Method for producing tetrafluoroiodobenzyl bromide

Abstract

To produce optically active tetrafluoroiodophenylalanine using a highly versatile and simple process.SOLUTION: Tetrafluoroiodobenzoic acid is produced by mixing tetrafluorobenzoic acid with an iodine solution and n-BuLi, and tetrafluoroiodobenzyl alcohol is produced by mixing the resultant tetrafluoroiodobenzoic acid with a boron reagent, and tetrafluoroiodophenylalanine is produced by mixing the resultant tetrafluoroiodobenzyl alcohol with CBr4 and PPh3 or PBr3.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing tetrafluoroiodobenzyl bromide, an optically active amino acid having a tetrafluoroiodophenyl group with excellent halogen bonding ability. [Background technology]

[0002] In current synthetic organic chemistry, research into the creation of organic compounds that exhibit new functionality is one of the most important challenges. Among these, halogen bonding is a non-covalent interaction similar to hydrogen bonding and π-π stacking, and the σ bond of halogen atoms * This is an interaction formed between an orbital and a Lewis base. Utilizing this halogen bond can lead to catalytic activity of organic molecules and the formation of precise high-dimensional spaces.

[0003] However, research based on halogen bonds is still a developing field, and research into the creation of novel halogen bond donor organic compounds is a useful challenge for the development of next-generation functional organic materials.

[0004] On the other hand, amino acids are the building blocks of peptides, and peptides can form higher-order structures through non-covalent interactions between amino acids. It is known that the construction of these higher-order structures gives peptides their unique functions.

[0005] Conventional peptide structures are limited to those formed from general non-covalent interactions. Peptide drug discovery has attracted attention in modern medicinal chemistry, and as part of this, there is a trend toward creating peptides with a new non-covalent bond, a halogen bond. For example, a method for producing optically active amino acids has been proposed, as shown in the technology disclosed in Patent Document 1. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2008 / 038578 Summary of the Invention [Problem to be solved by the invention]

[0007] However, the current situation is that no specific method for creating optically active amino acids has yet been devised.

[0008] Therefore, the present invention has been devised in consideration of the above-mentioned problems, and its object is to provide a method for producing tetrafluoroiodobenzyl bromide, an optically active amino acid having a tetrafluoroiodophenyl group with excellent halogen bonding ability. [Means for solving the problem]

[0009] In order to solve the above-mentioned problems, the present inventors have invented a method for producing tetrafluoroiodobenzyl bromide, in which tetrafluorobenzoic acid is mixed with an iodine solution and n-BuLi to produce tetrafluoroiodobenzoic acid, and the produced tetrafluoroiodobenzoic acid is used as an intermediate product to produce tetrafluoroiodobenzyl bromide.

[0010] The method for producing tetrafluoroiodobenzyl bromide according to the first invention is characterized by comprising a first step of producing tetrafluoroiodobenzoic acid by mixing iodine solution and n-BuLi with tetrafluorobenzoic acid based on the following chemical formula (1), a second step of producing tetrafluoroiodobenzyl alcohol by mixing a boron reagent with the tetrafluoroiodobenzoic acid produced through the first step, and a third step of producing tetrafluoroiodobenzyl bromide by mixing CBr4 and PPh3 or PBr3 with the tetrafluoroiodobenzyl alcohol produced through the second step. [ka] ········(1)

[0011] The second aspect of the present invention relates to a method for producing tetrafluoroiodobenzyl bromide, which is the same as the first aspect of the present invention, and the first step involves mixing 1.2 to 2.0 equivalents of an iodine solution and 2.0 to 2.5 equivalents of n-BuLi with respect to tetrafluorobenzoic acid, the second step involves mixing 1.2 to 5.0 equivalents of a boron reagent with respect to the tetrafluoroiodobenzoic acid, and the third step involves mixing 1.2 to 5.0 equivalents of CBr4 and PPh3 with respect to the tetrafluoroiodobenzyl alcohol. , or It is characterized by mixing 0.6 to 5.0 equivalents of PBr3.

[0012] The third invention relates to a method for producing tetrafluoroiodobenzyl bromide, which is characterized in that, in the first invention, the first step is carried out at -60 to -78°C, the second step is carried out at 0 to 70°C, and the third step is carried out at room temperature.

[0013] A fourth aspect of the present invention provides a method for producing L-tetrafluoroiodophenylalanine hydrochloride, comprising the steps of: a first step of mixing tetrafluorobenzoic acid with an iodine solution and n-BuLi to produce tetrafluoroiodobenzoic acid based on the following chemical formula (1); a second step of mixing a boron reagent with the tetrafluoroiodobenzoic acid produced in the first step to produce tetrafluoroiodobenzyl alcohol; a third step of mixing CBr4 and PPh3 or PBr3 with the tetrafluoroiodobenzyl alcohol produced in the second step to produce tetrafluoroiodobenzyl bromide; and a third step of mixing N-(diphenylmethylene)glycine t with the tetrafluoroiodobenzyl bromide produced in the third step based on the following chemical formula (2). The method is characterized by comprising a fourth step of producing N-(diphenylmethylene)-L-tetrafluoroiodo-phenylalanine tert-butyl ester by mixing tert-butyl ester with a 50% KOH aqueous solution; a fifth step of producing L-tetrafluoroiodo-phenylalanine tert-butyl ester by mixing citric acid with the N-(diphenylmethylene)-L-tetrafluoroiodo-phenylalanine tert-butyl ester produced through the fourth step according to the following chemical formula (3); and a sixth step of producing L-tetrafluoroiodo-phenylalanine hydrochloride by mixing hydrochloric acid with the L-tetrafluoroiodo-phenylalanine tert-butyl ester produced through the fifth step according to the following chemical formula (4). [ka] ········(1) [ka] ········(2) [ka] (3) [ka] (4)

[0014] A fifth aspect of the present invention relates to a method for producing L-tetrafluoroiodophenylalanine hydrochloride, which is the same as the fourth aspect of the present invention, and the first step involves mixing 1.2 to 2.0 equivalents of an iodine solution and 2.0 to 2.5 equivalents of n-BuLi with respect to tetrafluorobenzoic acid, the second step involves mixing 1.2 to 5.0 equivalents of a boron reagent with respect to the tetrafluoroiodobenzoic acid, and the third step involves mixing 1.2 to 5.0 equivalents of CBr4 and PPh3 with respect to the tetrafluoroiodobenzyl alcohol. , or It is characterized by mixing 0.6 to 5.0 equivalents of PBr3.

[0015] The sixth invention relates to a method for producing L-tetrafluoroiodo-phenylalanine hydrochloride according to the fifth invention, characterized in that the first step is carried out at -60 to -78°C, the second step is carried out at 0 to 70°C, and the third step is carried out at room temperature. [Effects of the Invention]

[0016] According to the method for producing tetrafluoroiodophenylalanine of the present invention, an optically active amino acid can be produced by a versatile and simple process. In particular, by using an iodine solution, an optically active amino acid can be produced without requiring expensive raw materials, thereby making it possible to further reduce production costs. DETAILED DESCRIPTION OF THE INVENTION

[0017] The method for producing tetrafluoroiodobenzyl bromide according to the present invention will be described in detail below.

[0018] The method for producing optically active tetrafluoroiodobenzyl bromide to which the present invention is applied involves the first to third steps as shown in the following chemical formula (1).

[0019] [ka] ········(1)

[0020] In the first step, tetrafluorobenzoic acid as a starting material is mixed with an iodine solution and n-BuLi to produce tetrafluoroiodobenzoic acid as an intermediate product (where n means normal). In the first step, a reaction solvent such as THF may be used. In this first step, 1.2 to 2.0 equivalents of iodine solution and 2.0 to 2.5 equivalents of n-BuLi are mixed with tetrafluorobenzoic acid. In this first step, the reaction is preferably carried out at a temperature of -60 to -78°C.

[0021] In the second step, a boron reagent is mixed with tetrafluoroiodobenzoic acid, an intermediate product produced through the first step, to produce tetrafluoroiodobenzyl alcohol. In the second step, a reaction solvent such as THF may be used. In this second step, 1.2 to 5.0 equivalents of a boron reagent are mixed with tetrafluoroiodobenzoic acid. Examples of the boron reagent that may be used include BH3·THF, BH3·Me2S, and NaBH4 / I2. In this second step, the reaction is preferably carried out at a temperature of 0 to 70°C.

[0022] In the third step, tetrafluoroiodobenzyl alcohol, an intermediate product produced in the second step, is mixed with CBr4 and PPh3 (triphenylphosphine) or PBr3 to produce tetrafluoroiodobenzyl bromide. In the third step, THF, CHCl, or the like may be used as a reaction solvent. In this third step, 1.2 to 5.0 equivalents of CBr4 and PPh3 and 0.6 to 5.0 equivalents of PBr3 are mixed with tetrafluoroiodobenzyl alcohol. In addition to CBr4 or PBr3, HBr may also be used. In the third step, the reaction is preferably carried out at a temperature of 0°C to room temperature.

[0023] [Iodine solution] The iodine solution to be mixed in the first step may be, but is not limited to, iodine, iodine monochloride, N-iodosuccinimide, 1,3-diiodo-5,5-dimethylhydantoin, etc., and may be composed of any compound containing an iodine atom that can promote iodination.

[0024] [solvent] The reaction solvent may be any solvent that does not inhibit the iodination reaction with the iodinating agent, but is preferably a solvent that is used in general iodination reactions and is stable even under radical reaction conditions. Specific examples of this reaction solvent include, in addition to THF, halogen-based solvents such as dichloroethane and chloroform, and ether-based solvents such as diethyl ether.

[0025] According to the method for producing tetrafluoroiodobenzyl bromide of the present invention, optically active amino acids can be produced by a versatile and simple process. In particular, by using an iodine solution, optically active amino acids can be produced without the need for expensive raw materials, thereby making it possible to further reduce production costs.

[0026] In the present invention, the obtained tetrafluoroiodobenzyl bromide can also be used as a starting material to produce L-tetrafluoroiodo-phenylalanine hydrochloride.

[0027] In such a case, N-(diphenylmethylene)-L-tetrafluoroiodo-phenylalanine tert-butyl ester is produced (step 4) by mixing N-(diphenylmethylene)glycine tert-butyl ester and a 50% aqueous solution of KOH with tetrafluoroiodobenzyl bromide produced through step 3 based on the following chemical formula (2).

[0028] [ka] ········(2)

[0029] Next, based on chemical formula (3), N-(diphenylmethylene)-L-tetrafluoroiodo-phenylalanine tert-butyl ester produced through step 4 is mixed with citric acid to produce L-tetrafluoroiodo-phenylalanine tert-butyl ester (step 5).

[0030] [ka] (3)

[0031] Based on the following chemical formula (4), L-tetrafluoroiodo-phenylalanine tert-butyl ester produced through the fifth step is mixed with hydrochloric acid to produce L-tetrafluoroiodo-phenylalanine hydrochloride (sixth step).

[0032] [ka] (4) [Example]

[0033] Hereinafter, an embodiment of the present invention will be described.

[0034] The following examples utilize ortho (o) tetrafluorobenzoic acid (2,3,4,5-tetrafluorobenzoic acid) as the starting material.

[0035] [ka]

[0036] In the first step, an iodine solution containing 1.7 equivalents of iodine relative to the starting material o-tetrafluorobenzoic acid (2,3,4,5-tetrafluorobenzoic acid) was mixed with 2.2 equivalents of n-BuLi, and the reaction was carried out in THF solvent at -78°C for 15 hours. As a result, o-tetrafluoroiodobenzoic acid (2,3,4,5-tetrafluoro-6-iodobenzoic acid) was produced in 90% yield.

[0037] In the first step, the starting material, o-tetrafluorobenzoic acid (2,3,4,5-tetrafluorobenzoic acid), was dissolved in THF and stirred at -78°C. To this solution, 2.2 equivalents of a hexane solution of n-BuLi was added and stirred at -78°C for 3 hours. Then, 1.7 equivalents of a THF solution of iodine was added and the reaction proceeded. After 15 hours, saturated aqueous sodium bisulfite solution was added and the solvent was removed. 1N hydrochloric acid was added to the residue to adjust the solution to pH 1, followed by separation and extraction with ethyl acetate and drying over sodium sulfate. The residue was recrystallized from hexane to obtain o-tetrafluoroiodobenzoic acid (2,3,4,5-tetrafluoro-6-iodobenzoic acid) in 90% yield.

[0038] In the second step, o-tetrafluoroiodobenzoic acid (2,3,4,5-tetrafluoro-6-iodobenzoic acid) was mixed with 1.4 equivalents of BH3·THF, and the mixture was allowed to react at 70°C for 18 hours using THF as the solvent. As a result, o-tetrafluoroiodobenzyl alcohol (2,3,4,5-tetrafluoro-6-iodobenzyl alcohol) was produced in 89% yield.

[0039] In the second step, o-tetrafluoroiodobenzoic acid (2,3,4,5-tetrafluoro-6-iodobenzoic acid) was dissolved in THF and stirred at 0°C. 1.4 equivalents of BH3·THF was added to this solution. The reaction solution was reacted at 70°C. After 18 hours, a mixture of water and THF was added, and the organic layer was washed with saturated brine and dried over sodium sulfate. The residue was purified by column chromatography (hexane:ethyl acetate=9:1) to obtain o-tetrafluoroiodobenzyl alcohol (2,3,4,5-tetrafluoro-6-iodobenzyl alcohol) in 89% yield.

[0040] In the third step, o-tetrafluoroiodobenzyl alcohol (2,3,4,5-tetrafluoro-6-iodobenzyl alcohol) was mixed with 1.2 equivalents of CBr4 and 1.2 equivalents of PPh3 in CHCl2 solvent and reacted at room temperature for 17 hours, resulting in the production of o-tetrafluoroiodobenzyl bromide (2,3,4,5-tetrafluoro-6-iodobenzyl bromide) in 71% yield.

[0041] In the third step, o-tetrafluoroiodobenzyl alcohol (2,3,4,5-tetrafluoro-6-iodobenzyl alcohol) was dissolved in dichloromethane and stirred at 0°C. 1.2 equivalents of CBr4 and 1.2 equivalents of PPh3 were added to this solution and allowed to react at room temperature. After 17 hours, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with chloroform and dried over sodium sulfate. The residue was purified by column chromatography (hexane) to obtain o-tetrafluoroiodobenzyl bromide (2,3,4,5-tetrafluoro-6-iodobenzyl bromide) in 71% yield.

[0042] The following examples utilize meta (m) tetrafluorobenzoic acid (2,3,4,6-tetrafluorobenzoic acid) as the starting material.

[0043] [ka]

[0044] In the first step, an iodine solution containing 1.7 equivalents of iodine relative to the starting material m-tetrafluorobenzoic acid (2,3,4,6-tetrafluorobenzoic acid) was mixed with 2.2 equivalents of n-BuLi, and the reaction was carried out in THF solvent at -78°C for 15 hours. As a result, m-tetrafluoroiodobenzoic acid (2,3,4,6-tetrafluoro-5-iodobenzoic acid) was produced in 49% yield.

[0045] In the first step, m-tetrafluorobenzoic acid (2,3,4,6-tetrafluorobenzoic acid) as the starting material was dissolved in THF and stirred at -78°C. To this solution, 2.2 equivalents of a hexane solution of n-BuLi was added and stirred at -78°C for 3 hours. Then, 1.7 equivalents of a THF solution of iodine was added and the reaction was allowed to proceed. After 15 hours, saturated aqueous sodium bisulfite solution was added and the solvent was removed. 1N hydrochloric acid was added to the residue to adjust the solution to pH 1, followed by separation and extraction with ethyl acetate and drying over sodium sulfate. The residue was recrystallized from hexane to obtain m-tetrafluoroiodobenzoic acid (2,3,4,6-tetrafluoro-5-iodobenzoic acid) in 49% yield.

[0046] In the second step, m-tetrafluoroiodobenzoic acid was mixed with 1.4 equivalents of BH3·THF, and the mixture was allowed to react at 70°C for 18 hours. As a result, m-tetrafluoroiodobenzyl alcohol (2,3,4,6-tetrafluoro-5-iodobenzyl alcohol) was produced in 97% yield.

[0047] In the second step, m-tetrafluoroiodobenzoic acid (2,3,4,6-tetrafluoro-5-iodobenzoic acid) was dissolved in THF and stirred at 0°C. 1.4 equivalents of BH3·THF was added to this solution. The reaction solution was allowed to react at 70°C. After 18 hours, a mixture of water and THF was added, and the organic layer was washed with saturated brine and dried over sodium sulfate. The residue was purified by column chromatography (hexane:ethyl acetate=9:1) to obtain m-tetrafluoroiodobenzyl alcohol (2,3,4,6-tetrafluoro-5-iodobenzyl alcohol) in 97% yield.

[0048] In the third step, m-tetrafluoroiodobenzyl alcohol (2,3,4,6-tetrafluoro-5-iodobenzyl alcohol) was mixed with 0.6 equivalents of PBr3, and the mixture was reacted in THF at 0°C for 3 hours. As a result, m-tetrafluoroiodobenzyl bromide (2,3,4,6-tetrafluoro-5-iodobenzyl bromide) was produced in 93% yield.

[0049] In the third step, m-tetrafluoroiodobenzyl alcohol (2,3,4,6-tetrafluoro-5-iodobenzyl alcohol) was dissolved in THF and stirred at 0°C. 0.6 equivalents of PBr3 was added to this solution and the reaction was allowed to proceed at 0°C. After 3 hours, the reaction solution was removed, and the residue was purified by column chromatography (hexane) to obtain m-tetrafluoroiodobenzyl bromide (2,3,4,6-tetrafluoro-5-iodobenzyl bromide) in 93% yield.

[0050] The following examples utilize para (p) tetrafluorobenzoic acid (2,3,5,6-tetrafluorobenzoic acid) as the starting material.

[0051] [ka]

[0052] In the first step, an iodine solution containing 1.7 equivalents of iodine relative to the starting material p-tetrafluorobenzoic acid (2,3,5,6-tetrafluorobenzoic acid) was mixed with 2.2 equivalents of n-BuLi, and the reaction was carried out in THF solvent at -78°C for 15 hours. As a result, p-tetrafluoroiodobenzoic acid (2,3,5,6-tetrafluoro-4-iodobenzoic acid) was produced in 59% yield.

[0053] In the first step, p-tetrafluorobenzoic acid (2,3,5,6-tetrafluorobenzoic acid) as the starting material was dissolved in THF and stirred at -78°C. To this solution, 2.2 equivalents of a hexane solution of n-BuLi was added and stirred at -78°C for 3 hours. Then, 1.7 equivalents of a THF solution of iodine was added and the reaction was allowed to proceed. After 15 hours, saturated aqueous sodium bisulfite solution was added and the solvent was removed. 1N hydrochloric acid was added to the residue to adjust the solution to pH 1, followed by separation and extraction with ethyl acetate and drying over sodium sulfate. The residue was recrystallized from hexane to obtain p-tetrafluoroiodobenzoic acid (2,3,5,6-tetrafluoro-4-iodobenzoic acid) in 59% yield.

[0054] In the second step, p-tetrafluoroiodobenzoic acid (2,3,5,6-tetrafluoro-4-iodobenzoic acid) was mixed with 1.4 equivalents of BH3·THF, and the mixture was allowed to react at 70°C for 18 hours using THF as the solvent. As a result, p-tetrafluoroiodobenzyl alcohol (2,3,5,6-tetrafluoro-4-iodobenzyl alcohol) was produced in 71% yield.

[0055] In the second step, p-tetrafluoroiodobenzoic acid (2,3,5,6-tetrafluoro-4-iodobenzoic acid) was dissolved in THF and stirred at 0°C. 1.4 equivalents of BH3·THF was added to this solution. The reaction solution was reacted at 70°C. After 18 hours, a mixture of water and THF was added, and the organic layer was washed with saturated brine and dried over sodium sulfate. The residue was purified by column chromatography (hexane:ethyl acetate=9:1) to obtain p-tetrafluoroiodobenzyl alcohol (2,3,5,6-tetrafluoro-4-iodobenzyl alcohol) in 71% yield.

[0056] In the third step, 1.2 equivalents of CBr4 and 1.2 equivalents of PPh3 were mixed with p-tetrafluoroiodobenzyl alcohol (2,3,5,6-tetrafluoro-4-iodobenzyl alcohol) in CHCl2 and reacted at room temperature for 17 hours. As a result, p-tetrafluoroiodobenzyl bromide (2,3,5,6-tetrafluoro-4-iodobenzyl bromide) was produced in 51% yield.

[0057] In the third step, p-tetrafluoroiodobenzyl alcohol (2,3,5,6-tetrafluoro-4-iodobenzyl alcohol) was dissolved in dichloromethane and stirred at 0°C. 1.2 equivalents of CBr4 and 1.2 equivalents of PPh3 were added to this solution and allowed to react at room temperature. After 17 hours, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with chloroform and dried over sodium sulfate. The residue was purified by column chromatography (hexane) to obtain p-tetrafluoroiodobenzyl bromide (2,3,5,6-tetrafluoro-4-iodobenzyl bromide) in 51% yield. [Example]

[0058] Hereinafter, an example of producing L-tetrafluoroiodo-phenylalanine hydrochloride using the obtained tetrafluoroiodobenzyl bromide as a starting material will be described.

[0059] The following chemical formula shows an example of the fourth step:

[0060] [ka]

[0061] First, N-(diphenylmethylene)glycine tert-butyl ester was mixed with 1 equivalent of tetrafluoroiodobenzyl bromide, and an optically active ammonium salt catalyst consisting of 4,5-dihydro-3H-dinaphtho[2,1-c:1',2'e]azepine was added. Then, 1.2 equivalents of 50% aqueous KOH solution was added. The solvent was toluene, and the reaction was carried out at 0°C for 24 hours, yielding N-(diphenylmethylene)-L-tetrafluoroiodo-phenylalanine tert-butyl ester.

[0062] First, N-(diphenylmethylene)glycine tert-butyl ester was mixed with 1 equivalent of tetrafluoroiodobenzyl bromide, then dissolved in toluene and stirred at 0°C. To this solution, 1.2 equivalents of 50% aqueous KOH and an optically active ammonium salt catalyst consisting of a 4,5-dihydro-3H-dinaphtho[2,1-c:1',2'e]azepine skeleton were added and the reaction was allowed to proceed at 0°C. After 24 hours, water was added, and the mixture was separated and extracted with ether, washed with saturated brine, and dried over sodium sulfate. The residue was purified by column chromatography (hexane:ether = 10:1) to obtain N-(diphenylmethylene)-L-tetrafluoroiodophenylalanine tert-butyl ester.

[0063] The yields of o-, m-, and p-N-(diphenylmethylene)-L-tetrafluoroiodo-phenylalanine tert-butyl ester obtained relative to each of o-, m-, and p-tetrafluoroiodobenzyl bromides are also shown.

[0064] The following chemical formula shows an example of the fifth step:

[0065] [ka]

[0066] The N-(diphenylmethylene)-L-tetrafluoroiodo-phenylalanine tert-butyl ester produced in step 4 was mixed with 1 M citric acid and reacted in THF as the solvent at room temperature for 16 hours to obtain L-tetrafluoroiodo-phenylalanine tert-butyl ester. The yields of o-, m-, and p-L-tetrafluoroiodo-phenylalanine tert-butyl esters obtained are also shown.

[0067] The N-(diphenylmethylene)-L-tetrafluoroiodo-phenylalanine tert-butyl ester produced in the fourth step was dissolved in THF and stirred at room temperature. 1 M citric acid was added to this solution and the reaction was allowed to proceed at room temperature. After 16 hours, solid sodium bicarbonate was added, and the mixture was separated and extracted with dichloromethane and dried over sodium sulfate. The residue was purified by column chromatography (hexane:ethyl acetate=3:2) to obtain L-tetrafluoroiodo-phenylalanine tert-butyl ester. The yields of o-, m-, and p-L-tetrafluoroiodo-phenylalanine tert-butyl esters obtained are also shown.

[0068] The following chemical formula shows an example of the sixth step:

[0069] [ka]

[0070] The L-tetrafluoroiodo-phenylalanine tert-butyl ester produced in step 5 was mixed with 6N hydrochloric acid and refluxed for 2 hours. As a result, L-tetrafluoroiodo-phenylalanine hydrochloride was obtained. The yields of the resulting o-, m-, and p-L-tetrafluoroiodo-phenylalanine hydrochlorides are also shown.

[0071] The L-tetrafluoroiodo-phenylalanine tert-butyl ester produced in step 5 was dissolved in 6N hydrochloric acid and heated to reflux. After 2 hours, the reaction solvent was removed to obtain L-tetrafluoroiodo-phenylalanine hydrochloride. The yields of o-, m-, and p-L-tetrafluoroiodo-phenylalanine hydrochloride are also shown.

Claims

1. A first step of producing tetrafluoroiodobenzoic acid by mixing tetrafluorobenzoic acid with an iodine solution and n-BuLi based on the following chemical formula (1); a second step of mixing the tetrafluoroiodobenzoic acid produced through the first step with a boron reagent to produce tetrafluoroiodobenzyl alcohol; The tetrafluoroiodobenzyl alcohol produced through the second step is reacted with CBr ４ and PPh ３ , or PBr ３ and a third step of mixing the above to form tetrafluoroiodobenzyl bromide. A method for producing tetrafluoroiodobenzyl bromide, characterized by: 【Chemistry 1】 ・・・・・・・・（１）

2. The first step involves mixing 1.2 to 2.0 equivalents of an iodine solution and 2.0 to 2.5 equivalents of n-BuLi relative to tetrafluorobenzoic acid; The second step comprises mixing 1.2 to 5.0 equivalents of a boron reagent with respect to the tetrafluoroiodobenzoic acid; In the third step, 1.2 to 5.0 equivalents of CBr 4 and PPh 3 or 0.6 to 5.0 equivalents of PBr 3 Mixing The method for producing tetrafluoroiodobenzyl bromide according to claim 1, characterized by:

3. The first step is carried out at −60 to −78° C. The second step is carried out at 0 to 70°C, The third step is carried out at room temperature. The method for producing tetrafluoroiodobenzyl bromide according to claim 1, characterized by:

4. A first step of producing tetrafluoroiodobenzoic acid by mixing tetrafluorobenzoic acid with an iodine solution and n-BuLi based on the following chemical formula (1); a second step of mixing the tetrafluoroiodobenzoic acid produced through the first step with a boron reagent to produce tetrafluoroiodobenzyl alcohol; The tetrafluoroiodobenzyl alcohol produced through the second step is reacted with CBr ４ and PPh ３ , or PBr ３ a third step of producing tetrafluoroiodobenzyl bromide by mixing A fourth step of producing N-(diphenylmethylene)-L-tetrafluoroiodo-phenylalanine tert-butyl ester by mixing N-(diphenylmethylene)glycine tert-butyl ester and a 50% aqueous solution of KOH with tetrafluoroiodobenzyl bromide produced through the third step based on the following chemical formula (2); a fifth step of producing L-tetrafluoroiodo-phenylalanine tert-butyl ester by mixing citric acid with N-(diphenylmethylene)-L-tetrafluoroiodo-phenylalanine tert-butyl ester produced through the fourth step based on the following chemical formula (3); and a sixth step of producing L-tetrafluoroiodo-phenylalanine hydrochloride by mixing hydrochloric acid with L-tetrafluoroiodo-phenylalanine tert-butyl ester produced through the fifth step based on the following chemical formula (4). The method for producing L-tetrafluoroiodo-phenylalanine hydrochloride, characterized by: 【Chemistry 1】 ・・・・・・・・（１） 【Chemistry 2】 ・・・・・・・・（２） 【Transformation 3】 ・・・・・・・・（３） 【Chemistry 4】 ・・・・・・・・（４）

5. The first step involves mixing 1.2 to 2.0 equivalents of an iodine solution and 2.0 to 2.5 equivalents of n-BuLi relative to tetrafluorobenzoic acid; The second step comprises mixing 1.2 to 5.0 equivalents of a boron reagent with respect to the tetrafluoroiodobenzoic acid; In the third step, 1.2 to 5.0 equivalents of CBr 4 and PPh 3 or 0.6 to 5.0 equivalents of PBr 3 5. The method for producing L-tetrafluoroiodo-phenylalanine hydrochloride according to claim 4, wherein the above are mixed.

6. The first step is carried out at −60 to −78° C. The second step is carried out at 0 to 70°C, The third step is carried out at room temperature.

6. The method for producing L-tetrafluoroiodo-phenylalanine hydrochloride according to claim 5,

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