium Hydride, zinc dichloride, sulfuric acid, palladium chloride, aluminum oxide.The preferred tetrahydrofuran (THF) of excellent catalyzer.The also preferred boron trifluoride diethyl etherate of original reagent and sodium borohydride.
Concrete, in step 1) in, the preparation temperature of grignard reagent preferably 70 ~ 85 DEG C; Magnesium chips consumption is 1.0 ~ 3.0 times of P-Bromofluorobenzene, preferably 1.2 times;
Concrete, in step 1) in, the temperature of linked reaction is 10 ~ 70 DEG C, preferably 30 ~ 50 DEG C; The mol ratio of Grignard reagent and 2-bromothiophene is 3.0:1.0 ~ 1.0:1.0, and preferred molar ratio is 1.2:1 ~ 1:0.8.
Concrete, in step 2) in, the mol ratio of acylating reagent and 2-methyl-5-bromo-benzoic acid is 2.0:1.0 ~ 1.0:1.0, preferred 1.2:1.0; The temperature of reaction of acylation reaction is 15 ~ 45 DEG C, preferably 35 DEG C; The temperature of reaction of Friedel-Crafts reaction is-30 ~ 50 DEG C, preferably-15 ~ 25 DEG C;
Concrete, in step 3) in, temperature of reaction is 35 ~ 85 DEG C, preferably 75 DEG C.
Reaction process of the present invention is as follows:
The present invention prepares 2-(4-fluorophenyl) thiophene by 2-bromothiophene and P-Bromofluorobenzene, 2-(4-fluorophenyl) thiophene and 2-methyl-5-bromo-benzoic acid react prepares the bromo-2-aminomethyl phenyl of 5--2-(4-fluorophenyl) thiophene ketone, and 5-bromo-2-aminomethyl phenyl-2-(4-fluorophenyl) thiophene ketone prepares 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene through reduction reaction.The present invention utilizes cheapness, the P-Bromofluorobenzene be easy to get and 2-methyl-5-bromo-benzoic acid to be the clean intermediate of Material synthesis Ka Gelie, and product is easily purified, and have easy and simple to handle, cost is low, environment amenable advantage.
Advantage of the present invention is by adopting transition metal-catalyzed coupling to obtain 2-(4-fluorophenyl) thiophene III with higher yield, obtains Ka Gelie clean intermediate 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene of purity > 99.5 subsequently through Friedel-Crafts reaction and reduction reaction.
Embodiment:
Embodiment 1 prepares 2-(4-fluorophenyl) thiophene III:
Prepared by Grignard reagent: N
2under protection; magnesium chips (11.7g is added in the 500mL there-necked flask that thermometer, reflux condensing tube, constant pressure funnel be housed; 480mmol), THF (15.0mL), drips 2 p-Fluoro bromo benzenes; add the initiation reaction of 2 iodine post-heating; p-Fluoro bromo benzene (70.0g, 400mmol) is dissolved in THF (250mL), after under reflux, drip the THF solution of p-Fluoro bromo benzene; drip Bi Baowen backflow 2h, GC detection feedstock conversion complete.
Linked reaction: N
2under protection; in the 1000mL there-necked flask that thermometer, reflux condensing tube, constant pressure funnel be housed, add 2-bromothiophene (52.2g, 320mmol), under stirring, add two (methyl ethyl diketone) palladium (23.4mg; 0.0320mmol); THF (200mL), is heated to 50 DEG C, the above-mentioned Grignard reagent prepared of rear dropping; drip to finish and be warming up to 60 DEG C; insulation 1h, GC detect to raw material reaction complete, terminate reaction.System is cooled to 30 DEG C, drips dilute hydrochloric acid (2M, 150mL) under ice-water bath, drips complete vigorous stirring 0.5h, removes ice-water bath and make system naturally rise to room temperature, stratification, water layer CH
2cl
2(100mL × 3) extract, merge organic phase saturated sodium-chloride 200mL to wash, rear drying, concentrating under reduced pressure obtain light tan solid, vacuum-drying to constant weight obtains 2-(4-fluorophenyl) thiophene III (57.4g, 312mmol), it is 98.5% that GC detects purity, and yield is 99.1%.
1H NMR(500MHz,CDCl
3)δ7.65～7.54(m,2H),7.33～7.22(m,2H),7.14～7.03(m,3H).Gc-Ms:178.1.
Embodiment 2 prepares 2-(4-fluorophenyl) thiophene III:
Prepared by Grignard reagent: N
2under protection; magnesium chips (11.7g is added in the 500mL there-necked flask that thermometer, reflux condensing tube, constant pressure funnel be housed; 480mmol), THF (15.0mL), drips 2 p-Fluoro bromo benzenes; add the initiation reaction of 2 iodine post-heating; p-Fluoro bromo benzene (70.0g, 400mmol) is dissolved in THF (250mL), after under reflux, drip the THF solution of p-Fluoro bromo benzene; drip Bi Baowen backflow 2h, GC detection feedstock conversion complete.
Linked reaction: N
2under protection, in the 1000mL there-necked flask that thermometer, reflux condensing tube, constant pressure funnel be housed, add 2-bromothiophene (52.2g, 320mmol), under stirring, add PdCl
2(dppf) (23.4mg, 0.0320mmol), THF (200mL), is heated to 50 DEG C, the above-mentioned Grignard reagent prepared of rear dropping, drips to finish to be warming up to 60 DEG C, and insulation 1h, GC detect to raw material reaction complete, terminate reaction.System is cooled to 30 DEG C, drips dilute hydrochloric acid (2M, 150mL) under ice-water bath, drips complete vigorous stirring 0.5h, removes ice-water bath and make system naturally rise to room temperature, stratification, water layer CH
2cl
2(100mL × 3) extract, merge organic phase saturated sodium-chloride 200mL to wash, rear drying, concentrating under reduced pressure obtain light tan solid, vacuum-drying to constant weight obtains 2-(4-fluorophenyl) thiophene III (57.4g, 312mmol), it is 98.5% that GC detects purity, and yield is 99.1%.
1H NMR(500MHz,CDCl
3)δ7.65～7.54(m,2H),7.33～7.22(m,2H),7.14～7.03(m,3H).Gc-Ms:178.1.
Embodiment 3 prepares 2-(4-fluorophenyl) thiophene III:
Prepared by Grignard reagent: N
2under protection; magnesium chips (11.7g is added in the 500mL there-necked flask that thermometer, reflux condensing tube, constant pressure funnel be housed; 480mmol), THF (15.0mL), drips 2 p-Fluoro bromo benzenes; add the initiation reaction of 2 iodine post-heating; p-Fluoro bromo benzene (70.0g, 400mmol) is dissolved in THF (250mL), after under reflux, drip the THF solution of p-Fluoro bromo benzene; drip Bi Baowen backflow 2h, GC detection feedstock conversion complete.
Linked reaction: N
2under protection, in the 1000mL there-necked flask that thermometer, reflux condensing tube, constant pressure funnel be housed, add 2-bromothiophene (52.2g, 320mmol), under stirring, add PdCl
2(dppf) (23.4mg, 0.0320mmol), THF (200mL), is heated to 50 DEG C, the above-mentioned Grignard reagent prepared of rear dropping, drips to finish to be warming up to 60 DEG C, and insulation 1h, GC detect to raw material reaction complete, terminate reaction.System is cooled to 30 DEG C, drips dilute hydrochloric acid (2M, 150mL) under ice-water bath, drips complete vigorous stirring 0.5h, removes ice-water bath and make system naturally rise to room temperature, stratification, water layer CH
2cl
2(100mL × 3) extract, merge organic phase saturated sodium-chloride 200mL to wash, rear drying, concentrating under reduced pressure obtain light tan solid, vacuum-drying to constant weight obtains 2-(4-fluorophenyl) thiophene III (57.4g, 312mmol), it is 98.5% that GC detects purity, and yield is 99.1%.
1H NMR(500MHz,CDCl
3)δ7.65～7.54(m,2H),7.33～7.22(m,2H),7.14～7.03(m,3H).Gc-Ms:178.1.
Embodiment 4 prepares the bromo-2-aminomethyl phenyl of 5--2-(4-fluorophenyl) thiophene ketone II
2-methyl-5-bromo-benzoic acid (43.0g, 200mmol) is added, CH in the 500mL there-necked flask that thermometer, constant pressure funnel and drying tube be housed
2cl
2(215mL), DMF (1mL), slowly drips oxalyl chloride (27.7g, 220mmol) under stirring at room temperature, and drip complete room temperature reaction 2h, TLC detection reaction completely, decompression is revolved and desolventized.2-(4-fluorophenyl) thiophene III (35.6g, 200mmol) and AlCl is added in the 1000mL there-necked flask that thermometer, constant pressure funnel, drying tube be housed
3(32.0g, 240mmol), is dissolved in CH
2cl
2(450mL), cryosel bath is cooled to-15 DEG C, stirs the lower CH dripping the acyl chlorides of above-mentioned preparation
2cl
2solution (200mL), reinforced complete at 0 DEG C of insulation 0.5h, recession deicing salt bath, naturally rises to incubation at room temperature and spends the night.It is complete that TLC detects raw material primitive reaction, and terminate reaction, reaction system slowly poured in 1000mL frozen water, vigorous stirring, rises to room temperature naturally, stratification, aqueous phase CH
2cl
2(150mL × 3) extract, merge organic phase, wash with saturated sodium-chloride (200mL), rear drying concentrates to obtain yellow solid 91.2g, after by crude product acetone (350mL) recrystallization, filter, dry the bromo-2-aminomethyl phenyl of product 5--2-(4-fluorophenyl) thiophene ketone II be yellow solid (53.5g, 143mmol), it is 99.7% that HPLC detects purity, and yield is 90%.
1H NMR(500MHz,CDCl
3)δ7.68(dd,J＝8.2,5.5Hz,2H),7.60(s,1H),7.54(d,J＝8.1Hz,1H),7.40(d,J＝3.9Hz,1H),7.29(s,1H),7.24～7.09(m,3H),2.36(s,3H).ESI-MS m/z:377.0(M+2)
+.
Embodiment 5 prepares the bromo-2-aminomethyl phenyl of 5--2-(4-fluorophenyl) thiophene ketone II
2-methyl-5-bromo-benzoic acid (43.0g, 200mmol) is added, CH in the 500mL there-necked flask that thermometer, constant pressure funnel and drying tube be housed
2cl
2(215mL), DMF (1mL), slowly drips oxalyl chloride (27.7g, 220mmol) under stirring at room temperature, and drip complete room temperature reaction 2h, TLC detection reaction completely, decompression is revolved and desolventized.2-(4-fluorophenyl) thiophene III (35.6g, 200mmol) and AlCl is added in the 1000mL there-necked flask that thermometer, constant pressure funnel, drying tube be housed
3(32.0g, 240mmol), is dissolved in CH
2cl
2(450mL), cryosel bath is cooled to-15 DEG C, stirs the lower CH dripping the acyl chlorides of above-mentioned preparation
2cl
2solution (200mL), reinforced complete at 0 DEG C of insulation 0.5h, recession deicing salt bath, naturally rises to incubation at room temperature and spends the night.It is complete that TLC detects raw material primitive reaction, and terminate reaction, reaction system slowly poured in 1000mL frozen water, vigorous stirring, rises to room temperature naturally, stratification, aqueous phase CH
2cl
2(150mL × 3) extract, merge organic phase, wash with saturated sodium-chloride (200mL), rear drying concentrates to obtain yellow solid 91.2g, after by crude product acetone (350mL) recrystallization, filter, dry the bromo-2-aminomethyl phenyl of product 5--2-(4-fluorophenyl) thiophene ketone II be yellow solid (53.5g, 143mmol), it is 99.7% that HPLC detects purity, and yield is 90%.
1H NMR(500MHz,CDCl
3)δ7.68(dd,J＝8.2,5.5Hz,2H),7.60(s,1H),7.54(d,J＝8.1Hz,1H),7.40(d,J＝3.9Hz,1H),7.29(s,1H),7.24～7.09(m,3H),2.36(s,3H).ESI-MS m/z:377.0(M+2)
+.
Embodiment 6 prepares 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene I
In the 2000mL there-necked flask that thermometer, reflux condensing tube, drying tube be housed, add II (51.5g, 137mmol), THF (500mL), adds NaBH under stirring at room temperature
4(26.0g, 687mmol), adds AlCl in batches
3(45.7g, 343mmol), system bubbling is violent, and it is complete that reinforced complete heating reflux reaction 3h, TLC detect raw material reaction, stopped reaction.System is slowly poured into after being down to room temperature in 400mL frozen water, vigorous stirring 0.5h, naturally room temperature is risen to, stratification, aqueous phase ethyl acetate (100mL × 3) extraction, merges organic phase, washs with saturated sodium-chloride (100mL × 2), obtaining I after drying is concentrated is yellow solid 49.4g, rear CH
2cl
2/ MeOH (1:1,300mL) recrystallization, obtaining product I is faint yellow solid (48.0g, 116mmol), and it is 99.5% that HPLC detects purity, and yield is 97.0%.
1H NMR(501MHz,CDCl
3)δ7.56～7.45(m,2H),7.37(s,1H),7.33(d,J＝8.1Hz,1H),7.13～6.93(m,4H),6.70(d,J＝3.5Hz,1H),4.10(s,2H),2.30(s,3H).ESI-MS m/z:362.0(M+1)
+.
Embodiment 7 prepares 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene I
In the 2000mL there-necked flask that thermometer, reflux condensing tube, drying tube be housed, add II (51.5g, 137mmol), THF (500mL), adds NaBH under stirring at room temperature
4(26.0g, 687mmol), adds AlCl in batches
3(45.7g, 343mmol), system bubbling is violent, and it is complete that reinforced complete heating reflux reaction 3h, TLC detect raw material reaction, stopped reaction.System is slowly poured into after being down to room temperature in 400mL frozen water, vigorous stirring 0.5h, naturally room temperature is risen to, stratification, aqueous phase ethyl acetate (100mL × 3) extraction, merges organic phase, washs with saturated sodium-chloride (100mL × 2), obtaining I after drying is concentrated is yellow solid 49.4g, rear CH
2cl
2/ MeOH (1:1,300mL) recrystallization, obtaining product I is faint yellow solid (48.0g, 116mmol), and it is 99.5% that HPLC detects purity, and yield is 97.0%.
1H NMR(501MHz,CDCl
3)δ7.56～7.45(m,2H),7.37(s,1H),7.33(d,J＝8.1Hz,1H),7.13～6.93(m,4H),6.70(d,J＝3.5Hz,1H),4.10(s,2H),2.30(s,3H).ESI-MS m/z:362.0(M+1)
+.
Embodiment 8 prepares 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene I
In the 2000mL there-necked flask that thermometer, reflux condensing tube, drying tube be housed, add II (51.5g, 137mmol), THF (500mL), adds NaBH under stirring at room temperature
4(26.0g, 687mmol), adds AlCl in batches
3(45.7g, 343mmol), system bubbling is violent, and it is complete that reinforced complete heating reflux reaction 3h, TLC detect raw material reaction, stopped reaction.System is slowly poured into after being down to room temperature in 400mL frozen water, vigorous stirring 0.5h, naturally room temperature is risen to, stratification, aqueous phase ethyl acetate (100mL × 3) extraction, merges organic phase, washs with saturated sodium-chloride (100mL × 2), obtaining I after drying is concentrated is yellow solid 49.4g, rear CH
2cl
2/ MeOH (1:1,300mL) recrystallization, obtaining product I is faint yellow solid (48.0g, 116mmol), and it is 99.5% that HPLC detects purity, and yield is 97.0%.
1H NMR(501MHz,CDCl
3)δ7.56～7.45(m,2H),7.37(s,1H),7.33(d,J＝8.1Hz,1H),7.13～6.93(m,4H),6.70(d,J＝3.5Hz,1H),4.10(s,2H),2.30(s,3H).ESI-MS m/z:362.0(M+1)
+.
The above is only the citing of embodiments of the present invention; it should be pointed out that for those skilled in the art, under the prerequisite not departing from the technology of the present invention principle; can also make some improvement and modification, these improve and modification also should be considered as protection scope of the present invention.
Claims (9)
1. a preparation method for 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene, is characterized in that comprising the steps:
1) 2-bromothiophene and P-Bromofluorobenzene obtain 2-(4-fluorophenyl) thiophene by linked reaction;
2) 2-(4-fluorophenyl) thiophene and 2-methyl-5-bromo-benzoic acid obtain the bromo-2-aminomethyl phenyl of 5--2-(4-fluorophenyl) thiophene ketone by Friedel-Crafts reaction;
3) 5-bromo-2-aminomethyl phenyl-2-(4-fluorophenyl) thiophene ketone obtains 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene through reduction reaction.
2. the preparation method of a kind of 2-as claimed in claim 1 (the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene, it is characterized in that: in step 1), first prepare grignard reagent by P-Bromofluorobenzene, then by described Grignard reagent and 2-bromothiophene in transition metal-catalyzed lower reaction, obtain compound 2-(4-fluorophenyl) thiophene.
3. the preparation method of a kind of 2-as claimed in claim 1 (the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene, it is characterized in that: in step 2) in, first prepare 2-methyl-5-bromo-benzoyl chloride by 2-methyl-5-bromo-benzoic acid, 2-methyl-5-bromo-benzoyl chloride and 2-(4-fluorophenyl) thiophene are carried out Friedel-Crafts reaction, obtain the bromo-2-aminomethyl phenyl of compound 5--2-(4-fluorophenyl) thiophene ketone.
4. the preparation method of a kind of 2-as claimed in claim 1 (the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene, it is characterized in that: in step 3), described 5-bromo-2-aminomethyl phenyl-2-(4-fluorophenyl) thiophene ketone carries out reduction reaction and obtains target compound 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene.
5. the preparation method of a kind of 2-as claimed in claim 1 (the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene, it is characterized in that: in step 1), temperature of reaction is 10 ~ 70 DEG C; Solvent is selected from one or more the combination in tetrahydrofuran (THF), ether, isopropyl ether, n-butyl ether, 2-methyltetrahydrofuran, toluene; The described reaction times is 5 ~ 24 h, catalyzer is selected from cobaltous acetate, cobalt dichloride, two (methyl ethyl diketone) cobalt, tri acetylacetonato cobalt, acid chloride, palladium chloride, [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride, tetrakis triphenylphosphine palladium, two (methyl ethyl diketone) palladium, (1,5-cyclooctadiene) palladium chloride, nickelous acetate, nickelous chloride, two (triphenyl phosphorus) nickelous chloride one or more combination.
6. the preparation method of a kind of 2-as claimed in claim 5 (the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene, it is characterized in that: in step 1), temperature of reaction is 35 ~ 85 DEG C; Reaction times is 2 ~ 12 h.
7. the preparation method of a kind of 2-as claimed in claim 1 (the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene, it is characterized in that: in step 2) in, temperature of reaction is-30 ~ 50 DEG C, solvent is selected from one or more the combination in methylene dichloride, oil of mirbane, ethylene glycol, tetrahydrofuran (THF), methyl-sulphoxide, dimethylbenzene, the described reaction times is 2 ~ 24 h, and catalyzer is selected from one or more the combination in zinc chloride, aluminum chloride, iron trichloride, titanium tetrachloride.
8. the preparation method of a kind of 2-as claimed in claim 7 (the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene, it is characterized in that: in step 2) in, described acylating reagent is oxalyl chloride or sulfur oxychloride, and temperature of reaction is 15 ~ 45 DEG C; The described reaction times is 2 ~ 15 h; Catalyzer is DMF.
9. the preparation method of a kind of 2-as claimed in claim 1 (the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene, it is characterized in that: in step 3), solvent is selected from tetrahydrofuran (THF), ether, isopropyl ether, n-butyl ether, 2-methyltetrahydrofuran, one or more combination in toluene, the described reaction times is 2 ~ 10 h, also original reagent is selected from aluminum chloride, tin tetrachloride, sodium borohydride, trifluoroacetic acid, boron trifluoride diethyl etherate, iron trichloride, Lithium Aluminium Hydride, zinc dichloride, sulfuric acid, palladium chloride, one or more combination in aluminum oxide.
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