CN116375746B - A preparation method of potassium (2-fluoro-6-hydroxyphenyl) trifluoroborate - Google Patents
A preparation method of potassium (2-fluoro-6-hydroxyphenyl) trifluoroborateInfo
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- CN116375746B CN116375746B CN202111589705.8A CN202111589705A CN116375746B CN 116375746 B CN116375746 B CN 116375746B CN 202111589705 A CN202111589705 A CN 202111589705A CN 116375746 B CN116375746 B CN 116375746B
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C07F5/02—Boron compounds
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Abstract
The invention provides a preparation method of (2-fluoro-6-hydroxyphenyl) potassium trifluoroborate. The preparation method comprises the following steps of (1) reacting 3-fluorophenol with chloromethyl diethyl ether to obtain a compound shown in a formula I, (2) reacting the compound shown in the formula I obtained in the step (1) with isopropanol pinacol borate in the presence of a lithium reagent to obtain a compound shown in a formula II, and (3) reacting the compound shown in the formula II obtained in the step (2) with potassium fluoride in the presence of an acid to obtain potassium (2-fluoro-6-hydroxyphenyl) trifluoroborate. The preparation process does not need to use a boron tribromide dangerous reagent, the yield is also greatly improved, the process is simple, the operation is convenient, and the industrial production is easy.
Description
Technical Field
The invention belongs to the field of synthesis of medical intermediates, and particularly relates to a preparation method of (2-fluoro-6-hydroxyphenyl) potassium trifluoroborate.
Background
The (2-fluoro-6-hydroxyphenyl) potassium trifluoroborate is a medical intermediate of a traditional Chinese medicine, and the original synthetic route is shown as follows:
The route is completed by starting from m-fluoroanisole, adding butyl lithium to prepare trimethyl borate, removing methyl, and preparing potassium trifluoroborate functional groups.
However, boron trifluoride is subjected to demethylation in the course of the route, deep cooling is required, volatility and corrosiveness of boron trifluoride are extremely high, the boron trifluoride is extremely harmful to human bodies, meanwhile, corrosion-resistant hastelloy kettles capable of being subjected to deep cooling are required, the cost of the whole route is greatly increased, the process is dangerous, and the industrial scale-up production of the variety is restricted.
Therefore, development of a preparation method of (2-fluoro-6-hydroxyphenyl) potassium trifluoroborate which avoids the use of boron tribromide dangerous reagent, greatly improves the yield, has simple process, is convenient to operate and is easy for industrial production is needed
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of (2-fluoro-6-hydroxyphenyl) potassium trifluoroborate. The preparation method avoids adopting the boron tribromide dangerous reagent, greatly improves the yield, has simple process and convenient operation, and is easy for industrial production.
To achieve the purpose, the invention adopts the following technical scheme:
The invention provides a preparation method of (2-fluoro-6-hydroxyphenyl) potassium trifluoroborate, which comprises the following steps:
(1) Reacting 3-fluorophenol with chloromethyl ether to obtain a compound shown in a formula I, wherein the reaction formula is shown as follows:
(2) Reacting the compound shown in the formula I obtained in the step (1) with isopropanol pinacol borate in the presence of a lithium reagent to obtain a compound shown in the formula II, wherein the reaction formula is as follows:
(3) Reacting the compound shown in the formula II obtained in the step (2) with potassium fluoride in the presence of acid to obtain (2-fluoro-6-hydroxyphenyl) potassium trifluoroborate, wherein the reaction formula is shown as follows:
In the invention, the preparation method starts from m-fluorophenol cheaper than m-fluoroanisole, adopts a lithium reagent to perform hydroboration at low temperature through hydroxy protection, and then completes three steps of removing hydroxy protection while preparing a potassium trifluoroborate functional group, and the method is changed to avoid adopting a boron tribromide dangerous reagent, so that the yield is also greatly improved, the process is simple, the operation is convenient, and the industrial production is easy.
Preferably, in the step (1), the molar ratio of the 3-fluorophenol to the chloromethyl ether is 1 (1-1.2), and for example, 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, etc. can be used.
Preferably, in step (1), the reaction is carried out in the presence of a base, the molar ratio of the 3-fluorophenol to the base being 1 (1-2), which may be, for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, etc.
Preferably, the base comprises any one or a combination of at least two of potassium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate, preferably potassium carbonate.
Preferably, in step (1), the reaction is carried out in a solvent.
Preferably, the solvent comprises any one or a combination of at least two of acetonitrile, tetrahydrofuran, dichloroethane, N-dimethylformamide, N-dimethylacetamide, isopropyl ether or methyl tert-butyl ether, preferably acetonitrile.
Preferably, in step (1), the temperature of the reaction is 20-60 ℃, which may be, for example, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃,50 ℃, 55 ℃ and the like, and the time of the reaction is 6-24 hours, which may be, for example, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours and the like.
Preferably, in step (1), the specific steps of the reaction are: after mixing 3-fluorophenol and a base in a solvent, chloromethyl ether is added dropwise under stirring at 20-30 ℃ (for example, 20 ℃ (22 ℃), 24 ℃ (26 ℃), 28 ℃ (30 ℃), etc.), the system is heated to 45-55 ℃ (for example, 45 ℃ (47 ℃), 49 ℃ (51 ℃), 53 ℃ (55 ℃), etc.), and then the reaction is carried out for 8-14 hours (for example, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, etc.).
Preferably, in the step (1), the post-treatment after the reaction is that the reaction solution is filtered, and the filtrate is taken and concentrated.
Preferably, in the step (2), the molar ratio of the compound shown in the formula I, the isopropanol pinacol borate and the lithium reagent is 1 (1-1.2): (1-1.2), for example, 1:1:1, 1:1:1.05, 1:1.05:1.05:1.1, 1:1.1:1.1, 1:1.1:1.15, 1:1.15:1.15, 1:1.2:1.2, and the like.
Preferably, the lithium reagent comprises any one or a combination of at least two of n-butyllithium, sec-butyllithium, lithium diisopropylamide or lithium tetramethylethylenediamine, preferably lithium diisopropylamide.
Preferably, in step (2), the reaction is carried out in a solvent.
Preferably, the solvent comprises any one or a combination of at least two of acetonitrile, tetrahydrofuran or diethyl ether, preferably tetrahydrofuran.
Preferably, in the step (2), the reaction temperature is-80 to-60 ℃, for example, the reaction temperature can be-80 ℃, 75 ℃, 70 ℃, 65 ℃, 60 ℃ and the like, and the reaction time is 3-5h, for example, 3h, 3.2h, 3.4h, 3.6h, 3.8h, 4h, 4.2h, 4.4h, 4.6h, 4.8h, 5h and the like.
Preferably, in the step (2), the specific steps of the reaction are that the compound shown in the formula I is dissolved in a solvent, the temperature is reduced to-80 to-60 ℃ (for example, the temperature can be-80 ℃, -75 ℃, -70 ℃, -65 ℃, -60 ℃ and the like), lithium diisopropylamide is dropwise added under stirring, the system is kept at-80 to-60 ℃ (for example, the temperature can be-80 ℃, -75 ℃, -70 ℃, -65 ℃, -60 ℃ and the like) after the dropwise addition, the stirring is carried out for 40 to 50min (for example, 40min, 42min, 44min, 46min, 48min, 50min and the like), isopropanol pinacolone borate is dropwise added under stirring, and the system is kept at-80 to-60 ℃ (for example, the temperature can be-80 ℃, -75 ℃, -70 ℃, -65 ℃, -60 ℃ and the like) after the dropwise addition, and the stirring is carried out for 2 to 4h (for example, 2h, 2.2h, 2.4h, 2h, 2.6h, 3.3 h, 3.4h and the like).
Preferably, in the step (2), the post-treatment after the reaction comprises the steps of dripping an aqueous solution of citric acid into the reaction solution, quenching, adding water for separating, extracting a water layer by adopting methyl tertiary butyl ether, merging organic phases, drying, filtering and concentrating the organic phases successively, dissolving a product obtained by concentration into a mixed solution of methanol and water, adding n-heptane, stirring, standing and separating the mixed solution successively, and drying, filtering and concentrating the organic phases successively to obtain a compound shown in a formula II;
Preferably, the concentration of the aqueous solution of citric acid is 0.1-1M, for example, 0.1M, 0.2M, 0.4M, 0.6M, 0.8M, 1M, etc., preferably 0.5M,
Preferably, the volume ratio of methanol to water is (1-3): 1, which may be, for example, 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3:1, etc., preferably 2:1;
Preferably, the volume ratio of the n-heptane to the mixed liquid of methanol and water is (0.5-2): 1, for example, 0.5:1, 0.6:1, 0.8:1, 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2:1, and the like, preferably 1:1.
Preferably, in the step (3), the molar ratio of the compound shown in the formula II, potassium fluoride and acid is 1 (3-5): 2-3, for example, 1:3:2, 1:3:2.5, 1:3:3, 1:3.5:2, 1:3.5:2.5, 1:3.5:3, 1:4:2, 1:4:2.5, 1:4:3, 1:5:2, 1:5:2.5, 1:5:3, etc.
Preferably, the acid comprises any one or a combination of at least two of formic acid, acetic acid or citric acid, preferably citric acid.
Preferably, in step (3), the reaction is carried out in a solvent.
Preferably, the solvent comprises any one or a combination of at least two of acetonitrile, tetrahydrofuran, 1, 4-dioxane or water, preferably a combination of tetrahydrofuran and water.
Preferably, in step (3), the temperature of the reaction is 20-30 ℃, for example, 20 ℃, 22 ℃, 24 ℃, 26 ℃, 28 ℃, 30 ℃ and the like, and the reaction time is 6-24 hours, for example, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours and the like.
Preferably, in the step (3), the specific step of the reaction is to dissolve the compound represented by the formula II and potassium fluoride in an aqueous solvent, add an acid in divided portions and make up the solvent, and then react at 20 to 30 ℃ for 6 to 24 hours (for example, 20 ℃, 22 ℃, 24 ℃, 26 ℃, 28 ℃, 30 ℃ and the like) and for example, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours and the like.
Preferably, in the step (3), the post-treatment after the reaction is that the reaction liquid is filtered, a filter cake is taken and placed in isopropanol for pulping, the filtration is carried out, the filter cake is taken and dissolved in ethyl acetate, the filtration is carried out, the filtrate is taken, concentrated and dried, and the (2-fluoro-6-hydroxyphenyl) potassium trifluoroborate is obtained.
Compared with the prior art, the invention has the following beneficial effects:
(1) The invention starts from m-fluorophenol cheaper than m-fluoroanisole, and is finished by three steps of hydroxy protection, low-temperature hydrogen-extracting and boration, and hydroxy protection removal while preparing potassium trifluoroborate functional groups, the process species bypass the hazardous reagent of boron tribromide, the yield is also greatly improved, the process is simple, the operation is convenient, and the industrial production is easy;
(2) The total yield of three steps of the synthetic route is more than 84%, and the purity of the prepared (2-fluoro-6-hydroxyphenyl) potassium trifluoroborate is more than 99%.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Example 1
The present embodiment provides a method for producing potassium (2-fluoro-6-hydroxyphenyl) trifluoroborate, comprising the steps of:
The synthetic route is as follows:
(1) 400g (3.57 mol) of 3-fluorophenol is dissolved in 3.5L of acetonitrile, potassium carbonate (739 g,5.35 mol) is added, stirred at 25 ℃, chloromethyl ether (371 g,3.92 mol) is added dropwise, slowly heated to 50 ℃, stirred at a constant temperature for 12h, filtered, concentrated at 40 ℃ to obtain 607g of colorless oily liquid with a yield of 100% and a purity of 98%;
1H NMR(CDCl3/400MHz)1.11(t,3H),3.42(q,2H),5.16(s,2H),6.71(m,1H),6.74-6.82(m,2H),7.21(m,1H);
(2) Dissolving a compound (420 g,2.47 mol) shown in a formula I in tetrahydrofuran (6L), cooling to-70 ℃, dropwise adding lithium diisopropylamide (2.72L, 1M,2.72 mol) under stirring, continuously stirring for 45min at-70 ℃, then dropwise adding pinacol borate (528 g,2.84 mol) of isopropanol, continuously stirring for 3h at-70 ℃, dropwise adding 300mL of 0.5M citric acid aqueous solution, quenching, naturally heating to 25 ℃, supplementing 2L of water, separating liquid, extracting 300mL of aqueous layer methyl tert-butyl ether twice respectively, merging organic phases, drying anhydrous sodium sulfate, filtering, concentrating at 40 ℃, dissolving the residues in a mixed solution of methanol and water (volume ratio of 2:1), adding n-heptane (2L), stirring for 1h at 25 ℃, standing, separating liquid, organically drying the upper layer, filtering, concentrating at 40 ℃ to obtain a colorless liquid 694g, 95% purity of which is 95%;
1H NMR(CDCl3,400M)δ:1.11(t,3H),1.26(s,12H),3.26(q,2H),5.03(s,2H),6.68(m,1H),6.70-6.75(m,2H),7.16(m,1H);
(3) Dissolving a compound (300 g,1.01 mol) shown in a formula II in 2L of tetrahydrofuran, stirring and dissolving, adding potassium fluoride (235 g,4.05 mol) and 350mL of water into a reaction kettle, adding citric acid (480 g,2.5 mol) in three batches, adding 300mL of water and 700mL of tetrahydrofuran, stirring for 12h at 25 ℃, carrying out suction filtration, pulping filter cake isopropanol, carrying out suction filtration, dissolving the filter cake in 5 times volume of ethyl acetate, filtering out insoluble matters, concentrating at 30 ℃, and drying to obtain 194g of powdery class powder, wherein the yield is 88%, and the purity is 99%;
1H NMR(CDCl3/400MHz):6.50-6.61(m,1H),6.83(q,1H),8.10(q,1H)。
example 2
The present embodiment provides a method for producing potassium (2-fluoro-6-hydroxyphenyl) trifluoroborate, comprising the steps of:
The synthetic route is as follows:
(1) 300g (2.67 mol) of 3-fluorophenol is dissolved in 4L of tetrahydrofuran, cesium carbonate (1.3 g,4.0 mol) is added, stirring is carried out at 25 ℃, chloromethyl diethyl ether (279 g,2.94 mol) is added dropwise, heating is slowly carried out to 55 ℃, stirring is carried out for 10 hours under heat preservation, filtering is carried out, concentration is carried out at 35 ℃, 455g of colorless oily liquid is obtained, the yield is 100%, and the purity is 98%;
1H NMR(CDCl3/400MHz)1.11(t,3H),3.42(q,2H),5.16(s,2H),6.71(m,1H),6.74-6.82(m,2H),7.21(m,1H);
(2) Dissolving a compound (400 g,2.35 mol) shown in a formula I in tetrahydrofuran (6L), cooling to-75 ℃, dropwise adding lithium diisopropylamide (2.58L, 1M,2.58 mol) under stirring, continuously stirring for 40min at-75 ℃, then dropwise adding isopropanol pinacol boric acid ester (502 g,2.70 mol) under stirring for 2.5h at-75 ℃, dropwise adding 300mL of 0.5M citric acid aqueous solution, quenching, naturally heating to 20 ℃, supplementing 1.5L of water, separating liquid, extracting 200mL of aqueous layer methyl tertiary butyl ether three times respectively, merging organic phases, drying anhydrous sodium sulfate, filtering, concentrating at 40 ℃, dissolving mixed liquid 2L of methanol and water (volume ratio of 2:1) in residues, adding n-heptane (2L), stirring for 40min at 25 ℃, separating liquid, performing organic coherence on an upper layer, filtering, concentrating at 40 ℃ to obtain colorless liquid 662g, and obtaining 96% purity;
1H NMR(CDCl3,400M)δ:1.11(t,3H),1.26(s,12H),3.26(q,2H),5.03(s,2H),6.68(m,1H),6.70-6.75(m,2H),7.16(m,1H);
(3) Dissolving a compound (500 g,1.69 mol) shown in a formula II in 3.5L of tetrahydrofuran, stirring for dissolving, adding potassium fluoride (332 g,6.76 mol) and 500mL of water into a reaction kettle, adding citric acid (810 g,4.22 mol) in four batches, adding 400mL of water and 800mL of tetrahydrofuran, stirring for 10h at 30 ℃, carrying out suction filtration, pulping filter cake isopropanol, carrying out suction filtration, dissolving the filter cake in 5 times volume of ethyl acetate, filtering out insoluble matters, concentrating at 30 ℃, and drying to obtain powdery powder 332g, wherein the yield is 90%, and the purity is 99%;
1H NMR(CDCl3/400MHz):6.50-6.61(m,1H),6.83(q,1H),8.10(q,1H)。
example 3
The present embodiment provides a method for producing potassium (2-fluoro-6-hydroxyphenyl) trifluoroborate, comprising the steps of:
The synthetic route is as follows:
(1) 400g (3.57 mol) of 3-fluorophenol is dissolved in 3.5L of dichloroethane, potassium carbonate (739 g,5.35 mol) is added, stirred at 30 ℃, chloromethyl ether (371 g,3.92 mol) is added dropwise, slowly heated to 45 ℃, stirred for 14h under heat preservation, filtered, concentrated at 40 ℃ to obtain 608g of colorless oily liquid with a yield of 100% and a purity of 99%;
1H NMR(CDCl3/400MHz)1.11(t,3H),3.42(q,2H),5.16(s,2H),6.71(m,1H),6.74-6.82(m,2H),7.21(m,1H);
(2) Dissolving a compound (420 g,2.47 mol) shown in a formula I in tetrahydrofuran (6L), cooling to-65 ℃, dropwise adding lithium diisopropylamide (2.72L, 1M,2.72 mol) under stirring, continuously stirring for 50min at-65 ℃, then dropwise adding isopropanol pinacol boric acid ester (528 g,2.84 mol) under stirring for 3.5h at-65 ℃, dropwise adding 300mL of 0.5M citric acid aqueous solution, quenching, naturally heating to 25 ℃, adding 2L of water, separating liquid, extracting 300mL of water layer methyl tert-butyl ether three times respectively, merging organic phases, drying anhydrous sodium sulfate, filtering, concentrating at 35 ℃, dissolving the residues in a mixed liquid of methanol and water (volume ratio of 2:1), adding n-heptane (2L), stirring for 2h at 20 ℃, standing, separating liquid, performing organic phase coherent drying on the upper layer, filtering, concentrating at 35 ℃ to obtain a colorless liquid, wherein the yield is 96%, and the purity is 94%;
1H NMR(CDCl3,400M)δ:1.11(t,3H),1.26(s,12H),3.26(q,2H),5.03(s,2H),6.68(m,1H),6.70-6.75(m,2H),7.16(m,1H);
(3) Dissolving a compound (300 g,1.01 mol) shown in a formula II in 2L of tetrahydrofuran, stirring and dissolving, adding potassium fluoride (235 g,4.05 mol) and 350mL of water into a reaction kettle, adding citric acid (480 g,2.5 mol) in two batches, adding 300mL of water and 700mL of tetrahydrofuran, stirring for 14h at 20 ℃, carrying out suction filtration, pulping filter cake isopropanol, carrying out suction filtration, dissolving the filter cake in 5 times volume of ethyl acetate, filtering out insoluble matters, concentrating at 30 ℃, and drying to obtain 194g of powdery class powder, wherein the yield is 88%, and the purity is 98%;
1H NMR(CDCl3/400MHz):6.50-6.61(m,1H),6.83(q,1H),8.10(q,1H)。
Comparative example 1
This comparative example provides a process for the preparation of potassium (2-fluoro-6-hydroxyphenyl) trifluoroborate, comprising the steps of:
The synthetic route is as follows:
(1) Adding 79g of diisopropylamine into a 2000mL three-necked flask, adding 400mL of tetrahydrofuran, protecting the mixture by nitrogen, cooling to the temperature of minus 30 ℃, dropwise adding 228g of n-butyllithium, stirring for 30min, cooling the mixture to the temperature of minus 70 ℃, dropwise adding 70g of 3-fluoroanisole 400mL of tetrahydrofuran mixed solution, stirring for 30min, dropwise adding 162g of triethyl borate, controlling the temperature not to exceed minus 70 ℃, continuously stirring for 1h after dropwise adding 2M of hydrochloric acid to be acidic, extracting the mixture three times by methyl tert-butyl ether, merging organic phases, concentrating the organic phases to half of the volume, adding n-heptane, stirring the mixture at the temperature of 5 ℃ for 3h, filtering, washing a filter cake by n-heptane, and drying to obtain 2-fluoro-6-methoxyphenylboric acid with the yield of about 75% and the purity of 93%;
(2) Dissolving 75g of 2-fluoro-6-methoxyphenylboronic acid in 400mL of dichloromethane, cooling to-35 ℃, slowly pumping 170g of boron tribromide with vacuum, controlling the temperature to be lower than-30 ℃, adding the solution to perform heat preservation reaction for 2h, dripping the solution, quenching the solution by ice water, adding 1L of additional methyl tertiary butyl ether, continuously stirring the solution for 2h, separating the solution, extracting the aqueous phase by the additional methyl tertiary butyl ether for two times, merging organic phases, concentrating the organic phases to about 100mL, adding 1L of n-heptane, stirring the solution for 2h, filtering the solution, and drying the solution at 30 ℃ to obtain 2-fluoro-6-hydroxyphenylboronic acid, wherein the yield is 80 percent and the purity is 92 percent;
(3) 1100mL of acetonitrile is added into a 2000mL of reaction bottle, 43g of 2-fluoro-6-hydroxyphenylboric acid is added, stirring and dissolution are carried out, 70.5g of potassium fluoride and 108g of water are continuously added, a mixed solution of tartaric acid (114 g of tartaric acid is dissolved in 540mL of tetrahydrofuran and 90g of water) is dropwise added, stirring is carried out for 2h, suction filtration is carried out, a filter cake is washed by tetrahydrofuran, the reaction solution is concentrated at 30 ℃ until a large amount of solid is separated out, 100mL of isopropanol is added, stirring is continuously carried out for 1h, filtration is carried out, the solid is washed by isopropanol, and the 2-fluoro-hydroxyphenylpotassium trifluoroborate is obtained, the yield is 75%, and the purity is 95%.
The applicant states that the present invention illustrates the preparation method of the (2-fluoro-6-hydroxyphenyl) potassium trifluoroborate according to the present invention by the above examples, but the present invention is not limited to the above examples, i.e., it does not mean that the present invention must be practiced by relying on the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (33)
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| CN103864831A (en) * | 2014-02-14 | 2014-06-18 | 上海工程技术大学 | Aromatic boric acid ester compound and synthetic method thereof |
| CN111801322A (en) * | 2017-10-31 | 2020-10-20 | 迈阿密大学 | Kinase inhibitors for the treatment of disorders of the central and peripheral nervous system |
| CN113015724A (en) * | 2018-11-16 | 2021-06-22 | 美国安进公司 | Improved synthesis of key intermediates of KRAS G12C inhibitor compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103864831A (en) * | 2014-02-14 | 2014-06-18 | 上海工程技术大学 | Aromatic boric acid ester compound and synthetic method thereof |
| CN111801322A (en) * | 2017-10-31 | 2020-10-20 | 迈阿密大学 | Kinase inhibitors for the treatment of disorders of the central and peripheral nervous system |
| CN113015724A (en) * | 2018-11-16 | 2021-06-22 | 美国安进公司 | Improved synthesis of key intermediates of KRAS G12C inhibitor compounds |
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