WO2016204096A1 - Pyridine-3-sulfonyl chloride production method - Google Patents

Pyridine-3-sulfonyl chloride production method Download PDF

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Publication number
WO2016204096A1
WO2016204096A1 PCT/JP2016/067433 JP2016067433W WO2016204096A1 WO 2016204096 A1 WO2016204096 A1 WO 2016204096A1 JP 2016067433 W JP2016067433 W JP 2016067433W WO 2016204096 A1 WO2016204096 A1 WO 2016204096A1
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pyridine
sulfonyl chloride
reaction solution
sulfonic acid
phosphorus pentachloride
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PCT/JP2016/067433
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French (fr)
Japanese (ja)
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延嶋　浩文
小林　仁
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タマ化学工業株式会社
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    • 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
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached

Definitions

  • the present invention relates to a method for producing pyridine-3-sulfonyl chloride, which is useful as a raw material for synthesis and intermediates of pharmaceuticals.
  • Pyridine-3-sulfonyl chloride is a useful compound as a raw material or intermediate for producing pharmaceuticals.
  • a method for producing such a compound having a chlorosulfonyl group at the 3-position of the pyridine ring such as pyridine-3-sulfonyl chloride, for example, a diazonium salt of 3-aminopyridine is prepared in the presence of a copper catalyst and thionyl chloride.
  • Patent Document 1 A method for producing pyridine-3-sulfonyl chloride by treating with a mixture of water is known (Patent Document 1).
  • Patent Document 2 a method for producing 2-chloropyridine-5-sulfonyl chloride by reacting N-methyl-2-pyridone-5-sulfonic acid with phosphorus pentachloride (PCl 5 ) and phosphorus oxychloride (POCl 3 ) ( Patent Document 2) and a method of chlorinating 3-pyridinesulfonic acid using phosphorus pentachloride (PCl 5 ) in a solvent such as chlorobenzene (Patent Document 3) are known.
  • Patent Document 4 a method for producing chlorinated pyridine sulfonic acid chloride by reacting hydroxypyridine sulfonic acid with phosphorus trichloride (PCl 3 ) and chlorine (Cl 2 ) gas is known (Patent Document 4).
  • Patent Document 2 describes that the target product, 2-chloropyridine-5-sulfonyl chloride, can be obtained almost quantitatively. However, there is no description about producing pyridine-3-sulfonyl chloride.
  • Patent Document 3 describes that pyridine-3-sulfonyl chloride was produced in a yield of 87.9%.
  • the yield was lower, and the by-product 5-chloropyridine-3- It was found that the sulfonyl chloride contained a considerable amount in the final product.
  • Patent Document 4 Furthermore, in the method described in Patent Document 4, a considerable amount of by-products in which chlorine atoms are introduced into the benzene ring are obtained. Patent Document 4 does not describe production of pyridine-3-sulfonyl chloride.
  • An object of the present invention is to provide a process for producing pyridine-3-sulfonyl chloride, which can obtain pyridine-3-sulfonyl chloride in a higher yield than conventional.
  • the present inventors have found that the following problems can be solved by adopting the following configuration, and have completed the present invention. That is, according to the present invention, the following method for producing pyridine-3-sulfonyl chloride is provided.
  • [2] The method for producing pyridine-3-sulfonyl chloride according to [1], wherein the phosphorus pentachloride is divided into 5 or more and added stepwise to the reaction solution over 1 hour or more.
  • [3] The method for producing pyridine-3-sulfonyl chloride according to the above [1], wherein the phosphorus pentachloride is continuously added to the reaction solution over 1 hour or more.
  • [4] The method for producing pyridine-3-sulfonyl chloride according to any one of [1] to [3], wherein the pyridine-3-sulfonic acid and the phosphorus pentachloride are reacted at 100 to 140 ° C.
  • the method for producing pyridine-3-sulfonyl chloride of the present invention it is possible to produce pyridine-3-sulfonyl chloride in a higher yield than the conventional method with less by-product formation. Therefore, the method for producing pyridine-3-sulfonyl chloride of the present invention can be easily applied to an industrial process with little load required for purification.
  • the method for producing pyridine-3-sulfonyl chloride of the present invention comprises a step of sequentially reacting pyridine-3-sulfonic acid and phosphorus pentachloride to form pyridine-3-sulfonyl chloride, and pyridine-sulfonyl chloride by distillation under reduced pressure. Purifying 3-sulfonyl chloride.
  • production method of pyridine-3-sulfonyl chloride of the present invention is also simply referred to as “production method of the present invention”.
  • Step 1 In the production method of the present invention, less than 1 molar equivalent of phosphorus pentachloride with respect to pyridine-3-sulfonic acid is added stepwise in a divided manner to a reaction solution containing pyridine-3-sulfonic acid. Or (ii) a step of continuously adding and sequentially reacting pyridine-3-sulfonic acid and phosphorus pentachloride to produce pyridine-3-sulfonyl chloride (hereinafter also referred to as “step 1”).
  • the present inventors examined the mechanism by which by-product 5-chloropyridine-3-sulfonyl chloride is formed. As a result, an excessive amount of phosphorus pentachloride present in the reaction system causes an unexpected reaction with pyridine-3-sulfonic acid, and a chloro group is introduced into the 5-position of the pyridine ring, thereby producing 5-chloropyridine-3-sulfonyl chloride. Was found to produce. Based on this result, the present inventors reduced the amount of phosphorus pentachloride used relative to the substrate pyridine-3-sulfonic acid to less than 1 molar equivalent, and put pyridine-3 in the reaction system (in the reaction solution).
  • step 1 to a reaction solution containing pyridine-3-sulfonic acid, less than 1 molar equivalent of phosphorus pentachloride with respect to pyridine-3-sulfonic acid is added stepwise (i) in multiple portions, or (Ii) Add continuously.
  • the added phosphorus pentachloride sequentially reacts with pyridine-3-sulfonic acid, so that phosphorus pentachloride in the reaction solution does not exist excessively relative to pyridine-3-sulfonic acid.
  • the reaction solution may contain a solvent.
  • the solvent examples include monochlorobenzene and dichlorobenzene. These solvents can be used alone or in combination of two or more.
  • phosphorus pentachloride is preferably continuously added to the reaction solution over 1 hour or more, more preferably continuously added to the reaction solution over 1.5 to 5 hours. It is particularly preferable to continuously add to the reaction solution over 2 to 4 hours.
  • phosphorus pentachloride is usually 0.4 molar equivalents or more, preferably 0.6 molar equivalents or more, more preferably 0.8 molar equivalents or more, and particularly preferably 0.85 moles. Use more than equivalent amount. If the amount of phosphorus pentachloride relative to pyridine-3-sulfonic acid is less than 1 molar equivalent, the formation of by-products can be suppressed. On the other hand, when the amount is less than 0.8 molar equivalent, the amount of unreacted pyridine-3-sulfonic acid remaining in the reaction system tends to increase.
  • the amount of phosphorus pentachloride relative to pyridine-3-sulfonic acid is small, it is preferably 0.3 molar equivalent or more, more preferably 0.4 molar equivalent or more, so that unreacted pyridine-3-sulfonic acid.
  • Step 1 Is recovered from the reaction system and the recovered pyridine-3-sulfonic acid is reacted again with phosphorus pentachloride (repeating “Step 1”) to further reduce the amount of by-products generated, Higher purity pyridine-3-sulfonyl chloride can be obtained.
  • the reaction system is cooled to, for example, 90 ° C. or less, preferably 85 ° C. or less, more preferably 80 ° C. or less, unreacted pyridine-3-sulfonic acid is precipitated. It can be easily recovered.
  • the reaction temperature of pyridine-3-sulfonic acid and phosphorus pentachloride is preferably 100 to 140 ° C, more preferably 105 to 135 ° C, and particularly preferably 110 to 130 ° C. By setting it as said temperature range, reaction can be advanced rapidly, suppressing the production
  • the temperature at the aging may be, for example, about the same as the temperature at the reaction (about 100 to 140 ° C.).
  • the aging time may be, for example, about 15 minutes to 2 hours.
  • the production method of the present invention includes a step of purifying pyridine-3-sulfonyl chloride by distillation under reduced pressure of the reaction solution obtained in the above step 1 (hereinafter also referred to as [step 2]).
  • the target product pyridine-3-sulfonyl chloride
  • the present inventors have found that the target product, pyridine-3-sulfonyl chloride, is unstable in water and easily hydrolyzed. Therefore, when the reaction solution after the reaction is mixed with a water-insoluble organic solvent (organic layer) and water (aqueous layer) and separated to separate and purify pyridine-3-sulfonyl chloride, During the separation operation, pyridine-3-sulfonyl chloride is hydrolyzed and the yield decreases.
  • Step 2 of the production method of the present invention the reaction solution after the reaction is distilled under reduced pressure as it is without adding a water-insoluble organic solvent or water to the reaction solution to purify pyridine-3-sulfonyl chloride.
  • a water-insoluble organic solvent or water to the reaction solution to purify pyridine-3-sulfonyl chloride.
  • the distillation of the reaction solution may be performed according to a conventional method. Specifically, first, an initial fraction such as phosphorus oxychloride generated by the solvent or reaction is allowed to flow out under constant heating and reduced pressure conditions. Next, when the distillation is further performed by appropriately changing the heating and decompression conditions, the target product, pyridine-3-sulfonyl chloride, is obtained as a main fraction in a high yield (for example, a distillation yield of 90% (Example 1)). be able to.
  • An example of heating and depressurizing conditions for flowing out the first fraction is temperature: 88 to 92 ° C., pressure: 2.5 to 4.5 kPa, and the like.
  • heating and decompression conditions when the main fraction is allowed to flow out are temperature: 92 to 98 ° C., pressure: 0.2 to 1.2 kPa, and the like.
  • reaction formula in the manufacturing method of this invention is shown below.
  • Example 1 A 100 mL four-necked flask was charged with 15.9 g (0.100 mol) of pyridine-3-sulfonic acid and 23.9 g of monochlorobenzene and heated to 120 ° C. with stirring. While maintaining the internal temperature at 119 to 122 ° C., 20.4 g (0.098 mol) of phosphorus pentachloride was divided into 20 portions and added every 15 minutes. After addition of phosphorus pentachloride, the mixture was further stirred for 1 hour. When the reaction solution was analyzed by gas chromatography (GC), the concentration of pyridine-3-sulfonyl chloride was 30.0% by mass.
  • GC gas chromatography
  • the yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (54.3 g) was 91.7%, and the byproduct of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product.
  • the area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.02%.
  • Step 2 The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, the solution was distilled under reduced pressure at 94 ° C. and 0.4 kPa to obtain 14.7 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 82.8%. The area ratio by GC analysis was 99.99% for pyridine-3-sulfonyl chloride and 0.01% for 5-chloropyridine-3-sulfonyl chloride.
  • Example 2 [Step 1] A 100 mL four-necked flask was charged with 15.9 g (0.100 mol) of pyridine-3-sulfonic acid and 23.9 g of monochlorobenzene and heated to 120 ° C. with stirring. While maintaining the internal temperature at 119 to 122 ° C., 18.7 g (0.09 mol) of phosphorus pentachloride was divided into 20 portions and added every 15 minutes. After addition of phosphorus pentachloride, the mixture was further stirred for 1 hour. When the reaction solution was analyzed by gas chromatography (GC), the concentration of pyridine-3-sulfonyl chloride was 28.7% by mass.
  • GC gas chromatography
  • the yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (52.0 g) was 84.0%, and the byproduct of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product.
  • the area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.01%.
  • Step 2 The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Subsequently, it was distilled under reduced pressure at 94 ° C. and 0.4 kPa to obtain 13.3 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 74.9%. The area ratio by GC analysis was 99.99% for pyridine-3-sulfonyl chloride and 0.01% for 5-chloropyridine-3-sulfonyl chloride.
  • the yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (52.0 g) was 84.6%, and the by-product of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product.
  • the area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.03%.
  • Step 2 The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and dichlorobenzene and by-product phosphorus oxychloride were distilled off. Subsequently, distillation was performed under reduced pressure at 94 ° C. and 0.4 kPa to obtain 13.4 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 75.5%. The area ratio by GC analysis was 99.98% for pyridine-3-sulfonyl chloride and 0.02% for 5-chloropyridine-3-sulfonyl chloride.
  • the yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (60.0 g) was 87.8%, and the by-product of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product.
  • the area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.32%.
  • Step 2 The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, distillation under reduced pressure at 94 ° C. and 0.4 kPa yielded 13.7 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 77.1%. The area ratio by GC analysis was 99.69% for pyridine-3-sulfonyl chloride and 0.31% for 5-chloropyridine-3-sulfonyl chloride.
  • the yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (54.3 g) was 82.2%, and the byproduct of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product.
  • the area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.98%.
  • Step 2 The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, distillation under reduced pressure at 94 ° C. and 0.4 kPa yielded 12.8 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 72.1% by mass. The area ratio by GC analysis was 99.00% for pyridine-3-sulfonyl chloride and 1.00% for 5-chloropyridine-3-sulfonyl chloride.
  • the yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (56.8 g) was 75.2%, and the by-product of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product.
  • the area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.09%.
  • the yield of pyridine-3-sulfonyl chloride calculated from the amount of organic phase (extracted phase) (93.2 g) was 24.0%, and the area by GC analysis of by-produced 5-chloropyridine-3-sulfonyl chloride.
  • the ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) was 0.27%.
  • the separated aqueous phase (73.1 g) was analyzed by HPLC, 13.4% by mass (0.616 mol, 61.6% in terms of yield) of pyridine-3-sulfonic acid was detected.
  • the produced pyridine-3-sulfonyl chloride is hydrolyzed by the post-treatment, extraction and washing operations of the reaction solution, and the area ratio by GC analysis of the by-produced 5-chloropyridine-3-sulfonyl chloride is expanded.
  • 5-chloropyridine-3-sulfonyl chloride which is a by-product, was concentrated less easily to hydrolyze than the target compound, pyridine-3-sulfonyl chloride.
  • the yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (54.2 g) was 84.2%, and the byproduct of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product.
  • the area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.11%.
  • Step 2 The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, distillation under reduced pressure at 94 ° C. and 0.4 kPa yielded 13.1 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 73.8%. The area ratio by GC analysis was 99.68% for pyridine-3-sulfonyl chloride and 0.12% for 5-chloropyridine-3-sulfonyl chloride.
  • Example 4 [Step 1] A 100 mL four-necked flask was charged with 15.9 g (0.100 mol) of pyridine-3-sulfonic acid and 23.9 g of monochlorobenzene and heated to 120 ° C. with stirring. While maintaining the internal temperature at 119 to 122 ° C., 19.7 g (0.095 mol) of phosphorus pentachloride was continuously added over 5 hours. After addition of phosphorus pentachloride, the mixture was further stirred for 1 hour. When the reaction solution was analyzed by gas chromatography (GC), the concentration of pyridine-3-sulfonyl chloride was 29.2% by mass.
  • GC gas chromatography
  • Step 2 The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, distillation under reduced pressure at 94 ° C. and 0.4 kPa yielded 14.0 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 78.8%. The area ratio by GC analysis was 99.9% for pyridine-3-sulfonyl chloride and 0.01% for 5-chloropyridine-3-sulfonyl chloride.
  • the yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (54.3 g) was 89.9%, and the by-product of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product.
  • the area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.02%.
  • the yield of pyridine-3-sulfonyl chloride calculated from the amount of organic phase (extracted phase) (92.7 g) was 21.4%, and the area by GC analysis of 5-chloropyridine-3-sulfonyl chloride as a by-product.
  • the ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) was 0.08%.
  • the separated aqueous phase (70.8 g) was analyzed by HPLC, 15.8% by mass (0.0704 mol, 70.4% in terms of yield) of pyridine-3-sulfonic acid was detected.
  • the produced pyridine-3-sulfonyl chloride is hydrolyzed by the post-treatment, extraction and washing operations of the reaction solution, and the area ratio by GC analysis of the by-produced 5-chloropyridine-3-sulfonyl chloride is expanded.
  • 5-chloropyridine-3-sulfonyl chloride which is a by-product, was concentrated less easily to hydrolyze than the target compound, pyridine-3-sulfonyl chloride.
  • the yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (54.4 g) was 90.0%, and GC analysis of 5-chloropyridine-3-sulfonyl chloride as a by-product was performed.
  • the area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) was 0.02%.
  • Step 2 The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, the solution was distilled under reduced pressure at 94 ° C. and 0.4 kPa to obtain 14.7 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 82.8%. The area ratio by GC analysis was 99.98% for pyridine-3-sulfonyl chloride and 0.02% for 5-chloropyridine-3-sulfonyl chloride.
  • the yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (54.3 g) was 90.2%, and the by-product of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product.
  • the area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.02%.
  • Step 2 The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, distillation under reduced pressure at 94 ° C. and 0.4 kPa yielded 14.9 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 83.9%. The area ratio by GC analysis was 99.99% for pyridine-3-sulfonyl chloride and 0.01% for 5-chloropyridine-3-sulfonyl chloride.
  • Step 2 The filtrate was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Subsequently, distillation was performed under reduced pressure at 94 ° C. and 0.4 kPa to obtain 13.2 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 37.2%. The area ratio by GC analysis was 100% for pyridine-3-sulfonyl chloride.
  • Step 3 On the other hand, the unreacted pyridine-3-sulfonic acid wet matter obtained by filtration in the above “Step 1”, 15.9 g of pyridine-3-sulfonic acid, and 45.5 g of monochlorobenzene were added to a 100 mL four-necked flask. And heated to 120 ° C. with stirring. While maintaining the internal temperature at 119 to 122 ° C., 20.8 g (0.100 mol (0.5 mol equivalent)) of phosphorus pentachloride was divided into 10 portions and added every 15 minutes. After addition of phosphorus pentachloride, the mixture was further stirred for 1 hour. The mixture was cooled to an internal temperature of 80 ° C., and the precipitated unreacted pyridine-3-sulfonic acid was filtered.
  • Step 4 The filtrate was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, distillation under reduced pressure at 94 ° C. and 0.4 kPa yielded 16.4 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 46.2% (92.4% from the theoretical yield of phosphorus pentachloride). The area ratio by GC analysis was 100% for pyridine-3-sulfonyl chloride.
  • the wet pyridine-3-sulfonic acid obtained by filtration in the above “Step 3” can be used in the next reaction step (Steps 5, 6,...) In the same manner.
  • the production method of the present invention is suitable as a method for industrially producing pyridine-3-sulfonyl chloride, which is useful as a raw material or an intermediate for producing a pharmaceutical product.

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Abstract

Provided is a pyridine-3-sulfonyl chloride production method which can be applied to industrial processes readily, undergoes the production of a byproduct in a reduced amount, and makes it possible to produce pyridine-3-sulfonyl chloride with higher yield compared with the conventional methods. A pyridine-3-sulfonyl chloride production method comprising the steps of: adding phosphorus pentachloride to a reaction solution containing pyridine-3-sulfonic acid in an amount of less than 1 molar equivalent relative to the amount of pyridine-3-sulfonic acid in multiple divided portions (i) stepwise or (ii) continuously, thereby causing the sequential reaction of pyridine-3-sulfonic acid with phosphorus pentachloride to produce pyridine-3-sulfonyl chloride; and subjecting the reaction solution to distillation under a reduced pressure to purify pyridine-3-sulfonyl chloride.

Description

ピリジン－３－スルホニルクロリドの製造方法Method for producing pyridine-3-sulfonyl chloride
　本発明は、医薬品の合成原料・合成中間体等として有用なピリジン－３－スルホニルクロリドの製造方法に関する。 The present invention relates to a method for producing pyridine-3-sulfonyl chloride, which is useful as a raw material for synthesis and intermediates of pharmaceuticals.
　ピリジン－３－スルホニルクロリドは医薬品を製造するための原料や中間体として有用な化合物である。このようなピリジン－３－スルホニルクロリド等のピリジン環の３位にクロロスルホニル基を有する化合物を製造する方法としては、例えば、３－アミノピリジンのジアゾニウム塩を、銅触媒の存在下、塩化チオニル及び水の混合物で処理してピリジン－３－スルホニルクロリドを製造する方法が知られている（特許文献１）。 Pyridine-3-sulfonyl chloride is a useful compound as a raw material or intermediate for producing pharmaceuticals. As a method for producing such a compound having a chlorosulfonyl group at the 3-position of the pyridine ring, such as pyridine-3-sulfonyl chloride, for example, a diazonium salt of 3-aminopyridine is prepared in the presence of a copper catalyst and thionyl chloride. A method for producing pyridine-3-sulfonyl chloride by treating with a mixture of water is known (Patent Document 1).
　また、Ｎ－メチル－２－ピリドン－５－スルホン酸と、五塩化リン（ＰＣｌ5）及びオキシ塩化リン（ＰＯＣｌ3）とを反応させて２－クロロピリジン－５－スルホニルクロリドを製造する方法（特許文献２）や、クロロベンゼン等の溶媒中、五塩化リン（ＰＣｌ5）を用いて３－ピリジンスルホン酸をクロロ化する方法（特許文献３）が知られている。さらに、ヒドロキシピリジンスルホン酸と、三塩化リン（ＰＣｌ3）及び塩素（Ｃｌ2）ガスとを反応させて塩素化されたピリジンスルホン酸クロリドを製造する方法が知られている（特許文献４）。 In addition, a method for producing 2-chloropyridine-5-sulfonyl chloride by reacting N-methyl-2-pyridone-5-sulfonic acid with phosphorus pentachloride (PCl 5 ) and phosphorus oxychloride (POCl 3 ) ( Patent Document 2) and a method of chlorinating 3-pyridinesulfonic acid using phosphorus pentachloride (PCl 5 ) in a solvent such as chlorobenzene (Patent Document 3) are known. Furthermore, a method for producing chlorinated pyridine sulfonic acid chloride by reacting hydroxypyridine sulfonic acid with phosphorus trichloride (PCl 3 ) and chlorine (Cl 2 ) gas is known (Patent Document 4).
特許第４０４６３６０号公報Japanese Patent No. 4046360 独国特許発明第６７８１４８号明細書German Patent Invention No. 678148 国際公開第２０１４／１３３０５９号International Publication No. 2014/133059 特許第４６９５７４２号公報Japanese Patent No. 4695742
　しかしながら、本発明者らが特許文献１で開示された方法にしたがってピリジン－３－スルホニルクロリドを製造しようとしたところ、目的物がほとんど得られないことが判明した。また、特許文献２には、目的物である２－クロロピリジン－５－スルホニルクロリドがほぼ定量的に得られることが記載されている。しかしながら、ピリジン－３－スルホニルクロリドを製造することについては記載されていない。 However, when the present inventors tried to produce pyridine-3-sulfonyl chloride according to the method disclosed in Patent Document 1, it was found that the desired product was hardly obtained. Patent Document 2 describes that the target product, 2-chloropyridine-5-sulfonyl chloride, can be obtained almost quantitatively. However, there is no description about producing pyridine-3-sulfonyl chloride.
　一方、特許文献３には、ピリジン－３－スルホニルクロリドを８７．９％の収率で製造したことが記載されている。しかしながら、本発明者らが、特許文献３で開示された方法にしたがってピリジン－３－スルホニルクロリドを製造したところ、その収率はより低く、しかも、副生成物である５－クロロピリジン－３－スルホニルクロリドが最終物に相当量含まれていることが判明した。 On the other hand, Patent Document 3 describes that pyridine-3-sulfonyl chloride was produced in a yield of 87.9%. However, when the present inventors produced pyridine-3-sulfonyl chloride according to the method disclosed in Patent Document 3, the yield was lower, and the by-product 5-chloropyridine-3- It was found that the sulfonyl chloride contained a considerable amount in the final product.
　さらに、特許文献４に記載の方法では、ベンゼン環に塩素原子が導入された相当量の副生成物が得られてしまう。また、特許文献４には、ピリジン－３－スルホニルクロリドを製造することについて記載されていない。 Furthermore, in the method described in Patent Document 4, a considerable amount of by-products in which chlorine atoms are introduced into the benzene ring are obtained. Patent Document 4 does not describe production of pyridine-3-sulfonyl chloride.
　本発明は、このような従来技術の有する問題点に鑑みてなされたものであり、その課題とするところは、工業的プロセスに容易に適用可能であるとともに、副生成物の生成量が少なく、従来よりも高収率でピリジン－３－スルホニルクロリドを得ることが可能なピリジン－３－スルホニルクロリドの製造方法を提供することにある。 The present invention has been made in view of such problems of the prior art, and the problem is that the present invention can be easily applied to industrial processes, and the amount of by-products generated is small. An object of the present invention is to provide a process for producing pyridine-3-sulfonyl chloride, which can obtain pyridine-3-sulfonyl chloride in a higher yield than conventional.
　本発明者らは上記課題を解決すべく鋭意検討した結果、以下の構成とすることによって、上記課題を解決することが可能であることを見出し、本発明を完成するに至った。すなわち、本発明によれば、以下に示すピリジン－３－スルホニルクロリドの製造方法が提供される。
　［１］ピリジン－３－スルホン酸を含む反応液に、前記ピリジン－３－スルホン酸に対して１モル当量未満の五塩化リンを、（ｉ）複数に分割して段階的に添加する、又は（ii）連続的に添加し、前記ピリジン－３－スルホン酸と前記五塩化リンを逐次反応させてピリジン－３－スルホニルクロリドを生成させる工程と、前記反応液を減圧蒸留して前記ピリジン－３－スルホニルクロリドを精製する工程と、を有するピリジン－３－スルホニルクロリドの製造方法。
　［２］前記五塩化リンを５以上に分割し、１時間以上かけて前記反応液に段階的に添加する前記［１］に記載のピリジン－３－スルホニルクロリドの製造方法。
　［３］前記五塩化リンを、１時間以上かけて前記反応液に連続的に添加する前記［１］に記載のピリジン－３－スルホニルクロリドの製造方法。
　［４］前記ピリジン－３－スルホン酸と前記五塩化リンを１００～１４０℃で反応させる前記［１］～［３］のいずれかに記載のピリジン－３－スルホニルクロリドの製造方法。
　［５］前記ピリジン－３－スルホン酸に対して、前記五塩化リンを０．４モル当量以上用いる前記［１］～［４］のいずれかに記載のピリジン－３－スルホニルクロリドの製造方法。
　［６］前記反応液が、モノクロロベンゼン及びジクロロベンゼンの少なくともいずれかの溶媒をさらに含む前記［１］～［５］のいずれかに記載のピリジン－３－スルホニルクロリドの製造方法。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that the following problems can be solved by adopting the following configuration, and have completed the present invention. That is, according to the present invention, the following method for producing pyridine-3-sulfonyl chloride is provided.
[1] To a reaction solution containing pyridine-3-sulfonic acid, less than 1 molar equivalent of phosphorus pentachloride with respect to pyridine-3-sulfonic acid is added stepwise (i) divided into a plurality of parts, or (Ii) a step of continuously adding and sequentially reacting the pyridine-3-sulfonic acid and the phosphorus pentachloride to form pyridine-3-sulfonyl chloride; and distilling the reaction solution under reduced pressure to form the pyridine-3 A method for producing pyridine-3-sulfonyl chloride, comprising the step of purifying the sulfonyl chloride.
[2] The method for producing pyridine-3-sulfonyl chloride according to [1], wherein the phosphorus pentachloride is divided into 5 or more and added stepwise to the reaction solution over 1 hour or more.
[3] The method for producing pyridine-3-sulfonyl chloride according to the above [1], wherein the phosphorus pentachloride is continuously added to the reaction solution over 1 hour or more.
[4] The method for producing pyridine-3-sulfonyl chloride according to any one of [1] to [3], wherein the pyridine-3-sulfonic acid and the phosphorus pentachloride are reacted at 100 to 140 ° C.
[5] The method for producing pyridine-3-sulfonyl chloride according to any one of the above [1] to [4], wherein the phosphorus pentachloride is used in an amount of 0.4 molar equivalent or more with respect to the pyridine-3-sulfonic acid.
[6] The method for producing pyridine-3-sulfonyl chloride according to any one of [1] to [5], wherein the reaction solution further contains at least one solvent of monochlorobenzene and dichlorobenzene.
　本発明のピリジン－３－スルホニルクロリドの製造方法によれば、副生成物の生成量が少なく、従来よりも高収率でピリジン－３－スルホニルクロリドを製造することができる。このため、本発明のピリジン－３－スルホニルクロリドの製造方法は、精製に要する負荷等も少なく、工業的プロセスに容易に適用することができる。 According to the method for producing pyridine-3-sulfonyl chloride of the present invention, it is possible to produce pyridine-3-sulfonyl chloride in a higher yield than the conventional method with less by-product formation. Therefore, the method for producing pyridine-3-sulfonyl chloride of the present invention can be easily applied to an industrial process with little load required for purification.
　以下、本発明の実施の形態について説明するが、本発明は以下の実施の形態に限定されるものではない。本発明のピリジン－３－スルホニルクロリドの製造方法は、ピリジン－３－スルホン酸と五塩化リンを逐次反応させてピリジン－３－スルホニルクロリドを生成させる工程と、反応液を減圧蒸留してピリジン－３－スルホニルクロリドを精製する工程とを有する。以下、本発明のピリジン－３－スルホニルクロリドの製造方法を、単に「本発明の製造方法」とも記す。 Hereinafter, embodiments of the present invention will be described, but the present invention is not limited to the following embodiments. The method for producing pyridine-3-sulfonyl chloride of the present invention comprises a step of sequentially reacting pyridine-3-sulfonic acid and phosphorus pentachloride to form pyridine-3-sulfonyl chloride, and pyridine-sulfonyl chloride by distillation under reduced pressure. Purifying 3-sulfonyl chloride. Hereinafter, the production method of pyridine-3-sulfonyl chloride of the present invention is also simply referred to as “production method of the present invention”.
［工程１］
　本発明の製造方法は、ピリジン－３－スルホン酸を含む反応液に、ピリジン－３－スルホン酸に対して１モル当量未満の五塩化リンを、（ｉ）複数に分割して段階的に添加する、又は（ii）連続的に添加し、ピリジン－３－スルホン酸と五塩化リンを逐次反応させてピリジン－３－スルホニルクロリドを生成させる工程（以下、「工程１」とも記す）を有する。 [Step 1]
In the production method of the present invention, less than 1 molar equivalent of phosphorus pentachloride with respect to pyridine-3-sulfonic acid is added stepwise in a divided manner to a reaction solution containing pyridine-3-sulfonic acid. Or (ii) a step of continuously adding and sequentially reacting pyridine-3-sulfonic acid and phosphorus pentachloride to produce pyridine-3-sulfonyl chloride (hereinafter also referred to as “step 1”).
　本発明者らは、副生成物である５－クロロピリジン－３－スルホニルクロリドが生成するメカニズムについて検討した。その結果、反応系内に過剰に存在する五塩化リンがピリジン－３－スルホン酸と想定外の反応を起こし、ピリジン環の５位にクロロ基を導入して５－クロロピリジン－３－スルホニルクロリドが生成することが判明した。この結果を踏まえ、本発明者らは、基質であるピリジン－３－スルホン酸に対する、五塩化リンの使用量を１モル当量未満にするとともに、反応系内（反応液中）に、ピリジン－３－スルホン酸に対して五塩化リンが過剰に存在しない状態とすることによって、副生成物の生成を抑制し、高純度のピリジン－３－スルホニルクロリドを高収率で得られることを見出した。 The present inventors examined the mechanism by which by-product 5-chloropyridine-3-sulfonyl chloride is formed. As a result, an excessive amount of phosphorus pentachloride present in the reaction system causes an unexpected reaction with pyridine-3-sulfonic acid, and a chloro group is introduced into the 5-position of the pyridine ring, thereby producing 5-chloropyridine-3-sulfonyl chloride. Was found to produce. Based on this result, the present inventors reduced the amount of phosphorus pentachloride used relative to the substrate pyridine-3-sulfonic acid to less than 1 molar equivalent, and put pyridine-3 in the reaction system (in the reaction solution). -It was found that by making phosphorus pentachloride not excessively present with respect to sulfonic acid, the formation of by-products was suppressed, and high-purity pyridine-3-sulfonyl chloride was obtained in high yield.
　工程１では、ピリジン－３－スルホン酸を含む反応液に、ピリジン－３－スルホン酸に対して１モル当量未満の五塩化リンを、（ｉ）複数に分割して段階的に添加する、又は（ii）連続的に添加する。これにより、添加された五塩化リンがピリジン－３－スルホン酸と逐次反応し、反応液中の五塩化リンが、ピリジン－３－スルホン酸に対して過剰に存在しない状態とすることができる。 In step 1, to a reaction solution containing pyridine-3-sulfonic acid, less than 1 molar equivalent of phosphorus pentachloride with respect to pyridine-3-sulfonic acid is added stepwise (i) in multiple portions, or (Ii) Add continuously. As a result, the added phosphorus pentachloride sequentially reacts with pyridine-3-sulfonic acid, so that phosphorus pentachloride in the reaction solution does not exist excessively relative to pyridine-3-sulfonic acid.
　反応液には溶媒を含有させてもよい。用いることができる溶媒としては、例えば、モノクロロベンゼン、及びジクロロベンゼンなどを挙げることができる。これらの溶媒は、一種単独で又は二種以上を組み合わせて用いることができる。 The reaction solution may contain a solvent. Examples of the solvent that can be used include monochlorobenzene and dichlorobenzene. These solvents can be used alone or in combination of two or more.
　上記（ｉ）の場合、五塩化リンを５以上に分割し、１時間以上かけて反応液に段階的に添加することが好ましく、１０～４０に分割し、１．５～５時間かけて反応液に段階的に添加することがさらに好ましく、１５～３０に分割し、２～４時間かけて反応液に段階的に添加することが特に好ましい。このように五塩化リンを反応液に段階的に添加することで、副生成物の生成をさらに抑制し、より高純度のピリジン－３－スルホニルクロリドを得ることができる。 In the case of (i) above, it is preferable to divide phosphorus pentachloride into 5 or more and add it stepwise to the reaction solution over 1 hour or more, and divide into 10 to 40 and react over 1.5 to 5 hours. It is more preferable to add stepwise to the solution, and it is particularly preferable to divide into 15 to 30 and add stepwise to the reaction solution over 2 to 4 hours. By adding phosphorus pentachloride stepwise to the reaction solution in this way, it is possible to further suppress the production of by-products and obtain pyridine-3-sulfonyl chloride with higher purity.
　また、上記（ii）の場合、五塩化リンを１時間以上かけて反応液に連続的に添加することが好ましく、１．５～５時間かけて反応液に連続的に添加することがさらに好ましく、２～４時間かけて反応液に連続的に添加することが特に好ましい。このように五塩化リンを反応液に連続的に添加することで、副生成物の生成をさらに抑制し、より高純度のピリジン－３－スルホニルクロリドを得ることができる。 In the case of (ii) above, phosphorus pentachloride is preferably continuously added to the reaction solution over 1 hour or more, more preferably continuously added to the reaction solution over 1.5 to 5 hours. It is particularly preferable to continuously add to the reaction solution over 2 to 4 hours. By continuously adding phosphorus pentachloride to the reaction solution in this manner, the formation of by-products can be further suppressed, and pyridine-3-sulfonyl chloride with higher purity can be obtained.
　ピリジン－３－スルホン酸に対して、五塩化リンを、通常、０．４モル当量以上、好ましくは０．６モル当量以上、さらに好ましくは０．８モル当量以上、特に好ましくは０．８５モル当量以上用いる。ピリジン－３－スルホン酸に対する五塩化リンの量を１モル当量未満にすれば、副生成物の生成を抑制することができる。一方、０．８モル当量未満とすると反応系内に残存する未反応のピリジン－３－スルホン酸の量が多くなる傾向にある。 With respect to pyridine-3-sulfonic acid, phosphorus pentachloride is usually 0.4 molar equivalents or more, preferably 0.6 molar equivalents or more, more preferably 0.8 molar equivalents or more, and particularly preferably 0.85 moles. Use more than equivalent amount. If the amount of phosphorus pentachloride relative to pyridine-3-sulfonic acid is less than 1 molar equivalent, the formation of by-products can be suppressed. On the other hand, when the amount is less than 0.8 molar equivalent, the amount of unreacted pyridine-3-sulfonic acid remaining in the reaction system tends to increase.
　但し、ピリジン－３－スルホン酸に対する五塩化リンの量が少なくても、好ましくは０．３モル当量以上、さらに好ましくは０．４モル当量以上であれば、未反応のピリジン－３－スルホン酸を反応系から回収するとともに、回収したピリジン－３－スルホン酸を五塩化リンと再度反応させる（「工程１」を繰り返す）、といったサイクルを繰り返すことによって、副生成物の生成量をさらに抑え、より高純度のピリジン－３－スルホニルクロリドを得ることができる。なお、反応系を、例えば９０℃以下、好ましくは８５℃以下、さらに好ましくは８０℃以下まで冷却すれば、未反応のピリジン－３－スルホン酸が析出するため、ろ過等することによって反応系から容易に回収することができる。 However, even if the amount of phosphorus pentachloride relative to pyridine-3-sulfonic acid is small, it is preferably 0.3 molar equivalent or more, more preferably 0.4 molar equivalent or more, so that unreacted pyridine-3-sulfonic acid. Is recovered from the reaction system and the recovered pyridine-3-sulfonic acid is reacted again with phosphorus pentachloride (repeating “Step 1”) to further reduce the amount of by-products generated, Higher purity pyridine-3-sulfonyl chloride can be obtained. If the reaction system is cooled to, for example, 90 ° C. or less, preferably 85 ° C. or less, more preferably 80 ° C. or less, unreacted pyridine-3-sulfonic acid is precipitated. It can be easily recovered.
　ピリジン－３－スルホン酸と五塩化リンとの反応温度は、１００～１４０℃とすることが好ましく、１０５～１３５℃とすることがさらに好ましく、１１０～１３０℃とすることが特に好ましい。上記の温度範囲とすることで、副生成物の生成を抑制しながら、速やかに反応を進行させることができる。 The reaction temperature of pyridine-3-sulfonic acid and phosphorus pentachloride is preferably 100 to 140 ° C, more preferably 105 to 135 ° C, and particularly preferably 110 to 130 ° C. By setting it as said temperature range, reaction can be advanced rapidly, suppressing the production | generation of a by-product.
　五塩化リンの添加後には、必要に応じて熟成させてもよい。熟成時の温度は、例えば、反応時の温度と同程度（１００～１４０℃程度）とすればよい。また、熟成時間は、例えば１５分～２時間程度とすればよい。 After the addition of phosphorus pentachloride, it may be aged as necessary. The temperature at the aging may be, for example, about the same as the temperature at the reaction (about 100 to 140 ° C.). The aging time may be, for example, about 15 minutes to 2 hours.
［工程２］
　本発明の製造方法は、上記の工程１で得られた反応液を減圧蒸留してピリジン－３－スルホニルクロリドを精製する工程（以下、［工程２］とも記す）を有する。検討の結果、本発明者らは、目的物であるピリジン－３－スルホニルクロリドは水中で不安定であり、加水分解されやすいことを見出した。このため、反応後の反応液と、非水溶性有機溶媒（有機層）及び水（水層）とを混合し、分液することによってピリジン－３－スルホニルクロリドを単離及び精製しようとすると、分液操作中にピリジン－３－スルホニルクロリドが加水分解して収率が低下してしまう。そこで、本発明の製造方法の工程２では、反応液に非水溶性有機溶媒や水を添加することなく、反応後の反応液をそのまま減圧蒸留して、ピリジン－３－スルホニルクロリドを精製する。これにより、加水分解等によるピリジン－３－スルホニルクロリドの損失を抑制し、収率を向上させることができる。 [Step 2]
The production method of the present invention includes a step of purifying pyridine-3-sulfonyl chloride by distillation under reduced pressure of the reaction solution obtained in the above step 1 (hereinafter also referred to as [step 2]). As a result of the study, the present inventors have found that the target product, pyridine-3-sulfonyl chloride, is unstable in water and easily hydrolyzed. Therefore, when the reaction solution after the reaction is mixed with a water-insoluble organic solvent (organic layer) and water (aqueous layer) and separated to separate and purify pyridine-3-sulfonyl chloride, During the separation operation, pyridine-3-sulfonyl chloride is hydrolyzed and the yield decreases. Therefore, in Step 2 of the production method of the present invention, the reaction solution after the reaction is distilled under reduced pressure as it is without adding a water-insoluble organic solvent or water to the reaction solution to purify pyridine-3-sulfonyl chloride. Thereby, loss of pyridine-3-sulfonyl chloride due to hydrolysis or the like can be suppressed, and the yield can be improved.
　反応液の蒸留は、常法にしたがって実施すればよい。具体的には、先ず、溶媒や反応により生じたオキシ塩化リン等の初留分を一定の加熱及び減圧条件で流出させる。次いで、加熱及び減圧条件を適宜変更してさらに蒸留すれば、目的物であるピリジン－３－スルホニルクロリドを本留分として高い収率（例えば、蒸留収率９０％（実施例１））で得ることができる。初留分を流出させる際の加熱及び減圧条件の一例は、温度：８８～９２℃、圧力：２．５～４．５ｋＰａなどである。また、本留分を流出させる際の加熱及び減圧条件の一例は、温度：９２～９８℃、圧力：０．２～１．２ｋＰａなどである。なお、本発明の製造方法における反応式の一例を以下に示す。 The distillation of the reaction solution may be performed according to a conventional method. Specifically, first, an initial fraction such as phosphorus oxychloride generated by the solvent or reaction is allowed to flow out under constant heating and reduced pressure conditions. Next, when the distillation is further performed by appropriately changing the heating and decompression conditions, the target product, pyridine-3-sulfonyl chloride, is obtained as a main fraction in a high yield (for example, a distillation yield of 90% (Example 1)). be able to. An example of heating and depressurizing conditions for flowing out the first fraction is temperature: 88 to 92 ° C., pressure: 2.5 to 4.5 kPa, and the like. Examples of heating and decompression conditions when the main fraction is allowed to flow out are temperature: 92 to 98 ° C., pressure: 0.2 to 1.2 kPa, and the like. In addition, an example of the reaction formula in the manufacturing method of this invention is shown below.
Figure JPOXMLDOC01-appb-I000001
Figure JPOXMLDOC01-appb-I000001
　以下、本発明を実施例に基づいて具体的に説明するが、本発明はこれらの実施例に限定されるものではない。 Hereinafter, the present invention will be specifically described based on examples, but the present invention is not limited to these examples.
（実施例１）
［工程１］
　１００ｍＬ四つ口フラスコに、ピリジン－３－スルホン酸１５．９ｇ（０．１００モル）及びモノクロロベンゼン２３．９ｇを入れ、撹拌しながら１２０℃に加熱した。内温を１１９～１２２℃に保持しながら、五塩化リン２０．４ｇ（０．０９８モル）を２０分割して１５分毎に投入した。五塩化リンの投入終了後、さらに１時間撹拌した。反応液についてガスクロマトグラフィー（ＧＣ）分析を行ったところ、ピリジン－３－スルホニルクロリドの濃度は３０．０質量％であった。また、反応液の量（５４．３ｇ）より算出した、反応液中でのピリジン－３－スルホニルクロリドの収率は９１．７％であり、副生した５－クロロピリジン－３－スルホニルクロリドのＧＣ分析による面積比率（５－クロロピリジン－３－スルホニルクロリド／ピリジン－３－スルホニルクロリド）は０．０２％であった。 (Example 1)
[Step 1]
A 100 mL four-necked flask was charged with 15.9 g (0.100 mol) of pyridine-3-sulfonic acid and 23.9 g of monochlorobenzene and heated to 120 ° C. with stirring. While maintaining the internal temperature at 119 to 122 ° C., 20.4 g (0.098 mol) of phosphorus pentachloride was divided into 20 portions and added every 15 minutes. After addition of phosphorus pentachloride, the mixture was further stirred for 1 hour. When the reaction solution was analyzed by gas chromatography (GC), the concentration of pyridine-3-sulfonyl chloride was 30.0% by mass. The yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (54.3 g) was 91.7%, and the byproduct of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product. The area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.02%.
［工程２］
　反応液を９０℃で３．６ｋＰａまで減圧濃縮し、モノクロロベンゼン及び副生したオキシ塩化リンを留去した。次いで、９４℃、０．４ｋＰａの条件で減圧蒸留し、ピリジン－３－スルホニルクロリド１４．７ｇを得た。ピリジン－３－スルホニルクロリドの収率は８２．８％であった。また、ＧＣ分析による面積比率は、ピリジン－３－スルホニルクロリドが９９．９９％であり、５－クロロピリジン－３－スルホニルクロリドが０．０１％であった。 [Step 2]
The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, the solution was distilled under reduced pressure at 94 ° C. and 0.4 kPa to obtain 14.7 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 82.8%. The area ratio by GC analysis was 99.99% for pyridine-3-sulfonyl chloride and 0.01% for 5-chloropyridine-3-sulfonyl chloride.
（実施例２）
［工程１］
　１００ｍＬ四つ口フラスコに、ピリジン－３－スルホン酸１５．９ｇ（０．１００モル）及びモノクロロベンゼン２３．９ｇを入れ、撹拌しながら１２０℃に加熱した。内温を１１９～１２２℃に保持しながら、五塩化リン１８．７ｇ（０．０９モル）を２０分割して１５分毎に投入した。五塩化リンの投入終了後、さらに１時間撹拌した。反応液についてガスクロマトグラフィー（ＧＣ）分析を行ったところ、ピリジン－３－スルホニルクロリドの濃度は２８．７質量％であった。また、反応液の量（５２．０ｇ）より算出した、反応液中でのピリジン－３－スルホニルクロリドの収率は８４．０％であり、副生した５－クロロピリジン－３－スルホニルクロリドのＧＣ分析による面積比率（５－クロロピリジン－３－スルホニルクロリド／ピリジン－３－スルホニルクロリド）は０．０１％であった。 (Example 2)
[Step 1]
A 100 mL four-necked flask was charged with 15.9 g (0.100 mol) of pyridine-3-sulfonic acid and 23.9 g of monochlorobenzene and heated to 120 ° C. with stirring. While maintaining the internal temperature at 119 to 122 ° C., 18.7 g (0.09 mol) of phosphorus pentachloride was divided into 20 portions and added every 15 minutes. After addition of phosphorus pentachloride, the mixture was further stirred for 1 hour. When the reaction solution was analyzed by gas chromatography (GC), the concentration of pyridine-3-sulfonyl chloride was 28.7% by mass. The yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (52.0 g) was 84.0%, and the byproduct of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product. The area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.01%.
［工程２］
　反応液を９０℃で３．６ｋＰａまで減圧濃縮し、モノクロロベンゼン及び副生したオキシ塩化リンを留去した。次いで、９４℃、０．４ｋＰａの条件で減圧蒸留し、ピリジン－３－スルホニルクロリド１３．３ｇを得た。ピリジン－３－スルホニルクロリドの収率は７４．９％であった。また、ＧＣ分析による面積比率は、ピリジン－３－スルホニルクロリドが９９．９９％であり、５－クロロピリジン－３－スルホニルクロリドが０．０１％であった。 [Step 2]
The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Subsequently, it was distilled under reduced pressure at 94 ° C. and 0.4 kPa to obtain 13.3 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 74.9%. The area ratio by GC analysis was 99.99% for pyridine-3-sulfonyl chloride and 0.01% for 5-chloropyridine-3-sulfonyl chloride.
（実施例３）
［工程１］
　１００ｍＬ四つ口フラスコに、ピリジン－３－スルホン酸１５．９ｇ（０．１００モル）及びジクロロベンゼン２３．９ｇを入れ、撹拌しながら１２０℃に加熱した。内温を１１９～１２２℃に保持しながら、五塩化リン１８．７ｇ（０．０９モル）を２０分割して１５分毎に投入した。五塩化リンの投入終了後、さらに１時間撹拌した。反応液についてガスクロマトグラフィー（ＧＣ）分析を行ったところ、ピリジン－３－スルホニルクロリドの濃度は２８．９質量％であった。また、反応液の量（５２．０ｇ）より算出した、反応液中でのピリジン－３－スルホニルクロリドの収率は８４．６％であり、副生した５－クロロピリジン－３－スルホニルクロリドのＧＣ分析による面積比率（５－クロロピリジン－３－スルホニルクロリド／ピリジン－３－スルホニルクロリド）は０．０３％であった。 (Example 3)
[Step 1]
A 100 mL four-necked flask was charged with 15.9 g (0.100 mol) of pyridine-3-sulfonic acid and 23.9 g of dichlorobenzene and heated to 120 ° C. with stirring. While maintaining the internal temperature at 119 to 122 ° C., 18.7 g (0.09 mol) of phosphorus pentachloride was divided into 20 portions and added every 15 minutes. After addition of phosphorus pentachloride, the mixture was further stirred for 1 hour. When the reaction solution was analyzed by gas chromatography (GC), the concentration of pyridine-3-sulfonyl chloride was 28.9% by mass. The yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (52.0 g) was 84.6%, and the by-product of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product. The area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.03%.
［工程２］
　反応液を９０℃で３．６ｋＰａまで減圧濃縮し、ジクロロベンゼン及び副生したオキシ塩化リンを留去した。次いで、９４℃、０．４ｋＰａの条件で減圧蒸留し、ピリジン－３－スルホニルクロリド１３．４ｇを得た。ピリジン－３－スルホニルクロリドの収率は７５．５％であった。また、ＧＣ分析による面積比率は、ピリジン－３－スルホニルクロリドが９９．９８％であり、５－クロロピリジン－３－スルホニルクロリドが０．０２％であった。 [Step 2]
The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and dichlorobenzene and by-product phosphorus oxychloride were distilled off. Subsequently, distillation was performed under reduced pressure at 94 ° C. and 0.4 kPa to obtain 13.4 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 75.5%. The area ratio by GC analysis was 99.98% for pyridine-3-sulfonyl chloride and 0.02% for 5-chloropyridine-3-sulfonyl chloride.
（比較例１）
［工程１］
　１００ｍＬ四つ口フラスコに、ピリジン－３－スルホン酸１５．９ｇ（０．１００モル）及びモノクロロベンゼン２３．９ｇを入れ、撹拌しながら１２０℃に加熱した。内温を１１９～１２２℃に保持しながら、五塩化リン２５．０ｇ（０．１２モル）を２０分割して１５分毎に投入した。五塩化リンの投入終了後、さらに１時間撹拌した。反応液についてガスクロマトグラフィー（ＧＣ）分析を行ったところ、ピリジン－３－スルホニルクロリドの濃度は２６．０質量％であった。また、反応液の量（６０．０ｇ）より算出した、反応液中でのピリジン－３－スルホニルクロリドの収率は８７．８％であり、副生した５－クロロピリジン－３－スルホニルクロリドのＧＣ分析による面積比率（５－クロロピリジン－３－スルホニルクロリド／ピリジン－３－スルホニルクロリド）は０．３２％であった。 (Comparative Example 1)
[Step 1]
A 100 mL four-necked flask was charged with 15.9 g (0.100 mol) of pyridine-3-sulfonic acid and 23.9 g of monochlorobenzene and heated to 120 ° C. with stirring. While maintaining the internal temperature at 119 to 122 ° C., 25.0 g (0.12 mol) of phosphorus pentachloride was divided into 20 portions and added every 15 minutes. After addition of phosphorus pentachloride, the mixture was further stirred for 1 hour. When the reaction solution was analyzed by gas chromatography (GC), the concentration of pyridine-3-sulfonyl chloride was 26.0% by mass. The yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (60.0 g) was 87.8%, and the by-product of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product. The area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.32%.
［工程２］
　反応液を９０℃で３．６ｋＰａまで減圧濃縮し、モノクロロベンゼン及び副生したオキシ塩化リンを留去した。次いで、９４℃、０．４ｋＰａの条件で減圧蒸留し、ピリジン－３－スルホニルクロリド１３．７ｇを得た。ピリジン－３－スルホニルクロリドの収率は７７．１％であった。また、ＧＣ分析による面積比率は、ピリジン－３－スルホニルクロリドが９９．６９％であり、５－クロロピリジン－３－スルホニルクロリドが０．３１％であった。 [Step 2]
The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, distillation under reduced pressure at 94 ° C. and 0.4 kPa yielded 13.7 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 77.1%. The area ratio by GC analysis was 99.69% for pyridine-3-sulfonyl chloride and 0.31% for 5-chloropyridine-3-sulfonyl chloride.
（比較例２）
［工程１］
　１００ｍＬ四つ口フラスコに、ピリジン－３－スルホン酸１５．９ｇ（０．１００モル）及びモノクロロベンゼン２３．９ｇを入れ、撹拌しながら五塩化リン２５．０ｇ（０．１２モル）を一括で投入した。その後、１２０℃に加熱して１時間撹拌した。反応液についてガスクロマトグラフィー（ＧＣ）分析を行ったところ、ピリジン－３－スルホニルクロリドの濃度は２６．９質量％であった。また、反応液の量（５４．３ｇ）より算出した、反応液中でのピリジン－３－スルホニルクロリドの収率は８２．２％であり、副生した５－クロロピリジン－３－スルホニルクロリドのＧＣ分析による面積比率（５－クロロピリジン－３－スルホニルクロリド／ピリジン－３－スルホニルクロリド）は０．９８％であった。 (Comparative Example 2)
[Step 1]
Into a 100 mL four-necked flask, put 15.9 g (0.100 mol) of pyridine-3-sulfonic acid and 23.9 g of monochlorobenzene and add 25.0 g (0.12 mol) of phosphorus pentachloride all at once with stirring. did. Then, it heated at 120 degreeC and stirred for 1 hour. When the reaction solution was analyzed by gas chromatography (GC), the concentration of pyridine-3-sulfonyl chloride was 26.9% by mass. The yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (54.3 g) was 82.2%, and the byproduct of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product. The area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.98%.
［工程２］
　反応液を９０℃で３．６ｋＰａまで減圧濃縮し、モノクロロベンゼン及び副生したオキシ塩化リンを留去した。次いで、９４℃、０．４ｋＰａの条件で減圧蒸留し、ピリジン－３－スルホニルクロリド１２．８ｇを得た。ピリジン－３－スルホニルクロリドの収率は７２．１質量％であった。また、ＧＣ分析による面積比率は、ピリジン－３－スルホニルクロリドが９９．００％であり、５－クロロピリジン－３－スルホニルクロリドが１．００％であった。 [Step 2]
The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, distillation under reduced pressure at 94 ° C. and 0.4 kPa yielded 12.8 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 72.1% by mass. The area ratio by GC analysis was 99.00% for pyridine-3-sulfonyl chloride and 1.00% for 5-chloropyridine-3-sulfonyl chloride.
（比較例３）
　１００ｍＬ四つ口フラスコに、ピリジン－３－スルホン酸１５．９ｇ（０．１００モル）、五塩化リン２２．９ｇ（０．１１０モル）、及びモノクロロベンゼン２３．９ｇを入れ、１０５℃に加熱して３時間撹拌した。反応液についてガスクロマトグラフィー（ＧＣ）分析を行ったところ、ピリジン－３－スルホニルクロリドの濃度は２３．５質量％であった。また、反応液の量（５６．８ｇ）より算出した、反応液中でのピリジン－３－スルホニルクロリドの収率は７５．２％であり、副生した５－クロロピリジン－３－スルホニルクロリドのＧＣ分析による面積比率（５－クロロピリジン－３－スルホニルクロリド／ピリジン－３－スルホニルクロリド）は０．０９％であった。 (Comparative Example 3)
A 100 mL four-necked flask is charged with 15.9 g (0.100 mol) of pyridine-3-sulfonic acid, 22.9 g (0.110 mol) of phosphorus pentachloride and 23.9 g of monochlorobenzene and heated to 105 ° C. And stirred for 3 hours. When the reaction solution was analyzed by gas chromatography (GC), the concentration of pyridine-3-sulfonyl chloride was 23.5% by mass. The yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (56.8 g) was 75.2%, and the by-product of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product. The area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.09%.
　別の３００ｍＬ四つ口フラスコにトルエン６５ｇ及び水４５ｇを入れ、５℃に冷却した後、内温を１５℃以下に保持しながら反応液を滴下した。５℃に冷却した後、内温を２０℃以下に保持しながら５０質量％炭酸カリウム水溶液を添加してｐＨ７．５に調整した。室温で分液した後、有機相についてＧＣ分析を行ったところ、ピリジン－３－スルホニルクロリドの濃度は４．６質量％であった。有機相（抽出相）の量（９３．２ｇ）より算出したピリジン－３－スルホニルクロリドの収率は２４．０％であり、副生した５－クロロピリジン－３－スルホニルクロリドのＧＣ分析による面積比率（５－クロロピリジン－３－スルホニルクロリド／ピリジン－３－スルホニルクロリド）は０．２７％であった。一方、分液した水相（７３．１ｇ）をＨＰＬＣ分析したところ、ピリジン－３－スルホン酸が１３．４質量％（０．６１６モル、収率換算で６１．６％）検出された。このことから、生成したピリジン－３－スルホニルクロリドが、反応液の後処理、抽出、及び洗浄操作によって加水分解され、副生した５－クロロピリジン－３－スルホニルクロリドのＧＣ分析による面積比率が拡大していたことから、副生成物である５－クロロピリジン－３－スルホニルクロリドは、目的化合物であるピリジン－３－スルホニルクロリドよりも加水分解しにくく濃縮されたことがわかる。 In another 300 mL four-necked flask, 65 g of toluene and 45 g of water were added and cooled to 5 ° C., and then the reaction solution was added dropwise while maintaining the internal temperature at 15 ° C. or lower. After cooling to 5 ° C, a 50 mass% aqueous potassium carbonate solution was added to adjust the pH to 7.5 while maintaining the internal temperature at 20 ° C or lower. After liquid separation at room temperature, the organic phase was subjected to GC analysis. As a result, the concentration of pyridine-3-sulfonyl chloride was 4.6% by mass. The yield of pyridine-3-sulfonyl chloride calculated from the amount of organic phase (extracted phase) (93.2 g) was 24.0%, and the area by GC analysis of by-produced 5-chloropyridine-3-sulfonyl chloride. The ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) was 0.27%. On the other hand, when the separated aqueous phase (73.1 g) was analyzed by HPLC, 13.4% by mass (0.616 mol, 61.6% in terms of yield) of pyridine-3-sulfonic acid was detected. From this, the produced pyridine-3-sulfonyl chloride is hydrolyzed by the post-treatment, extraction and washing operations of the reaction solution, and the area ratio by GC analysis of the by-produced 5-chloropyridine-3-sulfonyl chloride is expanded. Thus, it can be understood that 5-chloropyridine-3-sulfonyl chloride, which is a by-product, was concentrated less easily to hydrolyze than the target compound, pyridine-3-sulfonyl chloride.
（比較例４）
［工程１］
　１００ｍＬ四つ口フラスコに、ピリジン－３－スルホン酸１５．９ｇ（０．１００モル）及びモノクロロベンゼン２３．９ｇを入れ、撹拌しながら１２０℃に加熱し五塩化リン２０．４ｇ（０．０９８モル）を投入した。五塩化リンの投入終了後、さらに１時間撹拌した。反応液についてガスクロマトグラフィー（ＧＣ）分析を行ったところ、ピリジン－３－スルホニルクロリドの濃度は２７．６質量％であった。また、反応液の量（５４．２ｇ）より算出した、反応液中でのピリジン－３－スルホニルクロリドの収率は８４．２％であり、副生した５－クロロピリジン－３－スルホニルクロリドのＧＣ分析による面積比率（５－クロロピリジン－３－スルホニルクロリド／ピリジン－３－スルホニルクロリド）は０．１１％であった。 (Comparative Example 4)
[Step 1]
In a 100 mL four-necked flask, 15.9 g (0.100 mol) of pyridine-3-sulfonic acid and 23.9 g of monochlorobenzene were added and heated to 120 ° C. with stirring to 20.4 g (0.098 mol) of phosphorus pentachloride. ). After addition of phosphorus pentachloride, the mixture was further stirred for 1 hour. When the reaction solution was analyzed by gas chromatography (GC), the concentration of pyridine-3-sulfonyl chloride was 27.6% by mass. The yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (54.2 g) was 84.2%, and the byproduct of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product. The area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.11%.
［工程２］
　反応液を９０℃で３．６ｋＰａまで減圧濃縮し、モノクロロベンゼン及び副生したオキシ塩化リンを留去した。次いで、９４℃、０．４ｋＰａの条件で減圧蒸留し、ピリジン－３－スルホニルクロリド１３．１ｇを得た。ピリジン－３－スルホニルクロリドの収率は７３．８％であった。また、ＧＣ分析による面積比率は、ピリジン－３－スルホニルクロリドが９９．６８％であり、５－クロロピリジン－３－スルホニルクロリドが０．１２％であった。 [Step 2]
The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, distillation under reduced pressure at 94 ° C. and 0.4 kPa yielded 13.1 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 73.8%. The area ratio by GC analysis was 99.68% for pyridine-3-sulfonyl chloride and 0.12% for 5-chloropyridine-3-sulfonyl chloride.
（実施例４）
［工程１］
　１００ｍＬ四つ口フラスコに、ピリジン－３－スルホン酸１５．９ｇ（０．１００モル）及びモノクロロベンゼン２３．９ｇを入れ、撹拌しながら１２０℃に加熱した。内温を１１９～１２２℃に保持しながら、五塩化リン１９．７ｇ（０．０９５モル）を５時間かけて連続的に投入した。五塩化リンの投入終了後、さらに１時間撹拌した。反応液についてガスクロマトグラフィー（ＧＣ）分析を行ったところ、ピリジン－３－スルホニルクロライドの濃度は２９．２質量％であった。反応液の量（５３．０）ｇより算出した、反応液中でのピリジン－３－スルホニルクロリドの収率は８７．１％であり、副生した５－クロロピリジン－３－スルホニルクロリドのＧＣ分析による面積比率（５－クロロピリジン－３－スルホニルクロリド／ピリジン－３－スルホニルクロリド）は０．０１％であった。 Example 4
[Step 1]
A 100 mL four-necked flask was charged with 15.9 g (0.100 mol) of pyridine-3-sulfonic acid and 23.9 g of monochlorobenzene and heated to 120 ° C. with stirring. While maintaining the internal temperature at 119 to 122 ° C., 19.7 g (0.095 mol) of phosphorus pentachloride was continuously added over 5 hours. After addition of phosphorus pentachloride, the mixture was further stirred for 1 hour. When the reaction solution was analyzed by gas chromatography (GC), the concentration of pyridine-3-sulfonyl chloride was 29.2% by mass. The yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (53.0) g was 87.1%, and the GC of by-produced 5-chloropyridine-3-sulfonyl chloride was obtained. The area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by analysis was 0.01%.
［工程２］
　反応液を９０℃で３．６ｋＰａまで減圧濃縮し、モノクロロベンゼン及び副生したオキシ塩化リンを留去した。次いで、９４℃、０．４ｋＰａの条件で減圧蒸留し、ピリジン－３－スルホニルクロリド１４．０ｇを得た。ピリジン－３－スルホニルクロリドの収率は７８．８％であった。また、ＧＣ分析による面積比率は、ピリジン－３－スルホニルクロリドが９９．９％であり、５－クロロピリジン－３－スルホニルクロリドが０．０１％であった。 [Step 2]
The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, distillation under reduced pressure at 94 ° C. and 0.4 kPa yielded 14.0 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 78.8%. The area ratio by GC analysis was 99.9% for pyridine-3-sulfonyl chloride and 0.01% for 5-chloropyridine-3-sulfonyl chloride.
（比較例５）
　１００ｍＬ四つ口フラスコに、ピリジン－３－スルホン酸１５．９ｇ（０．１００モル）及びモノクロロベンゼン２３．９ｇを入れ、撹拌しながら１２０℃に加熱した。内温を１１９～１２２℃に保持しながら、五塩化リン２０．４ｇ（０．０９８モル）を２０分割して１５分毎に投入した。五塩化リンの投入終了後、さらに１時間撹拌した。反応液についてガスクロマトグラフィー（ＧＣ）分析を行ったところ、ピリジン－３－スルホニルクロリドの濃度は２９．４質量％であった。また、反応液の量（５４．３ｇ）より算出した、反応液中でのピリジン－３－スルホニルクロリドの収率は８９．９％であり、副生した５－クロロピリジン－３－スルホニルクロリドのＧＣ分析による面積比率（５－クロロピリジン－３－スルホニルクロリド／ピリジン－３－スルホニルクロリド）は０．０２％であった。 (Comparative Example 5)
A 100 mL four-necked flask was charged with 15.9 g (0.100 mol) of pyridine-3-sulfonic acid and 23.9 g of monochlorobenzene and heated to 120 ° C. with stirring. While maintaining the internal temperature at 119 to 122 ° C., 20.4 g (0.098 mol) of phosphorus pentachloride was divided into 20 portions and added every 15 minutes. After addition of phosphorus pentachloride, the mixture was further stirred for 1 hour. When the reaction solution was analyzed by gas chromatography (GC), the concentration of pyridine-3-sulfonyl chloride was 29.4% by mass. The yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (54.3 g) was 89.9%, and the by-product of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product. The area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.02%.
　別の３００ｍＬ四つ口フラスコにトルエン６５ｇ及び水４５ｇを入れ、５℃に冷却した後、内温を１５℃以下に保持しながら反応液を滴下した。５℃に冷却した後、内温を２０℃以下に保持しながら５０質量％炭酸カリウム水溶液を添加してｐＨ７．５に調整した。室温で分液した後、有機相についてＧＣ分析を行ったところ、ピリジン－３－スルホニルクロリドの濃度は４．１質量％であった。有機相（抽出相）の量（９２．７ｇ）より算出したピリジン－３－スルホニルクロリドの収率は２１．４％であり、副生した５－クロロピリジン－３－スルホニルクロリドのＧＣ分析による面積比率（５－クロロピリジン－３－スルホニルクロリド／ピリジン－３－スルホニルクロリド）は０．０８％であった。一方、分液した水相（７０．８ｇ）をＨＰＬＣ分析したところ、ピリジン－３－スルホン酸が１５．８質量％（０．０７０４モル、収率換算で７０．４％）検出された。このことから、生成したピリジン－３－スルホニルクロリドが、反応液の後処理、抽出、及び洗浄操作によって加水分解され、副生した５－クロロピリジン－３－スルホニルクロリドのＧＣ分析による面積比率が拡大していたことから、副生成物である５－クロロピリジン－３－スルホニルクロリドは、目的化合物であるピリジン－３－スルホニルクロリドよりも加水分解しにくく濃縮されたことがわかる。 In another 300 mL four-necked flask, 65 g of toluene and 45 g of water were added and cooled to 5 ° C., and then the reaction solution was added dropwise while maintaining the internal temperature at 15 ° C. or lower. After cooling to 5 ° C, a 50 mass% aqueous potassium carbonate solution was added to adjust the pH to 7.5 while maintaining the internal temperature at 20 ° C or lower. After liquid separation at room temperature, the organic phase was subjected to GC analysis. As a result, the concentration of pyridine-3-sulfonyl chloride was 4.1% by mass. The yield of pyridine-3-sulfonyl chloride calculated from the amount of organic phase (extracted phase) (92.7 g) was 21.4%, and the area by GC analysis of 5-chloropyridine-3-sulfonyl chloride as a by-product. The ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) was 0.08%. On the other hand, when the separated aqueous phase (70.8 g) was analyzed by HPLC, 15.8% by mass (0.0704 mol, 70.4% in terms of yield) of pyridine-3-sulfonic acid was detected. From this, the produced pyridine-3-sulfonyl chloride is hydrolyzed by the post-treatment, extraction and washing operations of the reaction solution, and the area ratio by GC analysis of the by-produced 5-chloropyridine-3-sulfonyl chloride is expanded. Thus, it can be understood that 5-chloropyridine-3-sulfonyl chloride, which is a by-product, was concentrated less easily to hydrolyze than the target compound, pyridine-3-sulfonyl chloride.
（実施例５）
［工程１］
　１００ｍＬ四つ口フラスコに、ピリジン－３－スルホン酸１５．９ｇ（０．１００モル）及びモノクロロベンゼン２３．９ｇを入れ、撹拌しながら１２０℃に加熱した。内温を１１９～１２２℃に保持しながら、五塩化リン２０．４ｇ（０．０９８モル）を５分割して１５分毎に投入した。五塩化リンの投入終了後、さらに１時間撹拌した。反応液についてガスクロマトグラフィー（ＧＣ）分析を行ったところ、ピリジン－３－スルホニルクロリドの濃度は２９．４質量％であった。反応液の量（５４．４ｇ）より算出した、反応液中でのピリジン－３－スルホニルクロリドの収率は９０．０％であり、副生した５－クロロピリジン－３－スルホニルクロリドのＧＣ分析による面積比率（５－クロロピリジン－３－スルホニルクロリド／ピリジン－３－スルホニルクロリド）は０．０２％であった。 (Example 5)
[Step 1]
A 100 mL four-necked flask was charged with 15.9 g (0.100 mol) of pyridine-3-sulfonic acid and 23.9 g of monochlorobenzene and heated to 120 ° C. with stirring. While maintaining the internal temperature at 119 to 122 ° C., 20.4 g (0.098 mol) of phosphorus pentachloride was divided into 5 portions and added every 15 minutes. After addition of phosphorus pentachloride, the mixture was further stirred for 1 hour. When the reaction solution was analyzed by gas chromatography (GC), the concentration of pyridine-3-sulfonyl chloride was 29.4% by mass. The yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (54.4 g) was 90.0%, and GC analysis of 5-chloropyridine-3-sulfonyl chloride as a by-product was performed. The area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) was 0.02%.
［工程２］
　反応液を９０℃で３．６ｋＰａまで減圧濃縮し、モノクロロベンゼン及び副生したオキシ塩化リンを留去した。次いで、９４℃、０．４ｋＰａの条件で減圧蒸留し、ピリジン－３－スルホニルクロリド１４．７ｇを得た。ピリジン－３－スルホニルクロリドの収率は８２．８％であった。また、ＧＣ分析による面積比率は、ピリジン－３－スルホニルクロリドが９９．９８％であり、５－クロロピリジン－３－スルホニルクロリドが０．０２％であった。 [Step 2]
The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, the solution was distilled under reduced pressure at 94 ° C. and 0.4 kPa to obtain 14.7 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 82.8%. The area ratio by GC analysis was 99.98% for pyridine-3-sulfonyl chloride and 0.02% for 5-chloropyridine-3-sulfonyl chloride.
（実施例６）
［工程１］
　１００ｍＬ四つ口フラスコに、ピリジン－３－スルホン酸１５．９ｇ（０．１００モル）及びモノクロロベンゼン２３．９ｇを入れ、撹拌しながら１２０℃に加熱した。内温を１１９～１２２℃に保持しながら、五塩化リン２０．４ｇ（０．０９８モル）を２０分割して５分毎に投入した。五塩化リンの投入終了後、さらに１時間撹拌した。反応液についてガスクロマトグラフィー（ＧＣ）分析を行ったところ、ピリジン－３－スルホニルクロリドの濃度は２９．５質量％であった。また、反応液の量（５４．３ｇ）より算出した、反応液中でのピリジン－３－スルホニルクロリドの収率は９０．２％であり、副生した５－クロロピリジン－３－スルホニルクロリドのＧＣ分析による面積比率（５－クロロピリジン－３－スルホニルクロリド／ピリジン－３－スルホニルクロリド）は０．０２％であった。 (Example 6)
[Step 1]
A 100 mL four-necked flask was charged with 15.9 g (0.100 mol) of pyridine-3-sulfonic acid and 23.9 g of monochlorobenzene and heated to 120 ° C. with stirring. While maintaining the internal temperature at 119 to 122 ° C., 20.4 g (0.098 mol) of phosphorus pentachloride was divided into 20 portions and added every 5 minutes. After addition of phosphorus pentachloride, the mixture was further stirred for 1 hour. When the reaction solution was analyzed by gas chromatography (GC), the concentration of pyridine-3-sulfonyl chloride was 29.5% by mass. The yield of pyridine-3-sulfonyl chloride in the reaction solution calculated from the amount of the reaction solution (54.3 g) was 90.2%, and the by-product of 5-chloropyridine-3-sulfonyl chloride was produced as a by-product. The area ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) by GC analysis was 0.02%.
［工程２］
　反応液を９０℃で３．６ｋＰａまで減圧濃縮し、モノクロロベンゼン及び副生したオキシ塩化リンを留去した。次いで、９４℃、０．４ｋＰａの条件で減圧蒸留し、ピリジン－３－スルホニルクロリド１４．９ｇを得た。ピリジン－３－スルホニルクロリドの収率は８３．９％であった。また、ＧＣ分析による面積比率は、ピリジン－３－スルホニルクロリドが９９．９９％であり、５－クロロピリジン－３－スルホニルクロリドが０．０１％であった。 [Step 2]
The reaction solution was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, distillation under reduced pressure at 94 ° C. and 0.4 kPa yielded 14.9 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 83.9%. The area ratio by GC analysis was 99.99% for pyridine-3-sulfonyl chloride and 0.01% for 5-chloropyridine-3-sulfonyl chloride.
（実施例７）
［工程１］
　１００ｍＬ四つ口フラスコに、ピリジン－３－スルホン酸３１．８ｇ（０．２００モル）及びモノクロロベンゼン４７．７ｇを入れ、撹拌しながら１２０℃に加熱した。内温を１１９～１２２℃に保持しながら、五塩化リン２０．８ｇ（０．１００モル（０．５モル等量））を１０分割して１５分毎に投入した。五塩化リンの投入終了後、さらに１時間撹拌した。内温が８０℃になるまで冷却し、析出した未反応のピリジン－３－スルホン酸をろ過した。 (Example 7)
[Step 1]
A 100 mL four-necked flask was charged with 31.8 g (0.200 mol) of pyridine-3-sulfonic acid and 47.7 g of monochlorobenzene and heated to 120 ° C. with stirring. While maintaining the internal temperature at 119 to 122 ° C., 20.8 g (0.100 mol (0.5 mol equivalent)) of phosphorus pentachloride was divided into 10 portions and added every 15 minutes. After addition of phosphorus pentachloride, the mixture was further stirred for 1 hour. The mixture was cooled to an internal temperature of 80 ° C., and the precipitated unreacted pyridine-3-sulfonic acid was filtered.
［工程２］
　ろ液を９０℃で３．６ｋＰａまで減圧濃縮し、モノクロロベンゼン及び副生したオキシ塩化リンを留去した。次いで、９４℃、０．４ｋＰａの条件で減圧蒸留し、ピリジン－３－スルホニルクロリド１３．２ｇを得た。ピリジン－３－スルホニルクロリドの収率は３７．２％であった。ＧＣ分析による面積比率は、ピリジン－３－スルホニルクロリドが１００％であった。 [Step 2]
The filtrate was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Subsequently, distillation was performed under reduced pressure at 94 ° C. and 0.4 kPa to obtain 13.2 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 37.2%. The area ratio by GC analysis was 100% for pyridine-3-sulfonyl chloride.
［工程３］
　一方、１００ｍＬ四つ口フラスコに、上記「工程１」でろ過して得た未反応のピリジン－３－スルホン酸の湿体、ピリジン－３－スルホン酸１５．９ｇ、及びモノクロロベンゼン４５．５ｇを入れ、撹拌しながら１２０℃に加熱した。内温を１１９～１２２℃に保持しながら、五塩化リン２０．８ｇ（０．１００モル（０．５モル等量））を１０分割して１５分毎に投入した。五塩化リンの投入終了後、さらに１時間撹拌した。内温が８０℃になるまで冷却し、析出した未反応のピリジン－３－スルホン酸をろ過した。 [Step 3]
On the other hand, the unreacted pyridine-3-sulfonic acid wet matter obtained by filtration in the above “Step 1”, 15.9 g of pyridine-3-sulfonic acid, and 45.5 g of monochlorobenzene were added to a 100 mL four-necked flask. And heated to 120 ° C. with stirring. While maintaining the internal temperature at 119 to 122 ° C., 20.8 g (0.100 mol (0.5 mol equivalent)) of phosphorus pentachloride was divided into 10 portions and added every 15 minutes. After addition of phosphorus pentachloride, the mixture was further stirred for 1 hour. The mixture was cooled to an internal temperature of 80 ° C., and the precipitated unreacted pyridine-3-sulfonic acid was filtered.
［工程４］
　ろ液を９０℃で３．６ｋＰａまで減圧濃縮し、モノクロロベンゼン及び副生したオキシ塩化リンを留去した。次いで、９４℃、０．４ｋＰａの条件で減圧蒸留し、ピリジン－３－スルホニルクロリド１６．４ｇを得た。ピリジン－３－スルホニルクロリドの収率は４６．２％（五塩化リンの理論収率から９２．４％）であった。ＧＣ分析による面積比率は、ピリジン－３－スルホニルクロリドが１００％であった。なお、上記「工程３」でろ過して得たピリジン－３－スルホン酸の湿体は、同様にして次の反応工程（工程５、６、…）に用いることができる。 [Step 4]
The filtrate was concentrated under reduced pressure at 90 ° C. to 3.6 kPa, and monochlorobenzene and by-product phosphorus oxychloride were distilled off. Next, distillation under reduced pressure at 94 ° C. and 0.4 kPa yielded 16.4 g of pyridine-3-sulfonyl chloride. The yield of pyridine-3-sulfonyl chloride was 46.2% (92.4% from the theoretical yield of phosphorus pentachloride). The area ratio by GC analysis was 100% for pyridine-3-sulfonyl chloride. The wet pyridine-3-sulfonic acid obtained by filtration in the above “Step 3” can be used in the next reaction step (Steps 5, 6,...) In the same manner.
　本発明の製造方法は、医薬品を製造するための原料や中間体として有用なピリジン－３－スルホニルクロリドを工業的に製造する方法として好適である。 The production method of the present invention is suitable as a method for industrially producing pyridine-3-sulfonyl chloride, which is useful as a raw material or an intermediate for producing a pharmaceutical product.

Claims (6)

  1. 　ピリジン－３－スルホン酸を含む反応液に、前記ピリジン－３－スルホン酸に対して１モル当量未満の五塩化リンを、（ｉ）複数に分割して段階的に添加する、又は（ii）連続的に添加し、前記ピリジン－３－スルホン酸と前記五塩化リンを逐次反応させてピリジン－３－スルホニルクロリドを生成させる工程と、
    　前記反応液を減圧蒸留して前記ピリジン－３－スルホニルクロリドを精製する工程と、を有するピリジン－３－スルホニルクロリドの製造方法。     To the reaction solution containing pyridine-3-sulfonic acid, less than 1 molar equivalent of phosphorus pentachloride with respect to the pyridine-3-sulfonic acid is added stepwise (i) in multiple portions, or (ii) Continuously adding and sequentially reacting the pyridine-3-sulfonic acid and the phosphorus pentachloride to produce pyridine-3-sulfonyl chloride;
    A step of purifying the pyridine-3-sulfonyl chloride by subjecting the reaction solution to distillation under reduced pressure, and a method for producing pyridine-3-sulfonyl chloride.
  2. 　前記五塩化リンを５以上に分割し、１時間以上かけて前記反応液に段階的に添加する請求項１に記載のピリジン－３－スルホニルクロリドの製造方法。 The method for producing pyridine-3-sulfonyl chloride according to claim 1, wherein the phosphorus pentachloride is divided into 5 or more and added stepwise to the reaction solution over 1 hour or more.
  3. 　前記五塩化リンを、１時間以上かけて前記反応液に連続的に添加する請求項１に記載のピリジン－３－スルホニルクロリドの製造方法。 The method for producing pyridine-3-sulfonyl chloride according to claim 1, wherein the phosphorus pentachloride is continuously added to the reaction solution over 1 hour or more.
  4. 　前記ピリジン－３－スルホン酸と前記五塩化リンを１００～１４０℃で反応させる請求項１～３のいずれか一項に記載のピリジン－３－スルホニルクロリドの製造方法。 The method for producing pyridine-3-sulfonyl chloride according to any one of claims 1 to 3, wherein the pyridine-3-sulfonic acid and the phosphorus pentachloride are reacted at 100 to 140 ° C.
  5. 　前記ピリジン－３－スルホン酸に対して、前記五塩化リンを０．４モル当量以上用いる請求項１～４のいずれか一項に記載のピリジン－３－スルホニルクロリドの製造方法。 The method for producing pyridine-3-sulfonyl chloride according to any one of claims 1 to 4, wherein 0.4 mol equivalent or more of the phosphorus pentachloride is used with respect to the pyridine-3-sulfonic acid.
  6. 　前記反応液が、モノクロロベンゼン及びジクロロベンゼンの少なくともいずれかの溶媒をさらに含む請求項１～５のいずれか一項に記載のピリジン－３－スルホニルクロリドの製造方法。 The method for producing pyridine-3-sulfonyl chloride according to any one of claims 1 to 5, wherein the reaction solution further contains at least one solvent of monochlorobenzene and dichlorobenzene.
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WO2023182391A1 (en) 2022-03-24 2023-09-28 住友化学株式会社 Method for controlling plant diseases

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JP6165373B1 (en) * 2017-02-24 2017-07-19 タマ化学工業株式会社 Method for producing pyridine-3-sulfonyl chloride
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