JP2017048131A - Method for producing amino-hydroxypyridine compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an amino-hydroxypyridinium salt and an amino-hydroxypyridine compound with good yield and without using explosive hydroxylamine.SOLUTION: Provided is a method for producing an amino-hydroxypyridinium salt and an amino-hydroxypyridine compound via an aralkyloxy-pyridine compound represented by a formula (4). (In the formula, PG is a t-butoxycarbonyl group, a diphenylmethyl group, a triphenylmethyl group, a p-methoxyphenyl-diphenylmethyl group or a di(p-methoxyphenyl)phenylmethyl group, Ris a hydrogen atom, an alkyl group or an alkoxy group, Rrepresents a hydrogen atom, an alkyl group or an aryl group, and n is an integer of 1 or 2.)SELECTED DRAWING: None

Description

The present invention relates to an aminohydroxypyridinium salt and a method for producing an aminohydroxypyridine compound.

  An aminohydroxypyridinium salt and an aminohydroxypyridine compound are useful compounds as pharmaceutical raw materials (see, for example, Patent Document 1 or 2). As a method for producing the aminohydroxypyridine compound, for example, 2-amino-5-iodopyridine, which is an aminohalopyridine compound, is reacted with 2,5-hexanedione, and the amino group is protected with a 2,5-dimethylpyrrole ring. The obtained compound is reacted with methanol in the presence of a copper catalyst and sodium to produce a coupling compound, and then the obtained compound is reacted with hydroxylamine to produce 2,5-dimethylpyrrole. After obtaining 2-amino-5-methoxypyridine with the ring deprotected, the resulting 2-amino-5-methoxypyridine was demethylated under strongly acidic conditions to give 2-amino-5-hydroxypyridine. The obtaining method is known (patent document 1). Further, a compound in which the amino group of 2-amino-5-iodopyridine is protected with a 2,5-dimethylpyrrole ring is reacted with benzyl alcohol in the presence of a copper catalyst and cesium carbonate to produce an aralkyloxypyridine compound, A method of reacting the obtained compound with hydroxylamine to deprotect the 2,5-dimethylpyrrole ring to obtain 2-amino-5-benzyloxypyridine, which is a synthetic intermediate of 2-amino-5-hydroxypyridine Is known (Non-Patent Document 1).

Special table 2009-533411 gazette Special table 2013-525286 The Journal of Organic Chemistry (2008), 73, 9326-9333, The Journal of Organic Chemistry.

  However, in the conventional production method, since explosive hydroxylamine is used as a reagent for deprotecting the 2,5-dimethylpyrrole ring, there is a problem in safety. Moreover, the yield of the demethylation reaction of 2-amino-5-methoxypyridine was as low as 44%, and the yield was not satisfactory.

  Therefore, the present inventors have intensively studied a method for producing an aminohydroxypyridinium salt and an aminohydroxypyridine compound using an aminohalopyridine compound as a starting material. As a key intermediate, an aralkyl represented by the following formula (4) is obtained. By passing through the oxypyridine compound, it was found that an aminohydroxypyridinium salt and an aminohydroxypyridine compound can be produced with good yield and without using explosive hydroxylamine, and the present invention has been completed.

That is, the present invention provides the following [1] to [18].
[1] Formula (1):

（式中、Ｘはハロゲン原子を示す。）
で表されるアミノハロピリジン化合物のアミノ基を保護して式（２）：

(In the formula, X represents a halogen atom.)
Protecting the amino group of the aminohalopyridine compound represented by formula (2):

（式中、ＰＧはｔ−ブトキシカルボニル基、ジフェニルメチル基、トリフェニルメチル基、ｐ−メトキシフェニルジフェニルメチル基又はジ（ｐ−メトキシフェニル）フェニルメチル基であり、ｎは１又は２の整数である。）
で表されるハロピリジン化合物を得、前記ハロピリジン化合物をさらに、銅化合物、アルカリ金属化合物及び配位子の存在下、式（３）：

(In the formula, PG is a t-butoxycarbonyl group, a diphenylmethyl group, a triphenylmethyl group, a p-methoxyphenyldiphenylmethyl group or a di (p-methoxyphenyl) phenylmethyl group, and n is an integer of 1 or 2) is there.)
In the presence of a copper compound, an alkali metal compound and a ligand, the halopyridine compound is further represented by the formula (3):

（式中、Ｒ^１は水素原子、アルキル基又はアルコキシ基、Ｒ^２は水素原子、アルキル基又はアリール基を示す。）
で表されるアラルキルアルコール化合物と反応させる、式（４）：

(Wherein R ¹ represents a hydrogen atom, an alkyl group or an alkoxy group, and R ² represents a hydrogen atom, an alkyl group or an aryl group.)
Wherein the compound is reacted with an aralkyl alcohol compound represented by formula (4):

（式中、ＰＧ、Ｒ^１、Ｒ^２及びｎは前記と同じ。）
で表されるアラルキルオキシピリジン化合物の製造方法。
［２］前記銅化合物がハロゲン化銅である［１］に記載のアラルキルオキシピリジン化合物の製造方法。
［３］前記アルカリ金属化合物がカリウムを含む化合物である［１］又は［２］に記載のアラルキルオキシピリジン化合物の製造方法。
［４］前記配位子が１−アルキルイミダゾール化合物である［１］〜［３］のいずれかに記載のアラルキルオキシピリジン化合物の製造方法。
［５］前記式（２）で表されるハロピリジン化合物に前記式（３）で表されるアラルキルアルコール化合物を反応させた後、得られた反応液をアンモニア水溶液及び／又はエチレンジアミン水溶液で洗浄する［１］〜［４］のいずれかに記載のアラルキルオキシピリジン化合物の製造方法。
［６］前記式（２）で表されるハロピリジン化合物に前記式（３）で表されるアラルキルアルコール化合物を反応させる際、さらに相間移動触媒を使用する［１］〜［５］のいずれかに記載のアラルキルオキシピリジン化合物の製造方法。
［７］Ｘが臭素原子又はヨウ素原子である［１］〜［６］のいずれかに記載のアラルキルオキシピリジン化合物の製造方法。
［８］ＰＧがトリフェニルメチル基である［１］〜［７］のいずれかに記載のアラルキルオキシピリジン化合物の製造方法。
［９］前記式（１）で表されるアミノハロピリジン化合物が２−アミノ−５−ハロピリジン化合物である［１］〜［８］のいずれかに記載のアラルキルオキシピリジン化合物の製造方法。
［１０］前記式（４）で表されるアラルキルオキシピリジン化合物を、酸と反応させて式（５）：

(In the formula, PG, R ¹ , R ² and n are the same as described above.)
The manufacturing method of the aralkyloxypyridine compound represented by these.
[2] The method for producing an aralkyloxypyridine compound according to [1], wherein the copper compound is a copper halide.
[3] The method for producing an aralkyloxypyridine compound according to [1] or [2], wherein the alkali metal compound is a compound containing potassium.
[4] The method for producing an aralkyloxypyridine compound according to any one of [1] to [3], wherein the ligand is a 1-alkylimidazole compound.
[5] After the aralkyl alcohol compound represented by the formula (3) is reacted with the halopyridine compound represented by the formula (2), the obtained reaction solution is washed with an aqueous ammonia solution and / or an ethylenediamine aqueous solution. [1] A method for producing an aralkyloxypyridine compound according to any one of [4].
[6] When the aralkyl alcohol compound represented by the above formula (3) is reacted with the halopyridine compound represented by the above formula (2), a phase transfer catalyst is further used in any one of [1] to [5] A process for producing the aralkyloxypyridine compound described.
[7] The method for producing an aralkyloxypyridine compound according to any one of [1] to [6], wherein X is a bromine atom or an iodine atom.
[8] The method for producing an aralkyloxypyridine compound according to any one of [1] to [7], wherein PG is a triphenylmethyl group.
[9] The method for producing an aralkyloxypyridine compound according to any one of [1] to [8], wherein the aminohalopyridine compound represented by the formula (1) is a 2-amino-5-halopyridine compound.
[10] The aralkyloxypyridine compound represented by the formula (4) is reacted with an acid to give a formula (5):

（式中、Ｒ^１及びＲ^２は前記と同じ、Ａは酸を示す。）
で表されるアミノアラルキルオキシピリジニウム塩を得、前記アミノアラルキルオキシピリジニウム塩をさらに、水素化触媒存在下、接触水素化させる、式（６）：

(In the formula, R ¹ and R ² are the same as described above, and A represents an acid.)
Wherein the aminoaralkyloxypyridinium salt is further catalytically hydrogenated in the presence of a hydrogenation catalyst, formula (6):

（式中、Ａは前記と同じ。）
で表されるアミノヒドロキシピリジニウム塩の製造方法。
［１１］前記式（４）で表されるアラルキルオキシピリジン化合物を、水素化触媒存在下、接触水素化させて式（７）：

(In the formula, A is the same as described above.)
The manufacturing method of the aminohydroxy pyridinium salt represented by these.
[11] The aralkyloxypyridine compound represented by the formula (4) is catalytically hydrogenated in the presence of a hydrogenation catalyst to obtain the formula (7):

（式中、ＰＧ及びｎは前記と同じ。）
で表されるヒドロキシピリジン化合物を得、前記ヒドロキシピリジン化合物をさらに、酸と反応させる、前記式（６）で表されるアミノヒドロキシピリジニウム塩の製造方法。
［１２］前記式（４）で表されるアラルキルオキシピリジン化合物を、酸及び水素化触媒存在下、接触水素化させる前記式（６）で表されるアミノヒドロキシピリジニウム塩の製造方法。
［１３］［１０］において、前記式（４）で表されるアラルキルオキシピリジン化合物を、酸と反応させる際に、さらに水を共存させる［１０］に記載のアミノヒドロキシピリジニウム塩の製造方法。
［１４］［１０］において、前記式（５）で表されるアミノアラルキルオキシピリジニウム塩を接触水素化させた後、得られた反応液に水を添加する［１０］に記載のアミノヒドロキシピリジニウム塩の製造方法。
［１５］前記酸が塩酸、臭化水素酸、硫酸、硝酸、リン酸、トリフルオロ酢酸、メタンスルホン酸、ｐ−トルエンスルホン酸及び酢酸からなる群より選ばれる少なくとも１種の酸である［１０］〜［１４］のいずれかに記載のアミノヒドロキシピリジニウム塩の製造方法。
［１６］前記水素化触媒がＰｄ／Ｃである［１０］〜［１５］のいずれかに記載のアミノヒドロキシピリジニウム塩の製造方法。
［１７］前記式（６）で表されるアミノヒドロキシピリジニウム塩を塩基で中和することを特徴とする式（８）：

(In the formula, PG and n are the same as described above.)
A method for producing an aminohydroxypyridinium salt represented by the formula (6), wherein the hydroxypyridine compound represented by the formula (6) is obtained, and the hydroxypyridine compound is further reacted with an acid.
[12] A process for producing an aminohydroxypyridinium salt represented by the formula (6), wherein the aralkyloxypyridine compound represented by the formula (4) is catalytically hydrogenated in the presence of an acid and a hydrogenation catalyst.
[13] The method for producing an aminohydroxypyridinium salt according to [10], wherein, when the aralkyloxypyridine compound represented by the formula (4) is reacted with an acid in [10], water is further allowed to coexist.
[14] The aminohydroxypyridinium salt according to [10], wherein the aminoaralkyloxypyridinium salt represented by the formula (5) is hydrogenated by contact, and then water is added to the resulting reaction solution. Manufacturing method.
[15] The acid is at least one acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and acetic acid. ] The manufacturing method of the aminohydroxy pyridinium salt in any one of [14].
[16] The process for producing an aminohydroxypyridinium salt according to any one of [10] to [15], wherein the hydrogenation catalyst is Pd / C.
[17] Formula (8), wherein the aminohydroxypyridinium salt represented by Formula (6) is neutralized with a base:

で表されるアミノヒドロキシピリジン化合物の製造方法。
［１８］前記式（５）で表されるアミノアラルキルオキシピリジニウム塩を塩基で中和して、式（９）：

The manufacturing method of the aminohydroxypyridine compound represented by these.
[18] The aminoaralkyloxypyridinium salt represented by the formula (5) is neutralized with a base to obtain the formula (9):

（Ｒ^１及びＲ^２は前記と同じ。）
で表されるアミノアラルキルオキシピリジン化合物を得、前記アミノアラルキルオキシピリジン化合物を、さらに水素化触媒存在下、接触水素化させる前記式（８）で表されるアミノヒドロキシピリジン化合物の製造方法。

(R ¹ and R ² are the same as above.)
A process for producing an aminohydroxypyridine compound represented by the formula (8), wherein the aminoaralkyloxypyridine compound represented by the formula (8) is obtained, and the aminoaralkyloxypyridine compound is further catalytically hydrogenated in the presence of a hydrogenation catalyst.

  According to the present invention, an aminohydroxypyridinium salt and an aminohydroxypyridine compound can be produced in high yield without using explosive hydroxylamine. Therefore, the present invention is very useful industrially.

  Hereinafter, the present invention will be specifically described.

The aminohydroxypyridinium salt represented by the formula (6) and the aminohydroxypyridine compound represented by the formula (8) are shown in the following reaction formula 1 having the aralkyloxypyridine compound represented by the formula (4) as an intermediate. It is manufactured by the manufacturing route. In the reaction formula, X, PG, R ¹ , R ² , A and n are the same as described above.

Reaction formula 1:

  First, the manufacturing method of the aralkyloxypyridine compound (henceforth an aralkyloxypyridine compound (4)) shown by Formula (4) is demonstrated. The aralkyloxypyridine compound (4) is a halopyridine compound represented by the formula (2) by protecting the amino group of the aminohalopyridine compound represented by the formula (1) (hereinafter referred to as the aminohalopyridine compound (1)). (Hereinafter referred to as halopyridine compound (2)) (hereinafter referred to as amino group protection reaction), and the halopyridine compound (2) is further represented by the formula (3) in the presence of a copper compound, an alkali metal compound and a ligand. It is obtained by reacting with an aralkyl alcohol compound (hereinafter referred to as aralkyl alcohol compound (3)) represented by the formula (hereinafter referred to as aralkyloxylation reaction).

  First, the amino group protecting reaction will be described.

  In formula (1), X is a halogen atom, preferably a chlorine atom, a bromine atom, or an iodine atom, more preferably a bromine atom or an iodine atom, and particularly preferably a bromine atom.

  As the aminohalopyridine compound (1), 2-amino-3-halopyridine compound, 2-amino-4-halopyridine compound, 2-amino-5-halopyridine compound, 2-amino-6-halopyridine compound, 3-amino- 2-halopyridine compound, 3-amino-4-halopyridine compound, 3-amino-5-halopyridine compound, 3-amino-6-halopyridine compound, 4-amino-2-halopyridine compound, 4-amino-3-halopyridine compound Preferably, it is a 2-amino-5-halopyridine compound.

  Specific examples of the aminohalopyridine compound (1) include 2-amino-3-chloropyridine, 2-amino-3-bromopyridine, 2-amino-3-iodopyridine, 2-amino-4-chloropyridine, 2 -Amino-4-bromopyridine, 2-amino-4-iodopyridine, 2-amino-5-chloropyridine, 2-amino-5-bromopyridine, 2-amino-5-iodopyridine, 2-amino-6- Chloropyridine, 2-amino-6-bromopyridine, 2-amino-6-iodopyridine, 2-amino-6-chloropyridine, 2-amino-6-bromopyridine, 2-amino-6-iodopyridine, 3- Amino-2-chloropyridine, 3-amino-2-bromopyridine, 3-amino-2-iodopyridine, 3-amino-4-chloropyridine, 3-amino 4-bromopyridine, 3-amino-4-iodopyridine 3-amino-5-chloropyridine, 3-amino-5-bromopyridine, 3-amino-5-iodopyridine, 3-amino-6-chloropyridine, 3 -Amino-6-bromopyridine, 3-amino-6-iodopyridine, 4-amino-2-chloropyridine, 4-amino-2-bromopyridine, 4-amino-2-iodopyridine, 4-amino-3- Examples include chloropyridine, 4-amino-3-bromopyridine, 4-amino-3-iodopyridine, preferably 2-amino-5-chloropyridine, 2-amino-5-bromopyridine, 2-amino-5- Iodopyridine, particularly preferably 2-amino-5-bromopyridine and 2-amino-5-iodopyridine.

  In the formula (2), X is the same as above, and PG is a t-butoxycarbonyl group, diphenylmethyl group, triphenylmethyl group, p-methoxyphenyldiphenylmethyl group, di (p-methoxyphenyl) phenylmethyl group. And preferably a diphenylmethyl group, a triphenylmethyl group, a p-methoxyphenyldiphenylmethyl group or a di (p-methoxyphenyl) phenylmethyl group, particularly preferably a triphenylmethyl group. n is an integer of 1 or 2.

  These protecting groups can be introduced by appropriately adopting methods described in the literature (Protecting Groups in Organic Chemistry 5th Edition, John Wiley and Sons, 2014 (Protecting Groups in Organic Chemistry Edition (John Wiley)). & Sons, Inc. 2014)).

  For example, when the amino protecting group is a triphenylmethyl group or t-butoxycarbonyl group, a triphenylmethylating agent such as triphenylmethyl chloride or triphenylmethyl bromide and an aminohalopyridine compound (1) It can be produced by reacting in a suitable solvent in the presence of a base compound such as dimethylaminopyridine.

  Specific examples of the halopyridine compound (2) include 2- (t-butoxycarbonyl) amino-5-chloropyridine, 2-di (t-butoxycarbonyl) amino-5-chloropyridine, 2- (diphenylmethyl) amino- 5-chloropyridine, 2- (triphenylmethyl) amino-5-chloropyridine, 2- (diphenylmethyleneamino) -5-chloropyridine, 2- (t-butoxycarbonyl) amino-5-bromopyridine, 2-di (T-Butoxycarbonyl) amino-5-bromopyridine, 2- (diphenylmethyl) amino-5-bromopyridine, 2- (triphenylmethyl) amino-5-bromopyridine, 2- (diphenylmethyleneamino) -5 Bromopyridine, 2- (t-butoxycarbonyl) amino-5-iodopyridine, 2-di (t Butoxycarbonyl) amino-5-iodopyridine, 2- (diphenylmethyl) amino-5-iodopyridine, 2- (triphenylmethyl) amino-5-iodopyridine, 2- (diphenylmethyleneamino) -5-iodopyridine, etc. Preferably, 2- (t-butoxycarbonyl) amino-5-chloropyridine, 2-di (t-butoxycarbonyl) amino-5-chloropyridine, 2- (triphenylmethyl) amino-5-chloropyridine 2- (t-butoxycarbonyl) amino-5-bromopyridine, 2-di (t-butoxycarbonyl) amino-5-bromopyridine, 2- (triphenylmethyl) amino-5-bromopyridine, 2- (t -Butoxycarbonyl) amino-5-iodopyridine, 2-di (t-butoxycarbonyl) Mino-5-iodopyridine and 2- (triphenylmethyl) amino-5-iodopyridine, more preferably 2- (triphenylmethyl) amino-5-chloropyridine and 2- (triphenylmethyl) amino-5 -Bromopyridine, 2- (triphenylmethyl) amino-5-iodopyridine, particularly preferably 2- (triphenylmethyl) amino-5-bromopyridine, 2- (triphenylmethyl) amino-5-iodopyridine .

  Next, the aralkyloxylation reaction will be described.

In formula (3), R ¹ is a hydrogen atom, an alkyl group or an alkoxy group, preferably a hydrogen atom. Specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group, and a methyl group is preferable. Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentoxy group, and a hexoxy group, and a methoxy group is preferable. R ² is a hydrogen atom or an alkyl group, preferably a hydrogen atom. Specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group, and a methyl group is preferable.

  Specific examples of the aralkyl alcohol compound (3) include benzyl alcohol, 4-methoxybenzyl alcohol, diphenyl alcohol and the like, preferably benzyl alcohol. The usage-amount of an aralkyl alcohol compound (3) is 1 mol or more normally normally with respect to 1 mol of halopyridine compounds (2), Preferably it is 1-15 mol, More preferably, it is 1-12 mol.

Examples of the copper compound used in the aralkyloxylation reaction include copper halide, copper oxide, copper nitrate, copper acetate, etc., preferably monovalent or divalent copper halide, particularly preferably 1. Valent copper halide. These copper compounds may use hydrates. Specific examples include CuI, CuBr, CuCl, CuCl ₂ · 2H ₂ O, Cu ₂ O, (CH ₃ COO) ₂ Cu · H ₂ O, and the like, and preferably CuI. The amount of the copper compound used is usually 0.01 mol or more, preferably 0.01 to 1 mol, particularly preferably 0.05 to 0.5 mol, per 1 mol of the halopyridine compound (2).

Examples of the alkali metal compound used in the aralkyloxylation reaction include Li ₂ CO ₃ , Li ₃ PO ₄ , K ₂ CO ₃ , K ₃ PO ₄ , Na ₂ CO ₃ , Na ₃ PO ₄ , and Cs ₂ CO _3. Preferably, it is a compound containing potassium such as K ₂ CO ₃ or K ₃ PO ₄ , and particularly preferably K ₂ CO ₃ . The amount of the alkali metal compound used is usually 0.5 mol or more, preferably 0.8 to 5 mol, particularly preferably 1 to 4 mol, relative to 1 mol of the halopyridine compound (2).

  As a ligand used in the aralkyloxylation reaction, a compound having a hetero atom capable of coordinating with a copper ion is used, preferably an organic compound having two or more nitrogen atoms, particularly preferably 1-alkyl. It is an imidazole compound. Specific examples of the ligand include 1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, 2,2′-bipyridyl, ethylenediamine, and N, N′-dimethylethylenediamine. , N, N′-tetramethylethylenediamine, 1-methylimidazole, 1-ethylimidazole, 1-butylimidazole and the like, preferably 1-methylimidazole, 1-ethylimidazole and 1-butylimidazole, particularly preferably. Is 1-methylimidazole. The usage-amount of a ligand is 0.1 mol or more normally with respect to 1 mol of halopyridine compounds (2), Preferably it is 0.1-5 mol.

  In the aralkyloxylation reaction, the aralkyl alcohol compound (3) or the ligand may be used as a reaction solvent as a solvent. Moreover, you may use a solvent separately. The solvent in the case of using a separate solvent is a solvent that can dissolve the halopyridine compound (2), and the solvent is not particularly limited as long as it does not affect the reaction. Specific examples include toluene, xylene, 1,4-dioxane, N, N-dimethylacetamide, and N-methyl-2-pyrrolidone. When using a solvent, the amount of the solvent used is usually 50 parts by weight or less, preferably 0.5 to 20 parts by weight.

  In the aralkyloxylation reaction, a phase transfer catalyst such as a tetraalkylammonium salt such as tetrabutylammonium bromide or a crown ether can be used as necessary. By using the phase transfer catalyst, generation of a by-product in which the halogen of the halopyridine compound (2) is replaced with hydrogen is suppressed, and the aralkyloxylation reaction is promoted.

  The reaction temperature of the aralkyloxylation reaction is usually 20 ° C. or higher, preferably 80 to 150 ° C.

  As a method for removing the aralkyloxypyridine compound (4) from the obtained reaction solution after completion of the reaction, for example, when the aralkyloxypyridine compound (4) is a crystal, after adding water and extracting with an organic solvent, The method of crystallizing is mentioned. When the aralkyloxypyridine compound (4) is an oil, a method of distillation after extraction with an organic solvent and a method of purification by contacting with an adsorbent such as silica gel can be used.

  Moreover, it is preferable to wash | clean the obtained reaction liquid with the aqueous solution of the compound which can be coordinated to copper. Examples of the aqueous solution of the compound capable of coordinating with copper include an aqueous ammonia solution and an aqueous ethylenediamine solution, and an aqueous ammonia solution is preferable. By washing the reaction solution with an aqueous solution of a compound capable of coordinating with copper, copper ions remaining in the reaction solution can be more efficiently removed. If a large amount of copper ions remain, it becomes a catalyst poison during the catalytic hydrogenation reaction described later, and the reaction may not proceed sufficiently.

In formula (4), PG, R ¹ , R ² and n are the same as described above. Specific examples of the aralkyloxypyridine compound (4) include 2- (t-butoxycarbonyl) amino-5-benzyloxypyridine, 2-di (t-butoxycarbonyl) amino-5-benzyloxypyridine, 2- (Diphenylmethyl) amino-5-benzyloxypyridine, 2- (triphenylmethyl) amino-5-benzyloxypyridine, 2- (diphenylmethyleneamino) -5-benzyloxypyridine and the like are preferable, and 2- ( t-butoxycarbonyl) amino-5-benzyloxypyridine, 2-di (t-butoxycarbonyl) amino-5-benzyloxypyridine, 2- (triphenylmethyl) amino-5-benzyloxypyridine, particularly preferred 2- (Triphenylmethyl) amino-5-benzyloxy It is a lysine.

  The aminohydroxypyridinium salt represented by formula (6) (hereinafter referred to as aminohydroxypyridinium salt (6)) can be produced by the following three methods.

  Method 1: The aralkyloxypyridine compound (4) is reacted with an acid to obtain an aminoaralkyloxypyridinium salt represented by the formula (5) (hereinafter referred to as aminoaralkyloxypyridinium salt (5)) (hereinafter referred to as “aralkyloxypyridinium salt (5)”). This reaction is referred to as deprotection reaction 1.) A method in which the aminoaralkyloxypyridinium salt (5) is further catalytically hydrogenated in the presence of a hydrogenation catalyst (hereinafter, this reaction is referred to as catalytic hydrogenation reaction 1).

  Method 2: The aralkyloxypyridine compound (4) is catalytically hydrogenated in the presence of a hydrogenation catalyst to obtain a hydroxypyridine compound represented by the formula (7) (hereinafter referred to as hydroxypyridine compound (7)) ( Hereinafter, this reaction is referred to as catalytic hydrogenation reaction 2), and the hydroxypyridine compound (7) is further reacted with an acid (hereinafter, this reaction is referred to as deprotection reaction 2).

  Method 3: A method in which the aralkyloxypyridine compound (4) is catalytically hydrogenated in the presence of an acid and a hydrogenation catalyst (hereinafter, this reaction is referred to as catalytic hydrogenation reaction 3).

  First, method 1 will be described.

In Formula (5), R ¹ and R ² are the same as described above, and A is an acid. The acid may be either an inorganic acid or an organic acid, but is preferably a Bronsted acid. Specifically, at least one acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and acetic acid is preferably used. Is hydrochloric acid or acetic acid, particularly preferably acetic acid.

  Specific examples of the aminoaralkyloxypyridinium salt (5) include 2-amino-5-benzyloxypyridine hydrochloride, 2-amino-5-benzyloxypyridine hydrobromide, 2-amino-5-benzyl. Oxypyridine sulfate, 2-amino-5-benzyloxypyridine nitrate, 2-amino-5-benzyloxypyridine phosphate, 2-amino-5-benzyloxypyridine trifluoroacetate, 2-amino-5-benzyl Examples include oxypyridine methanesulfonate, p-toluenesulfonate, 2-amino-5-benzyloxypyridine acetate, and 2-amino-5-benzyloxypyridine acetate is preferred.

  In formula (6), A is the same as described above. Specific examples of the aminohydroxypyridinium salt (6) include 2-amino-5-hydroxypyridinium hydrochloride, 2-amino-5-hydroxypyridinium hydrobromide, and 2-amino-5-hydroxypyridinium sulfate. 2-amino-5-hydroxypyridinium nitrate, 2-amino-5-hydroxypyridinium phosphate, 2-amino-5-hydroxypyridinium trifluoroacetate, 2-amino-5-hydroxypyridinium methanesulfonate, 2 -Amino-5-hydroxypyridinium p-toluenesulfonate 2-amino-5-hydroxypyridinium acetate etc. are mentioned, Preferably it is 2-amino-5-hydroxypyridinium acetate.

  In the deprotection reaction 1, the acid may be an acid represented by A of aminohydroxypyridinium salt (6). That is, the acid used may be either an inorganic acid or an organic acid, and a Bronsted acid is preferably used. Specifically, at least one acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and acetic acid is preferably used. Hydrochloric acid or acetic acid is used, and acetic acid is particularly preferably used. As the usage-amount of an acid, it is 1 mol or more normally with respect to 1 mol of aralkyloxypyridine compounds (4), Preferably it is 1-10 mol.

  In the deprotection reaction 1, the acid used may be used as a solvent, or a separate solvent may be used. In the case of using an acid as a solvent, acetic acid is preferably used. When a solvent is used separately, the solvent is not particularly limited as long as it does not affect the reaction, but an organic solvent is usually used. Examples of the organic solvent include toluene, methanol, tetrahydrofuran, etc., preferably toluene. As a usage-amount of a solvent, it is 50 weight part or less normally, Preferably it is 0.5-20 weight part.

  In the deprotection reaction 1, the reaction can be further promoted by allowing water to coexist in the reaction solution. When water is allowed to coexist, an acid may be used as an aqueous solution. The amount of water used in the presence of water is usually 1 mol or more, preferably 1 to 20 mol, particularly preferably 1 to 10 mol, per 1 mol of the aralkyloxypyridine compound (4).

  The reaction temperature of deprotection reaction 1 is usually 10 ° C. or higher, preferably 40 to 100 ° C.

  As a method for taking out the aminoaralkyloxypyridinium salt (5) after completion of the deprotection reaction 1, for example, water and an organic solvent are added to the reaction solution, and a by-product is extracted to the organic layer side to obtain aminoaralkyloxypyridinium. Examples include a method of concentrating the aqueous layer in which the salt (5) is dissolved, and a method of filtering the aminoaralkyloxypyridinium salt (5) precipitated in the reaction solution. From the viewpoint of efficiency, it is preferable that the aminoaralkyloxypyridinium salt (5) is used as it is in the catalytic hydrogenation reaction 1 without being isolated from the obtained reaction solution. Moreover, the obtained reaction liquid can also be used for the reaction 5a which is a manufacturing process of the aminoaralkyloxypyridine compound represented by the following formula (9).

  In the catalytic hydrogenation reaction 1, examples of the hydrogenation catalyst include a catalyst containing at least one transition metal selected from the group consisting of Pd, Pt, Rh, and Ni. Specific examples include Pd / C, Pt / C, Rh / C, and the like, preferably Pd / C. The amount of the hydrogenation catalyst used is usually 1% by weight or more, preferably 5 to 50% by weight, based on the aminoaralkyloxypyridinium salt (5). In addition, when the deprotection reaction 1 and the catalytic hydrogenation reaction 1 are performed continuously, the hydrogenation catalyst may be placed in the reaction vessel in advance when the deprotection reaction 1 is performed.

  The reaction temperature of the catalytic hydrogenation reaction 1 is usually 150 ° C. or lower, preferably 20 to 50 ° C. The hydrogen pressure of the catalytic hydrogenation reaction 1 is usually 10 MPa or less in absolute pressure, preferably 0.1 to 5 MPa. Since hydrogen is consumed as the catalytic hydrogenation proceeds, hydrogen is introduced into the reactor to maintain the hydrogen pressure, and the reaction is performed at the reaction temperature.

  In the catalytic hydrogenation reaction 1, a solvent may be used as necessary. The solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include alcohol solvents such as methanol, ethanol and propanol, ethyl acetate, toluene, hexane and the like, preferably methanol. You may use these in mixture of 2 or more types. After completion of the deprotection reaction 1, when the catalytic hydrogenation reaction 1 is carried out continuously without removing the aminoaralkyloxypyridinium salt (5) from the reaction solution, the solvent used in the deprotection reaction 1 is used as it is. It may be used as As a usage-amount of a solvent, it is 50 weight part or less normally, Preferably it is 0.5-20 weight part.

  As a method for removing the aminohydroxypyridinium salt (6) from the obtained reaction liquid after completion of the catalytic hydrogenation reaction 1, for example, the catalyst is filtered off from the obtained reaction liquid, the filtrate is concentrated, and toluene is added thereto. A method of putting an organic solvent such as methyl-t-butyl ether and cooling and precipitating the aminohydroxypyridinium salt (6) and then filtering the precipitated crystals. Moreover, the purity can be improved by filtering the precipitated crystals and further washing with a hydrocarbon solvent or the like.

  After the completion of the deprotection reaction 1, when the catalytic hydrogenation reaction 1 is carried out continuously without taking out the aminoaralkyloxypyridinium salt (5) from the reaction solution, after the catalytic hydrogenation reaction 1 is completed, It is preferable to perform filtration after adding water. In the reaction, an aralkyloxypyridine compound (4) in which the group represented by PG in the formula (4) is a diphenylmethyl group, a triphenylmethyl group, a p-methoxyphenyldiphenylmethyl group or a di (p-methoxyphenyl) phenylmethyl group is reacted. When used, diphenyl alcohol, triphenylmethyl alcohol, p-methoxyphenyl diphenylmethyl alcohol, or di (p-methoxyphenyl) phenylmethyl alcohol produced in the deprotection reaction 1 is precipitated by adding water, and filtered for efficiency. Can be removed.

  Next, method 2 will be described.

  In formula (7), PG and n are the same as described above. Specific examples of the hydroxypyridine compound (7) include 2- (t-butoxycarbonyl) amino-5-hydroxypyridine, 2-di (t-butoxycarbonyl) amino-5-hydroxypyridine, and 2- (diphenylmethyl). ) Amino-5-hydroxypyridine, 2- (triphenylmethyl) amino-5-hydroxypyridine, 2- (diphenylmethyleneamino) -5-hydroxypyridine and the like, preferably 2- (t-butoxycarbonyl) amino -5-hydroxypyridine, 2-di (t-butoxycarbonyl) amino-5-hydroxypyridine, 2- (triphenylmethyl) amino-5-hydroxypyridine, particularly preferably 2- (triphenylmethyl) amino- 5-hydroxypyridine.

  In the catalytic hydrogenation reaction 2, examples of the hydrogenation catalyst include a catalyst containing at least one transition metal selected from the group consisting of Pd, Pt, Rh, and Ni. Specific examples include Pd / C, Pt / C, Rh / C, and the like, preferably Pd / C. The amount of the hydrogenation catalyst used is usually 1% by weight or more, preferably 5 to 50% by weight, based on the dry weight of the aralkyloxypyridine compound (4).

  The reaction temperature of the catalytic hydrogenation reaction 2 is usually 150 ° C. or lower, preferably 20 to 50 ° C. The hydrogen pressure in the catalytic hydrogenation reaction 2 is usually 10 MPa or less in absolute pressure, preferably 0.1 to 5 MPa. Since hydrogen is consumed as the catalytic hydrogenation proceeds, hydrogen is introduced into the reactor to maintain the hydrogen pressure, and the reaction is performed at the reaction temperature.

  In the catalytic hydrogenation reaction 2, a solvent may be used as necessary. The solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include alcohol solvents such as methanol, ethanol and propanol, ethyl acetate, toluene, hexane and the like, preferably methanol. You may use these in mixture of 2 or more types.

  Examples of the method for removing the hydroxypyridine compound (7) from the obtained reaction solution after completion of the catalytic hydrogenation reaction 2 include a method of filtering the catalyst from the obtained reaction solution and concentrating the filtrate. Moreover, the purity can be improved by filtering the precipitated crystal and then washing it with a hydrocarbon solvent. Moreover, after the completion of the catalytic hydrogenation reaction 2, the deprotection reaction 2 may be continuously performed without taking out the hydroxypyridine compound (7) from the obtained reaction solution.

  In the deprotection reaction 2, the acid represented by A of the aminohydroxypyridinium salt (6) may be used for the reaction. That is, the acid used may be either an inorganic acid or an organic acid, and Bronsted. An acid is preferably used. Specifically, at least one acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and acetic acid is preferably used. Hydrochloric acid or acetic acid is used, and acetic acid is particularly preferably used. As the usage-amount of an acid, it is 1 mol or more normally with respect to 1 mol of hydroxypyridine compounds (7), Preferably it is 1-10 mol.

  In the deprotection reaction 2, the acid to be used may be used as a solvent, or a separate solvent may be used. In the case of using an acid as a solvent, acetic acid is preferably used. When a solvent is used separately, the solvent is not particularly limited as long as it does not affect the reaction, but an organic solvent is usually used. Examples of the organic solvent include toluene, methanol, tetrahydrofuran, etc., preferably toluene. As a usage-amount of a solvent, it is 50 weight part or less normally, Preferably it is 0.5-20 weight part.

  In the deprotection reaction 2, the reaction can be further promoted by coexisting water. When water is allowed to coexist, an acid may be used as an aqueous solution. The amount of water used in the presence of water is usually 1 mol or more, preferably 1 to 20 mol, particularly preferably 1 to 10 mol, per 1 mol of the hydroxypyridine compound (7).

  The reaction temperature of the deprotection reaction 2 is usually 10 ° C or higher, preferably 40 to 100 ° C.

  Examples of the method for removing the aminohydroxypyridinium salt (6) after completion of the deprotection reaction 2 include a method of filtering the aminohydroxypyridinium salt (6) deposited in the obtained reaction solution. When the deprotection reaction 2 was carried out continuously without removing the hydroxypyridine compound (7) from the obtained reaction solution after the completion of the catalytic hydrogenation reaction 2, the catalyst was filtered off from the obtained reaction solution, A method of concentrating the filtrate, adding an organic solvent such as toluene, methyl-t-butyl ether, and cooling to precipitate the aminohydroxypyridinium salt (6), followed by filtering the precipitated crystals. Moreover, it is preferable to add water to the reaction solution after completion of the reaction and perform filtration. A hydroxypyridine compound (7) in which the group represented by PG in the formula (7) is a diphenylmethyl group, a triphenylmethyl group, a p-methoxyphenyldiphenylmethyl group or a di (p-methoxyphenyl) phenylmethyl group is used for the reaction. In this case, diphenyl alcohol, triphenylmethyl alcohol, p-methoxyphenyl diphenylmethyl alcohol, or di (p-methoxyphenyl) phenylmethyl alcohol generated in the deprotection reaction 2 is precipitated by adding water, and is filtered efficiently. Can be removed.

  Method 3 will be described.

  In the catalytic hydrogenation reaction 3, an acid represented by A of aminohydroxypyridinium salt (6) may be used for the reaction. That is, the acid used may be either an inorganic acid or an organic acid. Sted acid is preferably used. Specifically, at least one acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and acetic acid is preferably used. Hydrochloric acid or acetic acid is used, and acetic acid is particularly preferably used. As the usage-amount of an acid, it is 1 mol or more normally with respect to 1 mol of aralkyloxypyridine compounds (4), Preferably it is 1-10 mol.

  In the catalytic hydrogenation reaction 3, examples of the hydrogenation catalyst include a catalyst containing at least one transition metal selected from the group consisting of Pd, Pt, Rh, and Ni. Specific examples include Pd / C, Pt / C, Rh / C, and the like, preferably Pd / C. The amount of the hydrogenation catalyst used is usually 1% by weight or more, preferably 5 to 50% by weight, based on the dry weight of the aralkyloxypyridine compound (4).

  The reaction temperature of the catalytic hydrogenation reaction 3 is usually 150 ° C. or lower, preferably 20 to 50 ° C. The hydrogen pressure of the catalytic hydrogenation reaction 3 is usually 10 MPa or less in absolute pressure, preferably 0.1 to 5 MPa. Since hydrogen is consumed as the catalytic hydrogenation proceeds, hydrogen is introduced into the reactor to maintain the hydrogen pressure, and the reaction is performed at the reaction temperature.

  In the catalytic hydrogenation reaction 3, the acid used may be a solvent, but a solvent may be used separately. When a solvent is used, the solvent is not particularly limited as long as it does not affect the reaction, but usually water or an organic solvent is used. Examples of the organic solvent include alcohol solvents such as methanol, ethanol and propanol, ethyl acetate, toluene, hexane and the like, preferably toluene. Two or more of these may be mixed. The amount of the solvent used is usually 50 parts by weight or less, preferably 0.5 to 20 parts by weight, based on the hydroxypyridine compound (7).

  In the catalytic hydrogenation reaction 3, the reaction can be promoted by further coexisting water. The amount of water used in the presence of water is usually 0.1 mol or more, preferably 1 to 20 mol, particularly preferably 1 to 10 mol, per 1 mol of the hydroxypyridine compound (7).

  As a method for removing the aminohydroxypyridinium salt (6) from the obtained reaction liquid after the catalytic hydrogenation reaction 3 is completed, for example, the catalyst is filtered off from the obtained reaction liquid, the filtrate is concentrated, and toluene is added thereto. A method of putting an organic solvent such as methyl-t-butyl ether and cooling and precipitating the aminohydroxypyridinium salt (6) and then filtering the precipitated crystals. Purity can be improved by filtering the precipitated crystals and further washing with a hydrocarbon solvent. Moreover, it is preferable to filter after adding water to the obtained reaction liquid. Aralkyloxypyridine in which the group represented by PG in formula (4) is a diphenylmethyl group, a triphenylmethyl group, a p-methoxyphenyldiphenylmethyl group or a di (p-methoxyphenyl) phenylmethyl group by adding water When compound (4) is used in the reaction, diphenyl alcohol, triphenylmethyl alcohol, p-methoxyphenyldiphenylmethyl alcohol, and di (p-methoxyphenyl) phenylmethyl alcohol generated in catalytic hydrogenation reaction 3 are precipitated by adding water. And can be efficiently removed by filtration.

  The aminohydroxypyridine compound represented by the formula (8) (hereinafter referred to as aminohydroxypyridine compound (8)) can be produced by the following two methods.

  Method 4: Method of neutralizing aminohydroxypyridinium salt (6) with a base

  Method 5: An aminoaralkyloxypyridinium salt (5), which is an intermediate of Method 1, is neutralized with a base (hereinafter referred to as reaction 5a), and an aminoaralkyloxypyridine compound represented by formula (9) (hereinafter referred to as “reaction 5a”). And an aminoaralkyloxypyridine compound (9)), and the aminoaralkyloxypyridine compound (9) is further reacted with hydrogen in the presence of a hydrogenation catalyst (hereinafter referred to as reaction 5b).

  Specific examples of the aminohydroxypyridine compound (8) include 2-amino-3-hydroxypyridine, 2-amino-4-hydroxypyridine, 2-amino-5-hydroxypyridine, and preferably 2-amino -5-hydroxypyridine.

  First, method 4 will be described.

  The base is not particularly limited as long as the aminohydroxypyridinium salt (6) can be neutralized, and may be an inorganic base or an organic base, but an inorganic base is preferably used from the viewpoint of purification. Is done. Examples of the base include potassium hydroxide, sodium hydroxide, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, ammonia, sodium methoxide and the like, preferably sodium hydroxide and sodium methoxide. The base may be used as a solid or as a solution dissolved in a solvent such as water. As the usage-amount of a base, it is 1 mol normally with respect to 1 mol of amino hydroxy pyridinium salts (6). When the amount of the base is small, neutralization becomes insufficient, and when the base is used in excess, the deprotonation of the hydroxyl group of the aminohydroxypyridine compound (8) occurs, which is not preferable.

  As the solvent, water or an alcohol solvent can be usually used. Water, methanol, and ethanol are preferable. The amount of the solvent used is usually 50 parts by weight or less, preferably 0.5 to 20 parts by weight, based on the aminohydroxypyridinium salt (6).

  As reaction temperature, it is 0 degreeC or more normally, Preferably it is 10-40 degreeC.

  After completion of the reaction, the aminohydroxypyridine compound (8) can be extracted by, for example, extracting the reaction solution with an organic solvent and then concentrating, filtering off the inorganic salt precipitated in the reaction solution, and concentrating the filtrate. Etc.

  Method 5 will be described.

In formula (9), R ¹ and R ² are the same as described above. Specific examples of the aminoaralkyloxypyridine compound (9) include 2-amino-5-benzyloxypyridine, and 2-amino-5-benzyloxypyridine is preferable.

  The aminoaralkyloxypyridinium salt (5) used in the reaction 5a may be the one isolated at the end of the deprotection reaction 1, or the reaction solution of the deprotection reaction 1 may be used as it is. From this point of view, it is preferable to use the reaction solution of deprotection reaction 1 as it is.

  The base used in the reaction 5a is not particularly limited as long as the acid of the aminoaralkyloxypyridinium salt (5) can be neutralized, but an inorganic base is preferably used, and a base containing an alkali metal atom is more preferably used. . Examples of the base include potassium hydroxide, sodium hydroxide, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, ammonia, sodium methoxide and the like, preferably sodium hydroxide and sodium methoxide. The base may be used as a solid or as a solution dissolved in a solvent such as water. The amount of the base used is not particularly limited as long as the aminoaralkyloxypyridinium salt (5) can be neutralized. In the reaction 5a, when the reaction solution of the deprotection reaction 1 is used as a raw material as it is, an excess acid may be present in the reaction solution of the deprotection reaction 1. In that case, an amount of base that can neutralize an excess of acid may be used in the reaction solution of deprotection reaction 1.

  As the solvent used in the reaction 5a, water is used. The amount of the solvent used is usually 50 parts by weight or less, preferably 1 to 20 parts by weight, based on the aminoaralkyloxypyridinium salt (5).

  Examples of the method for taking out the aminoaralkyloxypyridine compound (9) after completion of the reaction 5a include a method of adding an organic solvent such as toluene to the obtained reaction solution for extraction, and concentrating the organic layer.

  Examples of the hydrogenation catalyst used in the reaction 5b include a catalyst containing at least one transition metal selected from the group consisting of Pd, Pt, Rh, and Ni. Specific examples include Pd / C, Pt / C, Rh / C, and the like, preferably Pd / C. The use amount of the hydrogenation catalyst is usually 1% by weight or more, preferably 5 to 50% by weight, based on the aminoaralkyloxypyridine compound (9).

  The reaction temperature for reaction 5b is usually 150 ° C. or lower, preferably 20 to 50 ° C. The hydrogen pressure of the reaction 5b is usually 10 MPa or less in absolute pressure, and preferably 0.1 to 5 MPa. Since hydrogen is consumed as the catalytic hydrogenation proceeds, hydrogen is introduced into the reactor to maintain the hydrogen pressure, and the reaction is performed at the reaction temperature.

  In reaction 5b, a separate solvent may be used. When a solvent is used, the solvent is not particularly limited as long as it does not affect the reaction, but an organic solvent is usually used. Examples of the organic solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ethyl acetate and toluene, and methanol and ethanol are preferable. Two or more of these may be mixed. The amount of the solvent to be used is usually 50 parts by weight or less, preferably 0.5 to 20 parts by weight, based on the aminoaralkyloxypyridine compound (9).

  Examples of the method for removing the aminohydroxypyridine compound (8) from the obtained reaction solution after completion of the reaction 5b include a method of filtering the catalyst from the obtained reaction solution and concentrating the obtained filtrate.

  Moreover, an acid can also be added to the obtained reaction liquid and it can also take out as aminohydroxy pyridinium salt (6). In this case, an organic solvent such as toluene or methyl-t-butyl ether is added and cooled to precipitate the aminohydroxypyridinium salt (6), followed by filtration to remove the aminohydroxypyridinium salt (6) from the reaction solution. .

The present invention will be specifically described below based on examples. However, the present invention is not limited by these examples. In the following examples, hydrogen nuclear magnetic resonance (hereinafter abbreviated as ¹ H NMR) spectrum measurement and high performance liquid chromatography (hereinafter abbreviated as HPLC) analysis were performed under the following conditions.
(1) ¹ H NMR spectrum measurement:
・ Device: JEOL Nuclear Magnetic Resonance Device “AL-400”
Solvent: CDCl ₃ , THF-d ₈ or DMSO-d ₆
・ Measurement frequency: 400MHz
(2) HPLC analysis:
・ Apparatus: Liquid chromatograph “LC-20AD” manufactured by Shimadzu Corporation
Column: SUMPAX ODS Z-CLUE (length 50 mm, inner diameter 3.0
mm, particle diameter 2.0 μm)
・ Mobile phase:
A: 0.1% acetic acid aqueous solution B: acetonitrile for LC = 60: 40
(Gradient)
0 min. A: B = 50: 50
0.5 min. A: B = 50: 50
5.0 min. A: B = 5: 95
10 min. A: B = 5: 95
10.01 min. A: B = 50: 50
・ Detector: UV254nm
-Column temperature: 40 ° C
・ Flow rate: 1.0 ml / min ・ Analysis time: 13 minutes ・ Measurement method: area percentage method

Example 1-1
2-amino-5-bromopyridine (622.0 g, 3.595 mol), toluene (3740 g), triphenylchloromethane (1050 g, 3.766 mol) were mixed, and triethylamine (398.0 g, 3.933 mol) was mixed. ) Was added dropwise at 25 ° C., then the temperature was raised to 80 ° C. and reacted for 7 hours. After completion of the reaction, toluene (1240 g), ion-exchanged water (933 g), 48% aqueous sodium hydroxide solution (89.8 g, 1.08 mol) were added at 80 ° C., and the organic layer was separated by a liquid separation operation. The layer was washed twice with ion exchange water (1860 g). The organic layer was concentrated to 2.96 kg, n-heptane (3730 g) was added dropwise at 80 ° C., and the mixture was cooled to 20 ° C. The precipitated crystals were filtered, and the crystals obtained with n-heptane (971 g) were washed and then dried to obtain 2-triphenylmethylamino-5-bromopyridine (1398 g, 3.366 mol) ( Yield 94%).

The ¹ H NMR spectrum data of 2-triphenylmethylamino-5-bromopyridine is shown below.

¹ H NMR (CDCl ₃ ) δ (ppm): 8.06 (d, 1H, J = 2.4 Hz), 7.33-7.16 (m, 15H), 7.10 (dd, 1H, J = 2.4, 8.8 Hz), 6.15 (s, 1H), 5.74 (dd, 1H, J = 0.4, 9.2 Hz)

Example 1-2
2-amino-5-iodopyridine (6.60 g, 30.0 mmol), dichloromethane (318 g), triphenylchloromethane (9.20 g, 33.0 mmol) were mixed, and triethylamine (3.34 g, 33.33). 0 mmol) was added dropwise at 25 ° C., followed by reaction at 25 ° C. for 24 hours. After completion of the reaction, ion-exchanged water (194 g) was added, the organic layer was separated by a liquid separation operation, and the organic layer was washed twice with a 5% aqueous sodium hydrogen carbonate solution (100 g). The organic layer was concentrated to obtain 14.0 g of a residue, and then toluene (45.8 g) was added to the residue and dissolved at 60 ° C. Methanol (109 g) was added dropwise and cooled to 20 ° C. The precipitated crystals were filtered, washed with n-heptane (971 g), and dried to give 2-triphenylmethylamino-5-iodopyridine (10.96 g, 23.7 mmol) (yield). 79%).

The ¹ H NMR spectrum data of 2-triphenylmethylamino-5-iodopyridine is shown below.

¹ H NMR (CDCl ₃ ) δ (ppm): 8.17 (d, 1H, J = 2.0 Hz), 7.32-7.22 (m, 16H), 6.18 (s, 1H), 5.67 (d, 1H, J = 8.8 Hz)

Example 2-1
2-triphenylmethylamino-5-bromopyridine (30.0 g, 72.2 mmol), potassium carbonate (30.0 g, 217 mmol), copper iodide (2.75 g, 14.4 mmol), tetrabutylammonium Bromide (3.00 g, 9.31 mmol), benzyl alcohol (48.1 g, 447 mmol) and 1-methylimidazole (11.9 g, 145 mmol) were mixed and reacted at 120 ° C. for 48 hours in a nitrogen atmosphere. It was. After the reaction, the reaction solution was analyzed by HPLC. As a result, peak area ratios of 3-triphenylmethylamino-5-benzyloxypyridine, 2-triphenylmethylamino-5-bromopyridine and 2-triphenylmethylaminopyridine (three components) Ratio) were 97.0%, 0.9% and 2.1%, respectively. Toluene (57.9 g), ion-exchanged water (28.9 g) and 28% aqueous ammonia (57.9 g) were added to the reaction solution to dissolve inorganic substances. The organic layer was separated by a liquid separation operation, toluene (28.6 g) was added, and the mixture was washed 4 times with 7% aqueous ammonia (114 g). The organic layer was concentrated to 60.7 g, methanol (84.6 g) was added at 50 ° C., seed crystals were added, and ion-exchanged water (83.9 g) was added dropwise, and then cooled to 25 ° C. The precipitated crystals were filtered, washed with methanol (112.1 g), and dried to give 2-triphenylmethylamino-5-benzyloxypyridine (24.2 g, 54.7 mmol) (yield). (Rate 76%). When the obtained 2-amino-5-hydroxypyridine acetate was quantitatively analyzed for copper atoms by inductively coupled plasma emission spectrometry (hereinafter abbreviated as ICP), the copper content was 0.03% by weight.

The ¹ H NMR spectrum data of 2-triphenylmethylamino-5-benzyloxypyridine is shown below.

¹ H NMR (CDCl ₃ ) δ (ppm): 7.83 (d, 1H, J = 3.2 Hz), 7.37-7.19 (m, 20H), 6.76 (dd, 1H, J = 3.2, 9.2 Hz), 5.87 (s, 1H), 5.81 (d, 1H, J = 9.2 Hz), 4.90 (s, 2H)

Example 2-2
2-Triphenylmethylamino-5-bromopyridine (31.6 g, 76.0 mmol), potassium carbonate (31.5 g, 228 mmol), copper iodide (2.89 g, 15.2 mmol), tetrabutylammonium Bromide (3.16 g, 9.8 mmol), benzyl alcohol (49.3 g, 456 mmol) and 1-methylimidazole (12.5 g, 152 mmol) were mixed and reacted at 120 ° C. for 70 hours under a nitrogen atmosphere. It was. After the reaction, the reaction solution was analyzed by HPLC. As a result, peak area ratios of 3-triphenylmethylamino-5-benzyloxypyridine, 2-triphenylmethylamino-5-bromopyridine and 2-triphenylmethylaminopyridine (three components) Ratio) were 96.0%, 1.3%, and 2.7%, respectively. Ion exchanged water (63 g) was added to the reaction solution and stirred at 50 ° C., and the aqueous layer was removed by liquid separation. The organic layer was filtered, toluene (62 g) was added, washed twice with a 3.2% aqueous acetic acid solution (97 g), and then washed with ion-exchanged water (94 g). The obtained organic layer was concentrated to obtain 62 g of a residue. Methanol (94.5 g) was added dropwise thereto to precipitate crystals, cooled to 0 ° C. and filtered. The obtained crystals were washed with cold methanol, and the washed crystals were dried to obtain 2-triphenylmethylamino-5-benzyloxypyridine (21.5 g, 48.6 mmol) (yield 64%). ). When the obtained 2-amino-5-hydroxypyridine was analyzed by ICP, the copper content was 1.0% by weight.

Example 2-3
2-triphenylmethylamino-5-bromopyridine (0.207 g, 0.50 mmol), cesium carbonate (0.231 g, 0.70 mmol), copper iodide (9.5 mg, 0.050 mmol), benzyl Alcohol (0.541 g, 5.0 mmol) and 1,10-phenanthroline anhydride (19 mg, 0.10 mmol) were mixed and reacted at 140 ° C. for 9 hours under a nitrogen atmosphere. After the reaction, the reaction solution was analyzed by HPLC. As a result, peak area ratios of 3-triphenylmethylamino-5-benzyloxypyridine, 2-triphenylmethylamino-5-bromopyridine and 2-triphenylmethylaminopyridine (three components) Ratio) were 95.6%, 3.8% and 0.5%, respectively.

Example 2-4
The same procedure as in Example 2-3 was performed except that cesium carbonate was changed to potassium carbonate (0.097 g, 0.70 mmol) and the reaction time was changed to 18 hours. After the reaction, the reaction solution was analyzed by HPLC. As a result, peak area ratios of 3-triphenylmethylamino-5-benzyloxypyridine, 2-triphenylmethylamino-5-bromopyridine and 2-triphenylmethylaminopyridine (three components) Ratio) were 83.3%, 9.7%, and 7.0%, respectively.

Example 2-5
2-triphenylmethylamino-5-bromopyridine (0.415 g, 1.0 mmol), potassium carbonate (0.41 g, 3.0 mmol), copper iodide (38 mg, 0.20 mmol), benzyl alcohol ( 1.08 g, 10 mmol) and 1,10-phenanthroline monohydrate (40 mg, 0.20 mmol) were mixed and reacted at 120 ° C. for 22 hours under a nitrogen atmosphere. After the reaction, the reaction solution was analyzed by HPLC. As a result, peak area ratios of 3-triphenylmethylamino-5-benzyloxypyridine, 2-triphenylmethylamino-5-bromopyridine and 2-triphenylmethylaminopyridine (three components) Ratio) were 97.2%, 2.0% and 0.8%, respectively.

Example 2-6
Example 2-5 was the same as Example 2-5 except that 1,10-phenanthroline monohydrate was changed to 1-methylimidazole (0.164 g, 2.0 mmol) and the reaction time was 18 hours. Went to. After the reaction, the reaction solution was analyzed by HPLC. As a result, peak area ratios of 3-triphenylmethylamino-5-benzyloxypyridine, 2-triphenylmethylamino-5-bromopyridine and 2-triphenylmethylaminopyridine (three components) Ratio) were 92.6%, 5.8% and 1.6%, respectively.

Example 2-7
The same operation as in Example 2-6 except that 1-methylimidazole was changed to 1-butylimidazole (0.248 g, 2.0 mmol) in Example 2-6. After the reaction, the reaction solution was analyzed by HPLC. As a result, peak area ratios of 3-triphenylmethylamino-5-benzyloxypyridine, 2-triphenylmethylamino-5-bromopyridine and 2-triphenylmethylaminopyridine (three components) Ratio) were 92.0%, 6.5% and 1.5%, respectively.

Example 2-8
2-triphenylmethylamino-5-iodopyridine (2.72 g, 5.88 mmol), cesium carbonate (2.69 g, 8.3 mmol), copper iodide (0.11 g, 0.59 mmol), benzyl Alcohol (1.27 g, 11.7 mmol), 1,10-phenanthroline anhydride (0.21 g, 1.16 mmol) and 5.1 g of toluene were mixed and reacted at 110 ° C. for 21 hours in a nitrogen atmosphere. . After the reaction, the reaction mixture was analyzed by HPLC. As a result, peak area ratios of 3-triphenylmethylamino-5-benzyloxypyridine, 2-triphenylmethylamino-5-iodopyridine and 2-triphenylmethylaminopyridine (three components) Ratio) were 84.8%, 9.2%, and 6.0%, respectively. Toluene (2.6 g) was added to the resulting reaction solution, the solid was filtered, and the filtrate was concentrated to obtain 3.4 g of a residue. Toluene (3.4 g) was added to the residue, dissolved in toluene at 50 ° C., cooled to 25 ° C., methanol (15.9 g) was added, and the mixture was cooled to 0 ° C. to precipitate crystals. The precipitated crystals were filtered, washed with methanol (11.8 g), and dried to give 2-triphenylmethylamino-5-benzyloxypyridine (1.94 g, 4.38 mmol) ( Yield 74%).

Example 3-1
2-Triphenylmethylamino-5-benzyloxypyridine (30.0 g, 67.8 mmol, copper content: 0.03%), acetic acid (150 g), ion-exchanged water (12.4 g), 5% Pd / C (3.32 g, water content 55%) was charged into an autoclave, heated to 70 ° C. under a nitrogen atmosphere, and reacted for 1 hour. After cooling the reaction solution to 25 ° C., the reaction was carried out for 3 hours while introducing hydrogen at 0.2 MPa (absolute pressure). After completion of the reaction, ion exchange water (105 g) was added, the solid was filtered, and the residue was washed with ion exchange water (30.1 g). The filtrate was concentrated, and toluene was added thereto for azeotropic dehydration. The concentrated residue (38.7 g) was heated to 60 ° C., and toluene (147 g) was added dropwise, followed by cooling to 20 ° C. . The precipitated crystals were filtered, washed with toluene (15.8 g), and then dried under a nitrogen stream to obtain 2-amino-5-hydroxypyridine acetate (8.47 g, 49.8 mmol) (yield) 75%).

The ¹ H NMR spectrum data of 2-amino-5-hydroxypyridine acetate is shown below.

¹ H NMR (DMSO-d ₆ ) δ (ppm): 7.50 (d, 1H, J = 2.8 Hz), 6.91 (dd, 1H, J = 2.4, 8.4 Hz), 6.34 (d, 1H, J = 8.8 Hz), 5.22 (brs, 2H), 1.91 (s, 3H)

Example 3-2
2-Triphenylmethylamino-5-benzyloxypyridine (2.00 g, 4.52 mmol, copper content: 0.03%), tetrahydrofuran (3.0 g), 5% Pd / C (0.22 g, water content) The reaction was carried out at 25 ° C. under a hydrogen atmosphere (1 atm) for 4.5 hours. After completion of the reaction, ion exchange water (105 g) was added, Pd / C was filtered, and the residue was washed with tetrahydrofuran (2.0 g). The obtained filtrate was concentrated to give 2-triphenylmethylamino-5-hydroxypyridine (1.55 g, 4.40 mmol) (yield 97%).

The ¹ H NMR spectrum data of 2-triphenylmethylamino-5-hydroxypyridine is shown below.

¹ H NMR (THF-d ₈ ) δ (ppm): 7.52 (s, 1H), 7.50 (d, 1H, J = 2.8 Hz), 7.37-7.34 (m, 6H) ), 7.22-7.11 (m, 9H), 6.54 (dd, 1H, J = 3.2, 8.8 Hz), 6.01 (s, 1H), 5.87 (d, 1H, J = 8.8 Hz)

  The obtained 2-triphenylmethylamino-5-hydroxypyridine (0.25 g, 0.709 mmol), acetic acid (1.26 g), and ion-exchanged water (0.15 g) were charged into an autoclave, and 70 ° C. under a nitrogen atmosphere. The temperature was raised to 1, and the reaction was carried out for 1 hour. After cooling to 25 ° C., ion-exchanged water (2.05 g) was added and stirred, the precipitated solid was filtered, and the residue was washed with ion-exchanged water. The obtained filtrate was concentrated to give 2-amino-5-hydroxypyridine acetate (0.11 g, 0.646 mmol) (yield 91%).

Example 3-3
2-Triphenylmethylamino-5-benzyloxypyridine (0.92 g, 2.08 mmol, copper content: 0.03%), acetic acid (4.6 g), 5% Pd / C (0.21 g, water content) The reaction was carried out in a hydrogen atmosphere (1 atm) at 25 ° C. for 18.5 hours. After completion of the reaction, the solid was filtered and the residue was washed with acetic acid (19.6 g). The filtrate was concentrated, acetic acid (1.35 g) was added to the resulting concentrated residue (0.71 g) and stirred, and methyl-t-butyl ether (5.6 g) was added dropwise to precipitate crystals. The precipitated crystals were filtered and washed with methyl-t-butyl ether (1.4 g). The crystal after washing was dried to obtain 2-amino-5-hydroxypyridine acetate (0.22 g, 1.29 mmol) (yield 62%).

Example 4
2-Triphenylmethylamino-5-benzyloxypyridine (108.4 g, 0.25 mol, copper content: 0.03%), acetic acid (147.1 g, 2.45 mol) were charged, and the atmosphere was 70 under a nitrogen atmosphere. The temperature was raised to ° C. Ion exchange water (44.1 g) was added dropwise thereto and reacted for 1 hour. After completion of the reaction, the reaction mixture was cooled to 25 ° C., ion-exchanged water (208 g) was added and stirred. The solid precipitated in the obtained reaction solution was filtered, and the residue was washed with ion-exchanged water. Toluene (217 g) was added to the filtrate, 48% aqueous sodium hydroxide solution (197.9 g) and acetic acid (0.5 g) were added to adjust the pH of the aqueous layer to 8.8, and then the organic layer and aqueous layer Was separated. The organic layer was washed with ion-exchanged water (218 g) and then concentrated to obtain a toluene solution of 2-amino-5-benzyloxypyridine (331 g) (2-amino-5-benzyloxypyridine 47.2 g, 0 .236 mol).

  The obtained toluene solution (331 g) of 2-amino-5-benzyloxypyridine, ethanol (217 g) and 10% Pd / C (2.28 g, water content 53%) were charged into an autoclave and 0.2 MPa in a hydrogen atmosphere. The reaction was carried out at 25 ° C. for 4 hours while introducing at (absolute pressure). After completion of the reaction, Pd / C was filtered and the residue was washed with ethanol (76 g). The obtained filtrate was dried under reduced pressure to obtain 2-amino-5-hydroxypyridine (25.6 g, 0.23 mol) (yield 92%).

Claims (18)

Formula (1):

(In the formula, X represents a halogen atom.)
Protecting the amino group of the aminohalopyridine compound represented by formula (2):

(In the formula, PG is a t-butoxycarbonyl group, a diphenylmethyl group, a triphenylmethyl group, a p-methoxyphenyldiphenylmethyl group or a di (p-methoxyphenyl) phenylmethyl group, and n is an integer of 1 or 2) is there.)
In the presence of a copper compound, an alkali metal compound and a ligand, the halopyridine compound is further represented by the formula (3):

(Wherein R ¹ represents a hydrogen atom, an alkyl group or an alkoxy group, and R ² represents a hydrogen atom, an alkyl group or an aryl group.)
Wherein the compound is reacted with an aralkyl alcohol compound represented by formula (4):

(In the formula, PG, R ¹ , R ² and n are the same as described above.)
The manufacturing method of the aralkyloxypyridine compound represented by these. The method for producing an aralkyloxypyridine compound according to claim 1, wherein the copper compound is a copper halide. The method for producing an aralkyloxypyridine compound according to claim 1 or 2, wherein the alkali metal compound is a compound containing potassium. The method for producing an aralkyloxypyridine compound according to any one of claims 1 to 3, wherein the ligand is a 1-alkylimidazole compound. The halopyridine compound represented by the formula (2) is reacted with the aralkyl alcohol compound represented by the formula (3), and then the obtained reaction solution is washed with an aqueous ammonia solution and / or an aqueous ethylenediamine solution. 5. A method for producing an aralkyloxypyridine compound according to any one of 4 above. The aralkyloxypyridine according to any one of claims 1 to 5, wherein a phase transfer catalyst is further used when the aralkyl alcohol compound represented by the formula (3) is reacted with the halopyridine compound represented by the formula (2). Compound production method. X is a bromine atom or an iodine atom, The manufacturing method of the aralkyloxypyridine compound in any one of Claims 1-6. PG is a triphenylmethyl group, The manufacturing method of the aralkyloxypyridine compound in any one of Claims 1-7. The method for producing an aralkyloxypyridine compound according to any one of claims 1 to 8, wherein the aminohalopyridine compound represented by the formula (1) is a 2-amino-5-halopyridine compound. The aralkyloxypyridine compound represented by the formula (4) is reacted with an acid to give a formula (5):

(In the formula, R ¹ and R ² are the same as described above, and A represents an acid.)
Wherein the aminoaralkyloxypyridinium salt is further catalytically hydrogenated in the presence of a hydrogenation catalyst, formula (6):

(In the formula, A is the same as described above.)
The manufacturing method of the aminohydroxy pyridinium salt represented by these. The aralkyloxypyridine compound represented by the formula (4) is catalytically hydrogenated in the presence of a hydrogenation catalyst to obtain the formula (7):

(In the formula, PG and n are the same as described above.)
A method for producing an aminohydroxypyridinium salt represented by the formula (6), wherein the hydroxypyridine compound represented by the formula (6) is obtained, and the hydroxypyridine compound is further reacted with an acid. A process for producing an aminohydroxypyridinium salt represented by the formula (6), wherein the aralkyloxypyridine compound represented by the formula (4) is catalytically hydrogenated in the presence of an acid and a hydrogenation catalyst. The method for producing an aminohydroxypyridinium salt according to claim 10, wherein water is further allowed to coexist when the aralkyloxypyridine compound represented by the formula (4) is reacted with an acid. The method for producing an aminohydroxypyridinium salt according to claim 10, wherein the aminoaralkyloxypyridinium salt represented by the formula (5) in claim 10 is catalytically hydrogenated, and then water is added to the obtained reaction solution. . The acid is at least one acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and acetic acid. The manufacturing method of the aminohydroxy pyridinium salt in any one of. The method for producing an aminohydroxypyridinium salt according to any one of claims 10 to 15, wherein the hydrogenation catalyst is Pd / C. Formula (8), wherein the aminohydroxypyridinium salt represented by Formula (6) is neutralized with a base:

The manufacturing method of the aminohydroxypyridine compound represented by these. The aminoaralkyloxypyridinium salt represented by the formula (5) is neutralized with a base to obtain the formula (9):

(R ¹ and R ² are the same as above.)
A process for producing an aminohydroxypyridine compound represented by the formula (8), wherein the aminoaralkyloxypyridine compound represented by the formula (8) is obtained, and the aminoaralkyloxypyridine compound is further catalytically hydrogenated in the presence of a hydrogenation catalyst.