Method for producing alkylsilyloxy-substituted benzylamine compounds

Abstract

Provided is an industrially useful method for producing an alkylsilyloxy-substituted benzylamine compound, in which impurities are easily removed and the method does not involve an alkylsilyloxy-substituted benzyl compound that is an intermediate compound that is unstable to acids.　The present invention relates to a method for producing a ketimine compound represented by general formula (3) (in the formula, R1b to R5b and RB are as defined below), the method being characterized by reacting a silazane compound with a benzoyl compound represented by general formula (2) (in the formula, 1 to 5 of R1b to R5b are hydroxyalkyloxy groups having 1-16 carbon atoms, with the remainder being hydrogen atoms, halogen atoms, or the like; and RB is a hydrogen atom, a hydroxyl group, an alkoxy group having 1-6 carbon atoms, or the like).

Description

[Technical field]

[0001] The present invention relates to a method for producing an alkylsilyloxy-substituted benzylamine compound. [Background technology]

[0002] In liquid-phase peptide synthesis, a support for liquid-phase peptide synthesis (Tag) has been reported. The support for liquid-phase peptide synthesis (Tag) is a highly hydrophobic compound, and therefore by binding highly hydrophilic amino acids, peptides, or amino acid amides (hereinafter sometimes referred to as amino acids, etc.) to the support, the solubility in an organic solvent can be greatly improved. Therefore, when a peptide elongation reaction is carried out in a state in which amino acids, etc. are bound to the support, the amino acids, etc. bound to the support are dissolved in the organic layer, and unnecessary components, such as the surplus raw amino acids used in the peptide elongation reaction, their decomposition products, and compounds produced as by-products when the protecting groups of the raw amino acids are deprotected, are dissolved in the aqueous layer, thereby providing the advantage that the amino acids, etc. bound to the support can be easily purified by liquid-liquid separation.

[0003] Among the liquid-phase peptide synthesis supports (Tags), the liquid-phase peptide synthesis supports (Tags) shown in Patent Documents 1 to 7 and Non-Patent Document 1 have a structure in which one or more alkyloxy side chains having 1 to 16 carbon atoms and to which alkylsilyloxy groups are bonded are bonded to a mother nucleus such as a benzyl skeleton, a diphenylmethane skeleton, or a xanthene skeleton. These liquid-phase peptide synthesis supports (Tags) exquisitely control the hydrophobicity of the entire liquid-phase peptide synthesis support (Tags) by the side chain structure to which the alkylsilyloxy groups are bonded, and are particularly useful as liquid-phase peptide synthesis supports (Tags). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 6116782 [Patent Document 2] Patent No. 6201076 [Patent Document 3] Patent No. 6283774 [Patent Document 4] Patent No. 6283775 [Patent Document 5] Patent No. 6322350 [Patent Document 6] Patent No. 6393857 [Patent Document 7] Patent No. 6531235 [Non-patent literature]

[0005] [Non-Patent Document 1] Molecules 2021, 26, 3497-3505. Summary of the Invention [Problem to be solved by the invention]

[0006] The manufacturing methods of these liquid phase peptide synthesis supports (TAGs) are shown in Patent Documents 1 to 7. However, in these conventional methods, Br-(CH2), one of the raw materials in the manufacturing process, 11 -O-TIPS was oily and had poor stability, making it difficult to handle. In addition, the physical properties of the raw material and the intermediate compound were both oily and similar, making liquid-liquid separation difficult. Therefore, the raw material or its decomposition products were likely to be mixed into the target product as impurities, and it was difficult to improve the purity of the liquid-phase peptide synthesis support (Tag) itself by normal industrial operations alone, so there was a problem that complicated operations such as precision purification by column chromatography were required. Furthermore, as described in the prior art, there was also a problem when converting an alkylsilyloxy-substituted benzyl compound to an alkylsilyloxy-substituted benzylamine compound. The present inventors have clarified that the intermediate alkylsilyloxy-substituted benzyl compound has a somewhat poor stability to acid, and that during storage of the alkylsilyloxy-substituted benzyl compound or during the conversion process to an amine, two main types of side reactions proceed. The first is a side reaction in which the hydroxyl group portion of the benzyl compound is decomposed and the alkylsilyloxy-substituted benzyl compound is dimerized. This dimer has physical properties similar to those of the target alkylsilyloxy-substituted benzylamine compound, and is difficult to separate. The second is a side reaction in which an alkylsilyl group is released from an alkylsilyloxy group. It is also difficult to separate the dealkylated silyl compound from the alkylsilyloxy-substituted benzylamine compound. Therefore, an object of the present invention is to provide an industrial method for producing an alkylsilyloxy-substituted benzylamine compound, which can easily remove impurities and does not involve the intermediate alkylsilyloxy-substituted benzyl compound, which is unstable to acid. [Means for solving the problem]

[0007] The present inventors have discovered an industrial method for producing alkylsilyloxy-substituted benzylamine compounds by introducing a hydroxyalkyloxy group into a compound having a benzoyl skeleton, a diphenyl ketone skeleton (benzophenone skeleton) or a xanthone skeleton, reacting the hydroxyalkyloxy-substituted compound with a disilazane compound, and then reacting the compound with an acid or base to remove the tri-substituted silyl group on the hydroxyl group, thereby obtaining an intermediate compound in which the carbonyl group bonded to each skeleton of the hydroxyalkyloxy-substituted compound is converted into an imino group, and then converting the imino group into a 9-fluorenylmethyloxycarbonyl-protected amino group, and then introducing an alkylsilyl group into the hydroxyl group. According to the method of the present invention, the raw material Br-(CH2), which has been a problem in the conventional method due to its poor stability and difficulty in separating it from the intermediate compound, can be produced without any problems. 11-O-TIPS is not required. In addition, since the intermediate compound is a solid, the raw material or decomposition products of the raw material, and other impurities generated or carried over in the system can be easily removed by filtration, crystallization, or the like. Furthermore, the target product can be obtained in high purity and high yield without passing through an alkylsilyloxy-substituted benzyl compound, which is an intermediate compound unstable to acid. As described above, the present inventors have found that an alkylsilyloxy-substituted benzylamine compound can be obtained industrially advantageously, and have completed the present invention. In the present invention, the term "solid" refers to both a substance having a crystalline structure and an amorphous solid.

[0008] That is, the present invention provides the following inventions [1] to [7]. [1] General formula (2)

[0009] [ka]

[0010] (In the formula, R 1b ~R 5b among which 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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; R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0011] [ka]

[0012] (R 1b ~R 5b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 B When shows the structure of this formula, R 5b is R in Eq. (2). 5bIt may form an ether bond (-O-) together with R. B The binding site is shown.) (representing a group represented by the formula: The reaction of a silazane compound with a benzoyl compound represented by the general formula (3) is then carried out with an acid or a base.

[0013] [ka]

[0014] (In the formula, R 1b ~R 5b among which 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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; R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0015] [ka]

[0016] (R 1b ~R 5b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 B When shows the structure of this formula, R 5b is R in Eq. (3). 5b It may form an ether bond (-O-) together with R. B ) represents the bonding site with A method for producing a ketimine compound represented by the formula: [2] General formula (2)

[0017] [ka]

[0018] (In the formula, R 1b ~R 5b among which 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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; R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0019] [ka]

[0020] (R 1b ~R 5b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 B When shows the structure of this formula, R 5b is R in Eq. (2). 5b It may form an ether bond (-O-) together with R. B The binding site is shown.) (representing a group represented by the formula: A silazane compound is reacted with a benzoyl compound represented by the general formula (3), and then an acid or a base is reacted therewith to obtain a compound represented by the general formula (3)

[0021] [ka]

[0022] (In the formula, R 1b ~R 5b among which 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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; R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0023] [ka]

[0024] (R 1b ~R 5b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 B When shows the structure of this formula, R 5b is R in Eq. (3). 5b It may form an ether bond (-O-) together with R. B ) represents the bonding site with and reacting the resulting ketimine compound with a reducing agent and an Fmoc reagent,

[0025] [ka]

[0026] (In the formula, R 1b ~R 5b among which 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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; R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0027] [ka]

[0028] (R 1b ~R 5b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 B When shows the structure of this formula, R 5b is R in Eq. (4). 5bIt may form an ether bond (-O-) together with R. B ) represents the bonding site with A method for producing a benzylamine compound represented by the formula: [3] General formula (2)

[0029] [ka]

[0030] (In the formula, R 1b ~R 5b among which 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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; R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0031] [ka]

[0032] (R 1b ~R 5b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 B When shows the structure of this formula, R 5b is R in Eq. (2). 5b It may form an ether bond (-O-) together with R. B The binding site is shown.) (representing a group represented by the formula: A silazane compound is reacted with a benzoyl compound represented by the general formula (3), and then an acid or a base is reacted therewith to obtain a compound represented by the general formula (3)

[0033] [ka]

[0034] (In the formula, R 1b ~R 5b among which 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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; R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0035] [ka]

[0036] (R 1b ~R 5b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 B When shows the structure of this formula, R 5b is R in Eq. (3). 5b It may form an ether bond (-O-) together with R. B ) represents the bonding site with The ketimine compound represented by the general formula (4) is obtained by reacting the resulting ketimine compound with a reducing agent and an Fmoc reagent.

[0037] [ka]

[0038] (In the formula, R 1b ~R 5b among which 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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; R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0039] [ka]

[0040] (R 1b ~R 5b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 B When shows the structure of this formula, R 5b is R in Eq. (4). 5b It may form an ether bond (-O-) together with R. B ) represents the bonding site with and then reacting the benzylamine compound with an alkylsilylating agent,

[0041] [ka]

[0042] (In the formula, R 1c ~R 5c among which 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyloxy 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

[0043] [ka]

[0044] (R 1c ~R 5c Among these, 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the remainder 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 shows the structure of this formula, R 5cis R in Eq. (5). 5c It may form an ether bond (-O-) together with R. C The binding site is shown.) (representing a group represented by the formula: A method for producing an alkylsilyloxy-substituted benzylamine compound represented by the following formula: [4] The alkylsilyloxy-substituted benzoyl compound represented by the general formula (2) is represented by the general formula (1)

[0045] [ka]

[0046] (In the formula, R 1a ~R 5a among which 1 to 5 represent a hydroxy group, and the remainder 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; R A represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0047] [ka]

[0048] (R 1a ~R 5a Among these, 1 to 5 represent a hydroxy group, and the remainder 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 A When shows the structure of this formula, R 5a is R in formula (1). 5a It may form an ether bond (-O-) together with R. A The binding site is shown.) The method according to any one of [1] to [3], wherein the compound represented by the formula (I) is reacted with a halogenated alcohol to obtain the compound. [5] General formula (6)

[0049] [ka]

[0050] (In the formula, R 1b ~R 5b among which 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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; R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0051] [ka]

[0052] (R 1b ~R 5b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 B When shows the structure of this formula, R 5b is R in equation (6). 5b It may form an ether bond (-O-) together with R. B The binding site is shown.) represents a group represented by NY represents an imino group (=NH) or NHFmoc. A compound represented by the formula: [6] General formula (4)

[0053] [ka]

[0054] (In the formula, R 1b ~R 5b among which 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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; RB represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0055] [ka]

[0056] (R 1b ~R 5b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 B When shows the structure of this formula, R 5b is R in Eq. (4). 5b It may form an ether bond (-O-) together with R. B ) represents the bonding site with The benzylamine compound represented by the general formula (5) is reacted with an alkylsilylating agent.

[0057] [ka]

[0058] (In the formula, R 1c ~R 5c among which 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyloxy 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

[0059] [ka]

[0060] (R 1c ~R 5cAmong these, 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the remainder 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 shows the structure of this formula, R 5c is R in Eq. (5). 5c It may form an ether bond (-O-) together with R. C The binding site is shown.) (representing a group represented by the formula: A method for producing an alkylsilyloxy-substituted benzylamine compound represented by the following formula: [7] General formula (3)

[0061] [ka]

[0062] (In the formula, R 1b ~R 5b among which 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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; R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0063] [ka]

[0064] (R 1b ~R 5b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 B When shows the structure of this formula, R 5b is R in Eq. (3). 5b It may form an ether bond (-O-) together with R. B ) represents the bonding site with The ketimine compound represented by the general formula (4) is reacted with a reducing agent and an Fmoc reagent to obtain a compound represented by the general formula (4):

[0065] [ka]

[0066] (In the formula, R 1b ~R 5b among which 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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; R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0067] [ka]

[0068] (R 1b ~R 5b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 B When shows the structure of this formula, R 5b is R in Eq. (4). 5b It may form an ether bond (-O-) together with R. B ) represents the bonding site with and then reacting the benzylamine compound with an alkylsilylating agent,

[0069] [ka]

[0070] (In the formula, R 1c ~R 5camong which 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyloxy 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

[0071] [ka]

[0072] (R 1c ~R 5c Among these, 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the remainder 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 shows the structure of this formula, R 5c is R in Eq. (5). 5c It may form an ether bond (-O-) together with R. C The binding site is shown.) (representing a group represented by the formula: A method for producing an alkylsilyloxy-substituted benzylamine compound represented by the following formula: Effect of the Invention

[0073] According to the method of the present invention, it is not necessary to use raw materials that have been problematic in the conventional methods due to poor stability or difficulty in separating them from intermediate compounds. In addition, since the intermediate compounds are solid, it is easy to remove the raw materials or decomposition products of the raw materials, and other impurities generated or carried over in the system by filtration, crystallization, etc. Furthermore, it is not necessary to go through an alkylsilyloxy-substituted benzyl compound, which is an intermediate compound unstable to acid, and an alkylsilyloxy-substituted benzylamine compound can be obtained industrially advantageously. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0074] The reaction from the compound of general formula (1) to the compound of general formula (5) in the present invention is shown in the following reaction scheme.

[0075] [ka]

[0076] (In the formula, R 1a ~R 5a among which 1 to 5 represent a hydroxy group, and the remainder 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; R A represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0077] [ka]

[0078] (R 1a ~R 5a Among these, 1 to 5 represent a hydroxy group, and the remainder 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 A When shows the structure of this formula, R 5a is R in formula (1). 5a It may form an ether bond (-O-) together with R. A The binding site is shown.) represents a group represented by the formula: R 1b ~R 5b among which 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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; R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0079] [ka]

[0080] (R 1b ~R 5b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 B When shows the structure of this formula, R 5b is R in formulas (2) to (4). 5b It may form an ether bond (-O-) together with R. B The binding site is shown.) represents a group represented by the formula: R 1c ~R 5c among which 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the remainder 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; R C represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0081] [ka]

[0082] (R 1c ~R 5c Among these, 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the remainder 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 shows the structure of this formula, R 5c is R in Eq. (5). 5c It may form an ether bond (-O-) together with R. C The binding site is shown.) It represents a group represented by the following formula:

[0083] One aspect of the present invention is a method for producing a ketimine compound represented by general formula (3), which comprises reacting a benzoyl compound represented by general formula (2) with a silazane compound and then reacting the benzoyl compound with an acid or a base. Another aspect of the present invention is a method for producing a benzylamine compound represented by general formula (4), which comprises reacting a benzoyl compound represented by general formula (2) with a silazane compound, then reacting the benzoyl compound with an acid or a base to obtain a ketimine compound represented by general formula (3), and reacting the ketimine compound with a reducing agent and an Fmoc reagent. Another aspect of the present invention is a method for producing an alkylsilyloxy-alkyloxybenzylamine compound represented by general formula (5), which comprises reacting a silazane compound with a benzoyl compound represented by general formula (2) and then reacting with an acid or base to obtain a ketimine compound represented by general formula (3), reacting the ketimine compound with a reducing agent and an Fmoc reagent to obtain a benzylamine compound represented by general formula (4), and reacting the benzylamine compound with an alkylsilylating agent. When the term "alkylsilyloxy-substituted benzylamine compound" is used in the specification, this structure is intended to be indicated. 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. Another aspect of the present invention is a method for producing an alkylsilyloxy-alkyloxybenzylamine compound represented by general formula (5), which comprises reacting a benzylamine compound represented by general formula (4) with an alkylsilylation agent. Another aspect of the present invention is a method for producing an alkylsilyloxy-alkyloxybenzylamine compound represented by general formula (5), comprising reacting a ketimine compound represented by general formula (3) with a reducing agent and an Fmoc reagent to obtain a benzylamine compound represented by general formula (4), and reacting the obtained benzylamine compound with an alkylsilylating agent. In addition, the ketimine compound represented by the general formula (3) and the benzylamine compound represented by the general formula (4) are novel compounds. Therefore, another aspect of the present invention is a compound represented by the following general formula (6):

[0084] [ka]

[0085] (In the formula, R 1b ~R 5b among which 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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; R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0086] [ka]

[0087] (R 1b ~R 5b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 B When shows the structure of this formula, R 5b is R in equation (6). 5b It may form an ether bond (-O-) together with R. B The binding site is shown.) represents a group represented by NY represents an imino group (=NH) or NHFmoc. The present invention provides a compound represented by the formula:

[0088] First, the compound of general formula (1), which is the raw material compound, will be described. R 1a ~R 5aAmong these, 1 to 5 represent a hydroxy group, and the remainder 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 number of the hydroxy groups is preferably 1 to 4, more preferably 2 to 4, even more preferably 2 to 3, and still more preferably 2. The remaining group 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, with a hydrogen atom being preferred, a halogen atom, or an alkyl group having 1 to 4 carbon atoms, and a hydrogen atom being more preferred. Here, examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, etc. Examples of the alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, an n-butyloxy group, etc. Examples of the halogen atom include a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom.

[0089] R A represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0090] [ka]

[0091] (R 1a ~R 5a Among these, 1 to 5 represent a hydroxy group, and the remainder 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 A When shows the structure of this formula, R 5a is R in formula (1). 5a It may form an ether bond (-O-) together with R. A The binding site is shown.) The group represented by the formula: Examples of the alkoxy group having 1 to 6 carbon atoms include a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, an n-butyloxy group, a tert-butyloxy group, an isobutyloxy group, an n-pentyl group, an n-hexyl group, etc. Among these, an alkoxy group having 1 to 5 carbon atoms is preferred, and an alkoxy group having 1 to 4 carbon atoms is more preferred. R 1a ~R 5a The group represented by the formula (I) is preferably the same as the group described above. R A is preferably a group represented by the following formula:

[0092] [ka]

[0093] (R 1a ~R 5a Among these, 1 to 5 represent a hydroxy group, and the remainder 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. A The binding site is shown.) The group represented by the formula:

[0094] The compound of general formula (1) is reacted with a halogenated alcohol (represented as Hal-alcohol in the formula) to obtain a benzoyl compound of general formula (2). The halogenated alcohol may be a halogenated alcohol having 1 to 16 carbon atoms, preferably a halogenated alcohol having 2 to 16 carbon atoms, more preferably a halogenated alcohol having 4 to 16 carbon atoms, further preferably a halogenated alcohol having 6 to 16 carbon atoms, and further preferably a halogenated alcohol having 8 to 16 carbon atoms. The halogen atom may be a bromine atom, a chlorine atom, an iodine atom, or a fluorine atom, and preferably a bromine atom, a chlorine atom, or an iodine atom. The alcohol may be a linear or branched chain alcohol.

[0095] The reaction of the compound of formula (1) with a halogenated alcohol is preferably carried out in a solvent in the presence of a base. Examples of the reaction solvent used include amide-based solvents such as dimethylformamide (hereinafter, DMF), diethylformamide, 1-methyl-2-pyrrolidone (hereinafter, NMP), and dimethylacetamide, urea-based solvents such as 1,3-dimethyl-2-imidazolidinone (hereinafter, DMI), halogenated solvents such as methylene chloride, ethers such as tetrahydrofuran and 2-methyltetrahydrofuran, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, alcohol-based solvents such as methanol, ethanol, isopropanol, n-propanol, and n-butanol, polar solvents such as acetonitrile, and mixed solvents of these. Among these, amide-based solvents and urea-based solvents are preferred, and DMF and DMI are more preferred. Examples of the base include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, and potassium hydride, as well as 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. The reaction may be carried out at a temperature of 0° C. to 200° C., preferably 50 to 150° C., and more preferably 70 to 120° C. The reaction is preferably carried out for 15 minutes to 48 hours.

[0096] The benzoyl compound of formula (2) obtained by this reaction can be isolated as a solid, and therefore is easy to purify and easy to handle. The isolation and purification can be easily carried out by a method that is usually adopted in industry, such as washing and recrystallization.

[0097] R in general formula (2) 1b ~R 5bAmong these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 number of the hydroxyalkyloxy groups is preferably 1 to 4, more preferably 2 to 4, even more preferably 2 to 3, and still more preferably 2. The remaining group 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, with a hydrogen atom being preferred, a halogen atom, or an alkyl group having 1 to 4 carbon atoms, and a hydrogen atom being more preferred.

[0098] R B represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0099] [ka]

[0100] (R 1b ~R 5b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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 B When shows the structure of this formula, R 5b is R in Eq. (2). 5b It may form an ether bond (-O-) together with R. B The binding site is shown.) The group represented by the formula: Here, the group having 1 to 16 carbon atoms, such as a hydroxyalkyloxy group, is 1b ~R 5b The same as above is preferred.

[0101] Among the compounds represented by the general formula (2), R B But the following equation

[0102] [ka]

[0103] (R 1b ~R 4b Among these, 1 to 5 represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder 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. B The binding site is shown.) It is preferable that the compound is a compound having a group represented by the following formula:

[0104] The benzoyl compound of the general formula (2) is reacted with a silazane compound, and then with an acid or base to obtain a ketimine compound of the general formula (3). Specifically, when the compound of the general formula (2) is reacted with a silazane compound in the presence of a catalyst, a compound in which a tri-substituted silyl group is bonded to the hydroxyl group of the hydroxyalkyloxy group is obtained. Then, the obtained compound is reacted with an acid or base to eliminate the tri-substituted silyl group, thereby obtaining a ketimine compound of the general formula (3). The reaction using a silazane compound is a reaction that converts the carbonyl group in formula (2) to an imino group (=NH), and at the same time, the terminal alcohol of the hydroxyalkyloxy group in the side chain is protected with a tri-substituted silyl group.

[0105] The silazane compound is a compound having a Si-NH-Si bond. Examples of the chain silazane compound include di-substituted disilazane (1,3-di-substituted disilazane), tetra-substituted disilazane (1,1,3,3-tetra-substituted disilazane), and hexa-substituted disilazane (1,1,1,3,3,3-hexa-substituted disilazane). The substituent in the silazane compound may be any of linear, branched, and cyclic aliphatic groups, and may be either saturated or unsaturated. Among these, saturated or unsaturated linear aliphatic groups having 1 to 4 carbon atoms are 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, with hexamethyldisilazane (1,1,1,3,3,3-hexamethyldisilazane) being most preferred. Examples of cyclic silazane compounds include 2,2,4,4,6,6-hexa-substituted cyclotrisilazane. The substituent may be any of linear, branched, and cyclic aliphatic groups, and may be either saturated or unsaturated. Among these, saturated or unsaturated linear aliphatic groups having 1 to 4 carbon atoms are preferred, and examples thereof include 2,2,4,4,6,6-hexamethylcyclotrisilazane and 2,4,6-trimethyl-2,4,6-trivinylcyclotrisilazane.

[0106] Specific examples of the catalyst include catalysts containing metal salts having Lewis acidity. Metal salts include triflate salts, nonaflate salts, and trifluoromethanesulfonylimide salts, and more 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)2, Bi(OTf)3, and Sc(ONf)3. butExamples include Sc(NO3)3 and BiBr3, as well as tetrabutylammonium fluoride and tetrabutylammonium dihydrogen fluoride. The metal is preferably at least one selected from Sc, Y, Eu, Er, Yb, Fe, Sn, and Bi, and the metal salt is preferably Sc(OTf)3.

[0107] This 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, ether solvents such as tetrahydrofuran and 1,4-dioxane, and halogen solvents such as 1,2-dichloroethane, and chlorobenzene and toluene are particularly preferred, with toluene being most preferred. In addition, water, alcohol, silanol, and the like may be added as a reaction promoter.

[0108] After this reaction, the terminal tri-substituted silyl group on the hydroxyalkyloxy group of the side chain is deprotected by reacting with an acid or base, and converted to a terminal alcohol. Examples of the acid include inorganic acids such as hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, 10-camphorsulfonic acid, and hydrogen fluoride-pyridine. Examples of the base include inorganic bases such as tetraalkylammonium fluoride, cesium fluoride, and potassium fluoride in the presence of an alcohol solvent, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, and potassium hydride, as well as hydrates thereof, and metal alkoxides such as lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide. Among these, it is preferable to use a base to deprotect the compound, and it is particularly preferable to use an alkali metal carbonate or an alkali metal hydrogen carbonate in the presence of a C1-4 alcohol such as methanol or ethanol. The deprotection reaction of the tri-substituted silyl group can be carried out continuously by adding an appropriate solvent after the completion of the reaction of converting the benzoyl group to an imino group (=NH). A deprotection agent for the tri-substituted silyl group may be added and the reaction may be carried out at 0 to 100°C for 15 minutes to 24 hours. The ketimine compound of general formula (3) obtained by this reaction can be isolated as a solid, and therefore is easy to purify and easy to handle. The isolation and purification can be easily carried out by a means usually adopted in industry, such as washing and recrystallization.

[0109] A benzylamine compound of general formula (4) can be obtained by reacting a ketimine compound of general formula (3) with a reducing agent and an Fmoc reagent. This reaction converts the imino group (=NH) of formula (3) into a fluorenylmethyloxycarbonylamino group (-NHFmoc). Examples of reducing agents include 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, SBAH), borane complexes, diisobutylaluminum hydride, and nickel borohydride. Other examples include reduction using silicon hydrides such as trialkylsilane, and reactions using palladium-carbon as a catalyst in the presence of hydrogen gas. Of these, lithium borohydride is most preferred. The reduction reaction is preferably carried out in an aromatic hydrocarbon solvent such as benzene or toluene, an ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, or cyclopentyl methyl ether, or an alcohol solvent such as methanol, ethanol, isopropanol, n-propanol, or n-butanol, or a mixed solvent thereof, at a temperature of 0° C. to 100° C. for 15 minutes to 48 hours.

[0110] Next, the Fmoc reagent is reacted. The Fmoc reagent may be any compound capable of introducing a 9-fluorenylmethyloxycarbonyl (Fmoc) group, and may be fluorenylmethyl halogenoformate, Fmoc-OSu, 9-fluorenylmethyl carbamate, 9-fluorenylmethyl carbazate, 1-(Fmoc-oxy)benzotriazole, 9-fluorenylmethyl pentafluorophenyl carbonate, or Fmoc-Amox described in Org. Process Res. Dev. 2017,21(10),1533-41. The Fmoc reaction can be carried out immediately after the reduction reaction, and there is no need to change the reaction solvent, etc. The Fmoc reaction can be carried out at 0 to 100° C. for 10 minutes to 3 hours after adding an Fmoc agent. The benzylamine compound of general formula (4) obtained by this reaction can be isolated as a solid, and therefore is easy to purify and has good handleability. The isolation and purification can be easily carried out by a means usually adopted in industry, such as washing and recrystallization.

[0111] An alkylsilyloxy-alkyloxybenzylamine compound of general formula (5) can be obtained by reacting the benzylamine compound of general formula (4) with an alkylsilylating agent. The alkylsilylating agent used in this reaction is a silylating agent having 1 to 3 alkylsilyl groups, and is preferably a silylating agent having an alkylsilyl group represented by the following formulas (7) to (17), in which * indicates the bond point with the oxygen atom of the hydroxyl group.

[0112] [ka]

[0113] (where R 7 , R 8 , R 9 are the same or different and each represents a linear or branched alkyl group having 1 to 6 carbon atoms or an aryl group which may have a substituent; R 10represents a single bond or a linear or branched alkylene group having 1 to 3 carbon atoms; R 11 , R 12 and R 13 each represents a linear or branched alkylene group having 1 to 3 carbon atoms.

[0114] Examples of the linear or branched alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, etc. Among these, an alkyl group having 1 to 4 carbon atoms is more preferred, and a methyl group, a tert-butyl group, and an isopropyl group are further preferred. The aryl group which may have a substituent includes an aryl group having 6 to 10 carbon atoms, specifically, a phenyl group or a naphthyl group which may be substituted with an alkyl group having 1 to 3 carbon atoms. Of these, a phenyl group is more preferred.

[0115] Examples of the alkylsilylation agent include alkylsilyl halides, alkylsilylimidazoles, alkylsilylbenztriazoles, alkylsilyltrifluoromethanesulfonyl, etc. Here, examples of the halogen atom include a bromine atom, a chlorine atom, and an iodine atom.

[0116] The reaction of the benzylamine compound of the general formula (4) with an alkylsilylating agent is preferably carried out in a solvent in the presence of a base. Examples of the reaction solvent to be used include amide solvents such as DMF, diethylformamide, NMP, and dimethylacetamide, urea solvents such as DMI, halogenated solvents such as methylene chloride, 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 these, amide solvents and urea solvents are preferred, and DMF, NMP, and DMI are more preferred. Examples of the base include inorganic salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, and potassium hydride, as well as 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. A preferred base is imidazole. The reaction may be carried out 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 carried out for 15 minutes to 48 hours. In this reaction, a small amount of a silyl compound derived from the alkylsilylation agent may be produced as a by-product in the reaction mixture. In that case, it is preferable to remove the silyl compound by liquid-liquid separation. The target alkylsilyloxy-substituted benzylamine compound (5) dissolves in an alkane solvent such as heptane. It is preferable to carry out liquid-liquid separation using a polar solvent such as acetonitrile, methanol, DMF, or dimethyl sulfoxide. It is preferable to use a mixture of the polar solvent with water, and a combination of acetonitrile and water is particularly preferable.

[0117] R in general formula (5) 1c ~R 5c Among these, 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder 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 this alkyloxy group having 1 to 29 carbon atoms substituted with an alkylsilyloxy group is represented by the following formula.

[0118] [ka] (18)

[0119] (R Erepresents a straight or branched alkyl group having 1 to 16 carbon atoms, and A represents one of the formulas (7) to (17). Note that * represents the bonding site with the carbon atom on the benzoyl skeleton, diphenyl ketone skeleton, or xanthone skeleton, which is the parent nucleus. The number of carbon atoms of the alkyloxy group is 1 to 29, and the number of carbon atoms of the hydroxyalkyloxy chain having 1 to 16 carbon atoms derived from a halogenated alcohol and the number of carbon atoms of the silylating agent represented by the formulas (7) to (17), R 10 , R 11 , R 12 and R 13 is the total number of carbon atoms contained in The alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups preferably has 1 to 4 carbon atoms, more preferably 2 to 4 carbon atoms, even more preferably 2 to 3 carbon atoms, and even more preferably 2 carbon atoms. The remaining group 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, with a hydrogen atom being preferred, a halogen atom, or an alkyl group having 1 to 4 carbon atoms, and a hydrogen atom being more preferred.

[0120] R C represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or

[0121] [ka]

[0122] (R 1b ~R 5b Among these, 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the remainder represents 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 shows the structure of this formula, R 5c is R in Eq. (5). 5c It may form an ether bond (-O-) together with R. C The binding site is shown.) The group represented by the formula: Here, examples of the alkyloxy group having 1 to 29 carbon atoms and substituted with 1 to 3 alkylsilyloxy groups include the same as those of the alkylsilyl group. 1c ~R 5c The other substituents of R 1b ~R 5b The same as above is preferred.

[0123] The alkylsilyloxylation reaction gives an alkylsilyloxy-alkyloxybenzylamine compound of general formula (5). The alkylsilyloxy-alkyloxybenzylamine compound of general formula (5) obtained by this reaction can be isolated as a solid, and therefore is easy to purify and has good handling properties. The isolation and purification can be easily carried out by a means that is usually industrially applicable, such as washing and recrystallization. As described in Patent Documents 1-3, the alkylsilyloxy-alkyloxybenzylamine compound of the general formula (5) is useful as a support for liquid phase peptide synthesis.

[0124] According to the method of the present invention, the benzoyl compound represented by the general formula (2), the ketimine compound represented by the general formula (3), the benzylamine compound represented by the general formula (4), and the alkylsilyloxy-alkyloxybenzylamine compound represented by the general formula (5) can all be obtained in solid form. In the present invention, "solid" refers to both a substance having a crystalline structure and an amorphous-like solid, but when each compound has the following structure, it is more likely to be obtained as a solid with a structure closer to a crystalline structure, and it is more likely to exhibit a useful function as a support (Tag) for liquid-phase peptide synthesis.

[0125] In the compound represented by the general formula (1), R 1a ~R 5a It is preferable that 1 to 5 of R are hydroxy groups and the remainder are hydrogen atoms. 3a is preferably a hydroxy group and the remainder is a hydrogen atom. A is expressed as follows:

[0126] [ka]

[0127] (R 1a ~R 5a It is preferable that 1 to 5 of R are hydroxy groups and the remainder are hydrogen atoms. 3a is preferably a hydroxy group and the remainder is preferably a hydrogen atom (note that * is preferably R A The binding site is shown.) It is preferable that the group is represented by the following formula:

[0128] In the compound represented by the general formula (2), (3) or (4), R 1b ~R 5b It is preferable that 1 to 5 of R are hydroxyalkyloxy groups having 1 to 16 carbon atoms, and the remainder are hydrogen atoms. 3a is preferably a hydroxyalkyloxy group having 1 to 16 carbon atoms, the remainder being a hydrogen atom. The number of carbon atoms in the hydroxyalkyloxy group is more preferably 4 to 16, further preferably 8 to 16, further preferably 10 to 16, and most preferably 11 to 16. B is expressed as follows:

[0129] [ka]

[0130] (R 1b ~R 5b It is preferable that 1 to 5 of R are hydroxyalkyloxy groups having 1 to 16 carbon atoms, and the remainder are hydrogen atoms. 3b is preferably a hydroxyalkyloxy group having 1 to 16 carbon atoms, the remainder being a hydrogen atom. The number of carbon atoms in the hydroxyalkyloxy group is more preferably 4 to 16, further preferably 8 to 16, further preferably 10 to 16, and most preferably 11 to 16. Note that * is R B The binding site is shown.) It is preferable that the group is represented by the following formula:

[0131] In the compound represented by the general formula (5), R 1c ~R 5c Among R, it is preferred that 1 to 5 are alkyloxy groups having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder are hydrogen atoms. 3b is preferably an alkylsilyloxy group having 1 to 29 carbon atoms substituted with one alkylsilyloxy group, and the remainder is a hydrogen atom. In particular, the alkylsilyloxy group is preferably one synthesized with an alkylsilylating agent represented by formula (7). In formula (7), R 7 , R 8 , R 9 is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, or a phenyl group; R C is expressed as follows:

[0132] [ka]

[0133] (R 1c ~R 5c It is preferred that 1 to 5 of R represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder are hydrogen atoms. 3b is preferably an alkylsilyloxy group having 1 to 29 carbon atoms substituted with one alkylsilyloxy group, and the remainder is a hydrogen atom. In particular, the alkylsilyloxy group is preferably one synthesized with an alkylsilylating agent represented by formula (7). In formula (7), R 7 , R 8 , R 9 is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, or a phenyl group. C The binding site is shown.) It is preferable that the group is represented by the following formula: EXAMPLES

[0134] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples in any way.

[0135] Comparative Example 1: Synthesis of Fmoc-D2-STag by the conventional method

[0136] [ka]

[0137] (Hereinafter, Br-(CH2) 11 -OTIPS, TIPS2-Dpm-C=O, TIPS2-Dpm-OH, and Fmoc-D2-STag represent the structures in the formula.

[0138] (1-a)Br-(CH2) 11 -O-TIPS 0.90g (3.58mmol) of 11-bromo-1-undecanol was dissolved in 12.8mL of dichloromethane, 0.61g (8.96mmol) of imidazole was added, the mixture was cooled to 5℃, and 0.91mL (4.30mmol) of triisopropylsilyl chloride (hereinafter, TIPS-Cl) was added dropwise. After 5 minutes, the mixture was returned to room temperature and stirred for 2 hours. 51.2mL of cyclopentyl methyl ether was added to the reaction solution, and the mixture was washed once with 12.8mL of distilled water, once with 12.8mL of 1M aqueous hydrochloric acid, and three times with 12.8mL of distilled water, and the organic layer was distilled off. The residue was dissolved in 51.2mL of heptane, and the mixture was separated and washed with 25.6mL of acetonitrile. 12.8mL of heptane was added to the obtained heptane layer, and the mixture was separated and washed with 25.6mL of acetonitrile. After washing with heptane and acetonitrile once more, the solvent was distilled off to obtain Br-(CH2) 11 The obtained Br-(CH2) was 1.45 g (yield 99.3%) of -O-TIPS. 11 -O-TIPS was in an oily state.

[0139] 1 H-NMR(400MHz,CDCl3)δ 1.03-1.20(m,21H),1.24-1.49(m,14H),1.54(quin.,2H),1.85(quin.,2H),3.41(t,2H),3.66(t,2H) ESIMS MH+407.1

[0140] (1-b) TIPS2-Dpm-C=O Br-(CH2) 11 9.81g (24.1mmol) of -OTIPS, 2.29g (10.7mmol) of 4,4'-dihydroxybenzophenone, and 5.33g (38.5mmol) of potassium carbonate were suspended in 3.2mL of DMF, heated to 85℃, and stirred for 2 hours. The reaction solution was filtered, and the residue was washed with 150mL of heptane. The filtrate was separated, and 71mL of heptane was added to the obtained heptane layer, and the mixture was washed with 71mL of DMF. The above-mentioned separation and washing with heptane and DMF was performed once more. 71mL of heptane was added to the obtained heptane layer, and the mixture was washed with 71mL of 1M aqueous hydrochloric acid solution once, with 71mL of 5% aqueous sodium bicarbonate solution once, and with 71mL of distilled water once. 71mL of heptane was added to the obtained heptane layer, and the mixture was washed with 71mL of DMF once, and with 71mL of acetonitrile once. The heptane layer was concentrated under reduced pressure to give 10.7 g of TIPS2-Dpm-C=O, which was a viscous oil.

[0141] 1 H-NMR(400MHz,CDCl3)δ 1.04-1.08(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) 1 3 C-NMR(100MHz,CDCl3)δ 12.2(6C),18.2(12C),26.0(2C),26.2(2C),29.2-29.8(12C),33.2(2C),6 3.7(2C),68.4(2C),114.0(4C),130.7(2C),132.4(4C),162.6(2C),194.6 ESIMS MNa+889.8

[0142] (1-c)TIPS2-Dpm-OH 0.81g (0.93mmol) of TIPS2-Dpm-C=O was dissolved in a mixed solution of 7.1mL of THF (anhydrous) and 0.36mL of methanol, 42mg (1.12mmol) of sodium borohydride was added, and the mixture was stirred for 1.5 hours. 0.89mL of 1M aqueous hydrochloric acid was added to the reaction solution to stop the reaction, 20.3mL of cyclopentyl methyl ether was added, and the mixture was washed once with 6.1mL of 1M aqueous hydrochloric acid, once with 6.1mL of 5% aqueous sodium bicarbonate, once with 6.1mL of distilled water, and the organic layer was concentrated under reduced pressure. The resulting residue was dissolved in 20.0mL of heptane and washed with 10.0mL of DMF. 10.0mL of heptane was added to the obtained heptane layer, and the mixture was washed with 10.0mL of acetonitrile. After the above-mentioned separation and washing with heptane and acetonitrile was carried out once more, the heptane layer was concentrated under reduced pressure to obtain 0.81 g of TIPS2-Dpm-OH. The resulting TIPS2-Dpm-OH was in the form of a viscous oil.

[0143] 1 H-NMR(400MHz,Benzene-d)δ 1.12-1.16(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) 1 3 C-NMR(100MHz,Benzene-d)δ 12.8(6C),18.7(12C),26.7(2C),26.8(2C),30.2-30.5(12C),33.9(2C), 64.1(2C),68.3(2C),75.9,114.9(4C),128.6(4C),137.8(2C),159.4(2C)

[0144] HO-(CH2) contained as an impurity in the crude product of TIPS2-Dpm-OH 11 The content of -OTIPS was analyzed by HPLC and found to be 5.1% by weight. Analysis conditions (HPLC) Column: YMC-Triart C18 (inner diameter 3.0mm, length 100mm, particle size 1.9μm) Mobile phase A: 0.01M ammonium formate, acetonitrile:water = 8:2 solution Mobile phase B: 0.01M ammonium formate, isopropanol:water = 100:1 solution Flow rate: 0.25mL / min Column temperature: 35℃ Detection wavelength: 200 nm 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)

[0145] (1-d) Fmoc-D2-STag 1.00g (1.15mmol) of TIPS2-Dpm-OH and 0.29g (1.25mmol) of Fmoc-NH2 were dissolved in 6.5mL of toluene. 0.04g (0.32mmol) of oxalic acid dihydrate was added, and the mixture was heated to 85℃ and stirred for 4 hours. 10mL of heptane and 10mL of 90% methanol were added and washed by separation. 5mL of 5% sodium bicarbonate solution was added to the obtained upper layer and washed by separation. 10mL of 90% methanol was added to the obtained upper layer and washed by separation three times. The obtained upper layer was concentrated under reduced pressure. The obtained residue was dissolved in 2mL of tetrahydrofuran, and the tetrahydrofuran solution was added dropwise to 20mL of methanol while stirring, and the mixture was stirred for 30 minutes after the dropwise addition. The process liquid in which the target product had crystallized was filtered, and the filtered residue was washed with methanol. After drying under reduced pressure, 0.94 g (yield 74.9%) of Fmoc-D2-STag was obtained. The obtained Fmoc-D2-STag was a solid.

[0146] 1H-NMR(400MHz,CDCl3)δ 0.99-1.12(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) 13 C-NMR(100MHz,CDCl3)δ 12.0,18.0,25.8,26.0,29.3,29.40,29.55(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 ESIMS MNa+1112.8

[0147] HO-(CH2) contained as an impurity in the crude Fmoc-D2-STag by HPLC under the same conditions as in step (1-c) 1 1 Analysis of the ratio of -OTIPS revealed that the crude TIPS2-Dpm-OH product contained HO-(CH2) as an impurity. 1 1 -OTIPS was carried over as it was. Furthermore, there was a problem that TIPS2-Dpm-OH, the target product of step (1-c), was decomposed by a small amount of acid and dimerized during storage. For example, when TIPS2-Dpm-OH was stored at 30°C, 10.0% of the dimer was generated after 30 days. For this reason, TIPS2-Dpm-OH was a compound that was difficult to store for a long time. In addition, in step (1-d), a side reaction occurred in which the TIPS group was eliminated by an acid catalyst, and in the comparative example, 0.2% of the dealkylsilyl product was generated. Both side reactions caused a decrease in the yield of Fmoc-D2-STag.

[0148] Analytical conditions for Fmoc-D2-STag, dimerized TIPS2-Dpm-OH and dealkylsilyl derivatives (HPLC) Column: YMC-Triart C18 (inner diameter 3.0mm, length 100mm, particle size 1.9μm) Mobile phase A: isopropanol:acetonitrile:water = 5:90:5 solution with 0.1% v / v formic acid Mobile phase B: 0.1% v / v formic acid in isopropanol Flow rate: 0.35mL / min Column temperature: 35℃ Detection wavelength: 254 nm 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)

[0149] Example 1 Synthesis of Fmoc-D2-STag by the method of the present invention

[0150] [ka]

[0151] (Hereinafter, HO-Dpm-C=O, HO-Dpm-C=NH, HO-Dpm-C-NHFmoc, and Fmoc-D2-STag represent the structures in the formula.)

[0152] (2-a)HO-Dpm-C=O 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℃, and stirred for 4 hours. The reaction solution was adjusted to 80℃, water 2.25L was added, and stirred at the same temperature for 1 hour. After cooling to 30℃, the slurry was filtered, and the filter cake was washed once with 0.56L of water and once again with 0.56L of water. After washing, the filter cake was collected, water 2.25L was added, and stirred at 80℃ for 1 hour. After cooling to 30℃, the slurry was filtered, and the filter cake was washed once with 0.56L of water and once again with 0.56L of water. After washing, the filter cake was collected, methanol 1.78L was added, and stirred at 60℃ for 1 hour. After cooling to 30°C, the slurry was filtered, and the residue was washed once with 0.56 L of methanol and once again with 0.56 L of methanol. It was then 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 a solid.

[0153] 1 H-NMR(400MHz,Pyridine-D5)δ 1.20-1.39(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) 1 3 C-NMR(100MHz,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 ESIMS MNa+577.4

[0154] (2-b)HO-Dpm-C=NH 461g (831mmol) of HO-Dpm-C=O and 40.9g (83.1mmol) of scandium trifluoromethanesulfonate were suspended in 0.83L of toluene, 0.70L of hexamethyldisilazane was added, and the mixture was heated to 90°C and stirred for 21 hours. The reaction solution was cooled to 30°C, 0.83L of methanol and 345g (2.49mol) of potassium carbonate were added, and the mixture was stirred at 30°C for 3 hours. 1.84L of water was added, and the mixture was stirred at 50°C for 1 hour. After cooling to 30°C, the slurry was filtered, and the residue was washed once with 0.92L of water and once again with 0.92L of water. After washing, the residue was collected, 1.84L of 50% methanol water was added, and the mixture was stirred at 50°C for 1 hour. After cooling to 30°C, the slurry was filtered, and the residue was washed once with 0.92L of 50% aqueous methanol, and once again with 0.92L of 50% aqueous methanol. After washing, the residue was collected, 1.84L of acetonitrile was added, and the mixture was stirred at 50°C for 1 hour. After cooling to 30°C, the slurry was filtered, and the residue was washed once with 1.84L of acetonitrile. The mixture was then dried under reduced pressure at 40°C to obtain 437g of HO-Dpm-C=NH (yield 94.9%). The obtained HO-Dpm-C=NH was a solid.

[0155] 1 H-NMR(400MHz,Pyridine-D5)δ 1.18-1.37(m,20H),1.37-1.45(m,4H),1.45-1.55(m,4H),1.70-1.82(m,4H),3.8 8(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) 1 3 C-NMR(100MHz,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 ESIMS MNa+576.4

[0156] (2-c)HO-Dpm-C-NHFmoc 104.65g (2.47mol) of lithium chloride and 93.40g (2.47mmol) of sodium borohydride were suspended in 1.25L of tetrahydrofuran and stirred at 10℃ or less for 10 minutes. 3.74L of methanol and 414g (748mmol) of HO-Dpm-C=NH were added, and the mixture was heated to 40℃ and stirred for 2 hours. 328g (973mmol) of Fmoc-OSu was added and stirred at 40℃ for 2 hours. 4.97L of 50% aqueous methanol was added and stirred at 40℃ for 1 hour. After cooling to 30℃, the slurry was filtered and the residue was washed once with 2.9L of 50% aqueous methanol. After washing, the residue was collected, 4.97L of 50% aqueous methanol was added, and the mixture was stirred at 40℃ for 1 hour. After cooling to 30°C, the slurry was filtered, and the residue was washed once with 2.90L of 50% aqueous methanol, and once again with 2.90L of 50% aqueous methanol. After washing, the residue was collected, 4.97L of acetonitrile was added, and the mixture was stirred at 40°C for 1 hour. After cooling to 30°C, the slurry was filtered, and the residue was washed once with 2.90L of acetonitrile. The mixture was then dried under reduced pressure at 40°C to obtain 549g of HO-Dpm-C-NHFmoc (yield 94.3%). The obtained HO-Dpm-C-NHFmoc was a solid.

[0157] 1 H-NMR(400MHz,CDCl3)δ 1.20-1.39(m,24H),1.38-1.50(m,4H),1.50-1.60(m,4H),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(b r,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) 1 3C-NMR(100MHz,CDCl3)δ 25.7,26.0,29.2,29.3,29.37,29.45(2C),29.49(2C),29.53,32.8,63.1,68.0,7 7.2,114.5,119.9,125.0,127.0,127.6,128.3,133.8,141.3,143.9,155.5,158.4 ESIMS MK+816.5

[0158] (2-d)Fmoc-D2-STag 524g (673mmol) of HO-Dpm-C=NH and 206g (3.03mmol) of imidazole were suspended in 1.68L of DMF, and 0.51L of triisopropylsilyl chloride was added dropwise at 30°C. After stirring for 3 hours, 5.05L of heptane, 0.56L of diisopropylethylamine, and 5.05L of water were added and stirred for 10 minutes. The mixture was washed with 0.84L of heptane and separated for washing. 3.37L of 50% acetonitrile water was added to the obtained upper layer and separated for washing. 3.37L of 50% acetonitrile water was added to the obtained upper layer again and separated for washing. The upper layer was washed with 0.84L of heptane and concentrated under reduced pressure. 0.84L of tetrahydrofuran was added to the obtained residue and concentrated again under reduced pressure. The resulting 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 process liquid in which the target product had crystallized was filtered, and the residue 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 resulting residue, which was then stirred at 25°C for 1 hour. The slurry was filtered, and the residue was washed with 2.0 L of acetonitrile. The mixture was then dried under reduced pressure at 40°C to obtain 521 g of Fmoc-D2-STag (70.9% yield). The resulting Fmoc-D2-STag was a solid.

[0159] 1H-NMR(400MHz,CDCl3)δ 0.99-1.12(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) 1 3 C-NMR(100MHz,CDCl3)δ 12.0,18.0,25.8,26.0,29.3,29.40,29.55(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 ESIMS MNa+1112.8

[0160] Analytical conditions for Fmoc-D2-STag, dimerized TIPS2-Dpm-OH, and dealkylsilyl derivatives (HPLC) Column: YMC-Triart C18 (inner diameter 3.0mm, length 100mm, particle size 1.9μm) Mobile phase A: isopropanol:acetonitrile:water = 5:90:5 solution with 0.1% v / v formic acid Mobile phase B: 0.1% v / v formic acid in isopropanol Flow rate: 0.35mL / min Column temperature: 35℃ Detection wavelength: 254 nm 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)

[0161] HO-(CH2) 11 -OTIPS analysis conditions (HPLC) Column: YMC-Triart C18 (inner diameter 3.0mm, length 100mm, particle size 1.9μm) Mobile phase A: 0.01M ammonium formate, acetonitrile:water = 8:2 solution Mobile phase B: 0.01M ammonium formate, isopropanol:water = 100:1 solution Flow rate: 0.25mL / min Column temperature: 35℃ Detection wavelength: 200 nm 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)

[0162] In the comparative example, HO-(CH2) contained as an impurity in the crude product of TIPS2-Dpm-OH was 1 1 -OTIPS was carried over as it was. This component was not detected in the examples. In addition, in the comparative examples, there was also a problem that the intermediate TIPS2-Dpm-OH was decomposed by a small amount of acid and dimerized during storage. In the examples, the dimerized form of TIPS2-Dpm-OH, which is difficult to separate, was not detected because the production method does not involve TIPS2-Dpm-OH.

[0163] Furthermore, in the step (1-d) of Comparative Example 1, a side reaction occurred in which the TIPS group was eliminated by an acid catalyst. In Example 1, TIPS formation was carried out in the final step, and the condition of using an acid catalyst was avoided, so that no dealkylated silyl product was detected, and this problem was solved.

[0164] In Comparative Example 1, Br-(CH2) 11 -O-TIPS was added in an amount of 2.25 equivalents to 4,4'-dihydroxybenzophenone. The excess amount of 0.25 equivalents of Br-(CH2) 11 -O-TIPS and the decomposition product HO-(CH2) 11-O-TIPS is lipophilic and has similar physical properties to the target compounds TIPS2-Dpm-C=O and TIPS2-Dpm-OH, making it difficult to separate them. Since the intermediates TIPS2-Dpm-C=O and TIPS2-Dpm-OH, which are the side chain-extended intermediates, are both oil-like compounds, it was necessary to solidify TIPS2-Dpm-C=O or TIPS2-Dpm-OH to obtain Br-(CH2) 11 It was not possible to remove -O-TIPS by washing with a specific solvent. Therefore, the compounds derived from the raw materials of these side chain elongation reactions were contaminated into TIPS2-Dpm-OH in a large amount, nearly 0.25 equivalents relative to 4,4'-dihydroxybenzophenone. TIPS2-Dpm-OH contains HO-(CH2) 11 -OTIPS was also present at 5.1 wt%. Furthermore, when TIPS2-Dpm-OH was amidated and converted to Fmoc-D2-STag, HO-(CH2) 11 -O-TIPS was not removed and was mixed in. In contrast, in Example 1, the intermediate HO-Dpm-C=O, in which the side chain was extended using 11-bromo-1-undecanol, was a solid. Therefore, 11-bromo-1-undecanol could be easily removed by washing HO-Dpm-C=O with an organic solvent such as methanol, which has a high dissolving power for 11-bromo-1-undecanol. The content of the compound derived from 11-bromo-1-undecanol contained in Fmoc-D2-STag was 0.03 wt%. Furthermore, unlike the comparative example, all intermediates could be obtained in solid form, which made it possible to roughly purify the intermediates by solid-liquid separation, and the purity of the final target product, Fmoc-D2-STag, could be improved.

[0165] In addition, in Comparative Example 1, there was a problem that the intermediate TIPS2-Dpm-OH was decomposed by a small amount of acid and dimerized during storage, whereas in Example 1, this problem was solved because the intermediate was not TIPS2-Dpm-OH.

[0166] Furthermore, in step (1-d) of Comparative Example 1, a side reaction occurred in which the TIPS group was eliminated by an acid catalyst. In Example 1, TIPS formation was carried out in the final step, and the condition of using an acid catalyst was avoided, thereby solving this problem.

[0167] From the above, it is considered that the impurity HO-(CH2) which is difficult to separate in the production method of the present invention 11 The amount of -OTIPS contamination was significantly reduced compared to the conventional method. In addition, by obtaining all intermediates in the process as solids, crude purification by solid-liquid separation became possible. In the conventional method, HO-(CH2) 11 In addition to the process of separating -OTIPS, precise purification by column chromatography etc. was required. For this reason, it was difficult to mass-produce alkylsilyloxy-alkyloxybenzylamine compounds on an industrial scale using conventional methods. In contrast, the production method of the present invention uses HO-(CH2) 11 The amount of -OTIPS contamination can be significantly reduced, and it has become possible to industrially advantageously obtain alkylsilyloxy-substituted benzylamine compounds. Furthermore, the production method of the present application solves the problem of decomposition of intermediates by acid catalysts, which was a problem in the conventional method. In addition, Br-(CH2) used in the conventional method 11 Another advantage of the method of the present invention is that it avoids the use of unstable raw materials, since -O-TIPS is an unstable compound that slowly decomposes at room temperature.

Claims

1. General formula (2) 【Chemistry 1】 (In the formula, R 1b ~R 5b among which, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted with only a hydroxy group, and the remainder 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; R B is expressed as follows: 【Chemistry 2】 (R 1b ~R 5b Among these, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted only with a hydroxy group, and the remainder 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 B When represents the structure of this formula, R 5b is R in formula (2) 5b may form an ether bond (-O-) together with R B ) represents a bonding site with The benzoyl compound represented by the formula: 3 , Y(OTf) 3 , Sm(OTf) 3 , Eu(OTf) 3 , Gd(OTf) 3 , Er(OTf) 3 , Yb(OTf) 3 , Fe(OTf) 3 , Sn(OTf)2, Bi(OTf) 3 , Sc(ONf) 3 and tetrabutylammonium fluoride, and then reacting the resulting compound having a hydroxyl group of a hydroxyalkyloxy group bonded to a tri-substituted silyl group with an inorganic acid, an inorganic base, or a metal alkoxide, represented by the general formula (3): 【Chemistry 3】 (In the formula, R 1b ~R 5b among which, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted with only a hydroxy group, and the remainder 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; R B is expressed as follows: 【Chemistry 4】 (R 1b ~R 5b Among these, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted only with a hydroxy group, and the remainder 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 B When represents the structure of this formula, R 5b is R in formula (3). 5b may form an ether bond (-O-) together with R B ) represents a bonding site with A method for producing a ketimine compound represented by the formula:

2. General formula (2) 【Chemistry 5】 (In the formula, R 1b ~R 5b among which, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted with only a hydroxy group, and the remainder 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; R B is expressed as follows: 【Chemistry 6】 (R 1b ~R 5b Among these, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted only with a hydroxy group, and the remainder 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 B When represents the structure of this formula, R 5b is R in formula (2) 5b may form an ether bond (-O-) together with R B ) represents a bonding site with The benzoyl compound represented by the formula: 3 , Y(OTf) 3 , Sm(OTf) 3 , Eu(OTf) 3 , Gd(OTf) 3 , Er(OTf) 3 , Yb(OTf) 3 , Fe(OTf) 3 , Sn(OTf)2, Bi(OTf) 3 , Sc(ONf) 3 and tetrabutylammonium fluoride, and then reacting a silazane compound with the resulting compound having a hydroxyl group of a hydroxyalkyloxy group bonded to a tri-substituted silyl group with an inorganic acid, an inorganic base or a metal alkoxide to obtain a compound represented by the general formula (3): 【Chemistry 7】 (In the formula, R 1b ~R 5b among which, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted with only a hydroxy group, and the remainder 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; R B is expressed as follows: 【Chemistry 8】 (R 1b ~R 5b Among these, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted only with a hydroxy group, and the remainder 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 B When represents the structure of this formula, R 5b is R in formula (3). 5b may form an ether bond (-O-) together with R B ) represents a bonding site with and reacting the resulting ketimine compound with a reducing agent and an Fmoc reagent, 【Chemistry 9】 (In the formula, R 1b ~R 5b among which, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted with only a hydroxy group, and the remainder 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; R B is expressed as follows: 【Chemistry 10】 (R 1b ~R 5b Among these, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted only with a hydroxy group, and the remainder 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 B When represents the structure of this formula, R 5b is R in formula (4). 5b may form an ether bond (-O-) together with R B ) represents a bonding site with A method for producing a benzylamine compound represented by the formula:

3. General formula (2) 【Chemistry 11】 (In the formula, R 1b ~R 5b among which, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted with only a hydroxy group, and the remainder 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; R B is expressed as follows: 【Chemistry 12】 (R 1b ~R 5b Among these, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted only with a hydroxy group, and the remainder 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 B When represents the structure of this formula, R 5b is R in formula (2) 5b may form an ether bond (-O-) together with R B ) represents a bonding site with The benzoyl compound represented by the formula: 3 , Y(OTf) 3 , Sm(OTf) 3 , Eu(OTf) 3 , Gd(OTf) 3 , Er(OTf) 3 , Yb(OTf) 3 , Fe(OTf) 3 , Sn(OTf)2, Bi(OTf) 3 , Sc(ONf) 3 and tetrabutylammonium fluoride, and then reacting a silazane compound with the resulting compound having a hydroxyl group of a hydroxyalkyloxy group bonded to a tri-substituted silyl group with an inorganic acid, an inorganic base or a metal alkoxide to obtain a compound represented by the general formula (3): 【Chemistry 13】 (In the formula, R 1b ~R 5b among which, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted with only a hydroxy group, and the remainder 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; R B is expressed as follows: 【Chemistry 14】 (R 1b ~R 5b Among these, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted only with a hydroxy group, and the remainder 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 B When represents the structure of this formula, R 5b is R in formula (3). 5b may form an ether bond (-O-) together with R B ) represents a bonding site with The ketimine compound represented by the general formula (4) is reacted with a reducing agent and an Fmoc reagent to obtain a ketimine compound represented by the general formula (4): 【Chemistry 15】 (In the formula, R 1b ~R 5b among which, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted with only a hydroxy group, and the remainder 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; R B is expressed as follows: 【Chemistry 16】 (R 1b ~R 5b Among these, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted only with a hydroxy group, and the remainder 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 B When represents the structure of this formula, R 5b is R in formula (4). 5b may form an ether bond (-O-) together with R B ) represents a bonding site with and then reacting the benzylamine compound with an alkylsilylating agent, 【Chemistry 17】 (In the formula, R 1c ~R 5c among which, 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyloxy group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms; R C is expressed as follows: 【Chemistry 18】 (R 1c ~R 5c Among these, 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder 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 represents the structure of this formula, R 5c is R in formula (5) 5c may form an ether bond (-O-) together with R C ) represents a bonding site with A method for producing an alkylsilyloxy-substituted benzylamine compound represented by the following formula:

4. The benzoyl compound represented by the general formula (2) is represented by the general formula (1) 【Chemistry 19】 (In the formula, R 1a ~R 5a among which, 1 to 5 represent a hydroxy group, and the remainder 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; R A is expressed as follows: 【Chemistry 20】 (R 1a ~R 5a of which 1 to 5 represent a hydroxy group, and the remainder 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 A When represents the structure of this formula, R 5a is R in formula (1) 5a may form an ether bond (-O-) together with R A The binding site is shown.) The method according to any one of claims 1 to 3, which is obtained by reacting a compound represented by the following formula (I) with a halogenated alcohol.

5. General formula (6) 【Chemistry 21】 (In the formula, R 1b ~R 5b among which, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted with only a hydroxy group, and the remainder 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; R B is expressed as follows: 【Chemical 22】 (R 1b ~R 5b Among these, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted only with a hydroxy group, and the remainder 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 B When represents the structure of this formula, R 5b is R in formula (6) 5b may form an ether bond (-O-) together with R B NY represents an imino group (=NH) or NHFmoc. The compound represented by the formula:

6. General formula (4) 【Chemistry 23】 (In the formula, R 1b ~R 5b among which, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted with only a hydroxy group, and the remainder 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; R B is expressed as follows: 【Chemistry 24】 (R 1b ~R 5b Among these, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted only with a hydroxy group, and the remainder 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 B When represents the structure of this formula, R 5b is R in formula (4). 5b may form an ether bond (-O-) together with R B ) represents a bonding site with The benzylamine compound represented by the general formula (5) is reacted with an alkylsilylating agent. 【Chemistry 25】 (In the formula, R 1c ~R 5c among which, 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyloxy group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms; R C is expressed as follows: 【Chemistry 26】 (R 1c ~R 5c Among these, 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder 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 represents the structure of this formula, R 5c is R in formula (5) 5c may form an ether bond (-O-) together with R C ) represents a bonding site with A method for producing an alkylsilyloxy-substituted benzylamine compound represented by the following formula:

7. General formula (3) 【Chemical 27】 (In the formula, R 1b ~R 5b among which, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted with only a hydroxy group, and the remainder 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; R B is expressed as follows: 【Chemistry 28】 (R 1b ~R 5b Among these, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted only with a hydroxy group, and the remainder 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 B When represents the structure of this formula, R 5b is R in formula (3). 5b may form an ether bond (-O-) together with R B ) represents a bonding site with With a reducing agent and an Fmoc reagent, a ketimine compound represented by the general formula (4) is reacted to obtain a compound represented by the general formula (4): 【Chemical 29】 (In the formula, R 1b ~R 5b among which, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted with only a hydroxy group, and the remainder 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; R B is expressed as follows: 【Chemistry 30】 (R 1b ~R 5b Among these, 1 to 5 represent an alkyloxy group having 1 to 16 carbon atoms substituted only with a hydroxy group, and the remainder 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 B When represents the structure of this formula, R 5b is R in formula (4). 5b may form an ether bond (-O-) together with R B ) represents a bonding site with and then reacting the benzylamine compound with an alkylsilylating agent, 【Chemistry 31】 (In the formula, R 1c ~R 5c among which, 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyloxy group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms; R C is expressed as follows: 【Chemistry 32】 (R 1c ~R 5c Among these, 1 to 5 represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder 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 represents the structure of this formula, R 5c is R in formula (5) 5c may form an ether bond (-O-) together with R C ) represents a bonding site with A method for producing an alkylsilyloxy-substituted benzylamine compound represented by the following formula:

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