WO2024028999A1 - Method for producing n-[4-methylaminobenzoyl]-l-glutamic acid diethyl ester - Google Patents

Method for producing n-[4-methylaminobenzoyl]-l-glutamic acid diethyl ester Download PDF

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WO2024028999A1
WO2024028999A1 PCT/JP2022/029737 JP2022029737W WO2024028999A1 WO 2024028999 A1 WO2024028999 A1 WO 2024028999A1 JP 2022029737 W JP2022029737 W JP 2022029737W WO 2024028999 A1 WO2024028999 A1 WO 2024028999A1
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compound
diethyl ester
glutamic acid
mmol
reaction
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潤 竹原
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Ils株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring

Definitions

  • the present invention relates to a method for producing N-[4-methylaminobenzoyl]-L-glutamic acid diethyl ester.
  • N-[4-methylaminobenzoyl]-L-glutamic acid diethyl ester which is a compound useful as a pharmaceutical intermediate, is industrially produced by converting L-glutamic acid diethyl ester into 4-nitrobenzoic acid amidation. It is produced by subsequent reduction of the nitro group and N-monomethylation.
  • N monomethylation when using reductive amination with high yield and mild conditions, expensive reducing agents and catalysts are used and multiple steps are required (Non-Patent Document 1, Non-Patent Document 2).
  • a highly reactive and expensive alkylating agent is used to suppress racemization, but the yield is low (Patent Document 1, Patent Document 2, Non-Patent Document 3).
  • 4-monomethylaminobenzoic acid can be obtained by N-monomethylation of 4-aminobenzoic acid (Non-patent Document 4, Non-patent Document 5, Non-patent Document 6, Patent Document 4, Patent Document 5, Patent Document 6), It is synthesized by methylamine substitution of halobenzoic acid (Non-patent Document 7), demethylation of 4-N,N-dimethylaminobenzoic acid (Non-patent Document 8), etc.
  • these methods require special reaction equipment such as pressurization and photosensitization, use expensive catalysts and reactants, and require multiple steps, so they are not versatile and are difficult to achieve. The rate is also not sufficient.
  • Me represents a methyl group and Et represents an ethyl group.
  • N-[4-methylaminobenzoyl]-L-glutamic acid diethyl ester can be produced easily at low cost and with high selectivity.
  • Step 1 Step of deriving 4-aminobenzoic acid (compound (A)) into 4-(nitrophenylsulfonylamino)benzoic acid (compound (B))
  • This step is carried out in the presence of a base, and the base is , inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, and organic bases such as triethylamine and pyridine.
  • the amount of the base used is 1.0 to 10 times the molar amount, preferably 1.5 to 3 times the molar amount of 4-aminobenzoic acid (compound (A)).
  • 4-nitrobenzenesulfonyl chloride and 2-nitrobenzenesulfonyl chloride are used as the nitrophenylsulfonylating agent, and the amount of the nitrophenylsulfonylating agent used is 1 to 3 times the mole of 4-aminobenzoic acid (compound (A)). amount, preferably 1 to 1.5 times the molar amount.
  • the reaction temperature is 0 to 80°C, preferably 10 to 40°C.
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, but water, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, esters such as ethyl acetate, and ketones such as acetone and methyl ethyl ketone are used. Ethers such as THF and dioxane can be used, preferably water.
  • the reaction time is until the reaction is substantially completed, and is usually 1 to 3 hours.
  • Step 2 Step of deriving 4-(nitrophenylsulfonylamino)benzoic acid (compound (B)) into 4-(nitrophenylsulfonylmethylamino)benzoic acid (compound (C))
  • the sulfonamide group is To methylate, it is carried out in the presence of a base.
  • a base inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydride, and organic bases such as sodium t-butoxide and potassium t-butoxide are used, and preferably sodium carbonate and It is potassium carbonate.
  • the amount of the base used is 1.0 to 10 times the molar amount, preferably 2 to 3 times the molar amount of 4-(nitrophenylsulfonylamino)benzoic acid (compound (B)).
  • the methylating agent dimethyl sulfate, methyl chloride, methyl bromide, methyl iodide, methyl methanesulfonate, and methyl p-toluenesulfonate are used, with dimethyl sulfate being preferred.
  • the amount of the methylating agent used is 1 to 5 times the molar amount, preferably 2 to 3 times the molar amount of 4-(nitrophenylsulfonylamino)benzoic acid (compound (B)).
  • the reaction temperature is 0 to 100°C, preferably 60 to 80°C.
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, but water, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, esters such as ethyl acetate, and ketones such as acetone and methyl ethyl ketone are used. ethers such as THF and dioxane, dimethylformamide and N-methylpyrrolidone, preferably acetone and water.
  • the reaction time is until the reaction is substantially completed, and is usually 5 to 10 hours.
  • the product is a methyl ester, it is further hydrolyzed, made acidic by adding acid and water, and the precipitated solid is collected by filtration, or it is treated with halogenated hydrocarbons such as methylene chloride or chloroform, toluene, etc. Aromatic hydrocarbons and esters such as ethyl acetate are added to extract the product.
  • halogenated hydrocarbons such as methylene chloride or chloroform, toluene, etc.
  • Aromatic hydrocarbons and esters such as ethyl acetate are added to extract the product.
  • lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. are used as a base, and the amount of base used is based on 4-(nitrophenylsulfonylmethylamino)benzoic acid methyl ester.
  • the amount is 1.0 to 10 times the molar amount, preferably 2 to 3 times the molar amount.
  • reaction temperature is 0 to 100°C, preferably 60 to 80°C.
  • Reaction solvents are not particularly limited as long as they do not interfere with the reaction, but include water, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, ethers such as THF and dioxane, and alcohols such as methanol and ethanol.
  • a mixture of water and methanol or a mixture of water and THF can be used, preferably a mixture of water and methanol.
  • the reaction time is until the reaction is substantially completed, and is usually 5 to 10 hours.
  • Step 3 Step of deriving 4-(nitrophenylsulfonylmethylamino)benzoic acid (compound (C)) into 4-(nitrophenylsulfonylmethylamino)benzoic acid chloride (compound (D))
  • a chlorinating agent which converts the chloride into an acid chloride.
  • the chlorinating agent preferably thionyl chloride, phosphorus oxychloride, and phosphorus pentachloride are used.
  • a catalytic amount of N,N-dimethylformamide may be added to accelerate the reaction.
  • the amount of the chlorinating agent to be used is 1 to 10 times the molar amount, preferably 1 to 3 times the molar amount of the substrate (compound (C)). It is not necessary to use a reaction solvent, but halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, esters such as ethyl acetate, ketones such as acetone and methyl ethyl ketone, THF and dioxane Ethers such as can be used.
  • the reaction temperature is 0 to 100°C, preferably 50 to 80°C.
  • the reaction time is until the reaction is substantially completed, and is usually 1 to 10 hours. After the reaction, the solvent is distilled off to obtain the product.
  • Step 4 4-(nitrophenylsulfonylmethylamino)benzoic acid chloride (compound (D)) is converted to N-[4-(nitrophenylsulfonylmethylamino)benzoyl]-L-glutamic acid diethyl ester (compound (E))
  • a base is used to induce the amino group of the glutamic acid diester to an amide of N-protected aminobenzoic acid.
  • inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate, and organic bases such as triethylamine and pyridine are used.
  • the amount of base to be used is 1 to 10 times the molar amount, preferably 1 to 3 times the molar amount of the acid chloride (compound (D)).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, but water, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, esters such as ethyl acetate, acetone and methyl ethyl ketone, etc. Ketones, ethers such as THF and dioxane can be used, and preferably water and a mixed solvent of water and halogenated hydrocarbons are used.
  • the reaction temperature is 0 to 50°C, preferably 10 to 30°C.
  • the reaction time is until the reaction is substantially completed, and is usually 1 to 6 hours.
  • halogenated hydrocarbons such as methylene chloride and chloroform
  • aromatic hydrocarbons such as toluene
  • esters such as ethyl acetate
  • Step 5 N-[4-(nitrophenylsulfonylmethylamino)benzoyl]-L-glutamic acid diethyl ester (compound (E)) is converted to N-4-methylaminobenzoyl-L-glutamic acid diethyl ester (compound (F))
  • This step uses thiols to deprotect the nitrophenylsulfonyl group.
  • thiols thiophenol, thioglycolic acid, thioglycerol, etc. can be used, and the amount of thiols used is 1 to 10 equivalents, preferably 1.5 to 3 equivalents, relative to the substrate (compound (E)). It is.
  • Deprotection usually uses a base along with thiols.
  • a base inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate, and organic bases such as triethylamine and pyridine are used.
  • the amount of base to be used is 1 to 10 times the molar amount, preferably 2 to 6 times the molar amount of the substrate (compound (E)).
  • the reaction temperature is 0 to 100°C, preferably 30 to 60°C.
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, but water, alcohols such as methanol and ethanol, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, and esters such as ethyl acetate are used.
  • ethers such as THF and dioxane, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, and preferably alcohols, N,N-dimethylformamide and acetonitrile.
  • the reaction time is until the reaction is substantially completed, and is usually 1 to 20 hours.
  • the product can be extracted by adding halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, and esters such as ethyl acetate.
  • Step 6 Step of deriving 4-(nitrophenylsulfonylamino)benzoic acid (compound (B)) into 4-(nitrophenylsulfonylamino)benzoic acid chloride (compound (G)) This step It is carried out in the presence of a chlorinating agent which converts to chloride. The details are the same as in step 3.
  • Step 7 Inducing 4-(nitrophenylsulfonylamino)benzoic acid chloride (compound (G)) to N-[4-(nitrophenylsulfonylamino)benzoyl]-L-glutamic acid diethyl ester (compound (H)) Step
  • This step uses a base to induce the amino group of the glutamic acid diester into an amide of N-protected aminobenzoic acid. The details are the same as in step 4.
  • Example 1 To a mixed solution of 5.00 g (36.5 mmol) of 4-aminobenzoic acid (compound (A)), 3.87 g (36.5 mmol) of sodium carbonate, and 25 ml of water, 8.09 g (36.5 mmol) of 2-nitrobenzenesulfonyl chloride was added. ) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, 0.77 g (7.3 mmol) of sodium carbonate and 10 ml of water were added and stirred at room temperature for 0.5 hours. Then, 6N hydrochloric acid was added to adjust the pH to 1, and the precipitated solid was filtered, washed with water, and dried.
  • Step 1-2 To a mixture of 5.00 g (36.5 mmol) of 4-aminobenzoic acid (compound (A)), 3.87 g (36.5 mmol) of sodium carbonate, and 50 ml of water, 8.09 g (36.5 mmol) of 4-nitrobenzenesulfonyl chloride was added. ) was added at room temperature and stirred at room temperature overnight. After the reaction was completed, 6N hydrochloric acid was added to adjust the pH to 1, and the precipitated solid was filtered, washed with water, and dried to obtain 9.96 g of 4-(4-nitrophenylsulfonylamino)benzoic acid (compound (B2)). Yield 85%. CDCl3 insoluble.
  • Step 2-1 4-(2-nitrophenylsulfonylamino)benzoic acid (compound (B1)) obtained in step 1-1 5.00 g (15.53 mmol), potassium carbonate 4.71 g (34.17 mmol), dimethyl sulfate 4.11 g (32.61 mmol) and 50 ml of acetone was stirred under heating and reflux for 5 hours. After the reaction was completed, 25 ml of water was added, acetone was distilled off under reduced pressure, and the precipitated solid was filtered, washed with water, and dried to obtain 4.84 g of 4-(2-nitrophenylsulfonylmethylamino)benzoic acid methyl ester. Yield 89%.
  • Step 2-2 4-(4-nitrophenylsulfonylamino)benzoic acid (compound (B2)) obtained in step 1-2 5.00 g (15.53 mmol), potassium carbonate 4.71 g (34.17 mmol), dimethyl sulfate 4.11 g (32.61 mmol) and 50 ml of acetone was stirred under heating and reflux for 7 hours. After the reaction was completed, 40 ml of water was added, acetone was distilled off under reduced pressure, 6N hydrochloric acid was added to adjust the pH to 1, and the precipitated solid was filtered and washed with water.
  • Step 3-1 To 2.00 g (5.95 mmol) of 4-(2-nitrophenylsulfonylmethylamino)benzoic acid (compound (C1)) obtained in Step 2-1, 10 ml of dichloromethane and 0.05 g of N,N-dimethylformamide, 1.42 g (11.9 mmol) of thionyl chloride was added, and the mixture was stirred at 50° C. for 1.5 hours.
  • Step 3-2 To 1.50 g (4.46 mmol) of 4-(4-nitrophenylsulfonylmethylamino)benzoic acid (compound (C2)) obtained in Step 2-2, 7.5 ml of dichloromethane and 0.0 mL of N,N-dimethylformamide were added. 02 g, and 1.06 g (8.92 mmol) of thionyl chloride were added thereto, and the mixture was stirred at 50° C. for 2 hours.
  • Step 4-1 1.25 g (3.53 mmol) of 4-(2-nitrophenylsulfonylmethylamino)benzoic acid chloride (compound (D1)) obtained in Step 3-1, 0.85 g (3.53 mmol) of L-glutamic acid diethyl ester hydrochloride 3.51 g (6.71 mmol) of a 20% aqueous sodium carbonate solution was added to a mixture of 8.5 ml of dichloromethane and 1.1 ml of water, and the mixture was stirred overnight at room temperature.
  • Step 4-2 1.00 g (2.82 mmol) of 4-(4-nitrophenylsulfonylmethylamino)benzoic acid chloride (compound (D2)) obtained in Step 3-2, 0.68 g (2.82 mmol) of L-glutamic acid diethyl ester hydrochloride 2.87 g (5.36 mmol) of a 20% aqueous sodium carbonate solution was added to a mixture of 0.82 mmol), 6.8 ml of dichloromethane, and 0.9 ml of water, and the mixture was stirred at room temperature for 4.5 hours.
  • Step 5-1 A mixture of 1.5 ml of ethanol, 39 ⁇ L (0.57 mmol) of thioglycolic acid, and 0.16 g (1.14 mmol) of potassium carbonate was heated and stirred under reflux for 2 hours, and then the mixture obtained in step 4-1 was added to the mixture. 0.10 g (0.19 mmol) of N-[4-(2-nitrophenylsulfonylmethylamino)benzoyl]-L-glutamic acid diethyl ester (compound (E1)) and 1.5 ml of ethanol were added and the mixture was stirred at room temperature. Stirred for 5 hours.
  • Step 5-2 A mixture of 1.5 ml of ethanol, 39 ⁇ L (0.57 mmol) of thioglycolic acid, and 0.16 g (1.14 mmol) of potassium carbonate was heated and stirred under reflux for 2 hours, and then the mixture obtained in step 4-1 was added to the mixture. Add 0.10 g (0.19 mmol) of N-[4-(4-nitrophenylsulfonylmethylamino)benzoyl]-L-glutamic acid diethyl ester (compound (E2)) and 1.5 ml of ethanol and stir at room temperature for 1 hour. Stirred.
  • Example 2 To 1.00 g (3.11 mmol) of 4-(2-nitrophenylsulfonylamino)benzoic acid (compound (B1)) obtained in Step 1-1, 13 ml of dichloromethane, 0.02 g of N,N-dimethylformamide, and thionyl chloride. 0.74 g (6.22 mmol) was added and stirred at 50°C for 5.5 hours.
  • Step 6-2 To 1.00 g (3.11 mmol) of 4-(4-nitrophenylsulfonylamino)benzoic acid (compound (B2)) obtained in Step 1-2, 5 ml of dichloromethane, 0.02 g of N,N-dimethylformamide, and thionyl chloride. 0.74 g (6.22 mmol) was added and stirred at 50°C for 3 hours.
  • Step 7-1 0.81 g (2.38 mmol) of 4-(2-nitrophenylsulfonylamino)benzoic acid chloride (compound (G1)) obtained in Step 6-1, 0.57 g (2.38 mmol) of L-glutamic acid diethyl ester hydrochloride ), 0.99 ml (7.14 mmol) of triethylamine was added to a mixture of 5.7 ml of dichloromethane, and the mixture was stirred at room temperature overnight.
  • Step 7-2 0.81 g (2.38 mmol) of 4-(4-nitrophenylsulfonylamino)benzoic acid chloride (compound (G2)) obtained in Step 6-2, 0.57 g (2.38 mmol) of L-glutamic acid diethyl ester hydrochloride ), 0.99 ml (7.14 mmol) of triethylamine was added to a mixture of 5.7 ml of dichloromethane, and the mixture was stirred at room temperature overnight.
  • Step 8-1 N-[4-(2-nitrophenylsulfonylamino)benzoyl]-L-glutamic acid diethyl ester (compound (H1)) obtained in Step 7-1 0.31 g (0.61 mmol), dimethyl sulfate 0.15 g (1 A mixed solution of 0.17 g (1.22 mmol) of potassium carbonate, and 3 ml of acetone was stirred at room temperature for 2 hours.
  • Step 8-2 N-[4-(4-nitrophenylsulfonylamino)benzoyl]-L-glutamic acid diethyl ester (compound (H2)) obtained in Step 7-2 0.10 g (0.20 mmol), dimethyl sulfate 0.05 g (0 A mixture of 0.06 g (0.40 mmol), potassium carbonate, and 2 ml of acetone was stirred at room temperature for 1 hour.
  • Step 5-1 A mixture of 1 ml of ethanol, 33 ⁇ L (0.38 mmol) of ⁇ -thioglycerol, and 0.05 g (1.38 mmol) of potassium carbonate was heated and stirred under reflux for 1 hour, and then added to this mixture was the N obtained in step 4-1. 0.10 g (0.19 mmol) of -[4-(2-nitrophenylsulfonylmethylamino)benzoyl]-L-glutamic acid diethyl ester (compound (E1)) and 1 ml of ethanol were added, and the mixture was stirred at room temperature overnight.
  • N-4-methylaminobenzoyl-L-glutamic acid diethyl ester which is the target compound of the present invention, can be used as a pharmaceutical intermediate. It can be used as an anti-rheumatic drug.

Abstract

The present invention addresses the problem of providing a method for efficiently producing an N-[4-methylaminobenzoyl]-L-glutamic acid diethyl ester, which is a pharmaceutical intermediate. In this method for producing an N-[4-methylaminobenzoyl]-L-glutamic acid diethyl ester, 4-aminobenozic acid protected with an inexpensive nitrobenzenesulfonyl group is used as a starting material and N-monomethylated in an inexpensive and simple manner. Thus, the skeleton is constructed by a minimum number of steps with the inexpensive reagent.

Description

Ｎ－［４－メチルアミノベンゾイル］－Ｌ－グルタミン酸ジエチルエステルの製造方法Method for producing N-[4-methylaminobenzoyl]-L-glutamic acid diethyl ester
　本発明は、Ｎ－［４－メチルアミノベンゾイル］－Ｌ－グルタミン酸ジエチルエステルの製造方法に関する。 The present invention relates to a method for producing N-[4-methylaminobenzoyl]-L-glutamic acid diethyl ester.
　医薬中間体として有用な化合物であるＮ－［４－メチルアミノベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（F））は、工業的にはＬ－グルタミン酸ジエチルエステルの４－ニトロ安息香酸アミド化とこれに続くニトロ基の還元およびNモノメチル化によって製造されている。
　しかしここでのNモノメチル化では、高収率で温和条件である還元アミノ化を用いる場合には高価な還元剤や触媒を使用し多工程を要すること（非特許文献１、非特許文献２）、直接アルキル化の場合にはラセミ化抑制のために反応性の高い高価なアルキル化剤を使用するものの収率が低い問題を有する（特許文献１、特許文献２、非特許文献３）。 N-[4-methylaminobenzoyl]-L-glutamic acid diethyl ester (compound (F)), which is a compound useful as a pharmaceutical intermediate, is industrially produced by converting L-glutamic acid diethyl ester into 4-nitrobenzoic acid amidation. It is produced by subsequent reduction of the nitro group and N-monomethylation.
However, in this N monomethylation, when using reductive amination with high yield and mild conditions, expensive reducing agents and catalysts are used and multiple steps are required (Non-Patent Document 1, Non-Patent Document 2). In the case of direct alkylation, a highly reactive and expensive alkylating agent is used to suppress racemization, but the yield is low (Patent Document 1, Patent Document 2, Non-Patent Document 3).
　一方で、Ｎ－［４－メチルアミノベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（F））の製法としては、４－モノメチルアミノ安息香酸を出発原料とする方法も知られているがアミノ基無保護での収率が低い問題がある（特許文献３）。
　さらに４－モノメチルアミノ安息香酸は４－アミノ安息香酸のＮ－モノメチル化（非特許文献４、非特許文献５、非特許文献６、特許文献４、特許文献５、特許文献６）や、４－ハロ安息香酸のメチルアミン置換（非特許文献７）や、４－Ｎ，Ｎ－ジメチルアミノ安息香酸の脱メチル化（非特許文献８）などによって合成される。
　しかし、これらの方法は、加圧や光増感反応など特殊な反応装置を必要としたり、高価な触媒や反応剤を用いたり、多工程を要するものであったりするため汎用的ではなく、収率も十分ではない。 On the other hand, as a method for producing N-[4-methylaminobenzoyl]-L-glutamic acid diethyl ester (compound (F)), a method using 4-monomethylaminobenzoic acid as a starting material is known, but it is There is a problem that the yield in protection is low (Patent Document 3).
Furthermore, 4-monomethylaminobenzoic acid can be obtained by N-monomethylation of 4-aminobenzoic acid (Non-patent Document 4, Non-patent Document 5, Non-patent Document 6, Patent Document 4, Patent Document 5, Patent Document 6), It is synthesized by methylamine substitution of halobenzoic acid (Non-patent Document 7), demethylation of 4-N,N-dimethylaminobenzoic acid (Non-patent Document 8), etc.
However, these methods require special reaction equipment such as pressurization and photosensitization, use expensive catalysts and reactants, and require multiple steps, so they are not versatile and are difficult to achieve. The rate is also not sufficient.
欧州公開特許204529号広報European Publication Patent No. 204529 Publication 中国公開特許102234266号広報China Publication Patent No. 102234266 Publication 韓国公開特許2009049001号広報Korean Publication Patent No. 2009049001 Publication 欧州公開特許1431274号広報Publication of European Patent Publication No. 1431274 国際公開特許2005039572号広報International Publication Patent No. 2005039572 Publication 国際公開特許2019024924号広報International Publication Patent No. 2019024924 Publication
　医薬中間体として有用な化合物であるＮ－［４－メチルアミノベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（F））の製造法に関して、従来知られている方法では不十分であり、より安価で簡便かつ高選択率な手段が望まれている。 Regarding the production method of N-[4-methylaminobenzoyl]-L-glutamic acid diethyl ester (compound (F)), which is a compound useful as a pharmaceutical intermediate, conventionally known methods are insufficient, and a cheaper method is required. A simple and highly selective method is desired.
　本発明者らは、かかる課題を解決するため鋭意検討を重ねた結果、安価なニトロベンゼンスルホニル基で保護した４－アミノ安息香酸を原料として、安価で完便な方法でN-モノメチル化することにより、骨格構築を最小限の工程と安価試剤で達成する方法を見出し、本発明を完成するに至った。 As a result of extensive studies to solve this problem, the present inventors have discovered that by using an inexpensive nitrobenzenesulfonyl group-protected 4-aminobenzoic acid as a raw material, N-monomethylation is carried out in an inexpensive and convenient manner. discovered a method for constructing a skeleton using minimal steps and inexpensive reagents, and completed the present invention.
　本発明によれば以下の発明が提供される。
＜１＞　４－アミノ安息香酸である下記化合物（A）のアミノ基をニトロフェニルスルホンアミド化して下記化合物（B）を製造する工程１：
前記化合物（B）のスルホンアミド基をメチル化して下記化合物（C）を製造する工程２：
前記化合物（C）のカルボキシル基をカルボン酸クロリドに変換して下記化合物（D）を製造する工程３：
前記化合物（D）からL-グルタミン酸ジエチルエステルのアミド誘導体である下記化合物（E）を製造する工程４：および
前記化合物（E）のニトロフェニルスルホニル基を除去する工程５：
を含む、Ｎ－［４－メチルアミノベンゾイル］－Ｌ－グルタミン酸ジエチルエステルである化合物(F)の製造方法。
式中、Ｍｅはメチル基を示し、Ｅｔはエチル基を示す。
＜２＞　４－アミノ安息香酸である下記化合物（A）のアミノ基をニトロフェニルスルホンアミド化して下記化合物（B）を製造する工程１：
前記化合物（B）のカルボキシル基をカルボン酸クロリドに変換して下記化合物（G）を製造する工程６：
前記化合物（G）からL-グルタミン酸ジエチルエステルのアミド誘導体である下記化合物（H）を製造する工程７：
前記化合物（H）のスルホンアミド基をメチル化して下記化合物（E）を製造する工程８：および
前記化合物（E）のニトロフェニルスルホニル基を除去する工程５：
を含む、Ｎ－［４－メチルアミノベンゾイル］－Ｌ－グルタミン酸ジエチルエステルである化合物(F)の製造方法。
式中、Ｍｅはメチル基を示し、Ｅｔはエチル基を示す。
＜３＞　下記で示される化合物（Ｅ１）および化合物（Ｅ２）
式中、Ｍｅはメチル基を示す。
＜４＞　下記式４で示される化合物（Ｄ１）および化合物（Ｄ２）
式中、Ｍｅはメチル基を示す。
＜５＞　下記式で示される化合物（Ｈ１）
式中、Ｅｔはエチル基を示す。 According to the present invention, the following inventions are provided.
<1> Step 1 of producing the following compound (B) by converting the amino group of the following compound (A), which is 4-aminobenzoic acid, into nitrophenylsulfonamidation:
Step 2 of producing the following compound (C) by methylating the sulfonamide group of the compound (B):
Step 3 of converting the carboxyl group of the compound (C) into a carboxylic acid chloride to produce the following compound (D):
Step 4 of producing the following compound (E) which is an amide derivative of L-glutamic acid diethyl ester from the compound (D): and Step 5 of removing the nitrophenylsulfonyl group of the compound (E):
A method for producing compound (F), which is N-[4-methylaminobenzoyl]-L-glutamic acid diethyl ester.
In the formula, Me represents a methyl group and Et represents an ethyl group.
<2> Step 1 of producing the following compound (B) by converting the amino group of the following compound (A), which is 4-aminobenzoic acid, into nitrophenylsulfonamidation:
Step 6 of converting the carboxyl group of the compound (B) into a carboxylic acid chloride to produce the following compound (G):
Step 7 of producing the following compound (H), which is an amide derivative of L-glutamic acid diethyl ester, from the compound (G):
Step 8 of producing the following compound (E) by methylating the sulfonamide group of the compound (H): and Step 5 of removing the nitrophenylsulfonyl group of the compound (E):
A method for producing compound (F), which is N-[4-methylaminobenzoyl]-L-glutamic acid diethyl ester.
In the formula, Me represents a methyl group and Et represents an ethyl group.
<3> Compound (E1) and compound (E2) shown below
In the formula, Me represents a methyl group.
<4> Compound (D1) and compound (D2) represented by the following formula 4
In the formula, Me represents a methyl group.
<5> Compound (H1) represented by the following formula
In the formula, Et represents an ethyl group.
　本発明によれば、安価で簡便かつ高選択率でＮ－［４－メチルアミノベンゾイル］－Ｌ－グルタミン酸ジエチルエステルを製造することができる。 According to the present invention, N-[4-methylaminobenzoyl]-L-glutamic acid diethyl ester can be produced easily at low cost and with high selectivity.
　以下に本発明における工程の詳細を述べる。
＜工程１＞４－アミノ安息香酸（化合物（A））を４－（ニトロフェニルスルホニルアミノ）安息香酸（化合物（B））に誘導する工程
　本工程は塩基の存在下で行われ、塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウムなどの無機塩基や、トリエチルアミン、ピリジンなどの有機塩基が用いられる。塩基の使用量は４－アミノ安息香酸（化合物（A））に対して１．０～１０倍モル量、好ましくは１．５～３倍モル量である。ニトロフェニルスルホニル化剤には４－ニトロベンゼンスルホニルクロリド、２－ニトロベンゼンスルホニルクロリドが用いられ、ニトロフェニルスルホニル化剤の使用量は４－アミノ安息香酸（化合物（A））に対して１～３倍モル量、好ましくは１～１．５倍モル量である。反応温度は０～８０℃であり、好ましくは１０～４０℃である。反応溶媒は反応に支障なければ特に制限はないが、水、塩化メチレンやクロロホルムなどのハロゲン化炭化水素類、トルエンなどの芳香族炭化水素類、酢酸エチルなどのエステル類、アセトンやメチルエチルケトンなどのケトン類、ＴＨＦやジオキサンなどのエーテル類を使用することができ、好ましくは水である。反応時間は実質的に反応が終了するまでであり、通常1～3時間である。反応後、酸および水を添加して酸性とし、析出した固体を濾取するか、塩化メチレンやクロロホルムなどのハロゲン化炭化水素類、トルエンなどの芳香族炭化水素類、酢酸エチルなどのエステル類を添加して生成物を抽出する。 The details of the steps in the present invention will be described below.
<Step 1> Step of deriving 4-aminobenzoic acid (compound (A)) into 4-(nitrophenylsulfonylamino)benzoic acid (compound (B)) This step is carried out in the presence of a base, and the base is , inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, and organic bases such as triethylamine and pyridine. The amount of the base used is 1.0 to 10 times the molar amount, preferably 1.5 to 3 times the molar amount of 4-aminobenzoic acid (compound (A)). 4-nitrobenzenesulfonyl chloride and 2-nitrobenzenesulfonyl chloride are used as the nitrophenylsulfonylating agent, and the amount of the nitrophenylsulfonylating agent used is 1 to 3 times the mole of 4-aminobenzoic acid (compound (A)). amount, preferably 1 to 1.5 times the molar amount. The reaction temperature is 0 to 80°C, preferably 10 to 40°C. The reaction solvent is not particularly limited as long as it does not interfere with the reaction, but water, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, esters such as ethyl acetate, and ketones such as acetone and methyl ethyl ketone are used. Ethers such as THF and dioxane can be used, preferably water. The reaction time is until the reaction is substantially completed, and is usually 1 to 3 hours. After the reaction, make it acidic by adding acid and water, and collect the precipitated solid by filtration, or add halogenated hydrocarbons such as methylene chloride or chloroform, aromatic hydrocarbons such as toluene, or esters such as ethyl acetate. to extract the product.
＜工程２＞４－（ニトロフェニルスルホニルアミノ）安息香酸（化合物（B））を４－（ニトロフェニルスルホニルメチルアミノ）安息香酸（化合物（C））に誘導する工程
　本工程はスルホンアミド基をNメチル化するために、塩基の存在下で行われる。塩基としては水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、水素化ナトリウムなどの無機塩基や、ナトリウム－ｔ－ブトキシド、カリウム－ｔ－ブトキシドなどの有機塩基が用いられ、好ましくは炭酸ナトリウムおよび炭酸カリウムである。塩基の使用量は４－（ニトロフェニルスルホニルアミノ）安息香酸（化合物（B））に対して１．０～１０倍モル量、好ましくは２～３倍モル量である。メチル化剤には硫酸ジメチル、塩化メチル、臭化メチル、ヨウ化メチル、メタンスルホン酸メチル、ｐ－トルエンスルホン酸メチルが用いられ、好ましくは硫酸ジメチルである。メチル化剤の使用量は４－（ニトロフェニルスルホニルアミノ）安息香酸（化合物（B））に対して１～５倍モル量、好ましくは２～３倍モル量である。反応温度は０～１００℃であり、好ましくは６０～８０℃である。反応溶媒は反応に支障なければ特に制限はないが、水、塩化メチレンやクロロホルムなどのハロゲン化炭化水素類、トルエンなどの芳香族炭化水素類、酢酸エチルなどのエステル類、アセトンやメチルエチルケトンなどのケトン類、ＴＨＦやジオキサンなどのエーテル類、ジメチルホルムアミドやＮメチルピロリドンを使用することができ、好ましくはアセトンおよび水である。反応時間は実質的に反応が終了するまでであり、通常５～１０時間である。反応後、酸および水を添加して酸性とし、析出した固体を濾取するか、塩化メチレンやクロロホルムなどのハロゲン化炭化水素類、トルエンなどの芳香族炭化水素類、酢酸エチルなどのエステル類を添加して生成物を抽出する。 <Step 2> Step of deriving 4-(nitrophenylsulfonylamino)benzoic acid (compound (B)) into 4-(nitrophenylsulfonylmethylamino)benzoic acid (compound (C)) In this step, the sulfonamide group is To methylate, it is carried out in the presence of a base. As the base, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydride, and organic bases such as sodium t-butoxide and potassium t-butoxide are used, and preferably sodium carbonate and It is potassium carbonate. The amount of the base used is 1.0 to 10 times the molar amount, preferably 2 to 3 times the molar amount of 4-(nitrophenylsulfonylamino)benzoic acid (compound (B)). As the methylating agent, dimethyl sulfate, methyl chloride, methyl bromide, methyl iodide, methyl methanesulfonate, and methyl p-toluenesulfonate are used, with dimethyl sulfate being preferred. The amount of the methylating agent used is 1 to 5 times the molar amount, preferably 2 to 3 times the molar amount of 4-(nitrophenylsulfonylamino)benzoic acid (compound (B)). The reaction temperature is 0 to 100°C, preferably 60 to 80°C. The reaction solvent is not particularly limited as long as it does not interfere with the reaction, but water, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, esters such as ethyl acetate, and ketones such as acetone and methyl ethyl ketone are used. ethers such as THF and dioxane, dimethylformamide and N-methylpyrrolidone, preferably acetone and water. The reaction time is until the reaction is substantially completed, and is usually 5 to 10 hours. After the reaction, make it acidic by adding acid and water, and collect the precipitated solid by filtration, or add halogenated hydrocarbons such as methylene chloride or chloroform, aromatic hydrocarbons such as toluene, or esters such as ethyl acetate. to extract the product.
　生成物がメチルエステルの場合は、さらにこれを加水分解し、酸および水を添加して酸性とし、析出した固体を濾取するか、塩化メチレンやクロロホルムなどのハロゲン化炭化水素類、トルエンなどの芳香族炭化水素類、酢酸エチルなどのエステル類を添加して生成物を抽出する。加水分解は、アルカリ加水分解の場合は、塩基に水酸化リチウム、水酸化ナトリウム、水酸化カリウム等が用いられ、塩基の使用量は４－（ニトロフェニルスルホニルメチルアミノ）安息香酸メチルエステルに対して１．０～１０倍モル量、好ましくは２～３倍モル量である。反応温度は０～１００℃であり、好ましくは６０～８０℃である。反応溶媒は反応に支障なければ特に制限はないが水、塩化メチレンやクロロホルムなどのハロゲン化炭化水素類、トルエンなどの芳香族炭化水素類、ＴＨＦやジオキサンなどのエーテル類、メタノールやエタノールなどのアルコール類を使用することができ、好ましくは水とメタノールの混合液または水とTHFの混合液である。反応時間は実質的に反応が終了するまでであり、通常５～１０時間である。 If the product is a methyl ester, it is further hydrolyzed, made acidic by adding acid and water, and the precipitated solid is collected by filtration, or it is treated with halogenated hydrocarbons such as methylene chloride or chloroform, toluene, etc. Aromatic hydrocarbons and esters such as ethyl acetate are added to extract the product. In the case of alkaline hydrolysis, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. are used as a base, and the amount of base used is based on 4-(nitrophenylsulfonylmethylamino)benzoic acid methyl ester. The amount is 1.0 to 10 times the molar amount, preferably 2 to 3 times the molar amount. The reaction temperature is 0 to 100°C, preferably 60 to 80°C. Reaction solvents are not particularly limited as long as they do not interfere with the reaction, but include water, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, ethers such as THF and dioxane, and alcohols such as methanol and ethanol. A mixture of water and methanol or a mixture of water and THF can be used, preferably a mixture of water and methanol. The reaction time is until the reaction is substantially completed, and is usually 5 to 10 hours.
＜工程３＞４－（ニトロフェニルスルホニルメチルアミノ）安息香酸（化合物（C））を４－（ニトロフェニルスルホニルメチルアミノ）安息香酸塩化物（化合物（D））に誘導する工程
　本工程はカルボキシル基を酸塩化物に変換する塩素化剤の存在下で行われる。塩素化剤としては、好ましくは塩化チオニル、オキシ塩化リン、五塩化リンが使用される。反応を加速させるためにＮ，Ｎ－ジメチルホルムアミドを触媒量添加しても良い。塩素化剤の使用量は基質（化合物（C））に対して１～１０倍モル、好ましくは１～３倍モルである。反応溶媒は使用しなくても良いが、塩化メチレンやクロロホルムなどのハロゲン化炭化水素類、トルエンなどの芳香族炭化水素類、酢酸エチルなどのエステル類、アセトンやメチルエチルケトンなどのケトン類、ＴＨＦやジオキサンなどのエーテル類を使用することができる。反応温度は０～１００℃であり、好ましくは５０～８０℃である。反応時間は実質的に反応が終了するまでであり、通常1～１０時間である。反応後、溶媒を留去して生成物を得る。 <Step 3> Step of deriving 4-(nitrophenylsulfonylmethylamino)benzoic acid (compound (C)) into 4-(nitrophenylsulfonylmethylamino)benzoic acid chloride (compound (D)) This step It is carried out in the presence of a chlorinating agent which converts the chloride into an acid chloride. As the chlorinating agent, preferably thionyl chloride, phosphorus oxychloride, and phosphorus pentachloride are used. A catalytic amount of N,N-dimethylformamide may be added to accelerate the reaction. The amount of the chlorinating agent to be used is 1 to 10 times the molar amount, preferably 1 to 3 times the molar amount of the substrate (compound (C)). It is not necessary to use a reaction solvent, but halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, esters such as ethyl acetate, ketones such as acetone and methyl ethyl ketone, THF and dioxane Ethers such as can be used. The reaction temperature is 0 to 100°C, preferably 50 to 80°C. The reaction time is until the reaction is substantially completed, and is usually 1 to 10 hours. After the reaction, the solvent is distilled off to obtain the product.
＜工程４＞４－（ニトロフェニルスルホニルメチルアミノ）安息香酸塩化物（化合物（D））をＮ－［４－（ニトロフェニルスルホニルメチルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（E））に誘導する工程
　本工程は、グルタミン酸ジエステルのアミノ基をN保護アミノ安息香酸のアミドに誘導するために、塩基を用いる。塩基としては水酸化リチウム、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウムなどの無機塩基や、トリエチルアミン、ピリジンなどの有機塩基が用いられる。塩基の使用料は酸塩化物（化合物（D））に対して１～１０倍モル、好ましくは１～3倍モルである。反応溶媒は、反応に支障なければ特に制限はないが、水、塩化メチレンやクロロホルムなどのハロゲン化炭化水素類、トルエンなどの芳香族炭化水素類、酢酸エチルなどのエステル類、アセトンやメチルエチルケトンなどのケトン類、ＴＨＦやジオキサンなどのエーテル類を使用することができ、好ましくは水および水とハロゲン化炭化水素類の混合溶媒である。反応温度は０～５０℃であり、好ましくは１０～３０℃である。反応時間は実質的に反応が終了するまでであり、通常1～６時間である。反応後、塩化メチレンやクロロホルムなどのハロゲン化炭化水素類、トルエンなどの芳香族炭化水素類、酢酸エチルなどのエステル類を添加して生成物を抽出する。 <Step 4> 4-(nitrophenylsulfonylmethylamino)benzoic acid chloride (compound (D)) is converted to N-[4-(nitrophenylsulfonylmethylamino)benzoyl]-L-glutamic acid diethyl ester (compound (E)) In this step, a base is used to induce the amino group of the glutamic acid diester to an amide of N-protected aminobenzoic acid. As the base, inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate, and organic bases such as triethylamine and pyridine are used. The amount of base to be used is 1 to 10 times the molar amount, preferably 1 to 3 times the molar amount of the acid chloride (compound (D)). The reaction solvent is not particularly limited as long as it does not interfere with the reaction, but water, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, esters such as ethyl acetate, acetone and methyl ethyl ketone, etc. Ketones, ethers such as THF and dioxane can be used, and preferably water and a mixed solvent of water and halogenated hydrocarbons are used. The reaction temperature is 0 to 50°C, preferably 10 to 30°C. The reaction time is until the reaction is substantially completed, and is usually 1 to 6 hours. After the reaction, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, and esters such as ethyl acetate are added to extract the product.
＜工程５＞Ｎ－［４－（ニトロフェニルスルホニルメチルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（E））をＮ－４－メチルアミノベンゾイル－Ｌ－グルタミン酸ジエチルエステル（化合物（F））に誘導する工程
　本工程はニトロフェニルスルホニル基の脱保護にチオール類を用いる。チオール類としては、チオフェノール、チオグリコール酸やチオグリセロールなどを用いることができ、チオール類の使用量は基質（化合物（Ｅ））に対して１～１０当量、好ましくは１．５～３当量である。通常脱保護ではチオール類と共に塩基を用いる。塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウムなどの無機塩基や、トリエチルアミン、ピリジンなどの有機塩基が用いられる。塩基の使用料は基質（化合物（Ｅ））に対して１～１０倍モル、好ましくは２～６倍モルである。反応温度は０～１００℃であり、好ましくは３０～６０℃である。反応溶媒は反応に支障なければ特に制限はないが、水、メタノールやエタノールなどのアルコール類、塩化メチレンやクロロホルムなどのハロゲン化炭化水素類、トルエンなどの芳香族炭化水素類、酢酸エチルなどのエステル類、ＴＨＦやジオキサンなどのエーテル類、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、Ｎメチルピロリドン、を使用することができ、好ましくはアルコール類、Ｎ，Ｎ－ジメチルホルムアミドおよびアセトニトリルである。反応時間は実質的に反応が終了するまでであり、通常1～２０時間である。反応後、塩化メチレンやクロロホルムなどのハロゲン化炭化水素類、トルエンなどの芳香族炭化水素類、酢酸エチルなどのエステル類を添加して生成物を抽出することができる。 <Step 5> N-[4-(nitrophenylsulfonylmethylamino)benzoyl]-L-glutamic acid diethyl ester (compound (E)) is converted to N-4-methylaminobenzoyl-L-glutamic acid diethyl ester (compound (F)) This step uses thiols to deprotect the nitrophenylsulfonyl group. As thiols, thiophenol, thioglycolic acid, thioglycerol, etc. can be used, and the amount of thiols used is 1 to 10 equivalents, preferably 1.5 to 3 equivalents, relative to the substrate (compound (E)). It is. Deprotection usually uses a base along with thiols. As the base, inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate, and organic bases such as triethylamine and pyridine are used. The amount of base to be used is 1 to 10 times the molar amount, preferably 2 to 6 times the molar amount of the substrate (compound (E)). The reaction temperature is 0 to 100°C, preferably 30 to 60°C. The reaction solvent is not particularly limited as long as it does not interfere with the reaction, but water, alcohols such as methanol and ethanol, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, and esters such as ethyl acetate are used. ethers such as THF and dioxane, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, and preferably alcohols, N,N-dimethylformamide and acetonitrile. The reaction time is until the reaction is substantially completed, and is usually 1 to 20 hours. After the reaction, the product can be extracted by adding halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, and esters such as ethyl acetate.
＜工程６＞４－（ニトロフェニルスルホニルアミノ）安息香酸（化合物（B））を４－（ニトロフェニルスルホニルアミノ）安息香酸塩化物（化合物（G））に誘導する工程
　本工程はカルボキシル基を酸塩化物に変換する塩素化剤の存在下で行われる。詳細は工程３と同様である。 <Step 6> Step of deriving 4-(nitrophenylsulfonylamino)benzoic acid (compound (B)) into 4-(nitrophenylsulfonylamino)benzoic acid chloride (compound (G)) This step It is carried out in the presence of a chlorinating agent which converts to chloride. The details are the same as in step 3.
＜工程７＞４－（ニトロフェニルスルホニルアミノ）安息香酸塩化物（化合物（G））をＮ－［４－（ニトロフェニルスルホニルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（H））に誘導する工程
　本工程は、グルタミン酸ジエステルのアミノ基をN保護アミノ安息香酸のアミドに誘導するために、塩基を用いる。詳細は工程４と同様である。 <Step 7> Inducing 4-(nitrophenylsulfonylamino)benzoic acid chloride (compound (G)) to N-[4-(nitrophenylsulfonylamino)benzoyl]-L-glutamic acid diethyl ester (compound (H)) Step This step uses a base to induce the amino group of the glutamic acid diester into an amide of N-protected aminobenzoic acid. The details are the same as in step 4.
＜工程８＞Ｎ－［４－（ニトロフェニルスルホニルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（H））をＮ－［４－（ニトロフェニルスルホニルメチルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（E））誘導する工程
　本工程はスルホンアミド基をNメチル化するために、塩基の存在下で行われる。詳細は工程２と同様である。 <Step 8> N-[4-(nitrophenylsulfonylamino)benzoyl]-L-glutamic acid diethyl ester (compound (H)) is converted to N-[4-(nitrophenylsulfonylamino)benzoyl]-L-glutamic acid diethyl ester (Compound (E)) Inducing step This step is carried out in the presence of a base in order to N-methylate the sulfonamide group. The details are the same as in step 2.
　以下に実施例を挙げて本発明を更に詳細に説明するが、本発明はこれらにより限定されない。 The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.
実施例１
（工程１－１）
　４－アミノ安息香酸（化合物（Ａ））５．００ｇ（３６．５ｍｍｏｌ）、炭酸ナトリウム３．８７ｇ（３６．５ｍｍｏｌ）、水２５ｍｌの混合液に、２－ニトロベンゼンスルホニルクロリド８．０９ｇ（３６．５ｍｍｏｌ）を氷冷にて添加し、室温にて３時間攪拌した。反応終了後、炭酸ナトリウム０．７７ｇ（７．３ｍｍｏｌ）および水１０ｍｌを加えて室温にて０．５時間攪拌し、次いで、６Ｎ塩酸を加えてｐＨ１とし、析出した固体を濾過、水洗、乾燥して、４－（２－ニトロフェニルスルホニルアミノ）安息香酸（化合物（B１））１０．３８ｇを得た。収率８８％。
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ７．３１（２Ｈ，ｄ），７．６３（１Ｈ，ｄｄｄ），７．７１（１Ｈ，ｄｄｄ），７．８７（１Ｈ，ｄｄ），７．９４（１Ｈ，ｄｄ），８．００（１Ｈ，ｄ）． Example 1
(Step 1-1)
To a mixed solution of 5.00 g (36.5 mmol) of 4-aminobenzoic acid (compound (A)), 3.87 g (36.5 mmol) of sodium carbonate, and 25 ml of water, 8.09 g (36.5 mmol) of 2-nitrobenzenesulfonyl chloride was added. ) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, 0.77 g (7.3 mmol) of sodium carbonate and 10 ml of water were added and stirred at room temperature for 0.5 hours. Then, 6N hydrochloric acid was added to adjust the pH to 1, and the precipitated solid was filtered, washed with water, and dried. Thus, 10.38 g of 4-(2-nitrophenylsulfonylamino)benzoic acid (compound (B1)) was obtained. Yield 88%.
1 H-NMR (400 MHz, CDCl 3 ) δ7.31 (2H, d), 7.63 (1H, ddd), 7.71 (1H, ddd), 7.87 (1H, dd), 7.94 ( 1H, dd), 8.00 (1H, d).
（工程１－２）
　４－アミノ安息香酸（化合物（Ａ））５．００ｇ（３６．５ｍｍｏｌ）、炭酸ナトリウム３．８７ｇ（３６．５ｍｍｏｌ）、水５０ｍｌの混合液に、４－ニトロベンゼンスルホニルクロリド８．０９ｇ（３６．５ｍｍｏｌ）を室温にて添加し、室温にて一晩攪拌した。反応終了後、６Ｎ塩酸を加えてｐＨ１とし、析出した固体を濾過、水洗、乾燥して、４－（４－ニトロフェニルスルホニルアミノ）安息香酸（化合物（B２））９．９６ｇを得た。収率８５％。ＣＤＣｌ3不溶。 (Step 1-2)
To a mixture of 5.00 g (36.5 mmol) of 4-aminobenzoic acid (compound (A)), 3.87 g (36.5 mmol) of sodium carbonate, and 50 ml of water, 8.09 g (36.5 mmol) of 4-nitrobenzenesulfonyl chloride was added. ) was added at room temperature and stirred at room temperature overnight. After the reaction was completed, 6N hydrochloric acid was added to adjust the pH to 1, and the precipitated solid was filtered, washed with water, and dried to obtain 9.96 g of 4-(4-nitrophenylsulfonylamino)benzoic acid (compound (B2)). Yield 85%. CDCl3 insoluble.
（工程２－１）
　工程１－１で得た４－（２－ニトロフェニルスルホニルアミノ）安息香酸（化合物（B１））５．００ｇ（１５．５３ｍｍｏｌ）、炭酸カリウム４．７１ｇ（３４．１７ｍｍｏｌ）、硫酸ジメチル４．１１ｇ（３２．６１ｍｍｏｌ）、アセトン５０ｍｌの混合液を、加熱還流下で５時間攪拌した。反応終了後、水２５ｍｌを加え、アセトンを減圧留去し、析出した固体を濾過、水洗、乾燥して、４－（２－ニトロフェニルスルホニルメチルアミノ）安息香酸メチルエステル４．８４ｇを得た。収率８９％。
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ３．４２（３Ｈ，ｓ），３．９２（３Ｈ，ｓ），７．３３（２Ｈ，ｄ），７．４９－７．７０（４Ｈ，ｍ），８．００（２Ｈ，ｄ）．
　ついで、この４－（２－ニトロフェニルスルホニルメチルアミノ）安息香酸メチルエステル４．００ｇ（１１．９１ｍｍｏｌ）に、メタノール１６ｍｌ、水８ｍｌ、水酸化ナトリウム０．７５ｇ（１８．８ｍｍｏｌ）を加え、７０℃で1時間攪拌した。反応後、メタノールを減圧留去し、水３２ｍｌを加え、６N－塩酸でｐＨ１として析出した固体を濾過、水洗、乾燥して、４－（２－ニトロフェニルスルホニルメチルアミノ）安息香酸（化合物（C１））３．６８ｇを得た。収率９２％。
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ３．４３（３Ｈ，ｓ），７．３８（２Ｈ，ｄ），７．５４－７．６９（４Ｈ，ｓ），８．０６（２Ｈ，ｄ）． (Step 2-1)
4-(2-nitrophenylsulfonylamino)benzoic acid (compound (B1)) obtained in step 1-1 5.00 g (15.53 mmol), potassium carbonate 4.71 g (34.17 mmol), dimethyl sulfate 4.11 g (32.61 mmol) and 50 ml of acetone was stirred under heating and reflux for 5 hours. After the reaction was completed, 25 ml of water was added, acetone was distilled off under reduced pressure, and the precipitated solid was filtered, washed with water, and dried to obtain 4.84 g of 4-(2-nitrophenylsulfonylmethylamino)benzoic acid methyl ester. Yield 89%.
1 H-NMR (400 MHz, CDCl 3 ) δ3.42 (3H, s), 3.92 (3H, s), 7.33 (2H, d), 7.49-7.70 (4H, m), 8.00 (2H, d).
Next, 16 ml of methanol, 8 ml of water, and 0.75 g (18.8 mmol) of sodium hydroxide were added to 4.00 g (11.91 mmol) of this 4-(2-nitrophenylsulfonylmethylamino)benzoic acid methyl ester, and the mixture was heated at 70°C. The mixture was stirred for 1 hour. After the reaction, methanol was distilled off under reduced pressure, 32 ml of water was added, the pH was adjusted to 1 with 6N-hydrochloric acid, and the precipitated solid was filtered, washed with water, and dried to obtain 4-(2-nitrophenylsulfonylmethylamino)benzoic acid (compound (C1 )) 3.68g was obtained. Yield 92%.
1 H-NMR (400 MHz, CDCl 3 ) δ3.43 (3H, s), 7.38 (2H, d), 7.54-7.69 (4H, s), 8.06 (2H, d).
（工程２－２）
　工程１－２で得た４－（４－ニトロフェニルスルホニルアミノ）安息香酸（化合物（B２））５．００ｇ（１５．５３ｍｍｏｌ）、炭酸カリウム４．７１ｇ（３４．１７ｍｍｏｌ）、硫酸ジメチル４．１１ｇ（３２．６１ｍｍｏｌ）、アセトン５０ｍｌの混合液を、加熱還流下で７時間攪拌した。反応終了後、水４０ｍｌを加え、アセトンを減圧留去し、６Ｎ塩酸を加えてｐＨ１とし、析出した固体を濾過、水洗した。次いで得られた固体にＴＨＦ２５ｍｌ、水５ｍｌおよび水酸化ナトリウム１．０４ｇ（２６．４０ｍｍｏｌ）を加え、、加熱還流下で１時間攪拌した。反応終了後、水５０ｍｌを加え、ＴＨＦを減圧留去し、６Ｎ塩酸を加えてｐＨ１とし、析出した固体を濾過、水洗、乾燥して、４－（４－ニトロフェニルスルホニルメチルアミノ）安息香酸（化合物（C２））４．２５ｇを得た。収率８１％。　ＣＤＣｌ3不溶。 (Step 2-2)
4-(4-nitrophenylsulfonylamino)benzoic acid (compound (B2)) obtained in step 1-2 5.00 g (15.53 mmol), potassium carbonate 4.71 g (34.17 mmol), dimethyl sulfate 4.11 g (32.61 mmol) and 50 ml of acetone was stirred under heating and reflux for 7 hours. After the reaction was completed, 40 ml of water was added, acetone was distilled off under reduced pressure, 6N hydrochloric acid was added to adjust the pH to 1, and the precipitated solid was filtered and washed with water. Next, 25 ml of THF, 5 ml of water, and 1.04 g (26.40 mmol) of sodium hydroxide were added to the obtained solid, and the mixture was stirred under heating under reflux for 1 hour. After the reaction, 50 ml of water was added, THF was distilled off under reduced pressure, 6N hydrochloric acid was added to adjust the pH to 1, and the precipitated solid was filtered, washed with water, and dried to give 4-(4-nitrophenylsulfonylmethylamino)benzoic acid ( 4.25 g of compound (C2)) was obtained. Yield 81%. CDCl3 insoluble.
（工程３―１）
　工程２―１で得られた４－（２－ニトロフェニルスルホニルメチルアミノ）安息香酸（化合物（C１））２．００ｇ（５．９５ｍｍｏｌ）にジクロロメタン１０ｍｌ、およびＮ，Ｎ－ジメチルホルムアミド０．０５ｇ、塩化チオニル１．４２ｇ（１１．９ｍｍｏｌ）を加え、５０℃にて１．５時間攪拌した。反応後、減圧濃縮し、ｎ－ヘキサン１０ｍｌを加えて析出した固体を濾過、ｎ－ヘキサン洗浄、乾燥して、４－（２－ニトロフェニルスルホニルメチルアミノ）安息香酸塩化物（化合物（Ｄ１））２．１２ｇを得た。収率１００％。
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ３．４４（３Ｈ，ｓ），７．３７－７．４５（２Ｈ，ｍ），７．５９－７．７２（４Ｈ，ｍ），８．０９（２Ｈ，ｍ）． (Step 3-1)
To 2.00 g (5.95 mmol) of 4-(2-nitrophenylsulfonylmethylamino)benzoic acid (compound (C1)) obtained in Step 2-1, 10 ml of dichloromethane and 0.05 g of N,N-dimethylformamide, 1.42 g (11.9 mmol) of thionyl chloride was added, and the mixture was stirred at 50° C. for 1.5 hours. After the reaction, it was concentrated under reduced pressure, 10 ml of n-hexane was added, and the precipitated solid was filtered, washed with n-hexane, and dried to obtain 4-(2-nitrophenylsulfonylmethylamino)benzoic acid chloride (compound (D1)). 2.12g was obtained. Yield 100%.
1H -NMR (400MHz, CDCl 3 ) δ 3.44 (3H, s), 7.37-7.45 (2H, m), 7.59-7.72 (4H, m), 8.09 (2H , m).
（工程３―２）
　工程２―２で得られた４－（４－ニトロフェニルスルホニルメチルアミノ）安息香酸（化合物（C２））１．５０ｇ（４．４６ｍｍｏｌ）にジクロロメタン７．５ｍｌ、およびＮ，Ｎ－ジメチルホルムアミド０．０２ｇ、塩化チオニル１．０６ｇ（８．９２ｍｍｏｌ）を加え、５０℃にて２時間攪拌した。反応後、減圧濃縮し、ｎ－ヘキサン１０ｍｌを加えて析出した固体を濾過、ｎ－ヘキサン洗浄、乾燥して、４－（４－ニトロフェニルスルホニルメチルアミノ）安息香酸塩化物（化合物（Ｄ２））１．５９ｇを得た。収率１００％。
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ３．２９（３Ｈ，ｓ），７．３２（２Ｈ，ｄ），７．７５（２Ｈ，ｄ），８．０９（２Ｈ，ｄ），８．３２（２Ｈ，ｄ）． (Step 3-2)
To 1.50 g (4.46 mmol) of 4-(4-nitrophenylsulfonylmethylamino)benzoic acid (compound (C2)) obtained in Step 2-2, 7.5 ml of dichloromethane and 0.0 mL of N,N-dimethylformamide were added. 02 g, and 1.06 g (8.92 mmol) of thionyl chloride were added thereto, and the mixture was stirred at 50° C. for 2 hours. After the reaction, it was concentrated under reduced pressure, 10 ml of n-hexane was added, and the precipitated solid was filtered, washed with n-hexane, and dried to obtain 4-(4-nitrophenylsulfonylmethylamino)benzoic acid chloride (compound (D2)). 1.59g was obtained. Yield 100%.
1 H-NMR (400 MHz, CDCl 3 ) δ 3.29 (3H, s), 7.32 (2H, d), 7.75 (2H, d), 8.09 (2H, d), 8.32 ( 2H, d).
（工程４－１）
　工程３－１で得られた４－（２－ニトロフェニルスルホニルメチルアミノ）安息香酸塩化物（化合物（Ｄ１））１．２５ｇ（３．５３ｍｍｏｌ）、Ｌ－グルタミン酸ジエチルエステル塩酸塩０．８５ｇ（３．５３ｍｍｏｌ）、ジクロロメタン８．５ｍｌ、水１．１ｍｌの混合液に、２０％炭酸ナトリウム水溶液３．５１ｇ（６．７１ｍｍｏｌ）を加え、室温にて一晩攪拌した。反応後、水７ｍｌおよびジクロロメタン６ｍｌを加え、分液して水相を除去し、さらにジクロロメタン相を水洗し、トルエン１２ｍｌを加えてジクロロメタンを減圧留去した。次いでｎ－ヘキサン２０ｍｌを加え、析出した固体を濾過、ｎ－ヘキサン洗浄、乾燥して、Ｎ－［４－（２－ニトロフェニルスルホニルメチルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（E１））１．５８ｇを得た。収率８６％。光学純度１００％ｅｅ。
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ１．２４（３Ｈ，ｔ），１．３１（３Ｈ，ｔ），２．１６（１Ｈ，ｍ），２．３０（１Ｈ，ｍ），２．４７（２Ｈ，ｍ），３．４１（３Ｈ，ｓ），４．１３（２Ｈ，ｍ），４．２４（２Ｈ，ｍ），４．７５（１Ｈ，ｍ），７．１６（１Ｈ，ｄ），７．３５（２Ｈ，ｄ），７．５２－７．７９（４Ｈ，ｍ），７．８０（２Ｈ，ｄ）． (Step 4-1)
1.25 g (3.53 mmol) of 4-(2-nitrophenylsulfonylmethylamino)benzoic acid chloride (compound (D1)) obtained in Step 3-1, 0.85 g (3.53 mmol) of L-glutamic acid diethyl ester hydrochloride 3.51 g (6.71 mmol) of a 20% aqueous sodium carbonate solution was added to a mixture of 8.5 ml of dichloromethane and 1.1 ml of water, and the mixture was stirred overnight at room temperature. After the reaction, 7 ml of water and 6 ml of dichloromethane were added, the layers were separated, the aqueous phase was removed, the dichloromethane phase was further washed with water, 12 ml of toluene was added, and dichloromethane was distilled off under reduced pressure. Next, 20 ml of n-hexane was added, and the precipitated solid was filtered, washed with n-hexane, and dried to obtain N-[4-(2-nitrophenylsulfonylmethylamino)benzoyl]-L-glutamic acid diethyl ester (compound (E1)). ) 1.58g was obtained. Yield 86%. Optical purity 100%ee.
1 H-NMR (400 MHz, CDCl 3 ) δ1.24 (3H, t), 1.31 (3H, t), 2.16 (1H, m), 2.30 (1H, m), 2.47 ( 2H, m), 3.41 (3H, s), 4.13 (2H, m), 4.24 (2H, m), 4.75 (1H, m), 7.16 (1H, d), 7.35 (2H, d), 7.52-7.79 (4H, m), 7.80 (2H, d).
（工程４－２）
　工程３－２で得られた４－（４－ニトロフェニルスルホニルメチルアミノ）安息香酸塩化物（化合物（Ｄ２））１．００ｇ（２．８２ｍｍｏｌ）、Ｌ－グルタミン酸ジエチルエステル塩酸塩０．６８ｇ（２．８２ｍｍｏｌ）、ジクロロメタン６．８ｍｌ、水０．９ｍｌの混合液に、２０％炭酸ナトリウム水溶液２．８７ｇ（５．３６ｍｍｏｌ）を加え、室温にて４．５時間攪拌した。反応後、分液水相を除去し、ジクロロメタン相を濃縮し、シリカゲルクロマトグラフィーにて精製して、Ｎ－［４－（４－ニトロフェニルスルホニルメチルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（E２））１．０７ｇを得た。収率７３％。光学純度１００％ｅｅ。
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ１．２５（３Ｈ，ｔ），１．３２（３Ｈ，ｔ），２．１６（１Ｈ，ｍ），２．３１（１Ｈ，ｍ），２．４７（２Ｈ，ｍ），３．２５（３Ｈ，ｓ），４．１３（２Ｈ，ｍ），４．２５（２Ｈ，ｍ），４．７６（１Ｈ，ｍ），７．２０（１Ｈ，ｄ），７．２１（２Ｈ，ｄ），７．７１（２Ｈ，ｄ），７．８０（２Ｈ，ｄ），８．３１（２Ｈ，ｄ）． (Step 4-2)
1.00 g (2.82 mmol) of 4-(4-nitrophenylsulfonylmethylamino)benzoic acid chloride (compound (D2)) obtained in Step 3-2, 0.68 g (2.82 mmol) of L-glutamic acid diethyl ester hydrochloride 2.87 g (5.36 mmol) of a 20% aqueous sodium carbonate solution was added to a mixture of 0.82 mmol), 6.8 ml of dichloromethane, and 0.9 ml of water, and the mixture was stirred at room temperature for 4.5 hours. After the reaction, the separated aqueous phase was removed, the dichloromethane phase was concentrated, and purified by silica gel chromatography to obtain N-[4-(4-nitrophenylsulfonylmethylamino)benzoyl]-L-glutamic acid diethyl ester (compound (E2)) 1.07g was obtained. Yield 73%. Optical purity 100%ee.
1 H-NMR (400 MHz, CDCl 3 ) δ1.25 (3H, t), 1.32 (3H, t), 2.16 (1H, m), 2.31 (1H, m), 2.47 ( 2H, m), 3.25 (3H, s), 4.13 (2H, m), 4.25 (2H, m), 4.76 (1H, m), 7.20 (1H, d), 7.21 (2H, d), 7.71 (2H, d), 7.80 (2H, d), 8.31 (2H, d).
（工程５－１）
　エタノール１．５ｍｌ、チオグリコール酸３９μＬ（０．５７ｍｍｏｌ）、炭酸カリウム０．１６ｇ（１．１４ｍｍｏｌ）の混合液を２時間加熱還流攪拌し、ついでこの混合液に、工程４－１で得られたＮ－［４－（２－ニトロフェニルスルホニルメチルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（E１））０．１０ｇ（０．１９ｍｍｏｌ）、およびエタノール１．５ｍｌを加えて室温にて２．５時間攪拌した。反応後、酢酸２２μＬ（０．３８ｍｍｏｌ）および水２ｍｌを加え、エタノールを減圧留去し、ジクロロメタンで抽出し、シリカゲルクロマトグラフィーで精製して、Ｎ－４－メチルアミノベンゾイル－Ｌ－グルタミン酸ジエチルエステル（化合物（F））０．０７ｇを得た。収率１００％。光学純度９９．３％ｅｅ。
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ１．２２（３Ｈ，ｔ），１．３０（３Ｈ，ｔ），２．１２（１Ｈ，ｍ），２．２９（１Ｈ，ｍ），２．４５（２Ｈ，ｍ），２．８８（３Ｈ，ｓ），４．１０（２Ｈ，ｍ），４．２２（２Ｈ，ｍ），４．７９（１Ｈ，ｍ），６．５７（２Ｈ，ｄ），６．７４（１Ｈ，ｄ），７．６７（２Ｈ，ｄ）． (Step 5-1)
A mixture of 1.5 ml of ethanol, 39 μL (0.57 mmol) of thioglycolic acid, and 0.16 g (1.14 mmol) of potassium carbonate was heated and stirred under reflux for 2 hours, and then the mixture obtained in step 4-1 was added to the mixture. 0.10 g (0.19 mmol) of N-[4-(2-nitrophenylsulfonylmethylamino)benzoyl]-L-glutamic acid diethyl ester (compound (E1)) and 1.5 ml of ethanol were added and the mixture was stirred at room temperature. Stirred for 5 hours. After the reaction, 22 μL (0.38 mmol) of acetic acid and 2 ml of water were added, ethanol was distilled off under reduced pressure, extracted with dichloromethane, and purified by silica gel chromatography to obtain N-4-methylaminobenzoyl-L-glutamic acid diethyl ester ( 0.07 g of compound (F)) was obtained. Yield 100%. Optical purity 99.3%ee.
1 H-NMR (400 MHz, CDCl 3 ) δ1.22 (3H, t), 1.30 (3H, t), 2.12 (1H, m), 2.29 (1H, m), 2.45 ( 2H, m), 2.88 (3H, s), 4.10 (2H, m), 4.22 (2H, m), 4.79 (1H, m), 6.57 (2H, d), 6.74 (1H, d), 7.67 (2H, d).
（工程５－２）
　エタノール１．５ｍｌ、チオグリコール酸３９μＬ（０．５７ｍｍｏｌ）、炭酸カリウム０．１６ｇ（１．１４ｍｍｏｌ）の混合液を２時間加熱還流攪拌し、ついでこの混合液に、工程４－１で得られたＮ－［４－（４－ニトロフェニルスルホニルメチルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（E２））０．１０ｇ（０．１９ｍｍｏｌ）、およびエタノール１．５ｍｌを加えて室温にて１時間攪拌した。反応後、酢酸２２μＬ（０．３８ｍｍｏｌ）および水１ｍｌを加え、エタノールを減圧留去し、ジクロロメタンで抽出し、シリカゲルクロマトグラフィーで精製して、Ｎ－４－メチルアミノベンゾイル－Ｌ－グルタミン酸ジエチルエステル（化合物（F））０．０７ｇを得た。収率１００％。光学純度９９．７％ｅｅ。 (Step 5-2)
A mixture of 1.5 ml of ethanol, 39 μL (0.57 mmol) of thioglycolic acid, and 0.16 g (1.14 mmol) of potassium carbonate was heated and stirred under reflux for 2 hours, and then the mixture obtained in step 4-1 was added to the mixture. Add 0.10 g (0.19 mmol) of N-[4-(4-nitrophenylsulfonylmethylamino)benzoyl]-L-glutamic acid diethyl ester (compound (E2)) and 1.5 ml of ethanol and stir at room temperature for 1 hour. Stirred. After the reaction, 22 μL (0.38 mmol) of acetic acid and 1 ml of water were added, ethanol was distilled off under reduced pressure, extracted with dichloromethane, and purified by silica gel chromatography to obtain N-4-methylaminobenzoyl-L-glutamic acid diethyl ester ( 0.07 g of compound (F)) was obtained. Yield 100%. Optical purity 99.7%ee.
実施例２
（工程６－１）
　工程１－１で得た４－（２－ニトロフェニルスルホニルアミノ）安息香酸（化合物（B１））１．００ｇ（３．１１ｍｍｏｌ）にジクロロメタン１３ｍｌ、およびＮ，Ｎ－ジメチルホルムアミド０．０２ｇ、塩化チオニル０．７４ｇ（６．２２ｍｍｏｌ）を加え、５０℃にて５．５時間攪拌した。反応後、減圧濃縮し、ｎ－ヘキサン１０ｍｌを加えて析出した固体を濾過、ｎ－ヘキサン洗浄、乾燥して、４－（２－ニトロフェニルスルホニルアミノ）安息香酸塩化物（化合物（Ｇ１））０．９９ｇを得た。収率９４％。
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ７．３５（２Ｈ，ｄ），７．６７－７．７７（２Ｈ，ｍ），７．８８－８．０４（２Ｈ，ｍ），８．０６（２Ｈ，ｄ）． Example 2
(Step 6-1)
To 1.00 g (3.11 mmol) of 4-(2-nitrophenylsulfonylamino)benzoic acid (compound (B1)) obtained in Step 1-1, 13 ml of dichloromethane, 0.02 g of N,N-dimethylformamide, and thionyl chloride. 0.74 g (6.22 mmol) was added and stirred at 50°C for 5.5 hours. After the reaction, it was concentrated under reduced pressure, 10 ml of n-hexane was added, and the precipitated solid was filtered, washed with n-hexane, and dried to give 4-(2-nitrophenylsulfonylamino)benzoic acid chloride (compound (G1)) 0 .99g was obtained. Yield 94%.
1 H-NMR (400 MHz, CDCl 3 ) δ7.35 (2H, d), 7.67-7.77 (2H, m), 7.88-8.04 (2H, m), 8.06 (2H , d).
（工程６－２）
　工程１－２で得た４－（４－ニトロフェニルスルホニルアミノ）安息香酸（化合物（B２））１．００ｇ（３．１１ｍｍｏｌ）にジクロロメタン５ｍｌ、およびＮ，Ｎ－ジメチルホルムアミド０．０２ｇ、塩化チオニル０．７４ｇ（６．２２ｍｍｏｌ）を加え、５０℃にて３時間攪拌した。反応後、減圧濃縮し、ｎ－ヘキサン１０ｍｌを加えて析出した固体を濾過、ｎ－ヘキサン洗浄、乾燥して、４－（４－ニトロフェニルスルホニルアミノ）安息香酸塩化物（化合物（Ｇ２））１．０１ｇを得た。収率９５％。
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ７．２２（２Ｈ，ｄ），８．０５（４Ｈ，ｄｄ），８．３４（２Ｈ，ｄ）． (Step 6-2)
To 1.00 g (3.11 mmol) of 4-(4-nitrophenylsulfonylamino)benzoic acid (compound (B2)) obtained in Step 1-2, 5 ml of dichloromethane, 0.02 g of N,N-dimethylformamide, and thionyl chloride. 0.74 g (6.22 mmol) was added and stirred at 50°C for 3 hours. After the reaction, it was concentrated under reduced pressure, 10 ml of n-hexane was added, and the precipitated solid was filtered, washed with n-hexane, and dried to obtain 4-(4-nitrophenylsulfonylamino)benzoic acid chloride (compound (G2)) 1 .01 g was obtained. Yield 95%.
1 H-NMR (400 MHz, CDCl 3 ) δ7.22 (2H, d), 8.05 (4H, dd), 8.34 (2H, d).
（工程７－１）
　工程６－１で得た４－（２－ニトロフェニルスルホニルアミノ）安息香酸塩化物（化合物（Ｇ１））０．８１ｇ（２．３８ｍｍｏｌ）、Ｌ－グルタミン酸ジエチルエステル塩酸塩０．５７ｇ（２．３８ｍｍｏｌ）、ジクロロメタン５．７ｍｌの混合液に、トリエチルアミン０．９９ｍｌ（７．１４ｍｍｏｌ）を加え、室温にて一晩攪拌した。反応後、シリカゲルクロマトグラフィーにて精製して、Ｎ－［４－（２－ニトロフェニルスルホニルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（Ｈ１））０．６２ｇを得た。収率５１％。
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ１．２２（３Ｈ，ｔ），１．３０（３Ｈ，ｔ），２．０７－２．１７（１Ｈ，ｍ），２．２４－２．２．３４（１Ｈ，ｍ），２．３８－２．５２（２Ｈ，ｍ），４．１０（２Ｈ，ｍ），４．２３（２Ｈ，ｍ），４．７３（１Ｈ，ｍ），７．０７（１Ｈ，ｄ），７．２９（２Ｈ，ｄｄ），７．６１（１Ｈ，ｄｄｄ），７．６８－７．７５（３Ｈ，ｍ），７．８７（２Ｈ，ｄｄｄ）． (Step 7-1)
0.81 g (2.38 mmol) of 4-(2-nitrophenylsulfonylamino)benzoic acid chloride (compound (G1)) obtained in Step 6-1, 0.57 g (2.38 mmol) of L-glutamic acid diethyl ester hydrochloride ), 0.99 ml (7.14 mmol) of triethylamine was added to a mixture of 5.7 ml of dichloromethane, and the mixture was stirred at room temperature overnight. After the reaction, the mixture was purified by silica gel chromatography to obtain 0.62 g of N-[4-(2-nitrophenylsulfonylamino)benzoyl]-L-glutamic acid diethyl ester (compound (H1)). Yield 51%.
1 H-NMR (400 MHz, CDCl 3 ) δ1.22 (3H, t), 1.30 (3H, t), 2.07-2.17 (1H, m), 2.24-2.2.34 (1H, m), 2.38-2.52 (2H, m), 4.10 (2H, m), 4.23 (2H, m), 4.73 (1H, m), 7.07 ( 1H, d), 7.29 (2H, dd), 7.61 (1H, ddd), 7.68-7.75 (3H, m), 7.87 (2H, ddd).
（工程７－２）
　工程６－２で得た４－（４－ニトロフェニルスルホニルアミノ）安息香酸塩化物（化合物（Ｇ２））０．８１ｇ（２．３８ｍｍｏｌ）、Ｌ－グルタミン酸ジエチルエステル塩酸塩０．５７ｇ（２．３８ｍｍｏｌ）、ジクロロメタン５．７ｍｌの混合液に、トリエチルアミン０．９９ｍｌ（７．１４ｍｍｏｌ）を加え、室温にて一晩攪拌した。反応後、シリカゲルクロマトグラフィーにて精製して、Ｎ－［４－（４－ニトロフェニルスルホニルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（Ｈ２））０．５０ｇを得た。収率４１％。 (Step 7-2)
0.81 g (2.38 mmol) of 4-(4-nitrophenylsulfonylamino)benzoic acid chloride (compound (G2)) obtained in Step 6-2, 0.57 g (2.38 mmol) of L-glutamic acid diethyl ester hydrochloride ), 0.99 ml (7.14 mmol) of triethylamine was added to a mixture of 5.7 ml of dichloromethane, and the mixture was stirred at room temperature overnight. After the reaction, the mixture was purified by silica gel chromatography to obtain 0.50 g of N-[4-(4-nitrophenylsulfonylamino)benzoyl]-L-glutamic acid diethyl ester (compound (H2)). Yield 41%.
（工程８－１）
　工程７－１で得たＮ－［４－（２－ニトロフェニルスルホニルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（Ｈ１））０．３１ｇ（０．６１ｍｍｏｌ）、硫酸ジメチル０．１５ｇ（１．２２ｍｍｏｌ）、炭酸カリウム０．１７ｇ（１．２２ｍｍｏｌ）、アセトン３ｍｌの混合液を、室温にて２時間攪拌した。反応後、水１０ｍｌを加えて析出した固体を濾過、水洗、乾燥して、Ｎ－［４－（２－ニトロフェニルスルホニルメチルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（E１））０．３１ｇを得た。収率９８％。光学純度１００％ｅｅ。 (Step 8-1)
N-[4-(2-nitrophenylsulfonylamino)benzoyl]-L-glutamic acid diethyl ester (compound (H1)) obtained in Step 7-1 0.31 g (0.61 mmol), dimethyl sulfate 0.15 g (1 A mixed solution of 0.17 g (1.22 mmol) of potassium carbonate, and 3 ml of acetone was stirred at room temperature for 2 hours. After the reaction, 10 ml of water was added and the precipitated solid was filtered, washed with water, and dried to give N-[4-(2-nitrophenylsulfonylmethylamino)benzoyl]-L-glutamic acid diethyl ester (compound (E1)) 0. 31 g was obtained. Yield 98%. Optical purity 100%ee.
（工程８－２）
　工程７－２で得たＮ－［４－（４－ニトロフェニルスルホニルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（Ｈ２））０．１０ｇ（０．２０ｍｍｏｌ）、硫酸ジメチル０．０５ｇ（０．４０ｍｍｏｌ）、炭酸カリウム０．０６ｇ（０．４０ｍｍｏｌ）、アセトン２ｍｌの混合液を、室温にて１時間攪拌した。反応後、水５ｍｌを加えて析出した固体を濾過、水洗、乾燥して、Ｎ－［４－（４－ニトロフェニルスルホニルメチルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（E２））０．０９ｇを得た。収率８６％。光学純度１００％ｅｅ。 (Step 8-2)
N-[4-(4-nitrophenylsulfonylamino)benzoyl]-L-glutamic acid diethyl ester (compound (H2)) obtained in Step 7-2 0.10 g (0.20 mmol), dimethyl sulfate 0.05 g (0 A mixture of 0.06 g (0.40 mmol), potassium carbonate, and 2 ml of acetone was stirred at room temperature for 1 hour. After the reaction, 5 ml of water was added and the precipitated solid was filtered, washed with water, and dried to obtain N-[4-(4-nitrophenylsulfonylmethylamino)benzoyl]-L-glutamic acid diethyl ester (compound (E2)). 09g was obtained. Yield 86%. Optical purity 100%ee.
（工程５－１）
　エタノール１ｍｌ、α－チオグリセロール３３μＬ（０．３８ｍｍｏｌ）、炭酸カリウム０．０５ｇ（１．３８ｍｍｏｌ）の混合液を１時間加熱還流攪拌し、ついでこの混合液に、工程４－１で得られたＮ－［４－（２－ニトロフェニルスルホニルメチルアミノ）ベンゾイル］－Ｌ－グルタミン酸ジエチルエステル（化合物（E１））０．１０ｇ（０．１９ｍｍｏｌ）、およびエタノール１ｍｌを加えて室温にて一晩攪拌した。反応後、酢酸１１μＬ（０．１９ｍｍｏｌ）および水４ｍｌを加え、エタノールを減圧留去し、ジクロロメタンで抽出し、シリカゲルクロマトグラフィーで精製して、Ｎ－４－メチルアミノベンゾイル－Ｌ－グルタミン酸ジエチルエステル（化合物（F））０．０７ｇを得た。収率１００％。光学純度９８．３％ｅｅ。 (Step 5-1)
A mixture of 1 ml of ethanol, 33 μL (0.38 mmol) of α-thioglycerol, and 0.05 g (1.38 mmol) of potassium carbonate was heated and stirred under reflux for 1 hour, and then added to this mixture was the N obtained in step 4-1. 0.10 g (0.19 mmol) of -[4-(2-nitrophenylsulfonylmethylamino)benzoyl]-L-glutamic acid diethyl ester (compound (E1)) and 1 ml of ethanol were added, and the mixture was stirred at room temperature overnight. After the reaction, 11 μL (0.19 mmol) of acetic acid and 4 ml of water were added, ethanol was distilled off under reduced pressure, extracted with dichloromethane, and purified by silica gel chromatography to obtain N-4-methylaminobenzoyl-L-glutamic acid diethyl ester ( 0.07 g of compound (F)) was obtained. Yield 100%. Optical purity 98.3%ee.
　本発明の製造対象化合物であるＮ－４－メチルアミノベンゾイル－Ｌ－グルタミン酸ジエチルエステルは、医薬中間体に利用でき、Ｎ－４－メチルアミノベンゾイル－Ｌ－グルタミン酸ジエチルエステルからメトトレキサートは抗がんおよび抗リュウマチ医薬品として利用できる。 N-4-methylaminobenzoyl-L-glutamic acid diethyl ester, which is the target compound of the present invention, can be used as a pharmaceutical intermediate. It can be used as an anti-rheumatic drug.

Claims (5)

  1. ４－アミノ安息香酸である下記化合物（A）のアミノ基をニトロフェニルスルホンアミド化して下記化合物（B）を製造する工程１：
    前記化合物（B）のスルホンアミド基をメチル化して下記化合物（C）を製造する工程２：
    前記化合物（C）のカルボキシル基をカルボン酸クロリドに変換して下記化合物（D）を製造する工程３：
    前記化合物（D）からL-グルタミン酸ジエチルエステルのアミド誘導体である下記化合物（E）を製造する工程４：および
    前記化合物（E）のニトロフェニルスルホニル基を除去する工程５：
    を含む、Ｎ－［４－メチルアミノベンゾイル］－Ｌ－グルタミン酸ジエチルエステルである化合物(F)の製造方法。
    式中、Ｍｅはメチル基を示し、Ｅｔはエチル基を示す。     Step 1 of producing the following compound (B) by converting the amino group of the following compound (A), which is 4-aminobenzoic acid, into nitrophenylsulfonamidation:
    Step 2 of producing the following compound (C) by methylating the sulfonamide group of the compound (B):
    Step 3 of converting the carboxyl group of the compound (C) into a carboxylic acid chloride to produce the following compound (D):
    Step 4 of producing the following compound (E) which is an amide derivative of L-glutamic acid diethyl ester from the compound (D): and Step 5 of removing the nitrophenylsulfonyl group of the compound (E):
    A method for producing compound (F), which is N-[4-methylaminobenzoyl]-L-glutamic acid diethyl ester.
    In the formula, Me represents a methyl group and Et represents an ethyl group.
  2. ４－アミノ安息香酸である下記化合物（A）のアミノ基をニトロフェニルスルホンアミド化して下記化合物（B）を製造する工程１：
    前記化合物（B）のカルボキシル基をカルボン酸クロリドに変換して下記化合物（G）を製造する工程６：
    前記化合物（G）からL-グルタミン酸ジエチルエステルのアミド誘導体である下記化合物（H）を製造する工程７：
    前記化合物（H）のスルホンアミド基をメチル化して下記化合物（E）を製造する工程８：および
    前記化合物（E）のニトロフェニルスルホニル基を除去する工程５：
    を含む、Ｎ－［４－メチルアミノベンゾイル］－Ｌ－グルタミン酸ジエチルエステルである化合物(F)の製造方法。
    式中、Ｍｅはメチル基を示し、Ｅｔはエチル基を示す。     Step 1 of producing the following compound (B) by converting the amino group of the following compound (A), which is 4-aminobenzoic acid, into nitrophenylsulfonamidation:
    Step 6 of converting the carboxyl group of the compound (B) into a carboxylic acid chloride to produce the following compound (G):
    Step 7 of producing the following compound (H), which is an amide derivative of L-glutamic acid diethyl ester, from the compound (G):
    Step 8 of producing the following compound (E) by methylating the sulfonamide group of the compound (H): and Step 5 of removing the nitrophenylsulfonyl group of the compound (E):
    A method for producing compound (F), which is N-[4-methylaminobenzoyl]-L-glutamic acid diethyl ester.
    In the formula, Me represents a methyl group and Et represents an ethyl group.
  3. 　下記で示される化合物（Ｅ１）および化合物（Ｅ２）
    式中、Ｍｅはメチル基を示す。     Compound (E1) and compound (E2) shown below
    In the formula, Me represents a methyl group.
  4. 下記式４で示される化合物（Ｄ１）および化合物（Ｄ２）
    式中、Ｍｅはメチル基を示す。     Compound (D1) and compound (D2) represented by the following formula 4
    In the formula, Me represents a methyl group.
  5. 下記式で示される化合物（Ｈ１）
    式中、Ｅｔはエチル基を示す。     Compound (H1) represented by the following formula
    In the formula, Et represents an ethyl group.
PCT/JP2022/029737 2022-08-03 2022-08-03 Method for producing n-[4-methylaminobenzoyl]-l-glutamic acid diethyl ester WO2024028999A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61282368A (en) * 1985-05-31 1986-12-12 ブリティッシュ・テクノロジー・グループ・リミテッド Anticancer quinazoline derivative
JPH05339268A (en) * 1992-01-27 1993-12-21 Chugai Pharmaceut Co Ltd New methotrexate derivative

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61282368A (en) * 1985-05-31 1986-12-12 ブリティッシュ・テクノロジー・グループ・リミテッド Anticancer quinazoline derivative
JPH05339268A (en) * 1992-01-27 1993-12-21 Chugai Pharmaceut Co Ltd New methotrexate derivative

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MAGERLEIN BARNEY J, WEISBLAT DAVID I: "£-[(2-Amino-4-hydrc>xy-6-pteridylmethyl)-j%nitrobenzenesulfonylamino ]-benzoic Acid and Intermediates", JOURNAL OF AMERICAN CHEMICAL SOCIET, vol. 46, no. 6, 20 March 1954 (1954-03-20), pages 1702 - 1703, XP093134686 *
SANTI DANIEL V.: "Syntheses of some analogs of a possible intermediate formed in the thymidylate synthetase reaction", JOURNAL OF HETEROCYCLIC CHEMISTRY, WILEY-BLACKWELL PUBLISHING, INC., US, vol. 4, no. 4, 1 December 1967 (1967-12-01), US , pages 475 - 481, XP093134685, ISSN: 0022-152X, DOI: 10.1002/jhet.5570040403 *

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