Method for producing alkylsiloxy-substituted benzylamine compound

Abstract

Provided is an industrially advantageous method for producing an alkylsiloxy-substituted benzylamine compound, which is easy to remove impurities and does not undergo the substitution of a benzyl compound with an alkylsiloxy group, which is an intermediate compound that is unstable with respect to an acid. The present invention relates to a method for producing a ketimine compound represented by general formula (3), which is characterized by reacting a benzoyl compound represented by general formula (2) with a silazane compound and then reacting with an acid or a base. (In formula (2), one to five of R1b to R5b represent a hydroxyalkoxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, or the like; rB represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1-6 carbon atoms, or the like); (In formula (3), R1b to R5b and RB are the same as described above). # imgabs0 #

Description

Technical Field

[0001] The invention relates to a method for preparing an alkylsiloxy-substituted benzylamine compound. Background Art

[0002] In liquid phase peptide synthesis, a carrier (Tag) for liquid phase peptide synthesis has been reported. The carrier (Tag) for liquid phase peptide synthesis is a highly hydrophobic compound, so by binding a highly hydrophilic amino acid, peptide or amino acid amide (hereinafter, sometimes referred to as amino acid, etc.) to the carrier, the solubility in an organic solvent can be greatly improved. Therefore, it has the following advantages: when a peptide extension reaction is carried out in a state where an amino acid, etc. is bound to the carrier, the amino acid, etc. bound to the carrier is dissolved in the organic layer, and useless components, such as the remaining raw amino acids used in the peptide extension reaction, or their decomposition products, and compounds generated as byproducts when the protecting groups of the raw amino acids are deprotected, etc. are dissolved in the aqueous layer, thereby making it possible to simply purify the amino acids, etc. bound to the carrier by liquid-liquid separation.

[0003] Among the carriers (Tags) for liquid phase peptide synthesis, the carriers (Tags) for liquid phase peptide synthesis shown in Patent Documents 1 to 7 and Non-Patent Document 1 are structures in which one or more alkoxy side chains having 1 to 16 carbon atoms bonded to an alkylsilyloxy group are bonded to a parent core such as a benzyl skeleton, a diphenylmethane skeleton or a xanthene skeleton. These carriers (Tags) for liquid phase peptide synthesis are particularly useful as carriers (Tags) for liquid phase peptide synthesis because the hydrophobicity of the entire carrier (Tag) for liquid phase peptide synthesis is exquisitely controlled by the side chain structure bonded to the alkylsilyloxy group.

[0004] Prior art literature

[0005] Patent Literature

[0006] Patent Document 1: Japanese Patent No. 6116782

[0007] Patent Document 2: Japanese Patent No. 6201076

[0008] Patent Document 3: Japanese Patent No. 6283774

[0009] Patent Document 4: Japanese Patent No. 6283775

[0010] Patent Document 5: Japanese Patent No. 6322350

[0011] Patent Document 6: Japanese Patent No. 6393857

[0012] Patent Document 7: Japanese Patent No. 6531235

[0013] Non-patent literature

[0014] Non-patent literature 1: Molecules 2021, 26, 3497-3505. Summary of the invention

[0015] The methods for producing these liquid phase peptide synthesis carriers (Tags) are shown in Patent Documents 1 to 7. However, in this conventional method, Br-(CH2) 11 -O-TIPS is oily and has poor stability and is difficult to handle. In addition, the physical properties of the raw material and the intermediate compound are both oily and similar, making liquid-liquid separation difficult. Therefore, the raw material or the decomposition product of the raw material is easily mixed into the target product as an impurity, and it is difficult to improve the purity of the liquid phase peptide synthesis carrier (Tag) itself by conventional industrial operations alone, so there is a problem of complicated operations such as precise purification by column chromatography.

[0016] Furthermore, as described in the prior art literature, there are also problems when converting an alkylsiloxy-substituted benzyl compound into an alkylsiloxy-substituted benzylamine compound. The inventors have made it clear that the alkylsiloxy-substituted benzyl compound as an intermediate has slightly poor stability to acid, and two main side reactions occur during the storage process of the alkylsiloxy-substituted benzyl compound or the process of converting it into amine. The first side reaction is a side reaction in which the hydroxyl portion of the benzyl compound decomposes and the alkylsiloxy-substituted benzyl compound dimerizes. The physical properties of the dimer are similar to those of the target alkylsiloxy-substituted benzylamine compound, and separation is more difficult. The second side reaction is a side reaction in which the alkylsilyl group is separated from the alkylsiloxy group. In addition, it is also difficult to separate the dealkylsilyl body from the alkylsiloxy-substituted benzylamine compound.

[0017] Therefore, an object of the present invention is to provide an industrial production method for an alkylsiloxy-substituted benzylamine compound, which allows easy removal of impurities and does not involve an alkylsiloxy-substituted benzyl compound as an intermediate compound that is unstable to acid.

[0018] Therefore, the present inventors have discovered an industrial production method for an alkylsiloxy-substituted benzylamine compound based on the following manner: a hydroxyalkoxy group is introduced into a compound having a benzoyl skeleton, a diphenyl ketone skeleton (benzophenone skeleton) or a xanthene skeleton, and then the hydroxyalkoxy-substituted product is reacted with a disilazane compound, and then reacted with an acid or a base to remove the trisubstituted silyl group on the hydroxyl group, thereby obtaining an intermediate compound in which the carbonyl group bonded to each skeleton of the hydroxyalkoxy-substituted product is converted into an imino group, and then the imino group is converted into a 9-fluorenylmethoxycarbonyl protected amino group, and then an alkylsilyl group is introduced into the hydroxyl group, thereby producing an alkylsiloxy-substituted benzylamine compound. According to the method of the present invention, there is no need to use Br-(CH2) as a raw material, which has poor stability and is difficult to separate from the intermediate compound in the existing method. 11 -O-TIPS. In addition, since the intermediate compound is solid, it is easy to remove the raw material or the decomposition product of the raw material, impurities generated or left in other systems by filtering or crystallization operations. Furthermore, the target product can be obtained with high purity and high yield without passing through the alkylsiloxy-substituted benzyl compound as an intermediate compound that is unstable to acid. In summary, the present inventors have found that the alkylsiloxy-substituted benzylamine compound can be obtained industrially, thereby completing the present invention.

[0019] In addition, in the present invention, "solid" refers to both a solid material having a crystal structure and an amorphous solid material.

[0020] That is, the present invention provides the following inventions [1] to [7].

[0021] [1] A method for producing a ketimine compound represented by the general formula (3), characterized in that a benzoyl compound represented by the general formula (2) is reacted with a silazane compound, and then reacted with an acid or a base.

[0022]

[0023] (Where R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms,

[0024] R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0025]

[0026] (R 1b ~R 5b1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be combined with R in formula (2) 5b Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R B bonding site);

[0027]

[0028] (Where R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms,

[0029] R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0030]

[0031] (R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (3) 5b Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R B bonding site. )).

[0032] [2] A method for producing a benzylamine compound represented by the general formula (4), characterized in that a benzoyl compound represented by the general formula (2) is reacted with a silazane compound, and then reacted with an acid or a base to obtain a ketimine compound represented by the general formula (3), and the obtained ketimine compound is reacted with a reducing agent and an Fmoc-forming agent.

[0033]

[0034] (Where R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms,

[0035] R Brepresents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0036]

[0037] (R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be combined with R in formula (2) 5b Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R B The bonding site.

[0038]

[0039] (Where R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms,

[0040] R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0041]

[0042] (R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (3) 5b Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R B The bonding site of . ));

[0043]

[0044] (Where R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms,

[0045] R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0046]

[0047] (R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be combined with R in formula (4) 5b Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R B bonding site. )).

[0048] [3] A method for producing an alkylsiloxy-substituted benzylamine compound represented by the general formula (5), characterized in that a benzoyl compound represented by the general formula (2) is reacted with a silazane compound, and then reacted with an acid or a base to obtain a ketimine compound represented by the general formula (3), the obtained ketimine compound is reacted with a reducing agent and an Fmoc-forming agent to obtain a benzylamine compound represented by the general formula (4), and then the benzylamine compound is reacted with an alkylsilylating agent.

[0049]

[0050] (Where R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms,

[0051] R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0052]

[0053] (R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be combined with R in formula (2) 5b Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R B The bonding site.

[0054]

[0055] (Where R1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms,

[0056] R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0057]

[0058] (R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (3) 5b Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R B The bonding site of . ));

[0059]

[0060] (Where R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms,

[0061] R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0062]

[0063] (R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (4) 5b Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R B The bonding site of . ));

[0064]

[0065] (Where R 1c ~R 5c1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms,

[0066] R C represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0067]

[0068] (R 1c ~R 5c 1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or R C When representing the structure of this formula, R 5c It can be compared with R in formula (5) 5c Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R C bonding site. )).

[0069] [4] The production method according to any one of [1] to [3], wherein the benzoyl compound represented by the general formula (2) is obtained by reacting a compound represented by the general formula (1) with a halohydrin,

[0070]

[0071] (Where R 1a ~R 5a 1 to 5 of them represent hydroxyl groups, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms,

[0072] R A represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0073]

[0074] (R 1a ~R 5a 1 to 5 of them represent hydroxyl groups, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R A When representing the structure of this formula, R 5a It can be combined with R in formula (1) 5a Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R A bonding site. )).

[0075] [5] A compound represented by the general formula (6),

[0076]

[0077] (Where R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms,

[0078] R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0079]

[0080] (R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (6) 5b Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R B Bonding site

[0081] NY represents an imino group (=NH) or NHFmoc.).

[0082] [6] A method for producing an alkylsiloxy-substituted benzylamine compound represented by the general formula (5), characterized in that a benzylamine compound represented by the general formula (4) is reacted with an alkyl silylating agent,

[0083]

[0084] (Where R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms,

[0085] R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0086]

[0087] (Among them, R 1b ~R 5b1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (4) 5b Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R B The bonding site of . ));

[0088]

[0089] (Where R 1c ~R 5c 1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms,

[0090] R C represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0091]

[0092] (R 1c ~R 5c 1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or R C When representing the structure of this formula, R 5c It can be compared with R in formula (5) 5c Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R C bonding site. )).

[0093] [7] A method for producing an alkylsiloxy-substituted benzylamine compound represented by the general formula (5), characterized in that a ketimine compound represented by the general formula (3) is reacted with a reducing agent and an Fmoc-forming agent to obtain a benzylamine compound represented by the general formula (4), and then the benzylamine compound is reacted with an alkylsilylating agent.

[0094]

[0095] (Where R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms,

[0096] RB represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0097]

[0098] (R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (3) 5b Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R B The bonding site of . ));

[0099]

[0100] (Where R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms,

[0101] R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0102]

[0103] (R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (4) 5b Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R B The bonding site of . ));

[0104]

[0105] (Where R 1c ~R 5c 1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms,

[0106] R Crepresents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0107]

[0108] (R 1c ~R 5c 1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or R C When representing the structure of this formula, R 5c It can be compared with R in formula (5) 5c Together they form an ether bond (-O-), which should be noted that * indicates that they are connected to R C bonding site. )).

[0109] According to the method of the present invention, it is not necessary to use raw materials that have poor stability and are difficult to separate from intermediate compounds in the conventional methods. In addition, since the intermediate compound is solid, it is easy to remove the raw materials or decomposition products of the raw materials, and impurities generated or left in other systems by filtration or crystallization operations. Furthermore, the alkylsiloxy-substituted benzylamine compound can be obtained industrially advantageously without going through the alkylsiloxy-substituted benzyl compound as an intermediate compound that is unstable to acid. DETAILED DESCRIPTION

[0110] If the reaction from the compound of the general formula (1) to the compound of the general formula (5) in the present invention is represented by a reaction formula, it is as shown below.

[0111]

[0112] (Where R 1a ~R 5a 1 to 5 of them represent hydroxyl groups, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms;

[0113] R A represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0114]

[0115] (R 1a ~R 5a 1 to 5 of them represent hydroxyl groups, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R A When representing the structure of this formula, R 5a It can be compared with R in formula (1) 5aTogether they form an ether bond (-O-); it should be noted that * indicates that they are connected to R A bonding site.)

[0116] R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms;

[0117] R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0118]

[0119] (R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be combined with R in formula (2) to (4) 5b Together they form an ether bond (-O-); it should be noted that * indicates that they are connected to R B bonding site.)

[0120] R 1c ~R 5c 1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;

[0121] R C represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0122]

[0123] (R 1c ~R 5c 1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or R C When representing the structure of this formula, R 5c It can be compared with R in formula (5) 5c Together they form an ether bond (-O-); it should be noted that * indicates that they are connected to R C bonding site. )).

[0124] One embodiment of the present invention is a method for producing a ketimine compound represented by the general formula (3), characterized by reacting a benzoyl compound represented by the general formula (2) with a silazane compound, and then reacting the reactant with an acid or a base.

[0125] In addition, another embodiment of the present invention is a method for producing a benzylamine compound represented by the general formula (4), characterized in that: the benzoyl compound represented by the general formula (2) is reacted with a silazane compound, and then reacted with an acid or a base to obtain a ketimine compound represented by the general formula (3), and the ketimine compound is reacted with a reducing agent and an Fmoc-forming agent.

[0126] In addition, another embodiment of the present invention is a method for producing an alkylsiloxy-alkoxybenzylamine compound represented by general formula (5), characterized in that: a benzoyl compound represented by general formula (2) is reacted with a silazane compound, and then reacted with an acid or a base to obtain a ketimine compound represented by general formula (3), the ketimine compound is reacted with a reducing agent and an Fmoc-forming agent to obtain a benzylamine compound represented by general formula (4), and the obtained benzylamine compound is reacted with an alkyl silylating agent. In the specification, when "alkylsiloxy-substituted benzylamine compound" is described, this structure is indicated.

[0127] Here, the benzoyl compound represented by the general formula (2) is preferably obtained by reacting the hydroxybenzoyl compound represented by the general formula (1) with a halogenated alcohol.

[0128] Another aspect of the present invention is a method for producing an alkylsilyloxy-alkoxybenzylamine compound represented by the general formula (5), characterized by reacting the benzylamine compound represented by the general formula (4) with an alkyl silylation agent.

[0129] In addition, another embodiment of the present invention is a method for producing an alkylsiloxy-alkoxybenzylamine compound represented by the general formula (5), characterized in that: the ketimine compound represented by the general formula (3) is reacted with a reducing agent and an Fmoc-forming agent to obtain a benzylamine compound represented by the general formula (4), and the obtained benzylamine compound is reacted with an alkylsilylating agent.

[0130] In addition, the ketimine compound represented by the above general formula (3) and the benzylamine compound represented by the general formula (4) are novel compounds. Therefore, another embodiment of the present invention provides a compound represented by the following general formula (6):

[0131]

[0132] (Where R 1b ~R 5b1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms;

[0133] R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0134]

[0135] (R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (6) 5b Together they form an ether bond (-O-); it should be noted that * indicates that they are connected to R B bonding site.)

[0136] NY represents an imino group (=NH) or NHFmoc).

[0137] First, the compound of the general formula (1) as a raw material compound will be described.

[0138] R 1a ~R 5a 1 to 5 of them represent hydroxyl groups, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms.

[0139] The number of the hydroxyl groups is preferably 1 to 4, more preferably 2 to 4, further preferably 2 to 3, and further preferably 2.

[0140] The remaining groups may be a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, preferably a hydrogen atom, a halogen atom or an alkyl group having 1 to 4 carbon atoms, more preferably a hydrogen atom.

[0141] Here, examples of the alkyl group having 1 to 4 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, etc. Examples of the alkoxy group having 1 to 4 carbon atoms include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, etc. Examples of the halogen atom include chlorine, bromine, fluorine, and iodine.

[0142] R A represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0143]

[0144] (R 1a ~R 5a 1 to 5 of them represent hydroxyl groups, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R A When representing the structure of this formula, R 5a It can be compared with R in formula (1) 5a Together they form an ether bond (-O-); it should be noted that * indicates that they are connected to R A bonding site.)

[0145] Examples of the alkoxy group having 1 to 6 carbon atoms include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentyl, n-hexyl, etc. Among them, an alkoxy group having 1 to 5 carbon atoms is preferred, and an alkoxy group having 1 to 4 carbon atoms is more preferred.

[0146] As R 1a ~R 5a The groups shown are preferably the same as those mentioned above.

[0147] R A Preferred are groups represented by the following formula.

[0148]

[0149] (R 1a ~R 5a 1 to 5 of them represent hydroxyl groups, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms. A bonding site.)

[0150] The benzoyl compound of the general formula (2) can be obtained by reacting the compound of the general formula (1) with a halogenated alcohol (represented as Hal-alcohol in the formula).

[0151] Examples of the halohydrin include halohydrin having 1 to 16 carbon atoms, preferably halohydrin having 2 to 16 carbon atoms, more preferably halohydrin having 4 to 16 carbon atoms, further preferably halohydrin having 6 to 16 carbon atoms, and further preferably halohydrin having 8 to 16 carbon atoms. Examples of the halogen atom include bromine atom, chlorine atom, iodine atom and fluorine atom, preferably bromine atom, chlorine atom and iodine atom. Examples of the alcohol include linear or branched alcohols.

[0152] The reaction of the compound of the general formula (1) with the halohydrin is preferably carried out in a solvent in the presence of a base.

[0153] As the reaction solvent used, there can be mentioned: amide solvents such as dimethylformamide (hereinafter, DMF), diethylformamide, 1-methyl-2-pyrrolidone (hereinafter, NMP), dimethylacetamide, etc.; urea solvents such as 1,3-dimethyl-2-imidazolidinone (hereinafter, DMI), etc.; halogenated solvents such as dichloromethane; ethers such as tetrahydrofuran and 2-methyltetrahydrofuran; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.; alcohol solvents such as methanol, ethanol, isopropanol, n-propanol, n-butanol, etc.; polar solvents such as acetonitrile, etc.; and various mixed solvents thereof. Among them, amide solvents and urea solvents are preferred, and DMF and DMI are more preferred.

[0154] Examples of the base include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, and hydrates thereof, metal alkoxides such as lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide, and organic bases such as 1,8-diazabicyclo[5.4.0]-7-undecene, diisopropylethylamine, triethylamine, dimethylaniline, and imidazole. Preferred bases include potassium carbonate and lithium hydroxide.

[0155] The reaction may be carried out at a temperature of 0° C. to 200° C., preferably 50° C. to 150° C., and more preferably 70° C. to 120° C. The reaction is preferably carried out for 15 minutes to 48 hours.

[0156] The benzoyl compound of the general formula (2) obtained in the reaction can be isolated as a solid, so it is easy to purify and has good handleability. It should be noted that separation and purification can be easily performed by a method generally used in industry, such as washing and recrystallization.

[0157] R in the general formula (2) 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms.

[0158] The number of the hydroxyalkoxy groups is preferably 1 to 4, more preferably 2 to 4, further preferably 2 to 3, further more preferably 2.

[0159] The remaining groups may be a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, preferably a hydrogen atom, a halogen atom or an alkyl group having 1 to 4 carbon atoms, more preferably a hydrogen atom.

[0160] R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula,

[0161]

[0162] (R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (2) 5b Together they form an ether bond (-O-); it should be noted that * indicates that they are connected to R B bonding site).

[0163] Here, the hydroxyalkoxy group having 1 to 16 carbon atoms is preferably 1b ~R 5b Same group.

[0164] Among the compounds represented by the above general formula (2), R B It represents a compound of a group represented by the following formula.

[0165]

[0166] (R 1b ~R 4b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms. B bonding site).

[0167] The benzoyl compound of the general formula (2) is reacted with a silazane compound, and then reacted with an acid or a base to obtain a ketimine compound of the general formula (3). Specifically, if the compound of the general formula (2) is reacted with a silazane compound in the presence of a catalyst, a compound having a trisubstituted silyl group bonded to the hydroxyl group of the hydroxyalkoxy group can be obtained. Then, the obtained compound is reacted with an acid or a base to remove the trisubstituted silyl group, and the ketimine compound of the general formula (3) can be obtained.

[0168] The reaction using the silazane compound is a reaction in which the carbonyl group in the formula (2) is converted into an imino group (=NH), while the terminal alcohol of the hydroxyalkoxy group of the side chain is protected by a trisubstituted silyl group.

[0169] Silazane compounds are compounds having Si-NH-Si bonds. Examples of chain silazane compounds include disubstituted disilazane (1,3-disubstituted disilazane), tetrasubstituted disilazane (1,1,3,3-tetrasubstituted disilazane), and hexasubstituted disilazane (1,1,1,3,3,3-hexasubstituted disilazane). The substituent in the silazane compound may be any aliphatic group, which may be linear, branched, or cyclic, and may be saturated or unsaturated. Among them, a saturated or unsaturated straight-chain aliphatic group having 1 to 4 carbon atoms is preferred, and tetramethyldisilazane (1,1,3,3-tetramethyldisilazane), hexamethyldisilazane (1,1,1,3,3,3-hexamethyldisilazane), 1,3-divinyl-1,1,3,3-tetramethyldisilazane, and 1,3-diphenyltetramethyldisilazane are preferred, and hexamethyldisilazane (1,1,1,3,3,3-hexamethyldisilazane) is most preferred.

[0170] Examples of cyclic silazane compounds include 2,2,4,4,6,6-hexasubstituted cyclotrisilazane. The substituent may be any aliphatic group, which may be linear, branched or cyclic, and may be saturated or unsaturated. Among them, a saturated or unsaturated linear aliphatic group having 1 to 4 carbon atoms is preferred, and examples thereof include 2,2,4,4,6,6-hexamethylcyclotrisilazane and 2,4,6-trimethyl-2,4,6-trivinylcyclotrisilazane.

[0171] As a specific catalyst, a catalyst containing a metal salt having Lewis acidity can be cited. The metal salt can be exemplified by trifluoromethanesulfonate, nonafluorobutanesulfonate, trifluoromethanesulfonyl imide salt, and specifically, Sc(OTf)3, Y(OTf)3, Sm(OTf)3, Eu(OTf)3, Gd(OTf)3, Er(OTf)3, Yb(OTf)3, Fe(OTf)3, In(OTf)3, Sn(OTf)3, Bi(OTf)3, Sc(ONf)3, Sc(ONf)3. Sc(NO3)3, BiBr3 can also be cited, and tetrabutylammonium fluoride and tetrabutylammonium dihydrofluoride can also be cited. The metal is particularly preferably selected from at least one of Sc, Y, Eu, Er, Yb, Fe, Sn and Bi, and as the metal salt, Sc(OTf)3 is particularly preferred.

[0172] The reaction can be carried out in a solvent or without a solvent at 0 to 150°C for 15 minutes to 48 hours. Examples of the solvent include aromatic hydrocarbon solvents such as chlorobenzene, toluene, and fluorobenzene; tetrahydrofuran, 1,4-dihydrofuran, and the like; Ether solvents such as oxane; halogen solvents such as 1,2-dichloroethane; chlorobenzene and toluene are particularly preferred, and toluene is most preferred. In addition, water, alcohol, silanol, etc. may be added as a reaction accelerator.

[0173] After the reaction, the terminal trisubstituted silyl group on the hydroxyalkoxy group of the side chain is reacted with an acid or a base to deprotect the terminal trisubstituted silyl group and convert it into a terminal alcohol. As an acid, inorganic acids such as hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, 10-camphorsulfonic acid, and hydrogen fluoride-pyridine can be cited. As a base, inorganic bases such as tetraalkylammonium fluoride, cesium fluoride, and potassium fluoride can be cited, or in the presence of an alcohol solvent, inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, and potassium hydride, and their hydrates, and metal alkoxides such as lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide can be cited. Among them, it is preferred to use a base for deprotection, and it is more desirable to make an alkali metal carbonate or an alkali metal bicarbonate work in the presence of a C1-4 alcohol such as methanol or ethanol.

[0174] The deprotection reaction of the trisubstituted silyl group can be carried out continuously by adding a suitable solvent after the reaction of converting the benzoyl group to the imino group (=NH) is completed. The deprotection agent of the trisubstituted silyl group is added and the reaction is carried out at 0 to 100° C. for 15 minutes to 24 hours.

[0175] The ketimine compound of the general formula (3) obtained in the reaction can be isolated as a solid, so it is easy to purify and has good handleability. It should be noted that separation and purification can be easily performed by a method generally used in industry, such as washing and recrystallization.

[0176] By reacting the ketimine compound of the general formula (3) with a reducing agent and an Fmoc-forming agent, a benzylamine compound of the general formula (4) can be obtained.

[0177] This reaction is a reaction of converting the imino group (=NH) of the formula (3) into a fluorenylmethoxycarbonylamino group (-NHFmoc).

[0178] As the reducing agent, metal hydrides such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride, lithium triethylborohydride, lithium tri(sec-butyl)borohydride, sodium bis(2-ethoxyethoxy)aluminum hydride (hereinafter referred to as SBAH), borane complex, diisobutylaluminum hydride, and nickel borohydride may be mentioned. In addition, reduction using silicon hydrides such as trialkylsilane or reaction in which palladium-carbon as a catalyst is used in the presence of hydrogen may also be mentioned. Among these, lithium borohydride is most preferred.

[0179] The reduction reaction is preferably carried out in an aromatic hydrocarbon solvent such as benzene, toluene, etc.; an ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, etc.; an alcohol solvent such as methanol, ethanol, isopropanol, n-propanol, n-butanol, etc., or a mixed solvent thereof, at a temperature of 0°C to 100°C for 15 minutes to 48 hours.

[0180] Then, the reaction is carried out with an Fmoc-forming agent. As the Fmoc-forming agent, any compound capable of introducing a 9-fluorenylmethoxycarbonyl group (Fmoc) may be used, and in addition to fluorenylmethyl haloformate, Fmoc-OSu, 9-fluorenylmethyl carbamate, 9-fluorenylmethyl hydrazinecarboxylate, 1-(Fmoc-oxy)benzotriazole, 9-fluorenylmethyl pentafluorophenyl carbonate, etc., Fmoc-Amox described in Org.Process Res.Dev.2017,21(10),1533-41 may also be used.

[0181] The Fmoc reaction can be carried out continuously after the reduction reaction is completed without changing the reaction solvent, etc. The Fmoc reaction can be carried out by adding an Fmoc agent and reacting at 0 to 100° C. for 10 minutes to 3 hours.

[0182] The benzylamine compound of the general formula (4) obtained in the reaction can be isolated as a solid, so it is easy to purify and has good handling properties. It should be noted that separation and purification can be easily performed by a method generally used in industry, such as washing and recrystallization.

[0183] By reacting the benzylamine compound of the general formula (4) with an alkyl silylating agent, an alkylsiloxy-alkoxybenzylamine compound of the general formula (5) can be obtained.

[0184] The alkylsilylating agent used in the reaction is a silylating agent having 1 to 3 alkylsilyl groups, and preferably a silylating agent having an alkylsilyl group represented by formula (7) to (17).

[0185] In addition, in the figure, * represents the bonding point with the oxygen atom of the hydroxyl group.

[0186]

[0187] (Here, R 7 , R 8 , R 9 R represents, identically or differently, a linear or branched alkyl group having 1 to 6 carbon atoms, or an aryl group which may have a substituent; 10 represents a single bond or a linear or branched alkylene group having 1 to 3 carbon atoms, R 11 , R 12 and R 13 respectively represent a linear or branched alkylene group having 1 to 3 carbon atoms).

[0188] Here, examples of the linear or branched alkyl group having 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc. Among them, an alkyl group having 1 to 4 carbon atoms is more preferred, and a methyl group, tert-butyl group, and isopropyl group are further preferred.

[0189] The aryl group which may have a substituent may be an aryl group having 6 to 10 carbon atoms, and specifically, a phenyl group or a naphthyl group which may be substituted with an alkyl group having 1 to 3 carbon atoms. Among them, a phenyl group is more preferred.

[0190] Examples of the alkyl silylation agent include alkyl silyl halides, alkyl silyl imidazoles, alkyl silyl benzotriazoles, alkyl trifluoromethanesulfonyl silanes, etc. Examples of the halogen atom include bromine atoms, chlorine atoms, and iodine atoms.

[0191] The reaction of the benzylamine compound of the general formula (4) with the alkylsilylating agent is preferably carried out in a solvent in the presence of a base.

[0192] Examples of the reaction solvent used include: amide solvents such as DMF, diethylformamide, NMP, and dimethylacetamide; urea solvents such as DMI; halogenated solvents such as dichloromethane; ethers such as tetrahydrofuran and 2-methyltetrahydrofuran; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; polar solvents such as acetonitrile; and various mixed solvents thereof. Among them, amide solvents and urea solvents are preferred, and DMF, NMP, and DMI are more preferred.

[0193] Examples of the base include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, and the like; and hydrates thereof, metal alkoxides such as lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; and organic bases such as 1,8-diazabicyclo[5.4.0]-7-undecene, diisopropylethylamine, triethylamine, dimethylaniline, and imidazole. Preferred bases include imidazole.

[0194] The reaction may be performed at a temperature of 0° C. to 150° C., preferably 20° C. to 100° C., and more preferably 30° C. to 50° C. The reaction is preferably performed for 15 minutes to 48 hours.

[0195] In this reaction, a trace amount of silyl compounds from the alkyl silylating agent is sometimes produced as a by-product in the reaction mixture. In this case, the silyl compounds are preferably removed by liquid-liquid separation. The target alkylsiloxy-substituted benzylamine compound (5) is dissolved in an alkane solvent such as heptane. For this, a polar solvent such as acetonitrile, methanol, DMF, dimethyl sulfoxide, etc. is used for liquid-liquid separation. The polar solvent is preferably a mixed solvent with water, and a combination of acetonitrile and water is particularly preferred.

[0196] R in the general formula (5) 1c ~R 5c1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsiloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. The structure of the alkoxy group having 1 to 29 carbon atoms substituted by the alkylsiloxy group is represented by the following formula.

[0197] *—O—R E —O—A (18)

[0199] (R E represents a linear or branched alkyl group having 1 to 16 carbon atoms, and A represents formulas (7) to (17). In addition, * represents a bonding site to a carbon atom on a benzoyl skeleton, a diphenyl ketone skeleton, or a xanthene skeleton as a parent nucleus).

[0200] The carbon number of the alkoxy group of 1 to 29 is the carbon number of the hydroxyalkoxy chain of 1 to 16 carbon atoms derived from the halohydrin, and R in the silylating agent represented by formula (7) to (17) 10 , R 11 , R 12 and R 13 The total number of carbon atoms contained.

[0201] The number of the alkoxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups is preferably 1 to 4, more preferably 2 to 4, further preferably 2 to 3, further more preferably 2.

[0202] As the remaining groups, there may be mentioned a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, preferably a hydrogen atom, a halogen atom or an alkyl group having 1 to 4 carbon atoms, more preferably a hydrogen atom.

[0203] R C It represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula.

[0204]

[0205] (R 1b ~R 5b 1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or R C When representing the structure of this formula, R 5c It can be compared with R in formula (5) 5c Together they form an ether bond (-O-); it should be noted that * indicates that they are connected to R C bonding site).

[0206] Here, the alkoxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups may be the same as the above-mentioned alkylsilyl group. 1c ~R 5c The other substituents are preferably the same as those in R 1b ~R 5b Same group.

[0207] By the above-mentioned alkylsilyloxylation reaction, an alkylsiloxy-alkoxybenzylamine compound of the general formula (5) can be obtained.

[0208] The alkylsilyloxy-alkoxybenzylamine compound of the general formula (5) obtained in the reaction can be isolated as a solid, so it is easy to purify and has good handleability. It should be noted that separation and purification can be easily performed by a method generally used in industry, such as washing and recrystallization.

[0209] The alkylsilyloxy-alkoxybenzylamine compound of the general formula (5) can be used as a carrier for liquid phase peptide synthesis as described in Patent Documents 1 to 3.

[0210] The method of the present invention can obtain all solid benzoyl compounds represented by the general formula (2), ketimine compounds represented by the general formula (3), benzylamine compounds represented by the general formula (4), and alkylsiloxy-alkoxybenzylamine compounds represented by the general formula (5). In the present invention, "solid" refers to both solids having a crystalline structure and amorphous solids. When each compound has the following structure, it is easy to obtain a solid in a form closer to a crystalline structure and it is easy to function as a carrier (Tag) for liquid phase peptide synthesis.

[0211] Among the compounds represented by the general formula (1), R 1a ~R 5a 1 to 5 of them are hydroxyl groups, and the rest are hydrogen atoms. 3a is a hydroxyl group, and the rest are hydrogen atoms. A Preferred are groups represented by the following formula.

[0212]

[0213] (Preferred R 1a ~R 5a 1 to 5 of them are hydroxyl groups, and the rest are hydrogen atoms. 3a is a hydroxyl group, and the rest are hydrogen atoms. A bonding site).

[0214] In the compounds represented by the general formula (2), (3) or (4), preferably R 1b ~R 5b1 to 5 of them are hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest are hydrogen atoms. 3a The hydroxyalkoxy group has 1 to 16 carbon atoms, and the remainder are hydrogen atoms. The hydroxyalkoxy group has more preferably 4 to 16 carbon atoms, further preferably 8 to 16, further preferably 10 to 16, and most preferably 11 to 16 carbon atoms. B Preferred are groups represented by the following formula.

[0215]

[0216] (Preferably R 1b ~R 5b 1 to 5 of them are hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest are hydrogen atoms. 3b is a hydroxyalkoxy group having 1 to 16 carbon atoms, and the remainder are hydrogen atoms. The number of carbon atoms in the hydroxyalkoxy group is more preferably 4 to 16, further preferably 8 to 16, further preferably 10 to 16, and most preferably 11 to 16. B bonding site).

[0217] Among the compounds represented by the general formula (5), R 1c ~R 5c 1 to 5 of them are alkoxy groups having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the rest are hydrogen atoms. 3b is an alkylsilyloxy group having 1 to 29 carbon atoms substituted with one alkylsilyloxy group, and the rest are hydrogen atoms. It is particularly preferred that the alkylsilyloxy group is synthesized using an alkyl silylating agent represented by formula (7). In formula (7), R 7 , R 8 , R 9 Preferably, it is a linear or branched alkyl group having 1 to 6 carbon atoms, or a phenyl group;

[0218] R C Preferred are groups represented by the following formula.

[0219]

[0220] (Preferably R 1c ~R 5c 1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest are hydrogen atoms. 3b is an alkylsilyloxy group having 1 to 29 carbon atoms substituted with one alkylsilyloxy group, and the remainder are hydrogen atoms. It is particularly preferred that the alkylsilyloxy group is synthesized using an alkyl silylating agent represented by formula (7). In formula (7), R 7 , R 8 , R 9Preferably, it is a linear or branched alkyl group having 1 to 6 carbon atoms, or a phenyl group. C bonding site).

[0221] Example

[0222] Next, the present invention will be described in further detail with reference to examples, but the present invention is not limited to these examples.

[0223] Comparative Example 1 Synthesis of Fmoc-D2-STag using existing methods

[0224]

[0225] (Hereinafter, Br-(CH2) 11 -OTIPS, TIPS2-Dpm-C=O, TIPS2-Dpm-OH, Fmoc-D2-STag (structures in the formula).

[0226] (1-a)Br-(CH2) 11 -O-TIPS

[0227] 0.90 g (3.58 mmol) of 11-bromo-1-undecanol was dissolved in 12.8 mL of dichloromethane, 0.61 g (8.96 mmol) of imidazole was added, and the mixture was cooled to 5°C, and 0.91 mL (4.30 mmol) of triisopropylsilyl chloride (hereinafter referred to as TIPS-Cl) was added dropwise. After 5 minutes, the mixture was returned to room temperature and stirred for 2 hours. 51.2 mL of cyclopentyl methyl ether was added to the reaction solution, and the mixture was washed once with 12.8 mL of distilled water, once with 12.8 mL of 1M hydrochloric acid aqueous solution, and three times with 12.8 mL of distilled water, and the organic layer was distilled off. The residue was dissolved in 51.2 mL of heptane, and the mixture was washed by liquid separation with 25.6 mL of acetonitrile. 12.8 mL of heptane was added to the obtained heptane layer, and the mixture was washed by liquid separation with 25.6 mL of acetonitrile. After the above-mentioned liquid separation and washing with heptane and acetonitrile were further performed once, the solvent was distilled off to obtain Br-(CH2) 11 -O-TIPS 1.45 g (yield 99.3%). The obtained Br-(CH2) 11 -O-TIPS are in oily form.

[0228] 1 H-NMR (400MHz, CDCl3) δ1.03-1.20(m,21H),1.24-1.49(m,14H),1.54(quin.,2H),1.85(quin.,2H),3.41(t,2H),3.66(t,2H)

[0229] ESIMS MH+407.1

[0230] (1-b)TIPS2-Dpm-C=O

[0231] Make Br-(CH2) 11 -OTIPS 9.81g (24.1mmol), 4,4'-dihydroxybenzophenone 2.29g (10.7mmol), potassium carbonate 5.33g (38.5mmol) were suspended in DMF 3.2mL, heated to 85°C and stirred for 2 hours. The reaction solution was filtered and the filtrate was washed with heptane 150mL. The filtrate was separated, and 71mL of heptane was added to the obtained heptane layer, and the separation and washing were performed with DMF 71mL. The above separation and washing with heptane and DMF were further performed once. 71mL of heptane was added to the obtained heptane layer, and the separation and washing were performed once with 71mL of 1M hydrochloric acid aqueous solution, 71mL of 5% sodium bicarbonate aqueous solution, and 71mL of distilled water. 71mL of heptane was added to the obtained heptane layer, and the separation and washing were performed once with 71mL of DMF, and 71mL of acetonitrile. The heptane layer was concentrated under reduced pressure to obtain 10.7 g of TIPS2-Dpm-C=O. The obtained TIPS2-Dpm-C=O was in the form of a viscous oil.

[0232] 1 H-NMR (400MHz, CDCl3) δ1.04-1.08(m,42H),1.20-1.39(m,24H),1.41-1.49(m,4H),1. 49-1.57(m,4H),1.71-1.85(m,4H),3.67(t,4H),4.03(t,4H),6.94(d,4H),7.77(d,4H)

[0233] 13 C-NMR(100MHz, CDCl3)δ12.2(6C),18.2(12C),26.0(2C),26.2(2C),29.2-29.8(12C), 33.2(2C),63.7(2C),68.4(2C),114.0(4C),130.7(2C),132.4(4C),162.6(2C),194.6

[0234] ESIMS MNa+889.8

[0235] (1-c)TIPS2-Dpm-OH

[0236] TIPS2-Dpm-C=O 0.81 g (0.93 mmol) was dissolved in a mixed solution of THF (anhydrous) 7.1 mL and methanol 0.36 mL, and sodium borohydride 42 mg (1.12 mmol) was added and stirred for 1.5 hours. 1M hydrochloric acid aqueous solution 0.89 mL was added to the reaction solution to terminate the reaction, cyclopentyl methyl ether 20.3 mL was added, and the mixture was washed once with 1M hydrochloric acid aqueous solution 6.1 mL, washed once with 5% sodium bicarbonate aqueous solution 6.1 mL, and washed once with distilled water 6.1 mL, and the organic layer was concentrated under reduced pressure. The obtained residue was dissolved in heptane 20.0 mL, and washed with DMF 10.0 mL. Heptane 10.0 mL was added to the obtained heptane layer, and washed with acetonitrile 10.0 mL. After the above liquid separation and washing with heptane and acetonitrile were further performed once, the heptane layer was concentrated under reduced pressure to obtain 0.81 g of TIPS2-Dpm-OH.

[0237] The obtained TIPS2-Dpm-OH was in the form of viscous oil.

[0238] 1 H-NMR(400MHz,Benzene-d)δ1.12-1.16(m,42H),1.23-1.54(m,32H),1.57-1.71(m ,4H),1.79(s,1H),3.68(t,8H),5.61(s,1H),6.84-6.89(m,4H),7.27-7.33(m,4H)

[0239] 13 C-NMR(100MHz,Benzene-d)δ12.8(6C),18.7(12C),26.7(2C),26.8(2C),30.2-30.5(12 C),33.9(2C),64.1(2C),68.3(2C),75.9,114.9(4C),128.6(4C),137.8(2C),159.4(2C)

[0240] HPLC was used to analyze the HO-(CH2) contained as an impurity in the crude purified TIPS2-Dpm-OH. 11 The ratio of -OTIPS was analyzed and found to be 5.1 wt %.

[0241] Analytical conditions (HPLC)

[0242] Chromatographic column: YMC-Triart C18

[0243] (Inner diameter 3.0mm, length 100mm, particle size 1.9μm)

[0244] Mobile phase A: containing 0.01M ammonium formate, acetonitrile: water = 8:2 solution

[0245] Mobile phase B: containing 0.01M ammonium formate, isopropanol: water = 100:1 solution

[0246] Flow rate: 0.25mL / min

[0247] Column temperature: 35°C

[0248] Detection wavelength: 200nm

[0249] Gradient conditions: 0% B (0 min) → 0% B (5 min) → 100% B (22 min) → 100% B (27 min) → 0% B (29 min) → 0% B (31 min)

[0250] (1-d)Fmoc-D2-STag

[0251] Dissolve 1.00 g (1.15 mmol) of TIPS2-Dpm-OH and 0.29 g (1.25 mmol) of Fmoc-NH2 in 6.5 mL of toluene. After adding 0.04 g (0.32 mmol) of oxalic acid dihydrate, heat to 85°C and stir for 4 hours. Add 10 mL of heptane and 10 mL of 90% methanol water to perform liquid separation and washing. Add 5 mL of 5% sodium bicarbonate water to the obtained upper layer and perform liquid separation and washing. Perform the operation of adding 10 mL of 90% methanol water to the obtained upper layer and performing liquid separation and washing 3 times. Concentrate the obtained upper layer under reduced pressure. Dissolve the obtained residue in 2 mL of tetrahydrofuran, add tetrahydrofuran solution to 20 mL of stirring methanol, and stir for 30 minutes after adding. Filter the treated liquid from which the target product is crystallized, and wash the filtrate with methanol. The residue was dried under reduced pressure to obtain 0.94 g (yield 74.9%) of Fmoc-D2-STag. The obtained Fmoc-D2-STag was a solid.

[0252] 1H-NMR (400MHz, CDCl3) δ0.99-1.12(m,6H),1.06(s,36H),1.18-1.38(m,24H),1.38-1.48(m,4H),1.48-1.60(m,4H) ,1.70-1.83(m,4H),3.66(dd,4H),3.93(dd,4H),4.21(br,1H),4.44(d,1H),5.00-5.13(br,0.18H),5.20-5.32(br d,0.82H),5.70-5.80(br,0.18H),5.82-5.92(br d,0.82H),6.84(d,4H),7.11(d,4H),7.28-7.34(m,2H),7.34-7.47(m,2H),7.55-7.65(br d,2H),7.70-7.85(br d,2H)

[0253] 13 C-NMR (100MHz, CDCl3) δ12.0,18.0,25.8,26.0,29.3,29.40,29.55(4C),29.62,33.0,63.5 ,68.0,77.2,114.5,119.9,125.0,127.0,127.6,128.3,133.8,141.3,143.9,155.5,158.4

[0254] ESIMS MNa+1112.8

[0255] HO-(CH2) contained as an impurity in the crude purified product of Fmoc-D2-STag was purified by HPLC under the same conditions as in step (1-c). 11 The results showed that HO-(CH2) was contained in the crude purified product of TIPS2-Dpm-OH as an impurity. 11 -OTIPS is left behind directly. Furthermore, TIPS2-Dpm-OH, the target product of step (1-c), also has the problem of being decomposed by trace amounts of acid and undergoing dimerization during storage. For example, if TIPS2-Dpm-OH is stored at 30°C, 10.0% dimer is produced after 30 days. Therefore, TIPS2-Dpm-OH is a compound that is difficult to store for a long time. In addition, in step (1-d), a side reaction occurs in which the TIPS gene is separated due to the acid catalyst, and 0.2% of dealkylated silane is produced in the comparative example. The two side reactions lead to a decrease in the yield of Fmoc-D2-STag.

[0256] Analysis conditions (HPLC) of dimer and dealkylated silane of Fmoc-D2-STag and TIPS2-Dpm-OH

[0257] Chromatographic column: YMC-Triart C18

[0258] (Inner diameter 3.0mm, length 100mm, particle size 1.9μm)

[0259] Mobile phase A: Add 0.1% v / v formic acid to a solution of isopropanol:acetonitrile:water = 5:90:5

[0260] Mobile phase B: Isopropanol supplemented with 0.1% v / v formic acid

[0261] Flow rate: 0.35mL / min

[0262] Column temperature: 35°C

[0263] Detection wavelength: 254nm

[0264] Gradient conditions: 40% B (0 min) → 40% B (3 min) → 100% B (28 min) → 100% B (40 min) → 40% B (41 min) → 40% B (51 min)

[0265] Example 1 Synthesis of Fmoc-D2-STag using the method of the present invention

[0266]

[0267] (Hereinafter, HO-Dpm-C=O, HO-Dpm-C=NH, HO-Dpm-C-NHFmoc, and Fmoc-D2-STag are structures in the expression)

[0268] (2-a) HO-Dpm-C=O

[0269] Make Br-(CH2) 11-OH 484g (1.93mol), 4.4'-dihydroxybenzophenone 187g (875mmol), potassium carbonate 339g (2.45mol) were suspended in DMF 1.75L, heated to 90°C and stirred for 4 hours. The reaction solution was adjusted to 80°C, 2.25L of water was added, and stirred at the same temperature for 1 hour. After cooling to 30°C, the slurry was filtered, and the filtrate was washed once with 0.56L of water, and washed once again with 0.56L of water. After washing, the filtrate was recovered, 2.25L of water was added, and stirred at 80°C for 1 hour. After cooling to 30°C, the slurry was filtered, and the filtrate was washed once with 0.56L of water, and washed once again with 0.56L of water. After washing, the filtrate was recovered, 1.78L of methanol was added, and stirred at 60°C for 1 hour. After cooling to 30°C, the slurry was filtered, and the filtrate was washed once with 0.56 L of methanol and once again with 0.56 L of methanol. Thereafter, it was dried under reduced pressure at 40°C to obtain 474 g of HO-Dpm-C=O (yield 97.6%). The obtained HO-Dpm-C=O was solid.

[0270] 1 H-NMR (400MHz, pyridine-D5) δ1.20-1.39(m,20H),1.39-1.59(m,8H),1.70-1.84(m,8H),3.90(t,J= 6.2Hz,4H),4.04(t,J=6.6Hz,4H),5.93(brs,2H),7.17(d,J=8.7Hz,4H),8.04(d,J=8.7Hz,4H)

[0271] 13 C-NMR (100 MHz, pyridine-D5) δ 26.3, 26.6, 29.4, 29.6, 29.8, 29.9, 30.0, 33.8, 62.1, 68.5, 114.6, 131.1, 132.6, 163.0, 194.0

[0272] ESIMS MNa+577.4

[0273] (2-b) HO-Dpm-C=NH

[0274] HO-Dpm-C=O 461g (831mmol) and scandium trifluoromethanesulfonate 40.9g (83.1mmol) were suspended in 0.83L of toluene, and 0.70L of hexamethyldisilazane was added, heated to 90°C and stirred for 21 hours. The reaction solution was cooled to 30°C, and 0.83L of methanol and 345g (2.49mol) of potassium carbonate were added, and stirred at 30°C for 3 hours. 1.84L of water was added, and stirred at 50°C for 1 hour. After cooling to 30°C, the slurry was filtered, and the filtrate was washed once with 0.92L of water, and washed again with 0.92L of water. After washing, the filtrate was recovered, 1.84L of 50% methanol water was added, and stirred at 50°C for 1 hour. After cooling to 30°C, the slurry was filtered, and the filtrate was washed once with 0.92 L of 50% methanol water, and then washed once again with 0.92 L of 50% methanol water. After washing, the filtrate was recovered, 1.84 L of acetonitrile was added, and stirred at 50°C for 1 hour. After cooling to 30°C, the slurry was filtered, and the filtrate was washed once with 1.84 L of acetonitrile. Thereafter, the filtrate was dried under reduced pressure at 40°C to obtain 437 g (yield 94.9%) of HO-Dpm-C=NH. The obtained HO-Dpm-C=NH was solid.

[0275] 1 H-NMR (400MHz, pyridine-D5) δ1.18-1.37(m,20H),1.37-1.45(m,4H),1.45-1.55(m,4H),1.70-1.82 (m,4H),3.88(dd,4H),3.99(dd,4H),5.93(s,4H),7.12(d,4H),7.60-8.20(br,4H),10.33(br s,1H),

[0276] 13 C-NMR (100 MHz, pyridine-D5) δ 26.3, 26.5, 29.5, 29.6, 29.8 (2C), 29.9, 30.0, 33.8, 62.1, 68.3, 114.6, 130.7 (br, 2C), 161.3, 176.2

[0277] ESIMS MNa+576.4

[0278] (2-c)HO-Dpm-C-NHFmoc

[0279] 104.65 g (2.47 mol) of lithium chloride and 93.40 g (2.47 mmol) of sodium borohydride were suspended in 1.25 L of tetrahydrofuran and stirred at 10°C or below for 10 minutes. 3.74 L of methanol and 414 g (748 mmol) of HO-Dpm-C=NH were added, the temperature was raised to 40°C and stirred for 2 hours. 328 g (973 mmol) of Fmoc-OSu were added, and the mixture was stirred at 40°C for 2 hours. 4.97 L of 50% methanol water was added, and the mixture was stirred at 40°C for 1 hour. After cooling to 30°C, the slurry was filtered, and the filtrate was washed once with 2.9 L of 50% methanol water. After washing, the filtrate was recovered, 4.97 L of 50% methanol water was added, and the mixture was stirred at 40°C for 1 hour. After cooling to 30°C, the slurry was filtered, and the filtrate was washed once with 2.90 L of 50% methanol water, and then washed once again with 2.90 L of 50% methanol water. After washing, the filtrate was recovered, 4.97 L of acetonitrile was added, and stirred at 40°C for 1 hour. After cooling to 30°C, the slurry was filtered, and the filtrate was washed once with 2.90 L of acetonitrile. Thereafter, it was dried under reduced pressure at 40°C to obtain HO-Dpm-C-NHFmoc 549 g (yield 94.3%). The obtained HO-Dpm-C-NHFmoc was solid.

[0280] 1 H-NMR (400MHz, CDCl3) δ1.20-1.39(m,24H),1.38-1.50(m,4H),1.50-1.60(m,4 H),1.67-1.84(m,4H),3.63(ddd,4H),3.93(dd,4H),4.21(t,1H),4.44(d,1H),5 .00-5.20(br,0.18H),5.33(d,0.82H),5.62-5.70(br,0.18H),5.71(d,0.82H) ,6.84(d,4H),7.11(d,4H),7.27-7.34(m,2H),7.34-7.46(m,2H),7.49-7.65(br d,2H),7.66-7.84(br d,2H)

[0281] 13 C-NMR (100MHz, CDCl3) δ25.7,26.0,29.2,29.3,29.37,29.45(2C),29.49(2C),29.53,32.8,6 3.1,68.0,77.2,114.5,119.9,125.0,127.0,127.6,128.3,133.8,141.3,143.9,155.5,158.4

[0282] ESIMS MK+816.5

[0283] (2-d)Fmoc-D2-STag

[0284] HO-Dpm-C=NH 524 g (673 mmol) and imidazole 206 g (3.03 mmol) were suspended in DMF 1.68 L, and triisopropylsilyl chloride 0.51 L was added dropwise at 30°C. After stirring for 3 hours, heptane 5.05 L, diisopropylethylamine 0.56 L, and water 5.05 L were added, and stirred for 10 minutes. The mixture was rinsed with heptane 0.84 L, and the mixture was washed by liquid separation. 50% acetonitrile water 3.37 L was added to the obtained upper layer, and the mixture was washed by liquid separation. 50% acetonitrile water 3.37 L was added to the obtained upper layer again, and the mixture was washed by liquid separation. The obtained upper layer was rinsed with heptane 0.84 L, and the obtained upper layer was concentrated under reduced pressure. 0.84 L of tetrahydrofuran was added to the obtained residue, and the mixture was concentrated again under reduced pressure. The obtained residue was dissolved in 0.42 L of tetrahydrofuran, and 6.31 L of isopropanol was added dropwise while stirring, and the mixture was stirred for 1 hour after the addition. The treated liquid from which the target product was crystallized was filtered, and the filtrate was washed with 2.0 L of isopropanol. The mixture was dried under reduced pressure at 40°C, and 4.0 L of acetonitrile was added to the obtained residue, and the mixture was stirred at 25°C for 1 hour. The slurry was filtered, and the filtrate was washed with 2.0 L of acetonitrile. Thereafter, the mixture was dried under reduced pressure at 40°C to obtain 521 g of Fmoc-D2-STag (yield 70.9%). The obtained Fmoc-D2-STag was solid.

[0285] 1 H-NMR (400MHz, CDCl3) δ0.99-1.12(m,6H),1.06(s,36H),1.18-1.38(m,24H),1.38-1.48(m,4H),1.48-1.60(m,4H) ,1.70-1.83(m,4H),3.66(dd,4H),3.93(dd,4H),4.21(br,1H),4.44(d,1H),5.00-5.13(br,0.18H),5.20-5.32(br d,0.82H),5.70-5.80(br,0.18H),5.82-5.92(br d,0.82H),6.84(d,4H),7.11(d,4H),7.28-7.34(m,2H),7.34-7.47(m,2H),7.55-7.65(br d,2H),7.70-7.85(br d,2H)

[0286] 13C-NMR (100MHz, CDCl3) δ12.0,18.0,25.8,26.0,29.3,29.40,29.55(4C),29.62,33.0,63.5 ,68.0,77.2,114.5,119.9,125.0,127.0,127.6,128.3,133.8,141.3,143.9,155.5,158.4

[0287] ESIMS MNa+1112.8

[0288] Analysis conditions (HPLC) of dimers and dealkylated silanes of Fmoc-D2-STag and TIPS2-Dpm-OH

[0289] Chromatographic column: YMC-Triart C18

[0290] (Inner diameter 3.0mm, length 100mm, particle size 1.9μm)

[0291] Mobile phase A: Add 0.1% v / v formic acid to a solution of isopropanol:acetonitrile:water = 5:90:5

[0292] Mobile phase B: Isopropanol supplemented with 0.1% v / v formic acid

[0293] Flow rate: 0.35mL / min

[0294] Column temperature: 35°C

[0295] Detection wavelength: 254nm

[0296] Gradient conditions: 40% B (0 min) → 40% B (3 min) → 100% B (28 min) → 100% B (40 min) → 40% B (41 min) → 40% B (51 min)

[0297] HO-(CH2) 11 -Analysis conditions of OTIPS (HPLC)

[0298] Chromatographic column: YMC-Triart C18

[0299] (Inner diameter 3.0mm, length 100mm, particle size 1.9μm)

[0300] Mobile phase A: containing 0.01M ammonium formate, acetonitrile: water = 8:2 solution

[0301] Mobile phase B: containing 0.01M ammonium formate, isopropanol: water = 100:1 solution

[0302] Flow rate: 0.25mL / min

[0303] Column temperature: 35°C

[0304] Detection wavelength: 200nm

[0305] Gradient conditions: 0% B (0 min) → 0% B (5 min) → 100% B (22 min) → 100% B (27 min) → 0% B (29 min) → 0% B (51 min)

[0306] In the comparative example, HO-(CH2) contained as an impurity in the crude purified product of TIPS2-Dpm-OH 11 -OTIPS is left directly. This component was not detected in the examples. In addition, in the comparative examples, TIPS2-Dpm-OH as an intermediate also has the problem of being decomposed by trace amounts of acid and undergoing dimerization during storage. In the examples, since the manufacturing method does not pass through TIPS2-Dpm-OH, the dimer of TIPS2-Dpm-OH, which is difficult to separate, was not detected.

[0307] Furthermore, in Comparative Example 1, a side reaction of TIPS generation being desorbed by an acid catalyst also occurred in step (1-d). In Example 1, TIPS formation was performed in the final step, avoiding the conditions of using an acid catalyst, and thus no dealkylated silyl product was detected, thus solving this problem.

[0308] In Comparative Example 1, 2.25 equivalents of Br-(CH2) was added to 4,4'-dihydroxybenzophenone. 11 -O-TIPS. Excess 0.25 equivalents of Br-(CH2) 11 -O-TIPS, and HO-(CH2) decomposed from this compound 11 -O-TIPS is fat-soluble and has similar physical properties to the target products TIPS2-Dpm-C=O and TIPS2-Dpm-OH, making it difficult to separate. TIPS2-Dpm-C=O and TIPS2-Dpm-OH, which are intermediates with extended side chains, are both oily compounds, so it is not possible to perform the following operations: solidify TIPS2-Dpm-C=O or TIPS2-Dpm-OH and use a specific solvent to separate Br-(CH2) 11 -O-TIPS is removed by washing. Therefore, these compounds from the raw materials of the side chain extension reaction are even mixed into TIPS2-Dpm-OH and maintained in a large amount, close to 0.25 equivalents relative to 4,4'-dihydroxybenzophenone. TIPS2-Dpm-OH also contains 5.1 wt% HO-(CH2) 11 -OTIPS. Furthermore, when TIPS2-Dpm-OH is amidated and converted to Fmoc-D2-STag, HO-(CH2) 11-O-TIPS is also mixed in and not removed.

[0309] In contrast, in Example 1, the intermediate HO-Dpm-C=O in which the side chain is extended by using 11-bromo-1-undecanol is a solid. Therefore, by washing HO-Dpm-C=O with an organic solvent such as methanol in which 11-bromo-1-undecanol has a high solubility, 11-bromo-1-undecanol is easily removed. The content of the compound derived from 11-bromo-1-undecanol contained in Fmoc-D2-STag is 0.03% by weight. Furthermore, since all the intermediates are obtained in a solid form unlike the comparative example, the intermediates can be roughly purified by solid-liquid separation, thereby improving the purity of Fmoc-D2-Stag as the final target.

[0310] In Comparative Example 1, TIPS2-Dpm-OH as an intermediate was also decomposed by a small amount of acid and dimerized during storage. In Example 1, this problem was solved because TIPS2-Dpm-OH was not involved.

[0311] Furthermore, in Comparative Example 1, a side reaction in which TIPS is removed by an acid catalyst also occurs in step (1-d). In Example 1, TIPS is performed in the final step, avoiding the conditions for using an acid catalyst, thereby solving this problem.

[0312] In summary, the manufacturing method of the present invention significantly reduces the amount of HO-(CH2) which is an impurity that is difficult to separate compared to the existing method. 11 -OTIPS. In addition, by obtaining all the intermediates in the process in solid form, it is possible to achieve rough purification by solid-liquid separation. The existing method requires first separating HO-(CH2) 11 -OTIPS process, and then accurately purified by column chromatography. Therefore, it is not easy to produce alkylsilyloxy-alkoxybenzylamine compounds in large quantities on an industrial scale in the existing methods. In contrast, in the production method of the present application, HO-(CH2) 11 -OTIPS is mixed in an amount that can industrially advantageously obtain an alkylsiloxy-substituted benzylamine compound. Furthermore, in the production method of the present application, the problem of decomposition of the intermediate by the acid catalyst, which has been a problem in the conventional method, is also solved.

[0313] It should be noted that the Br-(CH2) used in the conventional method 11 -O-TIPS is an unstable compound that will gradually decompose at room temperature. The method of the present invention also has the advantage of avoiding the use of unstable raw materials.

Claims

1. A method for producing a ketimine compound represented by general formula (3), characterized in that: The benzoyl compound represented by the general formula (2) is reacted with a silazane compound, and then reacted with an acid or a base. In formula (2), R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, Among them, R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (2) 5b Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R B The bonding site; In formula (3), R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, Among them, R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (3) 5b Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R B bonding part.

2. A method for producing a benzylamine compound represented by general formula (4), characterized in that: The benzoyl compound represented by the general formula (2) is reacted with a silazane compound, and then reacted with an acid or a base to obtain a ketimine compound represented by the general formula (3), and the obtained ketimine compound is reacted with a reducing agent and an Fmoc-forming agent, In formula (2), R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, Among them, R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (2) 5b Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R B The bonding site; In formula (3), R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, Among them, R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (3) 5b Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R B The bonding site; In formula (4), R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, Among them, R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be combined with R in formula (4) 5b Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R B bonding part.

3. A method for producing an alkylsiloxy-substituted benzylamine compound represented by general formula (5), characterized in that: A benzoyl compound represented by the general formula (2) is reacted with a silazane compound, and then reacted with an acid or a base to obtain a ketimine compound represented by the general formula (3), the obtained ketimine compound is reacted with a reducing agent and an Fmoc-forming agent to obtain a benzylamine compound represented by the general formula (4), and then the benzylamine compound is reacted with an alkyl silylating agent, In formula (2), R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms. R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, Among them, R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (2) 5b Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R B The bonding site; In formula (3), R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, Among them, R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (3) 5b Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R B The bonding site; In the formula, R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, Among them, R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be combined with R in formula (4) 5b Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R B The bonding site; In formula (5), R 1c ~R 5c 1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, R C represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, Among them, R 1c ~R 5c 1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or R C When representing the structure of this formula, R 5c It can be compared with R in formula (5) 5c Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R C bonding part.

4. The production method according to any one of claims 1 to 3, wherein The benzoyl compound represented by the general formula (2) is obtained by reacting the compound represented by the general formula (1) with a halogenated alcohol. In formula (1), R 1a ~R 5a 1 to 5 of them represent hydroxyl groups, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, R A represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, Among them, R 1a ~R 5a 1 to 5 of them represent hydroxyl groups, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R A When representing the structure of this formula, R 5a It can be combined with R in formula (1) 5a Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R A bonding part.

5. A compound represented by the general formula (6), In formula (6), R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, in, R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (6) 5b Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R B The bonding site, NY represents an imino group, that is, =NH or NHFmoc.

6. A method for producing an alkylsiloxy-substituted benzylamine compound represented by general formula (5), characterized in that: The benzylamine compound represented by the general formula (4) is reacted with an alkyl silylating agent. In formula (4), R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, Among them, R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be combined with R in formula (4) 5b Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R B The bonding site; In formula (5), R 1c ~R 5c 1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, R C represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, Among them, R 1c ~R 5c 1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or R C When representing the structure of this formula, R 5c It can be compared with R in formula (5) 5c Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R C bonding part.

7. A method for producing an alkylsiloxy-substituted benzylamine compound represented by general formula (5), characterized in that: The ketimine compound represented by the general formula (3) is reacted with a reducing agent and an Fmoc-forming agent to obtain a benzylamine compound represented by the general formula (4), and the benzylamine compound is then reacted with an alkyl silylating agent. In formula (3), R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, Among them, R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be compared with R in formula (3) 5b Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R B The bonding site; In formula (4), R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, Among them, R 1b ~R 5b 1 to 5 of them represent hydroxyalkoxy groups having 1 to 16 carbon atoms, and the rest represent hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or alkoxy groups having 1 to 4 carbon atoms, or R B When representing the structure of this formula, R 5b It can be combined with R in formula (4) 5b Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R B The bonding site; In formula (5), R 1c ~R 5c 1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, R C represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula, Among them, R 1c ~R 5c 1 to 5 of them represent an alkoxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the rest represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or R C When representing the structure of this formula, R 5c It can be compared with R in formula (5) 5c Together they form an ether bond, i.e. -O-, which should be noted. * indicates that they are connected to R C bonding part.

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