CN105669733A - Synthetic method of 1-methyl-1H-pyrazole-3-boronic acid pinacol ester - Google Patents
Synthetic method of 1-methyl-1H-pyrazole-3-boronic acid pinacol ester Download PDFInfo
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- pyrazoles
- isophthalic acid
- methyl isophthalic
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- pinacol borate
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 21
- BJMSXWLXFYZHIU-UHFFFAOYSA-N 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound CN1C=CC(B2OC(C)(C)C(C)(C)O2)=N1 BJMSXWLXFYZHIU-UHFFFAOYSA-N 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 238000000746 purification Methods 0.000 claims abstract description 13
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 6
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000000376 reactant Substances 0.000 claims description 19
- SFRBAIVGTMFEBA-UHFFFAOYSA-N IC1(CC(C(=O)O)(C=CC1)C)C(=O)O Chemical compound IC1(CC(C(=O)O)(C=CC1)C)C(=O)O SFRBAIVGTMFEBA-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 10
- MOGQNVSKBCVIPW-UHFFFAOYSA-N 1-methylpyrazol-3-amine Chemical compound CN1C=CC(N)=N1 MOGQNVSKBCVIPW-UHFFFAOYSA-N 0.000 claims description 9
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 9
- ZYGAMJLTPLERBC-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid propan-2-ol Chemical compound B(O)(O)OC(C)(C)C(C)(C)O.C(C)(C)O ZYGAMJLTPLERBC-UHFFFAOYSA-N 0.000 claims description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- 208000035126 Facies Diseases 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 5
- 230000004044 response Effects 0.000 claims description 5
- 235000010288 sodium nitrite Nutrition 0.000 claims description 5
- 229910052786 argon Inorganic materials 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 238000006193 diazotization reaction Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- UFYFLBNWAMCOML-UHFFFAOYSA-N n-methyl-1h-pyrazol-5-amine Chemical compound CNC1=CC=NN1 UFYFLBNWAMCOML-UHFFFAOYSA-N 0.000 abstract 2
- MRWWWZLJWNIEEJ-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-propan-2-yloxy-1,3,2-dioxaborolane Chemical compound CC(C)OB1OC(C)(C)C(C)(C)O1 MRWWWZLJWNIEEJ-UHFFFAOYSA-N 0.000 abstract 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 abstract 1
- 238000005271 boronizing Methods 0.000 abstract 1
- 239000011630 iodine Substances 0.000 abstract 1
- 229910052740 iodine Inorganic materials 0.000 abstract 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 abstract 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- -1 boric acid compound Chemical class 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000010921 in-depth analysis Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention discloses a synthetic method of 1-methyl-1H-pyrazole-3-boronic acid pinacol ester. The method comprises the following steps: step 1, 3-iodine-1-methyl-1H-pyrazole is synthesized from N-methyl-3-aminopyrazole through a diazotization reaction; step 2, 3-iodine-1-methyl-1H-pyrazole prepared in the step 1 is taken as a raw material of reaction, n-butyllithium is taken as a base, isopropoxyboronic acid pinacol ester is taken as a boronizing reagent, and 1-methyl-1H-pyrazole-3-boronic acid pinacol ester is obtained through synthesis. 1-methyl-1H-pyrazole-3-boronic acid pinacol ester with high purity is prepared with a simpler process, lower cost and higher yield. After deep analysis of a target product, N-methyl-3-aminopyrazole is taken as the raw material, iodine with higher activity is prepared through direct diazotization, and production of isomers during methyl introduction in the prior art is avoided, so that the yield is increased greatly and the purification difficulty is reduced greatly.
Description
Technical field
The present invention relates to boric acid compound synthesis technical field, be specifically related to the synthetic method of a kind of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate.
Background technology
The cross-coupling reaction (Suzuki reaction) of organoboron compound is very extensive in the application of the field such as organic synthesis and combinatorial chemistry. And pyrazole group is present in natural in a large number and the smaller ligand of synthesis, these smaller ligand with the multiple enzyme with pharmacological interest and acceptor interaction, can have multiple biological activity. And, boric acid compound, because of the architectural feature of its uniqueness, possesses good biological activity and pharmacological action, is widely used in the boron neutron capture therapy method of the potential enzyme inhibitor of synthesis, cancer. Additionally, 1-alkyl pyrazole boric acid is the important intermediate synthesizing and much having bioactive compound, it is as the substrate of Suzuki reaction, and to be condensed into ester rear stability good with pinacol, can long term storage be easy to be used as the reagent of organic synthesis and further medicine related activity research. Therefore, pyrazoles pinacol borate compounds has considerable development prospect, and 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate is the one of this compounds.
Currently, with respect to the synthetic route of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate, prior art is generally adopted following two synthetic route:
1,
Although the method only has single step reaction, but its product polarity very similar, and the fluorescence of product is more weak, single sterling can not be obtained by conventional purification process, and after phase participation is reacted behind, its purification is also difficulty very, and the yield obtaining sterling is extremely low, increases and is amplifying the production difficulty on producing and cost waste.
2,
The method is one of the more method that adopts at present, amino diazotising makes bromine, then the method adopting palladium chtalyst generates borate, but the method for this bibliographical information, amplify produce in also extremely difficult enforcement, relatively costly due to palladium catalyst, and its reaction is incomplete, reacting by heating afterproduct easily decomposes, and purification difficulty is also big, and production cost is costly.
Visible, about the synthetic method of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate in prior art, owing to product is impure, purification difficult, the reason such as relatively costly make this compound be difficult to amplificationization to produce.
Summary of the invention
It is an object of the invention to, the synthetic method of a kind of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate is provided, solves that the synthetic method product of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate in prior art is impure, purification difficult, the technical problem such as relatively costly.
The technical scheme that the present invention adopts for achieving the above object is as follows:
A kind of synthetic method of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate, the method is:
Described synthetic method comprises the steps:
Step 1, N-methyl-3-amino-pyrazol is by diazo-reaction synthesis 3-iodo-1-methyl isophthalic acid H-pyrazoles;
Step 2, aforementioned prepared 3-iodo-1-methyl isophthalic acid H-pyrazoles, as reaction raw materials, utilizes n-BuLi to do alkali, isopropanol pinacol borate does borating agent, and synthesis obtains 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate.
Preferably, the concrete course of reaction of described step 1 is: N-methyl-3-amino-pyrazol is dissolved in the mixed liquor of concentrated hydrochloric acid and water, sodium nitrite in aqueous solution is dropped in aforementioned mixed liquor at 0～5 DEG C and reacts, after having reacted, again reaction solution is dropped in potassium iodide aqueous solution and react, reactant liquor is carried out abstraction purification after terminating by reaction, obtains compound 3-iodo-1-methyl isophthalic acid H-pyrazoles.
Preferably, described sodium nitrite is 2～2.5:1 with the mol ratio of N-methyl-3-amino-pyrazol.
Preferably, described potassium iodide is 2～2.5:1 with the mol ratio of N-methyl-3-amino-pyrazol.
Preferably, described reactant liquor adopts extraction into ethyl acetate, and organic facies adopts purification by column chromatography after drying concentration, obtains compound 3-iodo-1-methyl isophthalic acid H-pyrazoles.
Preferably; the concrete course of reaction of described step 2 is: be dissolved in dry oxolane by iodo-for 3-1-methyl isophthalic acid H-pyrazoles and isopropanol pinacol borate; then-65～-50 DEG C, instill n-BuLi under argon shield; react at-65～-50 DEG C after dropwising; react and backward reactant liquor has added acid solution cancellation reaction; again through organic extractant phase, dry concentration, obtain compound 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate.
Preferably, described isopropanol pinacol borate is 1.5～2:1 with the mol ratio of 3-iodo-1-methyl isophthalic acid H-pyrazoles.
Preferably, described n-BuLi is 1.3～2:1 with the mol ratio of 3-iodo-1-methyl isophthalic acid H-pyrazoles.
Preferably, extraction into ethyl acetate is adopted after reactant liquor cancellation.
Preferably, reactant liquor response time at-65～-50 DEG C is 2～4 hours.
Compared with prior art, beneficial effects of the present invention is as follows:
1, synthetic method provided by the invention can with relatively simple technique, ratio prior art lower cost, and higher yield and high-purity prepare 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate.
2, after target product carries out in-depth analysis research, have employed N-methyl-3-amino-pyrazol as raw material, direct diazotization does Viability higher iodine, avoid the generation of isomer when upper methyl in prior art, be substantially reduced with purification difficulty so that yield is greatly improved. Second step adopts n-BuLi to do alkali, and isopropanol pinacol borate does borating agent, obtains the product of 98% purity.
Detailed description of the invention
Below by way of specific embodiment, technical scheme is described. Raw material used in the present invention and reagent are all commercially.
Embodiment 1
The preparation of 3-iodo-1-methyl isophthalic acid H-pyrazoles
Compound N-methy-3-amino-pyrazol (2000g, 20.6mol, 1.0eq) is dissolved in the mixed solution of 6000ml concentrated hydrochloric acid and 2000ml water, is placed in cryosel bath and is cooled to 0-5 DEG C, then drips the sodium nitrite saturated aqueous solution (NaNO of 3.5L22842.8g, 41.2mol, 2.0eq), after mechanic whirl-nett reaction 20min, this reaction solution is dropped in potassium iodide (8549.0g, 51.5mol, the 2.5eq) aqueous solution of 8000ml at 0 DEG C, after dropwising, reactant liquor is risen to naturally room temperature reaction 4h, TLC detection react completely after, add extraction into ethyl acetate 2 times, organic facies saturated aqueous common salt concentrates after drying, thick product obtains compound 3-iodo-1-methyl isophthalic acid H-pyrazoles (3473.8g, 16.7mol), productivity 81.0% through flash column.In this reactions steps, the product yield that the change mol ratio of reactant, response time obtain is referring to table 1.
Table 1, the conversion ratio of synthesis 3-iodo-1-methyl isophthalic acid H-pyrazoles
Embodiment 5
The preparation of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate
By iodo-for compound 3-1-methyl isophthalic acid H-pyrazoles (2000g, 9.6mol, 1.0eq) it is dissolved in the 8L oxolane dried, then in this solution, add isopropanol pinacol borate (2146.1g, 11.5mol, 1.2eq), solution is cooled to-65～-50 DEG C, under argon shield, instill n-BuLi (6.25L, 12.5mol, 1.3eq), mechanic whirl-nett reaction 2h at this low temperature after dropwising, aqueous hydrochloric acid solution (1mol/L) cancellation reaction is added in reactant liquor, reactant liquor is extracted with ethyl acetate 3 times, merge organic facies saturated aqueous common salt and concentrate organic facies after drying, obtain compound 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate (1080.9g, 0.24mol), productivity 54.0%, purity 97%+. 1HNMR (600MHz, CDCl3) δ 7.38 (d, J=2.1Hz, 1H), 6.66 (d, J=2.2Hz, 1H), 3.98 (s, 3H), 1.35 (s, 12H). In this reactions steps, change the mol ratio of reactant, the product yield of response time acquisition is listed in table 2.
The conversion ratio of table 2,1-methyl isophthalic acid H-pyrazoles-3-pinacol borate
Comparative example 1
Under nitrogen protection, by palladium catalyst Pd (dba) 3 (0.39g, 0.4mmol; catalytic amount) and triphenylphosphine (0.28g, 1mmol, catalytic amount) join in the anhydrous tetrahydro furan of 10ml; after stirring 10 minutes under room temperature, it is sequentially added into connection boric acid pinacol ester (5.3g, 15mmol; 1.1eq), potassium acetate (2.1g, 21mmol; 1.5eq); 3-iodo-1-methyl isophthalic acid H-pyrazoles (2.9g, 14mmol, 1.0eq). Heating reflux reaction 2h, after being subsequently cooled to room temperature, adds 10ml water, filters through kieselguhr, and extraction into ethyl acetate 3 times, after concentration, thick product crosses column purification, obtains thick product 0.5g, detects this set product impurity through nuclear-magnetism more. This is because product fluorescence is more weak, it is difficult to obtain sterling by conventional means purification.
Comparative example 2
By iodo-for compound 3-1-methyl isophthalic acid H-pyrazoles (20g, 0.096mol, 1.0eq) it is dissolved in the 100ml oxolane dried, then in this solution, add connection boric acid pinacol ester (36.6g, 0.144mol, 1.5eq), this reactant liquor is cooled to-65～-50 DEG C, under argon shield, instill n-BuLi (72ml, 0.144mol, 1.5eq), mechanic whirl-nett reaction 1h at this low temperature after dropwising, aqueous hydrochloric acid solution (1mol/L) cancellation reaction is added in reactant liquor, reactant liquor is extracted with ethyl acetate 3 times, merging organic facies saturated aqueous common salt concentrates organic facies after drying and obtains compound 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate (7.1g, 0.034mol), productivity 35.5%, purity 95%+. in this reactions steps, change the mol ratio of reactant, the product yield of response time acquisition is listed in table 3.
Table 3, the conversion ratio of synthesis 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate
Above are only the part preferred embodiment of the present invention, the present invention is not limited in the content of embodiment. To those skilled in the art, can there be various change and change, any change made and change in the concept of technical solution of the present invention, all within scope.
Claims (10)
1. a synthetic method for 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate, described synthetic method comprises the steps:
Step 1, N-methyl-3-amino-pyrazol is by diazo-reaction synthesis 3-iodo-1-methyl isophthalic acid H-pyrazoles;
Step 2, aforementioned prepared 3-iodo-1-methyl isophthalic acid H-pyrazoles, as reaction raw materials, utilizes n-BuLi to do alkali, isopropanol pinacol borate does borating agent, and synthesis obtains 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate.
2. the synthetic method of a kind of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate as claimed in claim 1, it is characterized in that, the concrete course of reaction of described step 1 is: N-methyl-3-amino-pyrazol is dissolved in the mixed liquor of concentrated hydrochloric acid and water, sodium nitrite in aqueous solution is dropped in aforementioned mixed liquor at 0～5 DEG C and reacts, after having reacted, again reaction solution is dropped in potassium iodide aqueous solution and react, reactant liquor is carried out abstraction purification after terminating by reaction, obtains compound 3-iodo-1-methyl isophthalic acid H-pyrazoles.
3. the synthetic method of a kind of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate as claimed in claim 2, it is characterised in that: the mol ratio of described sodium nitrite and N-methyl-3-amino-pyrazol is 2～2.5:1.
4. the synthetic method of a kind of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate as claimed in claim 2, it is characterised in that: the mol ratio of described potassium iodide and N-methyl-3-amino-pyrazol is 2～2.5:1.
5. the synthetic method of a kind of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate as claimed in claim 2, it is characterized in that: described reactant liquor adopts extraction into ethyl acetate, organic facies adopts purification by column chromatography after drying concentration, obtains compound 3-iodo-1-methyl isophthalic acid H-pyrazoles.
6. the synthetic method of a kind of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate as claimed in claim 1; it is characterized in that; the concrete course of reaction of described step 2 is: be dissolved in dry oxolane by iodo-for 3-1-methyl isophthalic acid H-pyrazoles and isopropanol pinacol borate; then-65～-50 DEG C, instill n-BuLi under argon shield; react at-65～-50 DEG C after dropwising; react and backward reactant liquor has added acid solution cancellation reaction; again through organic extractant phase; dry concentration, obtains compound 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate.
7. the synthetic method of a kind of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate as claimed in claim 6, it is characterised in that: the mol ratio of described isopropanol pinacol borate and 3-iodo-1-methyl isophthalic acid H-pyrazoles is 1.5～2:1.
8. the synthetic method of a kind of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate as claimed in claim 6, it is characterised in that: the mol ratio of described n-BuLi and 3-iodo-1-methyl isophthalic acid H-pyrazoles is 1.3～2:1.
9. the synthetic method of a kind of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate as claimed in claim 6, it is characterised in that: adopt extraction into ethyl acetate after reactant liquor cancellation.
10. the synthetic method of a kind of 1-methyl isophthalic acid H-pyrazoles-3-pinacol borate as claimed in claim 6, it is characterised in that: reactant liquor response time at-65～-50 DEG C is 2～4 hours.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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| CN107602602A (en) * | 2017-09-30 | 2018-01-19 | 上海毕得医药科技有限公司 | A kind of synthetic method of the pinacol borate of 3 cyanopyridine 5 |
| CN114181237A (en) * | 2021-12-01 | 2022-03-15 | 上海凌凯医药科技有限公司 | Synthesis method of 1-isopropylpyrazole-5-boronic acid pinacol ester |
| CN114213437A (en) * | 2021-12-01 | 2022-03-22 | 上海凌凯医药科技有限公司 | Central control method for 1-isopropylpyrazole-5-boronic acid pinacol ester synthesis reaction |
| CN114230540A (en) * | 2022-01-06 | 2022-03-25 | 西安爱德克美新材料有限公司 | Method for synthesizing alpha-BPDA |
| CN115057845A (en) * | 2022-06-14 | 2022-09-16 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of Abelide |
| US12043626B2 (en) | 2021-10-01 | 2024-07-23 | Nuvalent, Inc. | Solid forms, pharmaceutical compositions and preparation of heteroaromatic macrocyclic ether compounds |
| US12054498B2 (en) | 2020-05-05 | 2024-08-06 | Nuvalent, Inc. | Heteroaromatic macrocyclic ether chemotherapeutic agents |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107602602A (en) * | 2017-09-30 | 2018-01-19 | 上海毕得医药科技有限公司 | A kind of synthetic method of the pinacol borate of 3 cyanopyridine 5 |
| US12054498B2 (en) | 2020-05-05 | 2024-08-06 | Nuvalent, Inc. | Heteroaromatic macrocyclic ether chemotherapeutic agents |
| US12043626B2 (en) | 2021-10-01 | 2024-07-23 | Nuvalent, Inc. | Solid forms, pharmaceutical compositions and preparation of heteroaromatic macrocyclic ether compounds |
| CN114181237A (en) * | 2021-12-01 | 2022-03-15 | 上海凌凯医药科技有限公司 | Synthesis method of 1-isopropylpyrazole-5-boronic acid pinacol ester |
| CN114213437A (en) * | 2021-12-01 | 2022-03-22 | 上海凌凯医药科技有限公司 | Central control method for 1-isopropylpyrazole-5-boronic acid pinacol ester synthesis reaction |
| CN114181237B (en) * | 2021-12-01 | 2024-02-23 | 上海凌凯医药科技有限公司 | Synthesis method of 1-isopropyl pyrazole-5-boric acid pinacol ester |
| CN114230540A (en) * | 2022-01-06 | 2022-03-25 | 西安爱德克美新材料有限公司 | Method for synthesizing alpha-BPDA |
| CN115057845A (en) * | 2022-06-14 | 2022-09-16 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of Abelide |
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