CN111909078B - Synthetic method of (2-fluoro-6- (trifluoromethyl) pyridine-3-yl) methanol - Google Patents
Synthetic method of (2-fluoro-6- (trifluoromethyl) pyridine-3-yl) methanol Download PDFInfo
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- CN111909078B CN111909078B CN202010907003.9A CN202010907003A CN111909078B CN 111909078 B CN111909078 B CN 111909078B CN 202010907003 A CN202010907003 A CN 202010907003A CN 111909078 B CN111909078 B CN 111909078B
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention belongs to the technical field of medical intermediates, and particularly relates to a synthetic method of (2-fluoro-6- (trifluoromethyl) pyridine-3-yl) methanol. The method takes the compound A as an initial raw material, and reacts with diisopropylamine through the catalysis of n-butyllithium to obtain a compound B, and the compound B reacts with borane dimethyl sulfide to obtain the (2-fluoro-6- (trifluoromethyl) pyridin-3-yl) methanol.
Description
Technical Field
The invention belongs to the technical field of medical intermediates, and particularly relates to a synthetic method of (2-fluoro-6- (trifluoromethyl) pyridine-3-yl) methanol.
Background
The compound (2-fluoro-6- (trifluoromethyl) pyridin-3-yl) methanol and related derivatives have wide application in pharmaceutical chemistry and organic synthesis. At present, the synthesis method of (2-fluoro-6- (trifluoromethyl) pyridine-3-yl) methanol is only reported in documents. Therefore, it is necessary to develop a synthesis method which has easily available raw materials, convenient operation, easy control of reaction, proper overall yield and suitability for industrial production.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: aiming at the problems, the synthesis method of the (2-fluoro-6- (trifluoromethyl) pyridine-3-yl) methanol is provided.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method for synthesizing (2-fluoro-6- (trifluoromethyl) pyridin-3-yl) methanol, comprising the steps of:
(1) putting diisopropylamine and tetrahydrofuran into a reactor, stirring, protecting with nitrogen, cooling to-80-75 ℃, adding a hexane solution of n-butyllithium, stirring, adding the compound A, continuously stirring, introducing carbon dioxide, heating, and reacting to obtain a compound B
(2) And (2) uniformly mixing the compound B and tetrahydrofuran, carrying out nitrogen protection, cooling, dropwise adding borane dimethyl sulfide, heating after dropwise adding, and reacting to obtain a compound C, namely (2-fluoro-6- (trifluoromethyl) pyridine-3-yl) methanol.
Preferably, the mass ratio of the compound A to the diisopropylamine in the step (1) is 5: 3-5.
Preferably, in the step (1), the solid-liquid g/mL ratio of the compound A to tetrahydrofuran is 1:14, and the volume ratio of the tetrahydrofuran to the n-butyl lithium in the hexane solution is 5: 1.
Preferably, in the step (2), the solid-liquid g/mL ratio of the compound B to tetrahydrofuran is 1:20, and the volume ratio of borane dimethyl sulfide to tetrahydrofuran is 1: 13-15.
Compared with other methods, the method has the beneficial technical effects that:
(1) the invention provides a synthetic method of (2-fluoro-6- (trifluoromethyl) pyridine-3-yl) methanol for the first time, and provides a synthetic route for the synthesis of (2-fluoro-6- (trifluoromethyl) pyridine-3-yl) methanol;
(2) the synthetic method of the (2-fluoro-6- (trifluoromethyl) pyridine-3-yl) methanol provided by the invention is short in route, reasonable in design, simple to operate and easy to control;
(3) the compound A is used as an initial raw material and reacts with diisopropylamine under the catalysis of n-butyllithium to obtain a compound B, the compound B is reacted with borane dimethyl sulfide to obtain (2-fluoro-6- (trifluoromethyl) pyridine-3-yl) methanol, and the obtained product has high yield.
Detailed Description
The invention is further illustrated by the following examples, without restricting its scope to these examples. Numerous other changes and modifications can be made by those skilled in the art without departing from the spirit and scope of the invention. In particular, certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve the same or similar results, and reactions may be carried out under conditions outside the preferred ranges, albeit less than optimally. Accordingly, such obvious substitutions and modifications are intended to be included within the scope of the appended claims.
A method for synthesizing (2-fluoro-6- (trifluoromethyl) pyridin-3-yl) methanol, comprising the steps of:
(1) taking raw materials according to the mass ratio of 5: 3-5 of a compound A to diisopropylamine, the solid-liquid g/mL ratio of the compound A to tetrahydrofuran to 1:14 and the volume ratio of tetrahydrofuran to n-butyllithium hexane solution to 5:1, then putting diisopropylamine and tetrahydrofuran into a reactor, stirring, cooling to-80-75 ℃ under the protection of nitrogen, adding the n-butyllithium hexane solution, stirring for 1-1.5 h, adding the compound A, continuing stirring for 2-3 h, introducing carbon dioxide, heating to 30-35 ℃, and reacting for 1-2 h to obtain a compound B;
(2) taking raw materials according to the solid-liquid g/mL ratio of the compound B to tetrahydrofuran of 1:20 and the volume ratio of borane dimethyl sulfide to tetrahydrofuran of 1: 13-15, then uniformly mixing the compound B and tetrahydrofuran, carrying out nitrogen protection, cooling to-2-0 ℃, dropwise adding borane dimethyl sulfide, heating to 60-65 ℃ after dropwise adding, and reacting for 1-3 hours to obtain a compound C, namely (2-fluoro-6- (trifluoromethyl) pyridin-3-yl) methanol.
Example 1
Preparation of Compound B:
putting 5g of diisopropylamine and 70mL of tetrahydrofuran into a reactor, uniformly stirring, carrying out nitrogen protection, cooling to-80 ℃, adding 14mL of n-butyllithium hexane solution (2.5M), stirring for 1h, adding 5g of compound A, continuously stirring for 2h, introducing carbon dioxide for replacement, heating to 30 ℃, reacting for 2h, detecting by TLC, after the reaction of the raw materials is finished, dropwise adding water (50 mL) for quenching reaction, adding 5g of potassium carbonate into the reaction solution, extracting impurities (50 mL of 2) by ethyl acetate, adjusting the pH of the water phase to 2 by 4M of hydrochloric acid, extracting by ethyl acetate (50 mL of 2), and concentrating the organic phase to obtain 4.8g of colorless transparent oily substance, namely the compound B, wherein the yield is 75.8% and the purity is 96.8%.
Preparation of compound C, i.e. (2-fluoro-6- (trifluoromethyl) pyridin-3-yl) methanol:
uniformly mixing 3g of the compound B and 60mL of tetrahydrofuran, reducing the temperature to 0 ℃ under the protection of nitrogen, dropwise adding 4mL of borane dimethylsulfide (10 mL), after dropwise adding, heating to 60 ℃, reacting for 2h, detecting by TLC, after the reaction of the raw materials is finished, cooling the reaction system to 0 ℃, dropwise adding methanol (30 mL), concentrating, mixing the sample with silica gel, and passing through a column to obtain 2.1g of colorless transparent oily substance to obtain a compound C, namely (2-fluoro-6- (trifluoromethyl) pyridine-3-yl) methanol, wherein the yield is 75% and the purity is 99.1%.
2-fluoro-6- (trifluoromethyl) pyridin-3-yl) methanol nuclear magnetic data:
1H NMR（CDCl3）: 8.14(t, J=8.0Hz, 1H), 7.62(d, J=7.6Hz, 1H), 4.85(s, 2H)。
example 2
Preparation of Compound B:
putting 4g of diisopropylamine and 70mL of tetrahydrofuran into a reactor, uniformly stirring, reducing the temperature to-75 ℃ under the protection of nitrogen, adding 14mL of n-butyllithium hexane solution (2.5M), stirring for 1.5h, adding 5g of compound A, continuously stirring for 3h, introducing carbon dioxide, heating to 35 ℃, reacting for 2h, detecting by TLC, after the reaction of the raw materials is finished, dropwise adding water (50 mL) to quench the reaction, adding 5g of potassium carbonate into the reaction solution, extracting impurities (50 mL of 2) by ethyl acetate, adjusting the pH of the water phase to 2 by using 4M hydrochloric acid, extracting (50 mL of 2) by ethyl acetate, and concentrating the organic phase to obtain 5g of colorless transparent oily substance, namely the compound B, wherein the yield is 78.9% and the purity is 98.2%.
Preparation of compound C, i.e. (2-fluoro-6- (trifluoromethyl) pyridin-3-yl) methanol:
uniformly mixing 3g of the compound B and 60mL of tetrahydrofuran, reducing the temperature to-2 ℃ under the protection of nitrogen, dropwise adding 4.5mL of borane dimethyl sulfide, after the dropwise adding is finished, heating to 63 ℃, reacting for 3h, detecting by TLC, after the reaction of the raw materials is finished, cooling a reaction system to 0 ℃, dropwise adding methanol (30 mL), concentrating, mixing a sample with silica gel, and passing through a column to obtain 2.3g of colorless transparent oily substance and obtain a compound C, namely the (2-fluoro-6- (trifluoromethyl) pyridin-3-yl) methanol, wherein the yield is 82.16% and the purity is 99.5%.
2-fluoro-6- (trifluoromethyl) pyridin-3-yl) methanol nuclear magnetic data:
1H NMR（CDCl3）: 8.14(t, J=8.0Hz, 1H), 7.62(d, J=7.6Hz, 1H), 4.85(s, 2H)。
the present invention has been further described with reference to specific embodiments, but it should be understood that the detailed description should not be construed as limiting the spirit and scope of the present invention, and various modifications made to the above-described embodiments by those of ordinary skill in the art after reading this specification are within the scope of the present invention.
Claims (4)
1. A method for synthesizing (2-fluoro-6- (trifluoromethyl) pyridin-3-yl) methanol, comprising the steps of:
(1) putting diisopropylamine and tetrahydrofuran into a reactor, stirring, protecting with nitrogen, cooling to-80-75 ℃, adding a hexane solution of n-butyllithium, stirring, adding the compound A, continuously stirring, introducing carbon dioxide, heating, and reacting to obtain a compound B
(2) Mixing the compound B and tetrahydrofuran, nitrogen protection, cooling, dropping borane dimethyl sulfide, heating, reacting to obtain compound C (2-fluoro-6- (trifluoromethyl) pyridine-3-yl) methanol)
2. The method for synthesizing (2-fluoro-6- (trifluoromethyl) pyridin-3-yl) methanol according to claim 1, wherein the mass ratio of the compound A to diisopropylamine in the step (1) is 5:3 to 5.
3. The method for synthesizing (2-fluoro-6- (trifluoromethyl) pyridin-3-yl) methanol according to claim 1, wherein the solid-liquid g/mL ratio of the compound a to tetrahydrofuran in the step (1) is 1:14, and the volume ratio of the tetrahydrofuran to the n-butyllithium in the hexane solution is 5: 1.
4. The method for synthesizing (2-fluoro-6- (trifluoromethyl) pyridin-3-yl) methanol according to claim 1, wherein the solid-liquid g/mL ratio of the compound B to tetrahydrofuran in step (2) is 1:20, and the volume ratio of borane dimethyl sulfide to tetrahydrofuran is 1: 13-15.
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| CN112441968B (en) * | 2020-12-23 | 2022-05-10 | 阿里生物新材料（常州）有限公司 | Synthetic method of 2-amino-3-bromoisonicotinic acid methyl ester |
| CN112679361B (en) * | 2021-01-22 | 2022-05-13 | 阿里生物新材料（常州）有限公司 | Synthetic method of 3-fluoro-5-nitropyridine-2-formaldehyde |
| CN112979565B (en) * | 2021-03-24 | 2022-05-13 | 阿里生物新材料（常州）有限公司 | Synthetic method of 2-chloro-5- (difluoromethoxy) pyrazine |
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