Method for producing N-fluoroalkyl compounds
The synthesis of N-fluoroalkylated hydrazine derivatives is achieved efficiently and cost-effectively by reacting compounds with IF5 and HF in specific solvents at controlled temperatures, addressing the inefficiencies of previous methods that relied on expensive materials.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Patents
- Current Assignee / Owner
- DAIKIN INDUSTRIES LTD
- Filing Date
- 2022-12-28
- Publication Date
- 2026-06-29
AI Technical Summary
Existing methods for synthesizing N-fluoroalkylated hydrazine derivatives require expensive raw materials and reagents, such as silane compounds and azo compounds, making them inefficient and costly.
A method involving the reaction of a compound represented by Formula (2) with a fluorinating agent containing IF5, an amine, and HF at 80°C or lower, using a solvent such as (cyclo)alkanes, chlorine-containing organic solvents, aromatic solvents, nitrile-containing organic solvents, or fluorine-containing organic solvents, to produce N-fluoroalkylated hydrazine derivatives without the need for expensive materials.
This method allows for the efficient synthesis of N-fluoroalkylated hydrazine derivatives with improved yield and stability, reducing the reliance on costly reagents and optimizing reaction conditions.
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Abstract
Description
Technical Field
[0001] The present invention relates to a method for producing N-fluoroalkyl compounds.
Background Art
[0002] The following formula:
[0003]
Chemical Formula
[0004] N-fluoroalkylated hydrazine derivatives represented by compounds shown by the formula are useful as pharmaceutical intermediates and the like.
[0005] As a method for synthesizing N-fluoroalkylated hydrazine derivatives, for example, Non-Patent Document 1 describes that it is synthesized by the following reaction using di-tert-butyl azodicarboxylate as a substrate.
[0006]
Chemical Formula
Prior Art Documents
Non-Patent Documents
[0007]
Non-Patent Document 1
Summary of the Invention
Problems to be Solved by the Invention
[0008] The present disclosure aims to provide a method capable of efficiently synthesizing N-fluoroalkylated hydrazine derivatives.
Means for Solving the Problems
[0009] The present disclosure includes the following configurations.
[0010] Item 1. Formula (1):
[0011]
Chemical formula
[0012] [In the formula, R , , 1 , ,
[0015] , R 2 and R 3 are the same or different, R 1 represents -COR. R 2 and R 3 represent a hydrogen atom or -COR. R is the same or different and represents an alkoxy group having 1 to 12 carbon atoms or an aryloxy group having 6 to 12 carbon atoms, which may be substituted with one or more substituents.] A method for producing a compound represented by Formula (2):
[0013]
Chemical formula
[0014] s[In the formula, R 1 , R 2 and R 3 are the same as above. R 4 represents an alkyl group having 1 to 12 carbon atoms or an aryl group having 6 to 12 carbon atoms.] Reacting the compound represented by with a fluorinating agent containing IF5, an amine and HF at 80°C or lower throughout the period from the start to the end of the reaction, step A A production method including.
[0015] Item 2. In the above formulas (1) and (2), The above R 1This represents a tert-butyloxycarbonyl group, a benzyloxycarbonyl group, a (2,2,2-trichloroethoxy)carbonyl group, an ethoxycarbonyl group, or an isopropoxycarbonyl group. The aforementioned R 2 and R 3 These represent, either identically or differently, a hydrogen atom, a tert-butyloxycarbonyl group, a benzyloxycarbonyl group, a (2,2,2-trichloroethoxy)carbonyl group, an ethoxycarbonyl group, or an isopropoxycarbonyl group. The manufacturing method described in item 1.
[0016] Section 3. The compound represented by the general formula (2) above,
[0017] [ka]
[0018] The manufacturing method described in item 1 or 2.
[0019] Section 4. The compound represented by the general formula (2) above,
[0020] [ka]
[0021] The manufacturing method described in any one of items 1 to 3.
[0022] Section 5. The compound represented by the general formula (1) above,
[0023] [ka]
[0024] The manufacturing method described in any one of items 1 to 4.
[0025] Section 6. The compound represented by the general formula (1) above,
[0026] [ka]
[0027] The manufacturing method described in any one of items 1 to 5.
[0028] Item 7. The manufacturing method according to any one of items 1 to 6, wherein the reaction temperature of step A is 10 to 40°C.
[0029] Item 8. The manufacturing method according to any one of items 1 to 7, wherein step A is carried out in the presence of a solvent.
[0030] Item 9. The method for producing an organic solvent according to Item 8, wherein the solvent is at least one selected from the group consisting of (cyclo)alkanes, chlorine-containing organic solvents, aromatic solvents, nitrile-containing organic solvents, fluorine-containing organic solvents, and ester-containing organic solvents. [Effects of the Invention]
[0031] According to this disclosure, N-fluoroalkylated hydrazine derivatives can be efficiently synthesized. [Modes for carrying out the invention]
[0032] In this specification, "contains" is a concept that encompasses all of the following: "contains," "consist essentially of," and "consist of."
[0033] Furthermore, in this specification, when a numerical range is indicated as "A to B", it means A or greater and B or less.
[0034] In this disclosure, “yield” means the ratio (mol %) of the total molar amount of the target compound contained in the effluent gas from the reactor outlet to the molar amount of the raw material compound supplied to the reactor.
[0035] The manufacturing method disclosed herein is given by formula (1):
[0036] [ka]
[0037] [In the formula, R 1 , R 2 and R 3 They are the same or different, R 1 This indicates -COR. R 2 and R 3 This represents a hydrogen atom or -COR. R represents a C1-C12 alkoxy group or a C6-C12 aryloxy group, which may be substituted with one or more substituents, either identical or different. A method for producing a compound represented by, Formula (2):
[0038] [ka]
[0039] [In the formula, R 1 , R 2 and R 3 The same applies as above. R 4 This represents an alkyl group having 1 to 12 carbon atoms or an aryl group having 6 to 12 carbon atoms. Step A involves reacting the compound represented by with a fluorinating agent containing IF5, an amine, and HF. Includes.
[0040] Conventional methods, such as those described in Non-Patent Document 1, require the use of expensive raw materials and reagents, such as silane compounds and azo compounds. However, this disclosure allows for the synthesis of N-fluoroalkylated hydrazine derivatives without the use of expensive raw materials and reagents.
[0041] 1. Raw material compound In this disclosure, the starting compound is formula (2):
[0042] [ka]
[0043] [In the formula, R 1 , R 2 and R 3 They are the same or different, R 1 This indicates -COR. R 2 and R 3 This represents a hydrogen atom or -COR. R represents a C1-C12 alkoxy group or a C6-C12 aryloxy group, which may be the same or different and substituted with one or more substituents. R 4 This represents an alkyl group having 1 to 12 carbon atoms or an aryl group having 6 to 12 carbon atoms. Use the compound represented by [the formula shown].
[0044] In equation (2), R 1 , R 2 and R 3 Examples of alkoxy groups represented by R in -COR include linear or branched alkoxy groups having 1 to 12 carbon atoms (particularly 1 to 8), such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, neopentyloxy, n-hexyloxy, and benzyloxy groups.
[0045] The alkoxy group may have substituents. Examples of substituents that the alkoxy group may have include halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.) and aryl groups, as described later. When the alkoxy group has substituents, there is no particular limit to the number of substituents, and it can be 1 to 6, and especially 1 to 3.
[0046] In equation (2), R 1 , R 2 and R3 In the -COR shown, the aryloxy group indicated by R can be, for example, a monovalent group in which an aryl group is bonded to an oxygen atom. Examples of aryl groups include those with 6 to 12 carbon atoms, such as phenyl group, o-tolyl group (2-methylphenyl group), m-tolyl group (3-methylphenyl group), p-tolyl group (4-methylphenyl group), 1-naphthyl group, and 2-naphthyl group. Specifically, examples of aryloxy groups include phenoxy group, o-tolyloxy group (2-methylphenyloxy group), m-tolyloxy group (3-methylphenyloxy group), p-tolyloxy group (4-methylphenyloxy group), 1-naphthyloxy group, and 2-naphthyloxy group, which have 6 to 12 carbon atoms (especially 6 to 10).
[0047] The aryloxy group may have substituents. Examples of substituents that the aryloxy group may have include halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.), the alkoxy group mentioned above, the aryl group mentioned above, and alkyl groups described later. When the aryloxy group has substituents, there is no particular limit to the number of substituents, and it can be 1 to 6, and especially 1 to 3.
[0048] In particular, in equation (2), R 1From the viewpoint of easily stabilizing the resulting compound represented by formula (1) and easily improving the yield of the resulting compound represented by formula (1), it is preferable that the protecting group is an amino group, and is preferably a methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), p-methoxybenzyloxycarbonyl group, (2,2,2-trichloroethoxy)carbonyl group (Troc), p Examples include the methoxyphenyloxycarbonyl group, among which the ethoxycarbonyl group, isopropoxycarbonyl group, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), and (2,2,2-trichloroethoxy)carbonyl group (Troc) are preferred, the tert-butyloxycarbonyl group (Boc) and benzyloxycarbonyl group (Cbz) are more preferred, and the tert-butyloxycarbonyl group (Boc) is even more preferred.
[0049] Also, in equation (2), R 2 and R 3 For this, either a hydrogen atom or -COR may be used, but from the viewpoint of the yield of the compound represented by formula (1), R 2 and R 3 Preferably, at least one of them is a -COR (particularly an amino group protecting group), R 2 and R 3 It is more preferable that one of them is a hydrogen atom and the other is a -COR (especially an amino group protecting group). The amino group protecting group can be one of the above. That is, R 2 and R 3 Preferably, one of them is a hydrogen atom and the other is an ethoxycarbonyl group, isopropoxycarbonyl group, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), (2,2,2-trichloroethoxy)carbonyl group (Troc), etc. 2 and R 3 It is more preferable that one of them is a hydrogen atom and the other is a tert-butyloxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), etc. 2 and R3 It is even more preferable that one of them is a hydrogen atom and the other is a tert-butyloxycarbonyl group (Boc).
[0050] In equation (2), R 4 Examples of alkyl groups represented by include linear or branched alkyl groups having 1 to 12 carbon atoms (particularly 1 to 8), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, and n-hexyl groups.
[0051] The alkyl group may have substituents. Examples of substituents that the alkyl group may have include halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.), the alkoxy group, the aryl group, the aryloxy group, etc. When the alkyl group has substituents, there is no particular limit to the number of substituents, and it can be 1 to 6, and especially 1 to 3.
[0052] In equation (2), R 4 Examples of aryl groups represented by include phenyl groups, o-tolyl groups (2-methylphenyl groups), m-tolyl groups (3-methylphenyl groups), p-tolyl groups (4-methylphenyl groups), 1-naphthyl groups, and 2-naphthyl groups, which have 6 to 12 carbon atoms (especially 6 to 10 carbon atoms).
[0053] The aryl group may have substituents. Examples of substituents that the alkyl group may have include halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.), the alkoxy group mentioned above, and the aryl group mentioned above. When the alkyl group has substituents, there is no particular limit to the number of substituents, and it can be 1 to 6, and especially 1 to 3.
[0054] In equation (2), R 4 Alkyl alkyl groups are preferred from the viewpoint of easily stabilizing the resulting compound represented by formula (1) and easily improving the yield of the resulting compound represented by formula (1).
[0055] Examples of raw material compounds that satisfy the above conditions include:
[0056] [ka]
[0057] These are some examples. In particular, they are shown in the examples described below.
[0058] [ka]
[0059] The following are preferred:
[0060] [ka]
[0061] This is preferable.
[0062] 2. Fluorination reaction In step A of the manufacturing method of this disclosure, the dithiocarboxylic acid ester of the compound represented by formula (2) is fluorinated to a trifluoromethyl group by a fluorination reaction of the raw material compound represented by formula (2) to obtain the compound represented by formula (1).
[0063] 3. Fluorinating agents The fluorinating agent used in this disclosure is a fluorinating agent comprising IF5, an amine, and HF (hydrogen fluoride).
[0064] IF5 is a non-explosive, easy-to-handle liquid with a boiling point of 100.5°C and a melting point of 9.4°C, making it an industrially usable fluorinating agent. However, because fluorination with IF5 is difficult to control due to its high oxidizing properties, it has been used for applications such as the addition of IF to perfluoroolefins and the substitution of iodine with fluorine in iodized perfluoroolefins, but there are not many reports on its use in the fluorination reactions of organic compounds containing hydroxyl groups, carbonyl groups, etc.
[0065] According to this disclosure, by employing a fluorinating agent containing IF5, an amine, and HF (hydrogen fluoride), the dithiocarboxylic acid ester of the starting compound represented by formula (2) is fluorinated to form a trifluoromethyl group, thereby obtaining the compound represented by formula (1) through a fluorination reaction.
[0066] Furthermore, the HF (hydrogen fluoride) used as the acid here may be supported on various carriers. Examples of supports include SiO2, methylated SiO2, Al2O3, Al2O3-WB, MoO3, ThO2, ZrO2, TiO2, Cr2O3, SiO2-Al2O3, SiO2-TiO2, SiO2-ZrO2, TiO2-ZrO2, Al2O3-B2O3, SiO2-WO3, SiO2-NH4F, HSO3Cl-Al2O3, HF-NH4-Y, HF-Al2O3, NH4F-SiO2-Al2O3, AlF3-Al2O3, Ru-F-Al2O3, F-Al2O3, KF-Al2O3, AlPO4, AlF3, bauxite, kaolin, activated carbon, graphite, Pt-graphite, ion exchange resins, metal sulfates, chlorides, metals such as Al, alloys such as Al-Mg and Ni-Mo, and polymers such as polystyrene.
[0067] The amount of HF (hydrogen fluoride) used as the acid in this disclosure can be selected from a catalytic amount to a large excess, but from the viewpoint of easily stabilizing the resulting compound represented by formula (1) and easily improving the yield of the resulting compound represented by formula (1), 1 to 10 moles and more preferably 3 to 6 moles per 5 moles of IF is preferred. Furthermore, regarding the HF (hydrogen fluoride) used as the acid, hydrofluoric acid can also be used as the reaction solvent. In this case, the amount of solvent can be very small or a large excess.
[0068] Examples of amines used as bases in this disclosure include aliphatic amines (aliphatic primary amines, aliphatic secondary amines, aliphatic tertiary amines), alicyclic amines (alicyclic secondary amines, alicyclic tertiary amines), aromatic amines, heterocyclic amines, polymer-supported amines, and the like.
[0069] Examples of aliphatic primary amines include methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, cyclohexylamine, and ethylenediamine.
[0070] Examples of aliphatic secondary amines include dimethylamine, diethylamine, dipropylamine, dibutylamine, dipentylamine, dihexylamine, and dicyclohexylamine.
[0071] Examples of aliphatic tertiary amines include trimethylamine, triethylamine, diisopropylethylamine, and N,N,N',N'-tetramethylethylenediamine.
[0072] Examples of alicyclic secondary amines include piperidine, piperazine, pyrrolidine, and morpholine, while examples of alicyclic tertiary amines include N-methylpiperazine, N-methylpyrrolidine, 5-diazabicyclo[4.3.0]nonane-5-ene, and 1,4-diazabicyclo[2.2.2]octane.
[0073] Examples of aromatic amines include aniline, 2-methylaniline, 3-methylaniline, 4-methylaniline, N-methylaniline, 2,3-dimethylaniline, 2,6-dimethylaniline, 3,4-dimethylaniline, N,N-dimethylaniline, haloaniline, and nitroaniline.
[0074] Examples of heterocyclic amines include pyridine, pyrimidine, piperazine, quinoline, and imidazole.
[0075] Examples of polymer-supported amines include polyallylamine and polyvinylpyridine.
[0076] These amines can be used individually or in combination of two or more.
[0077] The amount of amine used as a base in this disclosure can be selected from a catalytic amount to a large excess, but from the viewpoint of easily stabilizing the resulting compound represented by formula (1) and easily improving the yield of the resulting compound represented by formula (1), 0.1 to 5 moles and more preferably 0.1 to 3 moles per 1 mole of IF5 is preferred.
[0078] In this disclosure, when hydrogen fluoride is used as the reaction solvent and an amine is used as the base, the reaction may produce hydrogen fluoride, either alone or two or more amine salts, such as ammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, or polyallylammonium fluoride, and this disclosure also includes cases where such salts are formed.
[0079] In this disclosure, the amount of fluorinating agent used can be selected from a catalytic amount to a large excess, but from the viewpoint of easily stabilizing the resulting compound represented by formula (1) and easily improving the yield of the resulting compound represented by formula (1), 0.1 to 20 parts by mass, and more preferably 0.5 to 5 parts by mass, is preferred per 100 parts by mass of the compound represented by formula (2).
[0080] 4. Solvent The manufacturing method disclosed herein is generally preferable to be carried out in the presence of a solvent, from the viewpoint of reaction efficiency and other factors. As described above, HF (hydrogen fluoride) can be used as the reaction solvent, or a reaction solvent other than hydrogen fluoride can be used.
[0081] The reaction solvents that can be used are not particularly limited, but examples include (cyclo)alkanes such as n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane; chlorine-containing organic solvents such as dichloromethane and chloroform; aromatic solvents such as benzene, toluene, and xylene; nitrile-containing organic solvents such as acetonitrile, propionitrile, and benzonitrile; fluorine-containing organic solvents such as perfluorohexane, perfluorooctane, perfluorodimethylcyclohexane, perfluorobenzene, and perfluorotoluene; and ester-containing organic solvents such as ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, and butyl propionate. These organic solvents can be used individually or in combination of two or more. In particular, from the viewpoint of yielding the compound represented by formula (1), (cyclo)alkanes, chlorine-containing organic solvents, aromatic solvents, nitrile-containing organic solvents, and ester-containing organic solvents are preferred, alkanes, chlorine-containing organic solvents, aromatic solvents, and nitrile-containing organic solvents are more preferred, and chlorine-containing organic solvents and aromatic solvents are even more preferred.
[0082] In this disclosure, the amount of solvent used can usually be in excess, but from the viewpoint of stabilizing the resulting compound represented by formula (1) and improving the yield of the resulting compound represented by formula (1), 0.1 to 100 parts by mass, more preferably 0.1 to 10 parts by mass, and even more preferably 0.1 to 5 parts by mass are preferred per 1 part by mass of the compound represented by formula (2).
[0083] 5. Other conditions In step A of this disclosure, the reaction atmosphere used when reacting the raw material compound (compound represented by formula (2)) with a fluorinating agent to obtain the compound represented by formula (1) is not particularly limited and can be an inert gas atmosphere such as a nitrogen gas atmosphere or an argon gas atmosphere.
[0084] In step A of this disclosure, the reaction temperature when reacting the raw material compound (compound represented by formula (2)) with a fluorinating agent to obtain the compound represented by formula (1) is 80°C or lower, preferably 70°C or lower, more preferably 60°C or lower, even more preferably 50°C or lower, and particularly preferably 40°C or lower, from the viewpoint of stabilizing the obtained compound represented by formula (1) and improving the yield of the obtained compound represented by formula (1), for the entire period from the start to the end of the reaction. Also, for similar reasons, the reaction temperature can usually be -20°C or higher, preferably -10°C or higher, more preferably 0°C or higher, and even more preferably 10°C or higher, from the start to the end of the reaction. Therefore, the reaction temperature can usually be -20 to 80°C, preferably -10 to 70°C, more preferably 0 to 60°C, even more preferably 10 to 50°C, and particularly preferably 10 to 40°C, from the entire period from the start to the end of the reaction.
[0085] In other words, it is preferable to maintain the reaction temperature within the above range from the start of the reaction to the end of the reaction (from the contact between the starting compound (compound represented by formula (2)) and the fluorinating agent until the reaction is completed). Since the reaction between the starting compound (compound represented by formula (2)) and the fluorinating agent in this disclosure is an exothermic reaction, if the reaction proceeds at room temperature, the reaction temperature will ultimately not fall below 80°C, resulting in a decrease in the yield of the target compound.
[0086] In step A of this disclosure, the reaction time for reacting the raw material compound (compound represented by formula (2)) with the fluorinating agent to obtain the compound represented by formula (1) can be set to a time sufficient for the reaction to proceed and can be adjusted as appropriate.
[0087] As described above, the compound represented by formula (1) can be obtained, but if necessary, various purification treatments can be performed according to conventional methods.
[0088] 6.Target compound The target compound obtained as described above is given by formula (1):
[0089] [ka]
[0090] [In the formula, R 1 , R 2 and R 3 They are the same or different, R 1 This indicates -COR. R 2 and R 3 This represents a hydrogen atom or -COR. R represents a C1-C12 alkoxy group or a C6-C12 aryloxy group, which may be substituted with one or more substituents, either identical or different. It is a compound represented by [formula].
[0091] Note that in equation (1), R 1 , R 2 and R 3 The above explanation can be adopted. The same applies to preferred examples.
[0092] Therefore, the target compound obtained by the manufacturing method of this disclosure is, for example,
[0093] [ka]
[0094] These are some examples. In particular, they are shown in the examples described below.
[0095] [ka]
[0096] The following are preferred:
[0097] [ka]
[0098] This is preferable.
[0099] In particular, compounds represented by general formula (1)
[0100] [ka]
[0101] The compound represented by general formula (2) is
[0102] [ka]
[0103] In this case, the reaction temperature is preferably 0°C or higher, and more preferably 10°C or higher, for the entire duration from the start to the end of the reaction. Furthermore, the reaction temperature is preferably 50°C or lower, and more preferably 40°C or lower, for the entire duration from the start to the end of the reaction. Therefore, the reaction temperature is preferably 0 to 50°C, and more preferably 10 to 40°C, for the entire duration from the start to the end of the reaction. [Examples]
[0104] The following examples illustrate the features of the present invention. The present invention is not limited to these examples.
[0105] [Examples 1-5]
[0106] [ka]
[0107] In the formula, Boc represents a tert-butyloxycarbonyl group, and Me represents a methyl group.
[0108] Example 1 Toluene (1.3g) was added to the reactor, followed by the addition of starting compound 1 (1.3g, 4.03 mmol). While stirring, IF5-Et3N-3HF (1.54g, 4.03 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 16 hours (during the addition and reaction, the reaction solution was heated, so the external temperature was adjusted to maintain the internal temperature at 10°C to 40°C). After stopping the reaction with an aqueous potassium hydroxide solution, the yield of target compound 2 was confirmed to be 70% by F-NMR.
[0109] Example 2 The solvent was changed from toluene to dichloromethane, and the reaction was carried out in the same manner as in Example 1 to obtain target compound 2 in a yield of 66%.
[0110] Example 3 The solvent was changed from toluene to n-heptane, and the reaction was carried out in the same manner as in Example 1 to obtain target compound 2 in a yield of 59%.
[0111] Example 4 The solvent was changed from toluene to ethyl acetate, and the reaction was carried out in the same manner as in Example 1 to obtain target compound 2 in a yield of 48%.
[0112] Example 5 The solvent was changed from toluene to acetonitrile, and the reaction was carried out in the same manner as in Example 1 to obtain target compound 2 in a yield of 53%.
[0113] Comparative Example 1 The reaction was carried out in the same manner as in Example 1, except that IF5-Et3N-3HF was added while stirring the reaction mixture at room temperature (internal temperature 27°C) without adjusting the external temperature, and it was confirmed that the internal temperature rose to 95°C. As a result, target compound 2 was obtained in a yield of 15%.
[0114] [Example 6]
[0115] [ka]
[0116] In the formula, Boc represents a tert-butyloxycarbonyl group, and Me represents a methyl group.
[0117] Toluene (1.7g) was added to the reactor, followed by the addition of starting compound 3 (1.7g, 4.03 mmol). While stirring, IF5-Et3N-3HF (1.85g, 4.84 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 19 hours (during the addition and reaction, the reaction solution was heated, so the external temperature was adjusted to maintain the internal temperature at 10°C to 40°C). After stopping the reaction with an aqueous potassium hydroxide solution, the yield of target compound 4 was confirmed to be 27% by F-NMR.
[0118] [Example 7]
[0119] [ka]
[0120] In the formula, Cbz represents a benzyloxycarbonyl group, and Me represents a methyl group.
[0121] Dichloromethane (290g) was added to the reactor, followed by the addition of starting compound 5 (1.82g, 4.03 mmol). While stirring, IF5-Et3N-3HF (3.87g, 10.1 mmol) was added dropwise, and the reaction was carried out at room temperature for 14.5 hours (during the addition and reaction, the reaction solution was heated, so the external temperature was adjusted to maintain the internal temperature at 10°C to 40°C). After stopping the reaction with aqueous potassium hydroxide solution, the yield of target compound 6 was confirmed to be 23% by F-NMR.
[0122] [Examples 10-11]
[0123] [ka]
[0124] In the formula, Troc represents a (2,2,2-trichloroethoxy)carbonyl group, and Me represents a methyl group.
[0125] Example 10 Dichloromethane (7.3g) was added to the reactor, followed by the addition of starting compound 7 (2.61g, 4.03 mmol). While stirring, IF5-Et3N-3HF (6.95g, 18.1 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 25 hours (during the addition and reaction, the reaction solution was heated, so the external temperature was adjusted to maintain the internal temperature at 10°C to 40°C). After stopping the reaction with aqueous potassium hydroxide solution, the yield of target compound 8 was confirmed to be 25% by F-NMR.
[0126] Example 11 The reaction temperature was maintained at 50°C to 60°C instead of 10°C to 40°C, and the solvent was changed from dichloromethane to 1,2-dichloroethane. The reaction was carried out in the same manner as in Example 10, and target compound 8 was obtained in a yield of 22%.
[0127] [Example 12]
[0128] [ka]
[0129] In the formula, Et represents an ethyl group, and Me represents a methyl group.
[0130] Dichloromethane (200g) was added to the reactor, followed by the addition of starting compound 9 (1.32g, 4.03 mmol). While stirring, IF5-Et3N-3HF (2.78g, 7.25 mmol) was added dropwise, and the reaction was carried out at room temperature for 18.5 hours (during the addition and reaction, the reaction solution was heated, so the external temperature was adjusted to maintain the internal temperature at 10°C to 40°C). After stopping the reaction with aqueous potassium hydroxide solution, the yield of target compound 10 was confirmed to be 23% by F-NMR.
[0131] [Example 13]
[0132] [ka]
[0133] In the formula, Me represents a methyl group.
[0134] Dichloromethane (200g) was added to the reactor, followed by the addition of starting compound 11 (1.44g, 4.03 mmol). While stirring, IF5-Et3N-3HF (3.70g, 9.67 mmol) was added dropwise, and the reaction was carried out at room temperature for 18.5 hours (during the addition and reaction, the reaction solution was heated, so the external temperature was adjusted to maintain the internal temperature at 10°C to 40°C). After stopping the reaction with aqueous potassium hydroxide solution, the yield of target compound 12 was confirmed to be 22% by F-NMR.
Claims
1. Formula (1): 【Chemistry 1】 [In the formula, R １ , R ２ and R ３ They are the same or different, R １ This indicates -COR. R ２ and R ３ This represents a hydrogen atom or -COR. R represents a C1-C12 alkoxy group or a C6-C12 aryloxy group, which may be substituted with one or more substituents, either identical or different. A method for producing a compound represented by, Formula (2): 【Chemistry 2】 [In the formula, R １ , R ２ and R ３ are the same as described above. R ４ This represents an alkyl group having 1 to 12 carbon atoms or an aryl group having 6 to 12 carbon atoms. The compound represented by is reacted at a temperature of 80°C or lower throughout the entire reaction, from start to finish, IF ５ Step A involves reacting with a fluorinating agent containing amine and HF. A manufacturing method that includes this.
2. In the above formulas (1) and (2), The aforementioned R １ This represents a tert-butyloxycarbonyl group, a benzyloxycarbonyl group, a (2,2,2-trichloroethoxy)carbonyl group, an ethoxycarbonyl group, or an isopropoxycarbonyl group. The aforementioned R ２ and R ３ These represent, either identically or differently, a hydrogen atom, a tert-butyloxycarbonyl group, a benzyloxycarbonyl group, a (2,2,2-trichloroethoxy)carbonyl group, an ethoxycarbonyl group, or an isopropoxycarbonyl group. The manufacturing method according to claim 1.
3. The compound represented by the general formula (2) above is 【Transformation 3】 The manufacturing method according to claim 1 or 2.
4. The compound represented by the general formula (2) above is 【Chemistry 4】 The manufacturing method according to claim 3.
5. The compound represented by the general formula (1) above is 【Transformation 5】 The manufacturing method according to claim 1 or 2.
6. The compound represented by the general formula (1) above is 【Transformation 6】 The manufacturing method according to claim 5.
7. The manufacturing method according to claim 1 or 2, wherein the reaction temperature of step A is 10 to 40°C.
8. The manufacturing method according to claim 1 or 2, wherein step A is carried out in the presence of a solvent.
9. The manufacturing method according to claim 1 or 2, wherein the reaction temperature of step A is 10 to 40°C, and step A is carried out in the presence of a solvent.
10. The manufacturing method according to claim 8, wherein the solvent is at least one selected from the group consisting of (cyclo)alkanes, chlorine-containing organic solvents, aromatic solvents, nitrile-containing organic solvents, fluorine-containing organic solvents, and ester-containing organic solvents.
11. The production method according to claim 9, wherein the solvent is at least one selected from the group consisting of (cyclo)alkanes, chlorine-containing organic solvents, aromatic solvents, nitrile-containing organic solvents, fluorine-containing organic solvents, and ester-containing organic solvents.