CN115611802A - Synthetic method of 3-acetyl-2-chloropyridine - Google Patents
Synthetic method of 3-acetyl-2-chloropyridine Download PDFInfo
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- CN115611802A CN115611802A CN202211532679.XA CN202211532679A CN115611802A CN 115611802 A CN115611802 A CN 115611802A CN 202211532679 A CN202211532679 A CN 202211532679A CN 115611802 A CN115611802 A CN 115611802A
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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 field of organic synthesis, and relates to a synthetic method of 3-acetyl-2-chloropyridine. The method comprises the following steps: taking 2-chloronicotinic acid as a raw material, reacting with a lithium-containing compound to generate 2-chloronicotinic acid lithium salt, drying the 2-chloronicotinic acid lithium salt, and then performing addition reaction with methyl magnesium bromide to generate 3-acetyl-2-chloropyridine; the lithium-containing compound is lithium hydroxide monohydrate and/or a lithium salt. The synthesis method has the advantages of high reaction yield, high product purity, mild reaction conditions, safe and easy operation of reaction, simple treatment after reaction, suitability for large-scale production and obvious industrial value.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthetic method of a drug intermediate, and more particularly relates to a synthetic method of 3-acetyl-2-chloropyridine.
Background
3-acetyl-2-chloropyridine (CAS: 55676-21-6) is an important organic synthesis intermediate and a drug intermediate, can be used for synthesizing azaquinolinone anticancer drugs (US 2012258982) and can be used for synthesizing triazolopyridine and triazolopyrazine anticancer drugs (WO 2011079804). The synthesis route of the 3-acetyl-2-chloropyridine is mainly three.
In the first route, 2-chloronicotinic acid or derivatives thereof are used as raw materials.
2-Chloronicotinic acid or its derivative (ester, weinreb amide, nitrile) can be added to an organometallic reagent (magnesium reagent, lithium reagent, tin reagent) to produce 3-acetyl-2-chloropyridine.
In 2010, and reported in patent WO2011079804 by cambodia medicine (shanghai) limited, 2-chloronicotinic acid reacts with 2.5 equivalents of methyl magnesium bromide, and 3-acetyl-2-chloropyridine is obtained after treatment with a yield of 77%. The inventor finds that a large amount of methane gas is discharged in the reaction during pilot plant test, so that great potential safety hazard exists, a byproduct 2- (2' -chloropyridin-3-yl) propan-2-ol (dimethyl impurity) is generated, the purification is not easy, the defects of long feeding time, long construction period, small batch, large energy waste and the like exist, and the route is not suitable for industrial production. Methyl 2-chloronicotinate can also react with methylmagnesium bromide to produce 3-acetyl-2-chloropyridine with a yield of 66% (Journal of Heterocyclic Chemistry, 1999, 36, 445-452), but methyl 2-chloronicotinate is also expensive and not suitable for scale-up production.
In 2012, hoffmann La Roche company, switzerland reported in patent WO2012136684, weinreb amide of 2-chloronicotinic acid reacted with 2.5 equivalents of methyl magnesium chloride, followed by post-treatment and column chromatography purification to obtain 3-acetyl-2-chloropyridine with a yield of 72%. In the synthesis of Weinreb amide, an expensive condensing agent BOP is used, the reaction time is long, and the intermediate also needs silica gel column chromatography purification before the next addition reaction with methyl magnesium chloride can be carried out. This route is not suitable for scale-up production.
In 2017, lee Jae In, university of Decheng women, korea, reported In patent KR101766414 that by reacting Weinreb amide with 2-chloronicotinic acid using methyllithium instead of Grignard reagent, the yield could be increased to 90%. However, the price of methyl lithium is several times that of a Grignard reagent, and the production cost is high, so that the method is not suitable for scale-up production.
Lee Jae In also reports (Bull. Korean chem. Soc. 2013, 34, 1253-1256) that the yield can be increased to 91% by reacting Weinreb amide with methyl magnesium chloride, instead of Weinreb amide, with an ester of 2-chloronicotinic acid with 2-hydroxypyridine. However, the ester of 2-hydroxypyridine has a large molecular weight, the atom economy of the route is not high, and the raw materials for synthesizing the ester are expensive, the production cost is high, and the method is not suitable for mass production.
In 2010, mcNab Hamish and Gaywood Alexander P, university of Edinburgh, UK, (Organic and Biomolecular Chemistry, 2010, 8, 5166-5173) 2-chloronicotinonitrile was reacted with 4.27 equivalents of methyl magnesium chloride to give 3-acetyl-2-chloropyridine after work-up in 65% yield. 2-chloronicotinonitrile is relatively expensive and requires the use of an excess of the Grignard reagent, which is not suitable for scale-up.
In addition to reacting with magnesium and lithium reagents, 3-acetyl-2-chloropyridine can also be synthesized by reacting nicotinoyl chloride with tetramethyltin. In 1997, U.S. Syntex Inc. reported in U.S. Pat. No. 5 U.S. Pat. No. 5,5688795 that 2-chloronicotinyl chloride was reacted with tetramethyltin under the catalysis of bis (benzonitrile) palladium (II) dichloride, and purified by silica gel column chromatography to give 3-acetyl-2-chloropyridine in 54% yield. The yield is not high, the raw material of tetramethyl tin is not easy to obtain, the cost is high, an expensive metal palladium catalyst is also needed, and the method is not suitable for industrial production.
In addition to the synthesis of 3-acetyl-2-chloropyridine by reaction with an organometallic reagent as described above, 3-acetyl-2-chloropyridine can also be synthesized by acylation, decarboxylation of nicotinoyl chloride with diethyl malonate. In 2007, memory Pharmaceuticals company reported in U.S. Pat. No. 5,000,8147, 2-chloronicotinic acid and oxalyl chloride reacted to produce 2-chloronicotinoyl chloride with a yield of 98%; reacting 2-chloronicotinoyl chloride with diethyl malonate under the catalysis of anhydrous magnesium chloride to generate 2- (2-chloronicotinoyl) diethyl malonate with the yield of 85%; the diethyl 2- (2-chloronicotinyl) malonate is decarboxylated in wet DMSO at 130 ℃, and the product is obtained by silica gel column chromatography purification, with the yield of 52%. The total yield of the three-step reaction is 43.3 percent and is not high.
And a second route, 3-acetylpyridine is used as a raw material.
In 2010, mcNab Hamish and Gaywood Alexander P, university of Edinburgh, UK, (Organic and Biomolecular Chemistry, 2010, 8, 5166-5173) 3-acetylpyridine was oxidized with 30% hydrogen peroxide to produce 3-acetylpyridine N-oxide, which was then reacted with phosphorus oxychloride at 100 ℃ for 1 hour and post-treated to produce 3-acetyl-2-chloropyridine, with a total yield of 33% in the two steps. The total yield is not high, the price of the raw material 3-acetylpyridine is expensive, the production cost is high, and the large-scale production is not available.
And the third route is to use 2-chloropyridine as a raw material.
In 2011, a newly prepared LDA is used as an alkali, 2-chloropyridine and acetaldehyde are subjected to an addition reaction, post-treatment and silica gel column chromatography purification are carried out to obtain 1- (2-chloropyridine-3-yl) ethanol, then chromium trioxide is used for oxidation to obtain an acetyl-2-chloropyridine crude product, and the silica gel column chromatography purification is carried out to obtain a pure product, wherein the addition reaction is reported in a patent WO2011005759 by the university of Kansas in the United states. The total yield of the two-step reaction is 51.8%. The total yield is not high, low temperature of minus 78 ℃ is required, silica gel column chromatography is also required for purification, and the method is not suitable for industrial production.
In summary, the existing processes present more or less drawbacks: or the raw material cost is high, or the total yield is low, or the reaction production period is long, or column chromatography purification and other operation steps which are not suitable for amplification are needed, and the like, so that the method is not suitable for industrial production. In order to provide a large amount of cheap 3-acetyl-2-chloropyridine product and provide guarantee for the subsequent drug development, a new method for synthesizing the compound is very necessary to be developed.
Disclosure of Invention
Aiming at the defects that the existing process is not suitable for industrial production due to high cost, low yield, long reaction production period or the need of column chromatography purification. The invention develops a synthesis method which has the advantages of cheap and easily obtained raw materials, safe and easily operated reaction, mild reaction conditions, simple treatment after the reaction, higher yield, suitability for mass production and obvious industrial value.
In order to achieve the above object, the present invention provides a method for synthesizing 3-acetyl-2-chloropyridine, the method comprising:
taking 2-chloronicotinic acid as a raw material, reacting with a lithium-containing compound to generate 2-chloronicotinic acid lithium salt, drying the 2-chloronicotinic acid lithium salt, and then performing addition reaction with methyl magnesium bromide to generate 3-acetyl-2-chloropyridine; the lithium-containing compound is lithium hydroxide monohydrate and/or a lithium salt.
According to a preferred embodiment of the present invention, the step of generating the lithium 2-chloronicotinate comprises: and (2) taking water as a solvent, and contacting the 2-chloronicotinic acid with a lithium-containing compound for reaction to obtain the 2-chloronicotinic acid lithium salt.
Further, the molar ratio of the 2-chloronicotinic acid to the lithium-containing compound is 0.9 to 1.0:1.
further, the reaction temperature for producing the lithium 2-chloronicotinate is 40 to 50 ℃.
According to the invention, the lithium salt is preferably lithium carbonate.
According to a preferred embodiment of the present invention, the step of performing an addition reaction of the lithium 2-chloronicotinate with methyl magnesium bromide comprises:
(1) Under the protection of inert gas, stirring and mixing a first organic solvent and 2-chloronicotinic acid lithium salt, then dropwise adding methyl magnesium bromide, and naturally heating to the addition reaction temperature for reaction after dropwise adding to obtain a reaction solution;
(2) Under the protection of inert gas, dropwise adding the reaction liquid into low-temperature water, stirring for the first time, dropwise adding hydrochloric acid, heating to 20-25 ℃ after dropwise adding, stirring for the second time, standing for liquid separation, extracting the water phase with a second organic solvent, combining the organic phases, and concentrating to obtain the target product.
Further, in the step (1), the first organic solvent is at least one selected from tetrahydrofuran and 2-methyltetrahydrofuran.
Further, in the step (1), the molar ratio of the 2-chloronicotinic acid lithium salt to the methyl magnesium bromide is 1:1 to 1.5, preferably 1:1.1 to 1.3.
In the step (1), the dropping speed of the methylmagnesium bromide is 0.9 to 1.8kg/min per 1000kg of the reaction system.
Further, in the step (1), before dropping the methyl magnesium bromide, the temperature of the system is controlled to be below-4 ℃, and the temperature of the system is controlled not to exceed 0 ℃ in the dropping process.
Further, in the step (1), the addition reaction temperature is 12 to 18 ℃, and the reaction time is 0.5 to 1.5 hours.
Further, in the step (2), the temperature of the low-temperature water is 4 ℃ or lower.
Further, in the step (2), the mass of the low-temperature water is 0.3 to 0.5kg per 1kg of the reaction solution.
Further, in the step (2), the temperature of the system is controlled not to exceed 15 ℃ during the dropping process.
Further, in the step (2), the first time is 0.5 to 1.5 hours.
In the step (2), the molar addition amount of the hydrochloric acid is 1.8 to 2.0 times of the molar addition amount of the 2-chloronicotinic acid lithium salt.
Further, in the step (2), the second time is 1.5 to 2.5 hours.
Further, in the step (2), the second organic solvent is at least one selected from ethyl acetate, dichloromethane and methyl tert-butyl ether.
The inert gas in each step of the present invention may be nitrogen.
According to the present invention, the time point for performing step (2) needs to be controlled, and specifically, the method and criteria for performing step (2) are determined as follows: and (3) detecting the reaction result by HPLC, wherein the 2-chloronicotinic acid in the system is less than 21 percent, and performing the step (2).
In the method of the present invention, the 2-chloronicotinic acid lithium salt generated by the reaction needs to be dried and then the subsequent addition reaction is performed, specifically, the 2-chloronicotinic acid lithium salt needs to be dried until the water content is less than 1%.
The synthesis method of the invention also comprises the rectification step: adding a 3-acetyl-2-chloropyridine crude product into a rectifying tower, starting heating, starting an oil pump to dry low-boiling-point substances, switching to a roots pump, gradually increasing the gas phase temperature until front fraction is evaporated, periodically sampling and detecting, switching to a main fraction collecting tank when the maximum impurity is less than 0.5%, periodically sampling and detecting, and stopping rectification when the impurity is more than 0.5% after a main peak to obtain a 3-acetyl-2-chloropyridine product.
The synthesis method of the invention has the following advantages:
(1) The reaction yield is high, the product purity is more than 99 percent, and the single impurity is less than 0.5 percent.
(2) By adding a low-cost lithium-containing compound such as lithium hydroxide monohydrate to form a lithium salt, 1 equivalent of methyl magnesium bromide can be saved, and the reaction economy is good.
(3) The method has the advantages of mild reaction conditions, safe reaction, easy operation, simple treatment after reaction (no need of column chromatography), suitability for large-scale production and obvious industrial value.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Drawings
The above and other objects, features and advantages of the present invention will become more apparent by describing in more detail exemplary embodiments thereof with reference to the attached drawings.
FIG. 1 is a nuclear magnetic spectrum of 3-acetyl-2-chloropyridine synthesized in example 1 of the present invention.
FIG. 2 is a GC diagram of 3-acetyl-2-chloropyridine synthesized in example 1 of the present invention.
FIG. 3 is a GC diagram of 3-acetyl-2-chloropyridine synthesized in example 2 of the present invention.
Detailed Description
Preferred embodiments of the present invention will be described in more detail below. While the following describes preferred embodiments of the present invention, it should be understood that the present invention may be embodied in various forms and should not be limited by the embodiments set forth herein.
Example 1
Synthesis of lithium 2-chloronicotinate:
325kg of tap water was charged into a 1000L reactor, and 171.8kg (1 eq.) of lithium hydroxide monohydrate was added with stirring. Opening cold brine, quickly adding 600kg of 2-chloronicotinic acid into the reaction kettle, controlling the temperature to be 40 to 50 ℃ for reaction for 2h, controlling the temperature to be 40 ℃ for discharging, cooling to be below 20 ℃, performing suction filtration, and drying the drying oven until the water content is less than 1% to obtain 660kg of the product 2-chloronicotinic acid lithium salt, wherein the yield is 98%.
Synthesis of acetyl-2-chloropyridine:
200kg of tetrahydrofuran is added into a 2000L reaction kettle, stirring is started, 100kg of 2-chloronicotinic acid lithium salt is added, then 250kg of tetrahydrofuran is added, air is replaced by nitrogen once (the nitrogen can be replaced when the pressure in the kettle is less than-0.08 MPa), an emptying valve is opened, and the temperature is reduced to be below-4 ℃ under the protection of nitrogen. 300kg (1.2 eq.) of methyl magnesium bromide is added dropwise by using a peristaltic pump, the dropping speed is controlled (the former 20 percent is 0.6kg/min, the later 80 percent is 0.8 kg/min), and the dropping temperature is not more than 0 ℃. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. The reaction result is detected by HPLC, the 2-chloronicotinic acid remains 19.9 percent, the content of the dimethyl impurity is 1.3 percent, and the content of the product is 78.5 percent. Adding 350kg of water into another 3000L reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into the reaction kettle of 2000L, wherein the dropwise adding temperature is not more than 10 ℃. After the dripping is finished, stirring for 1h. Then 182L of hydrochloric acid of 6mol/L is added dropwise, and the dropping temperature is not more than 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 200L of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. Then, the product is rectified under reduced pressure to obtain 73.5kg, and the yield is as follows: 73.8%, GC purity: 99.5 percent. FIG. 1 is a nuclear magnetic spectrum of 3-acetyl-2-chloropyridine synthesized in example 1. FIG. 2 is a GC diagram of 3-acetyl-2-chloropyridine synthesized in example 1.
The rectification method comprises the following steps: adding the crude product of 3-acetyl-2-chloropyridine into the rectifying tower, heating, pumping to dry the low-boiling-point substances, distilling off the fraction when the liquid phase temperature rises to about 80 ℃, and when the liquid phase temperature rises to 120 ℃, distilling off no obvious fraction when the gas phase temperature rises to 80 ℃. Switching to a Roots pump, gradually increasing the gas phase temperature to about 130 deg.C, gradually increasing the liquid phase temperature to about 140 deg.C, evaporating the front fraction, sampling and detecting once every 20 minutes until the maximum impurity is less than 0.5%, switching to a main fraction collection tank (gradually decreasing the gas phase temperature to 116 deg.C, decreasing the liquid phase temperature to 124 deg.C), and separately placing the front fraction. GC monitoring is carried out every 1h, impurities are gradually increased after the main peak, and rectification is stopped when the impurities after the main peak are more than 0.5 percent.
Example 2
Synthesis of lithium 2-chloronicotinate: the same as in example 1.
Synthesis of acetyl-2-chloropyridine:
adding 20kg of 2-methyltetrahydrofuran into a 200L reaction kettle, starting stirring, adding 10kg of 2-chloronicotinic acid lithium salt, then adding 25kg of 2-methyltetrahydrofuran, replacing air once by nitrogen (the nitrogen can be replaced when the pressure in the kettle is less than-0.08 MPa), opening an air release valve, and cooling to below-4 ℃ under the protection of nitrogen. 30kg (1.2 eq.) of a tetrahydrofuran solution of methylmagnesium bromide was added dropwise by a peristaltic pump, the dropping rate (0.5 kg/min) was controlled, and the dropping temperature was not allowed to exceed 0 ℃. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. The reaction result is detected by HPLC, the 2-chloronicotinic acid remains 19.8 percent, the content of the dimethyl impurity is 1.5 percent, and the content of the product is 78.3 percent. Adding 35kg of water into another 300L reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into a 200L reaction kettle, wherein the dropwise adding temperature is not more than 10 ℃. After the dripping is finished, stirring for 1h. Then, 18L of 6mol/L hydrochloric acid is added dropwise at a temperature of not more than 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20L of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then 6.7kg of product is obtained by adopting the method of the embodiment 1 to carry out vacuum rectification, and the yield is as follows: 69.3%, GC purity: 99.2 percent. FIG. 3 is a GC diagram of 3-acetyl-2-chloropyridine synthesized in example 2.
Example 3
Synthesis of lithium 2-chloronicotinate:
adding 200g of tap water into a 300mL reaction kettle, quickly adding 60g of 2-chloronicotinic acid into the reaction kettle, stirring, controlling the temperature to be 40-50 ℃, adding 50g of aqueous solution of 17.2g (1 eq.) of lithium hydroxide monohydrate, reacting for 2h, opening cold brine, cooling to be below 20 ℃, performing suction filtration, and drying in an oven until the water content is less than 1% to obtain 61g of the product 2-chloronicotinic acid lithium salt, wherein the yield is 98%.
Synthesis of acetyl-2-chloropyridine:
adding 20g of tetrahydrofuran into a 200mL reaction bottle, starting stirring, adding 10g of 2-chloronicotinic acid lithium salt, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (replacing nitrogen when the pressure in the kettle is less than-0.08 MPa), opening an air release valve, and cooling to below-4 ℃ under the protection of nitrogen. 25g (1.0 eq.) of a tetrahydrofuran solution of methylmagnesium bromide was added dropwise by a peristaltic pump, and the addition rate (0.5 g/min) was controlled so that the addition temperature did not exceed 0 ℃. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. The reaction result is detected by HPLC, 28.6 percent of 2-chloronicotinic acid is remained, the content of the dimethyl impurity is 1.5 percent, and the content of the product is 69.6 percent. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature not higher than 10 ℃. After the dripping is finished, stirring for 1h. Then 15mL of 6mol/L hydrochloric acid is added dropwise, and the dropping temperature is not higher than 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then the method of the embodiment 1 is adopted for reduced pressure rectification to obtain 6.1g of the product, and the yield is as follows: 63.1%, GC purity: 99.4 percent.
Example 4
Synthesis of lithium 2-chloronicotinate: the same as in example 3.
Synthesis of acetyl-2-chloropyridine:
adding 20g of tetrahydrofuran into a 200mL reaction bottle, starting stirring, adding 10g of 2-chloronicotinic acid lithium salt, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (replacing nitrogen when the pressure in the kettle is less than-0.08 MPa), opening an emptying valve, and cooling to below-4 ℃ under the protection of nitrogen. 30g (1.2 eq.) of a tetrahydrofuran solution of methylmagnesium bromide is added dropwise by using a peristaltic pump, the dropping speed is controlled (0.5 g/min), and the dropping temperature is controlled not to exceed 0 ℃. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. As a result of HPLC detection, 18.3% of 2-chloronicotinic acid is remained, the content of the dimethyl impurity is 1.6%, and the content of the product is 79.8%. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature of not more than 10 ℃. After the dripping is finished, stirring for 1h. Then, 18mL of 6mol/L hydrochloric acid was added dropwise at a temperature not exceeding 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then the method of the embodiment 1 is adopted to carry out vacuum rectification to obtain 7.2g of a product, and the yield is as follows: 74.5%, GC purity: 99.5 percent.
Example 5
Synthesis of lithium 2-chloronicotinate: the same as in example 3.
Synthesis of acetyl-2-chloropyridine:
adding 20g of tetrahydrofuran into a 200mL reaction bottle, starting stirring, adding 10g of 2-chloronicotinic acid lithium salt, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (replacing nitrogen when the pressure in the kettle is less than-0.08 MPa), opening an emptying valve, and cooling to below-4 ℃ under the protection of nitrogen. 37.5g (1.5 eq) of a tetrahydrofuran solution of methylmagnesium bromide was added dropwise by a peristaltic pump, and the dropping temperature was controlled so as not to exceed 0 ℃ at a rate of 0.5 g/min. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. The reaction result is detected by HPLC, 49.3 percent of 2-chloronicotinic acid is remained, the content of the dimethyl impurity is 3.5 percent, and the content of the product is 46.7 percent. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature of not more than 10 ℃. After the dripping is finished, stirring is carried out for 1h. Then 24mL of 6mol/L hydrochloric acid was added dropwise at a temperature not exceeding 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then the method of the embodiment 1 is adopted for reduced pressure rectification to obtain 7.0g of the product, and the yield is as follows: 72.4%, GC purity: 99.1 percent.
Example 6
Synthesis of lithium 2-chloronicotinate: the same as in example 3.
Synthesis of acetyl-2-chloropyridine:
adding 20g of 2-methyltetrahydrofuran into a 200mL reaction bottle, starting stirring, adding 10g of 2-chloronicotinic acid lithium salt, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (replacing nitrogen when the pressure in the kettle is less than-0.08 MPa), opening an emptying valve, and cooling to below-4 ℃ under the protection of nitrogen. 30g (1.2 eq) of a tetrahydrofuran solution of methylmagnesium bromide was added dropwise by a peristaltic pump, and the dropping temperature was controlled so as not to exceed 0 ℃ at a rate of 0.5 g/min. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. As a result of HPLC detection, 20.1% of 2-chloronicotinic acid remains, the content of the dimethyl impurity is 1.6%, and the content of the product is 77.9%. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature of not more than 10 ℃. After the dripping is finished, stirring for 1h. Then, 18mL of 6mol/L hydrochloric acid was added dropwise at a temperature not exceeding 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no fractions below 80 ℃. And then the method of the embodiment 1 is adopted for reduced pressure rectification to obtain 7.1g of the product, and the yield is as follows: 73.5%, GC purity: 99.5 percent.
Example 7
Synthesis of lithium 2-chloronicotinate:
adding 100g of tap water and 14g (0.5 eq.) of lithium carbonate into a 300mL reaction kettle, quickly adding 60g of 2-chloronicotinic acid into the reaction kettle, starting stirring, controlling the temperature to be 80 ℃, reacting for 2 hours, opening cold brine, cooling to below 20 ℃, performing suction filtration, and drying in an oven to obtain 55.8g of the product 2-chloronicotinic acid lithium salt, wherein the yield is 89.8%.
Synthesis of acetyl-2-chloropyridine:
adding 20g of tetrahydrofuran into a 200mL reaction kettle, starting stirring, adding 10g of 2-chloronicotinic acid lithium salt, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (replacing nitrogen when the pressure in the kettle is less than-0.08 MPa), opening an emptying valve, and cooling to below-4 ℃ under the protection of nitrogen. 30g (1.2 eq.) of a tetrahydrofuran solution of methyl magnesium bromide is added dropwise by using a peristaltic pump, the dropping speed (0.5 g/min) is controlled, and the dropping temperature is 10 to 15 ℃. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. And (3) detecting the reaction result by HPLC, wherein 19.2% of 2-chloronicotinic acid is remained, the content of the dimethyl impurity is 1.7%, the content of the product is 78.8%, and the reaction is stopped. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature not higher than 10 ℃. After the dripping is finished, stirring for 1h. Then, 18mL of 6mol/L hydrochloric acid was added dropwise at a temperature not exceeding 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then the method of the embodiment 1 is adopted to carry out vacuum rectification to obtain 7.1g of a product, and the yield is as follows: 73.7%, GC purity: 99.1 percent.
Comparative example 1
Synthesis of 2-chloronicotinic acid sodium salt:
adding 100g of tap water and 15.2g (1 eq.) of sodium hydroxide into a 300mL reaction kettle, adding 60g of 2-chloronicotinic acid into the reaction kettle, stirring, controlling the temperature to be 40-50 ℃, reacting for 2h, distilling under reduced pressure to dry, then adding 150g of methanol, cooling to below 20 ℃, carrying out suction filtration, and drying in an oven to obtain 60g of the product 2-chloronicotinate, wherein the yield is 87.7%.
Synthesizing 3-acetyl-2-chloropyridine by using 2-chloronicotinate:
adding 20g of tetrahydrofuran into a 200mL reaction kettle, starting stirring, adding 11g of 2-chloronicotinate sodium salt, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (the pressure in the kettle is less than-0.08 MPa, the nitrogen can be replaced), opening an emptying valve, and cooling to below-4 ℃ under the protection of nitrogen. 30g (1.2 eq) of a tetrahydrofuran solution of methylmagnesium bromide was added dropwise by a peristaltic pump, and the dropping temperature was controlled so as not to exceed 0 ℃ at a rate of 0.5 g/min. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. The reaction result is detected by HPLC, the 2-chloronicotinic acid is remained 38.8 percent, the content of the dimethyl impurity is 3.2 percent, and the content of the product is 56.4 percent. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature of not more than 10 ℃. After the dripping is finished, stirring for 1h. Then, 18mL of 6mol/L hydrochloric acid was added dropwise at a temperature not exceeding 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then the method of the embodiment 1 is adopted to carry out vacuum rectification to obtain 4.9g of the product, and the yield is as follows: 50.8%, GC purity: 98.1 percent.
Comparative example 2
Synthesis of 2-chloronicotinic acid sodium salt:
adding 100g of tap water and 20g of sodium carbonate (0.5 eq.) into a 300mL reaction kettle, quickly adding 60g of 2-chloronicotinic acid into the reaction kettle, stirring, controlling the temperature to be 40-50 ℃, reacting for 2h, opening cold brine, cooling to below 20 ℃, performing suction filtration, and drying in an oven to obtain 61.5g of the product 2-chloronicotinate, wherein the yield is 90%.
Synthesis of acetyl-2-chloropyridine:
adding 20g of tetrahydrofuran into a 200mL reaction kettle, starting stirring, adding 10g of 2-chloronicotinate, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (replacing nitrogen when the pressure in the kettle is less than-0.08 MPa), opening an emptying valve, and cooling to below-4 ℃ under the protection of nitrogen. 37.5g (1.5 eq.) of a tetrahydrofuran solution of methylmagnesium bromide was added dropwise by a peristaltic pump, and the addition rate (0.5 g/min) was controlled so that the addition temperature did not exceed 0 ℃. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. The reaction result is detected by HPLC, 32.1 percent of 2-chloronicotinic acid is remained, the content of the dimethyl impurity is 4.1 percent, and the content of the product is 63.2 percent. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature of not more than 10 ℃. After the dripping is finished, stirring is carried out for 1h. Then 24mL of 6mol/L hydrochloric acid is added dropwise, and the dropping temperature is not higher than 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then the method of the embodiment 1 is adopted to carry out vacuum rectification to obtain 4.8g of the product, and the yield is as follows: 55%, GC purity: 98.5 percent.
Comparative example 3
Synthesis of 2-chloronicotinic acid potassium salt:
adding 100g of tap water and 21.3g (1 eq.) of potassium hydroxide into a 300mL reaction kettle, adding 60g of 2-chloronicotinic acid into the reaction kettle, stirring, controlling the temperature to be 40-50 ℃, reacting for 2h, distilling under reduced pressure, adding 150g of methanol, cooling to below 20 ℃, filtering, and drying in an oven to obtain 66g of the 2-chloronicotinic acid potassium salt product with the yield of 88.6%.
Synthesizing 3-acetyl-2-chloropyridine by using 2-chloronicotinate:
adding 20g of tetrahydrofuran into a 200mL reaction bottle, starting stirring, adding 12g of 2-chlorine potassium nicotinate, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (replacing nitrogen when the pressure in the kettle is less than-0.08 MPa), opening an emptying valve, and cooling to below-4 ℃ under the protection of nitrogen. 30g (1.2 eq) of a tetrahydrofuran solution of methylmagnesium bromide was added dropwise by a peristaltic pump, and the dropping rate (0.5 g/min) was controlled so that the dropping temperature did not exceed 0 ℃. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. According to the reaction result of HPLC detection, 49.3 percent of 2-chloronicotinic acid remains, the content of the dimethyl impurity is 3.5 percent, and the content of the product is 46.7 percent. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature not higher than 10 ℃. After the dripping is finished, stirring is carried out for 1h. Then, 18mL of 6mol/L hydrochloric acid was added dropwise at a temperature not exceeding 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then 3.8g of product is obtained by adopting the method of the embodiment 1 to carry out vacuum rectification, and the yield is as follows: 39.3%, GC purity: 98.2 percent.
Having described embodiments of the present invention, the foregoing description is intended to be exemplary, not exhaustive, and not limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.
Claims (10)
1. A method for synthesizing 3-acetyl-2-chloropyridine, which is characterized by comprising the following steps:
taking 2-chloronicotinic acid as a raw material, reacting with a lithium-containing compound to generate 2-chloronicotinic acid lithium salt, drying the 2-chloronicotinic acid lithium salt, and then performing addition reaction with methyl magnesium bromide to generate 3-acetyl-2-chloropyridine; the lithium-containing compound is lithium hydroxide monohydrate and/or a lithium salt.
2. The method of claim 1, wherein the step of generating lithium 2-chloronicotinate comprises:
and (2) taking water as a solvent, and contacting the 2-chloronicotinic acid with a lithium-containing compound for reaction to obtain the 2-chloronicotinic acid lithium salt.
3. The synthesis method according to claim 2, wherein the molar ratio of the 2-chloronicotinic acid to the lithium-containing compound is 0.9 to 1.0:1;
the reaction temperature for generating the 2-chloronicotinic acid lithium salt is 40 to 50 ℃.
4. The method of synthesis of claim 2, wherein the lithium salt is lithium carbonate.
5. The method of claim 1, wherein the step of performing an addition reaction of the lithium 2-chloronicotinate salt with the methyl magnesium bromide comprises:
(1) Under the protection of inert gas, stirring and mixing a first organic solvent and 2-chloronicotinic acid lithium salt, then dropwise adding methyl magnesium bromide, and naturally heating to the addition reaction temperature for reaction after dropwise adding is finished to obtain a reaction solution;
(2) Under the protection of inert gas, dropwise adding the reaction liquid into low-temperature water, stirring for the first time, dropwise adding hydrochloric acid, heating to 20-25 ℃ after dropwise adding, stirring for the second time, standing for liquid separation, extracting the water phase with a second organic solvent, combining the organic phases, and concentrating to obtain the target product.
6. The synthetic method according to claim 5, wherein, in step (1),
the first organic solvent is at least one selected from tetrahydrofuran and 2-methyltetrahydrofuran;
the molar ratio of the 2-chloronicotinic acid lithium salt to the methyl magnesium bromide is 1:1 to 1.5;
the dropping speed of the methyl magnesium bromide is 0.9 to 1.8kg/min for every 1000kg of reaction system;
before dropping methyl magnesium bromide, controlling the temperature of the system to be below-4 ℃, and controlling the temperature of the system to be not more than 0 ℃ in the dropping process;
the addition reaction temperature is 12 to 18 ℃, and the reaction time is 0.5 to 1.5h;
the inert gas is nitrogen.
7. The synthetic method according to claim 5, wherein, in the step (2),
the temperature of the low-temperature water is below 4 ℃;
the mass of the low-temperature water is 0.3 to 0.5kg relative to 1kg of the reaction liquid;
the temperature of the system is controlled not to exceed 15 ℃ in the dropping process;
the first time is 0.5 to 1.5h;
the molar addition amount of the hydrochloric acid is 1.8 to 2.0 times of the molar feeding amount of the 2-chloronicotinic acid lithium salt;
the second time is 1.5 to 2.5 hours;
the second organic solvent is selected from at least one of ethyl acetate, dichloromethane and methyl tert-butyl ether;
the inert gas is nitrogen.
8. The synthesis method according to claim 5, wherein the method and criteria for performing step (2) are judged as: and (3) detecting the reaction result by HPLC, wherein the 2-chloronicotinic acid in the system is less than 21 percent, and performing the step (2).
9. The method of any one of claims 1-8, wherein the drying results in a water content of the lithium 2-chloronicotinate of less than 1%.
10. A synthesis method according to any one of claims 1 to 8, wherein the method further comprises a rectification step: adding a 3-acetyl-2-chloropyridine crude product into a rectifying tower, starting heating, starting an oil pump to dry low-boiling-point substances, switching to a roots pump, gradually increasing the gas phase temperature until front fractions are evaporated, periodically sampling and detecting, switching to a main fraction collecting tank when the maximum impurity is less than 0.5%, periodically sampling and detecting, and stopping rectification when the impurity is more than 0.5% after a main peak to obtain a 3-acetyl-2-chloropyridine product.
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| CN117682980A (en) * | 2024-02-02 | 2024-03-12 | 济南悟通生物科技有限公司 | Preparation method of 2-acetyl tetrahydropyridine |
| CN117682980B (en) * | 2024-02-02 | 2024-05-10 | 济南悟通生物科技有限公司 | Preparation method of 2-acetyl tetrahydropyridine |
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