CN103601749B - A kind of synthetic method of 1-alkyl pyrazole-4-pinacol borate - Google Patents
A kind of synthetic method of 1-alkyl pyrazole-4-pinacol borate Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- 239000011630 iodine Substances 0.000 claims abstract description 47
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 47
- 238000002360 preparation method Methods 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000002994 raw material Substances 0.000 claims abstract description 23
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 14
- 150000003217 pyrazoles Chemical class 0.000 claims abstract description 12
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000001350 alkyl halides Chemical class 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 7
- 229910000085 borane Inorganic materials 0.000 claims abstract description 5
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 14
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 8
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 8
- 238000010792 warming Methods 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 7
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 7
- WGLLSSPDPJPLOR-UHFFFAOYSA-N tetramethylethylene Natural products CC(C)=C(C)C WGLLSSPDPJPLOR-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000004327 boric acid Substances 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000002346 iodo group Chemical group I* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 235000021463 dry cake Nutrition 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 238000001914 filtration Methods 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 235000012970 cakes Nutrition 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- -1 tetramethyl ethylene ketone Chemical class 0.000 description 3
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000010009 beating Methods 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229940050176 methyl chloride Drugs 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- AKQAJYLKBCWJBV-UHFFFAOYSA-N 1-benzylpyrazole Chemical compound C1=CC=NN1CC1=CC=CC=C1 AKQAJYLKBCWJBV-UHFFFAOYSA-N 0.000 description 1
- KTFGWHSLIOZEKH-UHFFFAOYSA-N 5-benzyl-1h-pyrazole Chemical compound C=1C=CC=CC=1CC1=CC=NN1 KTFGWHSLIOZEKH-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- GASRPJFBDHLALP-UHFFFAOYSA-N N1N=CC=C1.C(C1=CC=CC=C1)I Chemical class N1N=CC=C1.C(C1=CC=CC=C1)I GASRPJFBDHLALP-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to organic chemical synthesis field.A synthetic method for 1-alkyl pyrazole-4-pinacol borate, comprises following three steps: the first step pyrazoles and iodine, hydroperoxidation generate 4-iodine pyrazoles A; Second step 4-iodine pyrazoles and haloalkane are obtained by reacting intermediate B; 3rd step with 1-alkyl-4-iodine pyrazoles for raw material, in 0 to-30
ounder C, adopt the method that sec.-propyl Grignard reagent exchanges, the Grignard reagent of raw materials, using BE001 as borane reagent, is obtained by reacting the finished product.Present invention process method raw material is easy to get, easy and simple to handle, cost is lower, is the proper method of preparation 1-alkyl pyrazole-4-pinacol borate compounds.
Description
Technical field:
The invention belongs to organic compound synthesis field, relate to the preparation method of 1-alkyl pyrazole-4-pinacol borate.
Background technology:
1-alkyl pyrazole-4-pinacol borate is the compound and important medicine intermediate that a class is more novel, has a wide range of applications.Current bibliographical information has two kinds about the synthetic method of this compounds, method one: with 1-alkyl-4-bromine pyrazoles for starting raw material, with n-Butyl Lithium-90
oc reacts 1 hour, is warming up to-70
oc, adds trimethyl borate, reacts 0.5 hour, uses aqueous ammonium chloride solution cancellation, separate oil phase, obtains 1-ethylpyrazol-4-boric acid (Ref:JournalofHeterocyclicChemistry after concentrated; Vol.41; P.931-940), then esterification obtains product.Synthetic route is as follows:
The shortcoming of this route is reaction needed very low temperature-90
oc, severe reaction conditions.
Method two: with 1-alkyl-4-bromine pyrazoles and tetramethyl ethylene ketone two boron for starting raw material, under [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex catalysis 100
oproduct (Ref:WO2013/53983) is obtained by reacting under C.The shortcoming of the method is expensive catalyst, is not easy to obtain.Synthetic route is as follows:
Method three: with 4-iodine pyrazoles and tetramethyl ethylene ketone borine for starting raw material, under [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex catalysis 80
opyrazoles-4-pinacol borate (Ref:US6680401) is obtained by reacting under C, and then alkylation.The shortcoming of the method is that all somewhat expensive cost of tetramethyl ethylene ketone borine and catalyzer is high and not easy to operate.Synthetic route is as follows:
Summary of the invention:
The present invention seeks to overcome above-mentioned not enough problem, provide a kind of synthetic method of 1-alkyl pyrazole-4-pinacol borate, its general routes outlined pyrazoles is that raw material is obtained by reacting product by iodo, alkylation, one-tenth ester.This method raw material is easy to get, easy and simple to handle, cost is lower, is the proper method of preparation 1-alkyl pyrazole-4-pinacol borate compounds.
The technical scheme that the present invention is adopted for achieving the above object is: a kind of synthetic method of 1-alkyl pyrazole-4-pinacol borate, and it comprises following three steps:
The preparation of the first step 4-iodine Pyrazol intermediate A: starting pyrazoles and ethanol stir by iodo, add iodine in batches, adding fashionable reaction solution has warming phenomenon (after mixing reacting liquid temperature 20 DEG C-30 DEG C); Then drip hydrogen peroxide, control temperature, not higher than 70 degree, dropwises stirring 1 hour, and TLC follows the tracks of reaction and terminates; Add the color fade of saturated aqueous solution of sodium bisulfite to iodine, add sodium bicarbonate solid and regulate Ph=8, continue stirring 1 hour; Filter to obtain white solid, washing filter cake, dry cake obtains sterling 4-iodine Pyrazol intermediate A;
, there is alkylated reaction in the preparation of second step intermediate B: mixed with intermediate A by haloalkane RX, this reaction is by controlling termination reaction in GC or TLC, and in haloalkane RX, R represents methyl, benzyl or sec.-propyl under the effect of alkali; X represents chlorine atom or bromine atoms, obtained 1-alkyl-4-iodine Pyrazol intermediate B;
3rd step becomes ester: with 1-alkyl-4-iodine Pyrazol intermediate B for raw material, under 0-30oC, and adopt the method that sec.-propyl Grignard reagent exchanges, the Grignard reagent of raw materials, using BE001 as borane reagent, is obtained by reacting the finished product.Through GC and
1h-NMR determines purity ﹥ 98%.
The mol ratio of described the first step Raw pyrazoles, iodine and hydrogen peroxide is 1:0.5 ~ 0.6:1.0 ~ 1.2.
In described second step, the mol ratio of 4-iodine pyrazoles and haloalkane is 1:1.0 ~ 1.3.
In described 3rd step, the mol ratio of 1-alkyl-4-iodine pyrazoles, sec.-propyl grignard reagent and BE001 is 1:1.0 ~ 1.2:1.0 ~ 1.2.
Reaction mechanism of the present invention is as follows:
In formula, R represents methyl, benzyl, sec.-propyl base; X represents chlorine atom, bromine atoms; BE001 represents sec.-propyl tetramethyl ethylene ketone boric acid ester.
Chemical synthesis route of the present invention is simple, and reaction conditions is gentle, easy handling, and raw materials cost is low simultaneously, compensate for shortcoming of the prior art, meets the widespread use of finished product.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail, but the present invention is not limited to specific embodiment.
Embodiment 1
Prepare a method for 1-alkyl pyrazole-4-pinacol borate, 1-methylpyrazole-4-pinacol borate is example:
The preparation of the first step 4-iodine pyrazoles:
Starting pyrazoles (10g) and ethanol (10g) stir, add iodine (22.4g) in batches, there is warming phenomenon (20 DEG C-30 DEG C), drip 30% hydrogen peroxide (16.7g), control temperature, not higher than 70 degree, dropwises stirring 1 hour, TLC follows the tracks of reaction and terminates, add the saturated aqueous solution of sodium bisulfite of 10g, stir 1 hour, filter to obtain white solid, 20g washes filter cake, filtrate concentrates, and has solid to separate out, again filtration washing, merge filtration cakes torrefaction, to weigh 25.7g, GC purity: 99%, yield 90%;
The preparation of second step 1-methyl-4-iodine pyrazoles:
4-iodine pyrazoles (20g) and ethanol (100ml), stir, add KOH(11.6g) and KI(0.9g), logical methyl chloride gas, slightly temperature rise under inserting liquid level, control temperature 30-45 DEG C, GC follows the tracks of reaction and terminates, and add water 100g, dichloromethane extraction (40gX3), be concentrated into not flow liquid, pull an oar with normal heptane 6ml, suction filtration obtains white solid, dry, to weigh 17.2g, GC purity 98%, yield 80%;
The preparation of the 3rd step 1-methylpyrazole-4-pinacol borate:
1-methyl-4-iodine pyrazoles is raw material 19.5g, in-5--10
ounder C, adopt the method that sec.-propyl grignard (94mL) reagent of 1.0mol/L exchanges, the Grignard reagent of raw materials, drip BE001(16.8g), be obtained by reacting the finished product 7.8g, this step yield 40%, determines purity ﹥ 97% through GC and 1H-NMR.1-methylpyrazole-4-pinacol borate
1hNMR (CDCl
3) δ 1.25 (s, 12H), 3.89(s, 1H) 7.63 (s, 1H), 7.75 (s, 1H).
Embodiment 2
Prepare a method for 1-alkyl pyrazole-4-pinacol borate, 1-methylpyrazole-4-pinacol borate is example:
The preparation of the first step 4-iodine pyrazoles:
Starting pyrazoles (10g) and ethanol (10g) stir, evenly, add iodine (22.4g) in batches, have warming phenomenon (20 DEG C-30 DEG C), drip hydrogen peroxide (16.7g), control temperature is not higher than 70 degree, dropwise stirring 1 hour, TLC follows the tracks of reaction and terminates, and adds the saturated aqueous solution of sodium bisulfite of 10g, stir 1 hour, filter to obtain white solid, 20g washes filter cake, and filtrate concentrates, solid is had to separate out, again filtration washing, merge filtration cakes torrefaction, weigh 25.7g, GC purity: 99%, yield 90%;
The preparation of second step 1-methyl-4-iodine pyrazoles:
4-iodine pyrazoles (20g) and ethanol (100ml), stir, add KOH(8.7g) and KI(0.9g), logical methyl chloride gas, slightly temperature rise under inserting liquid level, control temperature 30-45 DEG C, GC follows the tracks of reaction and terminates, and add water 100g, dichloromethane extraction (40gX3), be concentrated into not flow liquid, pull an oar with normal heptane 6ml, suction filtration obtains white solid, dry, to weigh 15.1g, GC purity 98%, yield 70%;
The preparation of the 3rd step 1-methylpyrazole-4-pinacol borate:
1-methyl-4-iodine pyrazoles is raw material 19.5g, in 0--5
oless than C DEG C, adopt 1mol/L sec.-propyl grignard (94ml
) reagent exchange method, the Grignard reagent of raw materials, drip BE001(16.8g), be obtained by reacting the finished product 7.8g, this step yield 40%, determines purity ﹥ 97% through GC and 1H-NMR.
Embodiment 3
Prepare a method for 1-alkyl pyrazole-4-pinacol borate, 1-isopropylpyrazol-4-pinacol borate is example:
The preparation of the first step 4-iodine pyrazoles:
Starting pyrazoles (10g) and ethanol (10g) stir, evenly, add iodine (18.6g) in batches, have warming phenomenon (20 DEG C-30 DEG C), drip 30% hydrogen peroxide (16.7g), control temperature is not higher than 70 degree, dropwise stirring 1 hour, TLC follows the tracks of reaction and terminates, and adds the saturated aqueous solution of sodium bisulfite of 10g, stir 1 hour, filter to obtain white solid, 20g washes filter cake, and filtrate concentrates, solid is had to separate out, again filtration washing, merge filtration cakes torrefaction, weigh 22.8g, GC purity: 99%, yield 80%;
The preparation of second step 1-sec.-propyl-4-iodine pyrazoles:
Sodium hydride (16.5g) is scattered in 90mlN, and in dinethylformamide, argon shield, temperature control is lower than 0 degree.Add after 4-iodine pyrazoles (40g) fed in raw material, be incubated 0 degree and stir 0.5h, added by isopropyl bromide (32.0g) subsequently, this reaction mixture is 100 in batches
ostir 3 hours under C, control in TLC, there is product rf=0.7(ethyl acetate: normal heptane=1:4), add 100ml water and stir 30 minutes, with 100ml extraction into ethyl acetate 4 times, merging oil phase, washing oil phase 8 times, with removing N with 50ml saturated aqueous common salt, dinethylformamide, use anhydrous magnesium sulfate drying oil phase, be spin-dried for obtain 42g weak yellow liquid (crude product), the 1-sec.-propyl-4-iodine pyrazoles 42g obtained is crossed post, elutriant is done with sherwood oil, post is high 12 centimetres, is spin-dried for obtain sterling 40g, yield 82.2%;
The preparation of the 3rd step 1-isopropylpyrazol-4-pinacol borate:
1-sec.-propyl-4-iodine pyrazoles is raw material 20g, at-10--15 DEG C, adopts the method that 1mol/L sec.-propyl grignard (85ml) reagent exchanges, the Grignard reagent of raw materials, drips BE001(17.2g), be obtained by reacting the finished product 9.0g.This step yield 45%, through GC and
1hNMR determines purity ﹥ 98%.1-isopropylpyrazol-4-pinacol borate
1hNMR (400MHz, DMSO-d
6): δ=1.25 (s, 12H), 1.41 (d, J=6.8Hz, 6H), 4.53 (m, J=6.7Hz, 1H), 7.57 (s, 1H), 7.95 (s, 1H).
Embodiment 4
Prepare a method for 1-alkyl pyrazole-4-pinacol borate, 1-isopropylpyrazol-4-pinacol borate is example:
The preparation of the first step 4-iodine pyrazoles:
Starting pyrazoles (10g) and ethanol (10g) stir, and evenly, add iodine (22.4g) in batches, have warming phenomenon (20 DEG C-30 DEG C).Drip 30% hydrogen peroxide (16.7g), control temperature, not higher than 70 degree, dropwises stirring 1 hour, and TLC follows the tracks of reaction and terminates, and adds the saturated aqueous solution of sodium bisulfite of 10g.Stir 1 hour.Filter to obtain white solid, 20g washes filter cake, and filtrate concentrates, and has solid to separate out, again filtration washing, merges filtration cakes torrefaction, 25.7g, GC purity of weighing: 99%, yield 90%;
The preparation of second step 1-sec.-propyl-4-iodine pyrazoles:
Sodium hydride (16.5g) is scattered in 90mlN, and in dinethylformamide, argon shield, temperature control is lower than 0 degree.Add after 4-iodine pyrazoles (40g) fed in raw material, be incubated 0 degree and stir 0.5h, added by isopropyl bromide (32.0g) subsequently, this reaction mixture is 100 in batches
ostir 3 hours under C, control in TLC, there is product rf=0.7(ethyl acetate: normal heptane=1:4), add 100ml water and stir 30 minutes, with 100ml extraction into ethyl acetate 4 times, merging oil phase, washing oil phase 8 times, with removing N with 50ml saturated aqueous common salt, dinethylformamide, use anhydrous magnesium sulfate drying oil phase, be spin-dried for obtain 42g weak yellow liquid (crude product), the 1-sec.-propyl-4-iodine pyrazoles 42g obtained is crossed post, elutriant is done with sherwood oil, post is high 12 centimetres, is spin-dried for obtain sterling 40g, yield 82.2%;
The preparation of the 3rd step 1-isopropylpyrazol-4-pinacol borate:
1-sec.-propyl-4-iodine pyrazoles is raw material 20g, in-15--20
obelow C, adopts the method that sec.-propyl grignard (85ml) reagent exchanges, the Grignard reagent of raw materials, drips BE001(17.2g), be obtained by reacting the finished product 10.0g.This step yield 50%, through GC and
1h-NMR determines purity ﹥ 98%.
Embodiment 5
Prepare a method for 1-alkyl pyrazole-4-pinacol borate, 1-benzyl pyrazole-4-pinacol borate is example:
The preparation of the first step 4-iodine pyrazoles:
Starting pyrazoles (10g) and ethanol (10g) stir, and evenly, add iodine (22.4g) in batches, have warming phenomenon (20 DEG C-30 DEG C).Drip 30% hydrogen peroxide (16.7g), control temperature is not higher than 70 degree.Dropwise stirring 1 hour, TLC follows the tracks of reaction and terminates.Add the saturated aqueous solution of sodium bisulfite of 10g.Stir 1 hour.Filter to obtain white solid, 20g washes filter cake, and filtrate concentrates, and has solid to separate out, again filtration washing, merges filtration cakes torrefaction and obtains 25.7g solid.GC purity: 99%.Yield 90%.
The preparation of second step 1-benzyl-4-iodine pyrazoles:
At ambient temperature, 32.2g benzyl chloride is dripped in liquid in the aqueous solution being added with 57.0g4-iodine pyrazoles, 20.0g potassium hydroxide and 2.9gTBAB, after dropwising, constant temperature stir about 48 hours, organic layer uses 40 DEG C of water washings three times again, after dried over mgso, obtains yellow oily product 66.0g, GC purity 97.0%, yield 79%.
The preparation of the 3rd step 1-benzyl pyrazole-4-pinacol borate:
15.0g1-benzyl-4-iodopyrazol theta is dissolved in THF, 0--10
odrip sec.-propyl grignard reagent under C, exchange completely, drip 21.0gBE001, stirring is spent the night, and after the cancellation that adds water, separates organic layer, washing twice, concentrated dry THF, and normal heptane insulation-20 ~-10 DEG C of making beating 2 hours, obtain product 6.4g,
1hNMR purity > 97%, productive rate 43%.
1HNMR(400MHz,DMSO-d
6):δ=1.25(s,12H),5.33(s,2H),7.32(m,5H),7.61(s,1H),8.03(s,1H)。
Embodiment 6
Prepare a method for 1-alkyl pyrazole-4-pinacol borate, 1-benzyl pyrazole-4-pinacol borate is example:
The preparation of the first step 1-benzyl pyrazole:
At ambient temperature, 32.2g benzyl chloride is dripped in liquid in the aqueous solution being added with 20.0g pyrazoles, 20.0g potassium hydroxide and 2.9gTBAB, after dropwising, constant temperature stir about 48 hours, organic layer uses 40 DEG C of water washings three times again, after dried over mgso, obtains yellow oily product 34.0g, GC purity 95.88%, yield 80%.
The preparation of second step 1-benzyl-4-iodine pyrazoles:
16.0g benzyl pyrazole is joined in acetonitrile, stir 20 minutes, be incubated 10 ~ 20 DEG C and add 56.0g ceric ammonium nitrate and 26.0g solid iodine, insulated and stirred 8 hours, add the washing of saturated sodium bisulfite, MTBE extracting twice, dried over mgso, concentrated dry MTBE, 0 DEG C of normal heptane is pulled an oar half an hour, filtration obtains benzyl iodide pyrazoles 15.0g, GC purity 98%, yield 52%.
The preparation of the 3rd step 1-benzyl pyrazole-4-pinacol borate:
15.0g1-benzyl-4-iodopyrazol theta is dissolved in THF, 0--10
odrip sec.-propyl grignard reagent under C, exchange completely, drip 21.0gBE001, stirring is spent the night, and after the cancellation that adds water, separates organic layer, washing twice, concentrated dry THF, and normal heptane insulation-20 ~-10 DEG C of making beating 2 hours, obtain product 6.4g,
1hNMR purity > 97%, productive rate 43%.
Claims (1)
1. a synthetic method for 1-alkyl pyrazole-4-pinacol borate, is characterized in that: it comprises following three steps:
The preparation of the first step 4-iodine Pyrazol intermediate A: the mol ratio of starting pyrazoles, iodine and hydrogen peroxide is 1:0.5 ~ 0.6:1.0 ~ 1.2; Starting pyrazoles and ethanol stir by iodo, add iodine in batches, and adding fashionable reaction solution has warming phenomenon; Then drip hydrogen peroxide, control temperature, not higher than 70 degree, dropwises stirring 1 hour, and TLC follows the tracks of reaction and terminates; Add the color fade of saturated aqueous solution of sodium bisulfite to iodine, add sodium bicarbonate solid and regulate pH=8, continue stirring 1 hour; Filter to obtain white solid, washing filter cake, dry cake obtains sterling 4-iodine Pyrazol intermediate A;
The preparation of second step intermediate B: haloalkane RX is mixed with intermediate A, the mol ratio of 4-iodine pyrazoles and haloalkane is 1:1.0 ~ 1.3, under the effect of alkali, alkylated reaction occurs, this reaction is by controlling termination reaction in GC or TLC, and in haloalkane RX, R represents methyl, benzyl or sec.-propyl; X represents chlorine atom or bromine atoms, obtained 1-alkyl-4-iodine Pyrazol intermediate B;
3rd step becomes ester: with 1-alkyl-4-iodine Pyrazol intermediate B for raw material, in 0-30
ounder C, adopt the method that sec.-propyl Grignard reagent exchanges, the Grignard reagent of raw materials, using sec.-propyl tetramethyl ethylene ketone boric acid ester as borane reagent, be obtained by reacting the finished product, wherein the mol ratio of 1-alkyl-4-iodine pyrazoles, sec.-propyl grignard reagent and sec.-propyl tetramethyl ethylene ketone boric acid ester is 1:1.0 ~ 1.2:1.0 ~ 1.2.
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