CN111606845B - Synthesis method of 4-chloro-6-fluoropyridine-2-alcohol - Google Patents
Synthesis method of 4-chloro-6-fluoropyridine-2-alcohol Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 13
- HEEWCFGKIPBJHY-UHFFFAOYSA-N 4-chloro-6-fluoro-1h-pyridin-2-one Chemical compound FC1=CC(Cl)=CC(=O)N1 HEEWCFGKIPBJHY-UHFFFAOYSA-N 0.000 claims abstract description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 238000010438 heat treatment Methods 0.000 claims description 19
- 229940126062 Compound A Drugs 0.000 claims description 18
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 18
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 18
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 17
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 16
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 16
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 16
- 229940045803 cuprous chloride Drugs 0.000 claims description 16
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 16
- 239000007788 liquid Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 235000009518 sodium iodide Nutrition 0.000 claims description 9
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 235000010288 sodium nitrite Nutrition 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 238000009826 distribution Methods 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 1
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 description 1
- RXHOMAQEDCPRAP-UHFFFAOYSA-N 5-chloro-2-pyridin-3-ylpyridin-3-amine Chemical compound NC1=CC(Cl)=CN=C1C1=CC=CN=C1 RXHOMAQEDCPRAP-UHFFFAOYSA-N 0.000 description 1
- BAOWVDHYZBLYMB-UHFFFAOYSA-N [F].C1=CC=NC=C1 Chemical compound [F].C1=CC=NC=C1 BAOWVDHYZBLYMB-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the technical field of synthesis of drug intermediates, and particularly relates to a synthesis method of 4-chloro-6-fluoropyridine-2-ol. The invention provides a synthetic method of 4-chloro-6-fluoropyridine-2-alcohol for the first time, provides a synthetic route for the synthetic method of 4-chloro-6-fluoropyridine-2-alcohol, and the synthetic method has the advantages of short route, reasonable design, simple operation and easy control, and the obtained product has high yield.
Description
Technical Field
The invention belongs to the technical field of synthesis of drug intermediates, and particularly relates to a synthesis method of 4-chloro-6-fluoropyridine-2-ol.
Background
The fluorine-containing pyridine and its derivatives are in hot tide. Because the pyridine ring is introduced with fluorine atoms with strong electron-withdrawing groups, the fluorine-containing pyridine compounds have unique physical, chemical, biological and other characteristics, and simultaneously, the alkalinity and the reaction activity of the fluorine-containing pyridine are slightly weaker than those of corresponding chloropyridine and bromopyridine, and the positioning selection for synthesizing the fluorine pyridine and the derivatives thereof still has great challenge.
The compound 4-chloro-6-fluoropyridin-2-ol is one of fluorine-containing pyridine and derivatives thereof, but the existing synthesis method of 4-chloro-6-fluoropyridin-2-ol and related derivatives thereof have wide application in pharmaceutical chemistry and organic synthesis. At present, the synthesis method of 4-chloro-6-fluoropyridin-2-ol 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 existing problems, a synthesis method of 5-chloro-2- (pyridine-3-yl) pyridine-3-amine is provided.
In order to solve the technical problems, the invention adopts the following technical scheme:
a synthetic method of 4-chloro-6-fluoropyridine-2-alcohol comprises the following reaction formula:
the synthesis method comprises the following steps:
(1) at low temperature, taking dioxane as a solvent, adding sodium methoxide and methanol, uniformly mixing, heating, reacting, cooling, adding the compound A, heating, and stirring for reacting to obtain a compound B;
(2) mixing the compound B and concentrated hydrochloric acid at low temperature, adding a sodium nitrite solution, carrying out heat preservation reaction, adding cuprous chloride, heating, and continuously stirring for reaction to obtain a compound C;
(3) and (3) uniformly mixing the compound C, sodium iodide and acetonitrile, adding trimethylchlorosilane, heating and reacting to obtain a compound D, namely 4-chloro-6-fluoropyridine-2-ol.
Preferably, in the step (1), the mass ratio of the compound A to the sodium methoxide to the methanol is 4-6: 1-3: 5-7, and the solid-to-liquid ratio g/mL of the compound A to the dioxane is 1: 10.
Preferably, the compound A in the step (1) is distributed according to equal mass and is added in 1-3 times, and the interval between every two times is 10-20 min.
Preferably, the mass ratio of the compound B, the sodium nitrite and the cuprous chloride in the step (2) is 4-5: 3-4: 9-10, and the solid-to-liquid ratio g/mL of the compound B and the concentrated sulfuric acid is 1: 9-10.
Preferably, in the step (2), cuprous chloride is distributed according to equal mass and is added in 1-4 times, and the interval between every two times is 15-20 min.
Preferably, the mass ratio of the compound C, sodium iodide and trimethylchlorosilane in the step (3) is 3-5: 10-12: 7-9, and the solid-to-liquid ratio g/mL of the compound C to acetonitrile is 1: 25.
Compared with other methods, the method has the beneficial technical effects that:
(1) the invention provides a synthetic method of 4-chloro-6-fluoropyridine-2-alcohol for the first time, and provides a synthetic route for the synthetic method of the 4-chloro-6-fluoropyridine-2-alcohol;
(2) the synthetic method of the 4-chloro-6-fluoropyridine-2-ol is short in route, reasonable in design, simple to operate and easy to control;
(3) the product obtained by the method 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 synthetic method of 4-chloro-6-fluoropyridin-2-ol comprises the following steps:
(1) taking raw materials, adding sodium methoxide and methanol into dioxane as a solvent at a low temperature of-3-0 ℃, uniformly mixing, heating to 28-35 ℃, reacting for 1h, cooling to 0 ℃, adding the compound A, distributing the compound A according to equal mass, adding the compound A in 1-3 times at an interval of 10-20 min every two times, heating to 28-35 ℃, and stirring for reacting for 17h to obtain a compound B, wherein the mass ratio of the compound A to the sodium methoxide to the methanol is 4-6: 1-3: 5-7, and the solid-to-liquid ratio g/mL of the compound A to the dioxane is 1: 10;
(2) taking materials according to the mass ratio of 4-5: 3-4: 9-10 of a compound B, sodium nitrite and cuprous chloride and the solid-liquid ratio g/mL of 1: 9-10 of the compound B and concentrated sulfuric acid, mixing the compound B and the concentrated sulfuric acid at the low temperature of-10 to-5 ℃, adding a sodium nitrite solution with the mass fraction of 30%, keeping the temperature at 0-3 ℃, keeping the temperature for 1.5 hours, adding cuprous chloride, distributing the cuprous chloride according to the equal mass, adding the cuprous chloride for 1-4 times at an interval of 15-20 min every two times, heating to 28-35 ℃, and continuing stirring for reaction for 3 hours to obtain a compound C;
(3) taking the compound C, sodium iodide and trimethylchlorosilane in a mass ratio of 3-5: 10-12: 7-9, wherein the solid-to-liquid ratio g/mL of the compound C to acetonitrile is 1:25, uniformly mixing the compound C, sodium iodide and acetonitrile, adding trimethylchlorosilane, heating to 78-83 ℃, and reacting for 18 hours to obtain a compound D, namely 4-chloro-6-fluoropyridin-2-ol.
Example 1
A synthetic method of 4-chloro-6-fluoropyridin-2-ol comprises the following steps:
(1) at the low temperature of-3 ℃, taking 100mL of dioxane as a solvent, adding 4g of sodium methoxide and 12g of methanol, uniformly mixing, heating to 30 ℃, reacting for 1h, cooling to 0 ℃, adding 10g of compound A, adding the compound A according to equal mass distribution for 2 times at intervals of 15min every two times, heating to 30 ℃, stirring for reacting for 17h, detecting by TLC (thin layer chromatography), cooling to 0 ℃, dropwise adding 100mL of water, extracting by ethyl acetate (150 mL of 3), concentrating an organic phase, mixing silica gel with a sample, and passing through a column to obtain 5g of white solid, namely compound B, wherein the product purity is 98.3%, and the yield is 45.77%
(2) Mixing 5g of compound B and 50mL of concentrated hydrochloric acid at a low temperature of-5 ℃, adding 15g of a 30% sodium nitrite solution by mass fraction, keeping the temperature at 1 ℃, keeping the temperature for reaction for 1.5h, adding 9.5g of cuprous chloride, distributing the cuprous chloride according to equal mass, adding the cuprous chloride for 2 times at intervals of 15min every two times, heating to 30 ℃, continuously stirring for reaction for 3h, detecting by TLC (thin layer chromatography), adding 100mL of water into a reaction solution after the reaction of the raw materials is finished, adding a sodium bicarbonate solid in an ice water bath to adjust the pH to 8, extracting ethyl acetate (150 mL of 3), washing with saturated saline (60 mL), drying with anhydrous sodium sulfate, filtering, and concentrating to obtain 4.2g of yellow oily matter, namely compound C, wherein the purity is 96.8%, and the yield is 73.9%;
(3) 4.2g of the compound C, 10.8g of sodium iodide and 105mL of acetonitrile are mixed uniformly, 8g of trimethylchlorosilane is added, the mixture is heated to 80 ℃ for reaction for 18h, TLC detection is carried out, ethyl acetate (80 mL) is added after the reaction of the raw materials is finished, the mixture is filtered, the filtrate is concentrated, silica gel is mixed and passed through a column, and 3.19g of white solid, namely the compound D, namely 4-chloro-6-fluoropyridin-2-ol, the purity of the product is 97.3 percent, and the yield is 83.6 percent is obtained.
And (3) characterization: 1H NMR (d 6-DMSO) 11.95(s, 1H), 6.83(s, 1H), 6.68(s, 1H).
Example 2
A synthetic method of 4-chloro-6-fluoropyridin-2-ol comprises the following steps:
(1) at a low temperature of 0 ℃, adding 2g of sodium methoxide and 6g of methanol into 50mL of dioxane serving as a solvent, uniformly mixing, heating to 30 ℃, reacting for 1h, cooling to 0 ℃, adding 5g of compound A, distributing the compound A according to equal mass, adding the compound A for 2 times at an interval of 10min every two times, heating to 30 ℃, stirring for reacting for 17h, detecting by TLC (thin layer chromatography), cooling to 0 ℃ after the reaction of raw materials is finished, dropwise adding 80mL of water, extracting with ethyl acetate (120 mL by 3), concentrating an organic phase, mixing silica gel, and passing through a column to obtain 3.2g of white solid, namely compound B, wherein the yield is 58.58%, and the purity is 98.2%;
(2) mixing 3g of compound B and 30mL of concentrated hydrochloric acid at a low temperature of-8 ℃, adding 7g of a sodium nitrite solution with the mass fraction of 30%, keeping the temperature at 2 ℃, keeping the temperature for reaction for 1.5h, adding 6g of cuprous chloride, distributing the cuprous chloride according to equal mass, adding the cuprous chloride for 2 times at intervals of 16min every two times, heating to 30 ℃, continuously stirring for reaction for 3h, detecting by TLC (thin layer chromatography), adding 100mL of water into the reaction solution after the reaction of the raw materials is finished, adding a sodium bicarbonate solid to adjust the pH to 8 in an ice water bath, extracting ethyl acetate (1220 mL of 3), washing with saturated saline (40 mL), drying with anhydrous sodium sulfate, filtering, and concentrating to obtain 2.8g of yellow oily matter to obtain compound C, wherein the yield is 82.11%, and the purity is 96.8%;
(3) taking a compound C, sodium iodide and trimethylchlorosilane in a mass ratio of 3-5: 10-12: 7-9, wherein the solid-to-liquid ratio g/mL of the compound C to acetonitrile is 1:25, uniformly mixing 2.8g of the compound C, 10g of sodium iodide and 70mL of acetonitrile, adding 7g of trimethylchlorosilane, heating to 80 ℃, reacting for 18h, detecting by TLC (thin layer chromatography), adding ethyl acetate (50 mL) after the raw materials are reacted, filtering, concentrating the filtrate, mixing the sample with silica gel, and passing through a column to obtain 3.19g of white solid which is a compound D, namely 4-chloro-6-fluoropyridin-2-ol, wherein the product purity is 98.1% and the yield is 83.6%.
And (3) characterization: 1H NMR (d 6-DMSO) 11.95(s, 1H), 6.83(s, 1H), 6.68(s, 1H).
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 (6)
1. A synthesis method of 4-chloro-6-fluoropyridine-2-alcohol is characterized in that the reaction formula of the synthesis method is as follows:
the synthesis method comprises the following steps:
(1) at low temperature, taking dioxane as a solvent, adding sodium methoxide and methanol, uniformly mixing, heating, reacting, cooling, adding the compound A, heating, and stirring for reacting to obtain a compound B;
(2) mixing the compound B and concentrated hydrochloric acid at low temperature, adding a sodium nitrite solution, carrying out heat preservation reaction, adding cuprous chloride, heating, and continuously stirring for reaction to obtain a compound C;
(3) and (3) uniformly mixing the compound C, sodium iodide and acetonitrile, adding trimethylchlorosilane, heating and reacting to obtain a compound D, namely 4-chloro-6-fluoropyridine-2-ol.
2. The method for synthesizing 4-chloro-6-fluoropyridin-2-ol according to claim 1, wherein the mass ratio of the compound A to sodium methoxide to methanol in step (1) is 4-6: 1-3: 5-7, and the solid-to-liquid ratio g/mL of the compound A to dioxane is 1: 10.
3. The method for synthesizing 4-chloro-6-fluoropyridin-2-ol according to claim 1, wherein the compound A is added in 1 to 3 times with an interval of 10 to 20min in step (1) with equal mass distribution.
4. The method for synthesizing 4-chloro-6-fluoropyridin-2-ol according to claim 1, wherein the mass ratio of the compound B to sodium nitrite to cuprous chloride in the step (2) is 4-5: 3-4: 9-10, and the solid-to-liquid ratio g/mL of the compound B to concentrated sulfuric acid is 1: 9-10.
5. The synthesis method of 4-chloro-6-fluoropyridin-2-ol as claimed in claim 1, wherein the cuprous chloride is added in 1 to 4 times with an interval of 15 to 20min in step (2) with equal mass distribution.
6. The method for synthesizing 4-chloro-6-fluoropyridin-2-ol according to claim 1, wherein the mass ratio of the compound C to sodium iodide to trimethylchlorosilane in the step (3) is 3-5: 10-12: 7-9, and the solid-to-liquid ratio g/mL of the compound C to acetonitrile is 1: 25.
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| CN111909078B (en) * | 2020-09-02 | 2022-03-11 | 阿里生物新材料（常州）有限公司 | Synthetic method of (2-fluoro-6- (trifluoromethyl) pyridine-3-yl) methanol |
| CN112574040B (en) * | 2021-01-28 | 2022-03-11 | 阿里生物新材料（常州）有限公司 | Synthesis method of ethyl 2, 3-dichloro-4-nitrobenzoate |
| 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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| CN110669001A (en) * | 2019-10-22 | 2020-01-10 | 阿里生物新材料（常州）有限公司 | Synthetic method of 3-fluoro-4-halogeno-5-methoxypyridine |
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| CN110724091A (en) * | 2019-12-04 | 2020-01-24 | 阿里生物新材料（常州）有限公司 | Synthetic method of 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride |
| CN110981793A (en) * | 2019-12-23 | 2020-04-10 | 阿里生物新材料（常州）有限公司 | Synthetic method of 2- (difluoromethyl) pyridine-3-alcohol |
| CN111303020A (en) * | 2020-04-26 | 2020-06-19 | 阿里生物新材料（常州）有限公司 | Synthetic method of 5-chloro-2- (pyridine-3-yl) pyridine-3-amine |
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