JP2024080578A - Method for producing mirabegron and its intermediates - Google Patents

Abstract

[Problem] To provide a method for producing mirabegron and its production intermediates, which is excellent in safety, efficiency and/or economy. [Solution] A method for producing mirabegron, comprising a step of reacting compound (III) or a free form thereof with compound (II) to obtain compound (I), and a step selected from the following (1), (2) and (3): (1) a first step of reacting compound (VII) with compound (VI) in the presence of a base, a condensing agent and a catalytic amount of an auxiliary catalyst such as 1-hydroxybenzotriazole monohydrate to obtain compound (V), (2) a second step of reacting compound (V) with a reducing agent in the presence of an alkylating agent to obtain compound (IV), and (3) a third step of reacting compound (IV) with hydrazine monohydrate in the presence of a base, activated carbon and iron(III) chloride hexahydrate to obtain compound (III) or a free form thereof. TIFF2024080578000032.tif35170 [Selected image] None

Description

The present invention relates to a novel method for producing mirabegron and its production intermediates.

Mirabegron (chemical name: 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide) is a compound represented by the following formula (I), which has adrenergic β3 receptor agonism and is known to be an effective compound for treating urgency, frequent urination, and urge urinary incontinence caused by overactive bladder.

For example, Patent Document 1 discloses a method for producing mirabegron, which is represented by the following chemical formula:

（式中、ＥＤＣＩ・ＨＣｌは１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩を、ＨＯＢｔは１－ヒドロキシベンゾトリアゾールを、Ｅｔ_３Ｎはトリエチルアミンを、ＤＭＦはＮ，Ｎ－ジメチルホルムアミドを、ＮａＢＨ_４は水素化ホウ素ナトリウムを、ＢＦ_３・ＴＨＦは三フッ化ホウ素テトラヒドロフラン錯体を、ＴＨＦはテトラヒドロフランを、ＤＭＩは１，３－ジメチル－２－イミダゾリジノンを、１０％Ｐｄ／Ｃは１０％パラジウム－炭素を、及びＭｅＯＨはメタノールを表す）
上記反応において、例えば、１－ヒドロキシベンゾトリアゾールや水素ガス（Ｈ_２）には爆発性があり、パラジウムは毒性が高く、水素化ホウ素ナトリウム及び三フッ化ホウ素テトラヒドロフラン錯体を用いるボラン還元では腐食性の高いフッ化水素（ＨＦ）が発生するなど、安全性、効率性及び／又は経済性の観点から、なお改善の余地がある。
また、特許文献２には、以下の化学式で表されるミラベグロンの製造中間体の製造方法が開示されている。

(In the formula, EDCI.HCl represents 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, HOBt represents 1-hydroxybenzotriazole, Et ₃ N represents triethylamine, DMF represents N,N-dimethylformamide, NaBH ₄ represents sodium borohydride, BF _3.THF represents boron trifluoride tetrahydrofuran complex, THF represents tetrahydrofuran, DMI represents 1,3-dimethyl-2-imidazolidinone, 10%Pd/C represents 10% palladium on carbon, and MeOH represents methanol.)
In the above reaction, for example, 1-hydroxybenzotriazole and hydrogen gas (H ₂ ) are explosive, palladium is highly toxic, and borane reduction using sodium borohydride and boron trifluoride tetrahydrofuran complex generates highly corrosive hydrogen fluoride (HF), so there is still room for improvement in terms of safety, efficiency, and/or economy.
Furthermore, Patent Document 2 discloses a method for producing a production intermediate of mirabegron represented by the following chemical formula:

（式中、ＭｅＯＨはメタノールを表す）
また、特許文献３には、以下の式Ｉの化合物又はその塩を溶媒中で還元剤と反応させてミラベグロンの製造中間体である式Ａの化合物の製造方法が開示されている。

(In the formula, MeOH represents methanol.)
Furthermore, Patent Document 3 discloses a method for producing a compound of formula A, which is a production intermediate of mirabegron, by reacting a compound of formula I below or a salt thereof with a reducing agent in a solvent.

特許文献２及び特許文献３に開示された製造方法では、過剰のヒドラジン一水和物（ＮＨ_２ＮＨ_２・Ｈ_２Ｏ）の使用を必要とするため、反応後の生成物の晶析を困難とし、また、ヒドラジン一水和物には爆発性があるため、過剰のヒドラジン一水和物の処理を困難となるなど、安全性、効率性及び／又は経済性の観点から、なお改善の余地がある。
また、特許文献４には、以下の式ＩＩＩの化合物又はその塩を適切なアルコール溶媒の存在下、好ましい温度でヒドラジン水和物、鉄化合物及び活性炭で還元して、ミラベグロンの製造中間体である式－ＩＩの化合物又は塩の製造方法が開示されている。

The production methods disclosed in Patent Documents 2 and 3 require the use of an excess of hydrazine monohydrate (NH ₂ NH _{2.H 2} O), which makes it difficult to crystallize the product after the reaction. In addition, hydrazine monohydrate is explosive, which makes it difficult to dispose of excess hydrazine monohydrate. Thus, there is still room for improvement in terms of safety, efficiency, and/or economy.
Furthermore, Patent Document 4 discloses a method for producing a compound of formula-II, which is a production intermediate of mirabegron, by reducing a compound of formula III below or a salt thereof with hydrazine hydrate, an iron compound and activated carbon in the presence of a suitable alcohol solvent at a preferred temperature.

特許文献４に開示された製造方法では、過剰のヒドラジン一水和物（ＮＨ_２ＮＨ_２・Ｈ_２Ｏ）の使用を必要とするため、反応後の生成物の晶析を困難とし、また、ヒドラジン一水和物には爆発性があるため、過剰のヒドラジン一水和物の処理を困難とするため、安全性、効率性及び／又は経済性の観点から、なお改善の余地がある。
また、特許文献５には、以下の還元剤の存在下で式ＩＩのニトロ化合物又はその塩を還元して、ミラベグロンの製造中間体である式ＩＩＩのアミン化合物又はその塩の製造方法が開示されている。

The production method disclosed in Patent Document 4 requires the use of an excess of hydrazine monohydrate (NH ₂ NH _{2.H 2} O), which makes it difficult to crystallize the product after the reaction. In addition, hydrazine monohydrate is explosive, which makes it difficult to dispose of the excess hydrazine monohydrate. Therefore, there is still room for improvement in terms of safety, efficiency, and/or economy.
Furthermore, Patent Document 5 discloses a method for producing an amine compound of formula III or a salt thereof, which is a production intermediate of mirabegron, by reducing a nitro compound of formula II or a salt thereof in the presence of the following reducing agent:

特許文献５に開示された製造方法では、還元剤としてラネーニッケルを使用している。ラネーニッケルは安価で経済性の面で利点があるが、乾燥状態で空気に触れることで自然発火の危険性があり、大スケールでの製造では、特に安全性の観点から、改善の余地がある。

The production method disclosed in Patent Document 5 uses Raney nickel as a reducing agent. Although Raney nickel is inexpensive and has the advantage of being economical, there is a risk of spontaneous combustion when exposed to air in a dry state, and there is room for improvement in large-scale production, particularly from the viewpoint of safety.

JP 2011-105685 A China Patent Publication No. 113880720 Chinese Patent Publication No. 113816864 Publication IN202141028209 IN02679CH2015 Publication

One object of the present invention is to provide a method for producing mirabegron, which is excellent in safety, efficiency, and/or economy. Another object of the present invention is to provide a method for producing a production intermediate of mirabegron, which is excellent in safety, efficiency, and/or economy.

The inventors conducted extensive research to achieve the above object, improved the method for producing mirabegron, and completed the present invention.

That is, the present invention has the following aspects.
<1> Reacting a compound represented by formula (VII) with a compound represented by formula (VI),

式（Ｖ）で表される化合物を得る第一工程；

A first step of obtaining a compound represented by formula (V);

式（Ｖ）で表される化合物から式（ＩＶ）で表される化合物を得る第二工程；

A second step of obtaining a compound represented by formula (IV) from a compound represented by formula (V);

式（ＩＶ）で表される化合物から式（ＩＩＩ）で表される化合物又はそのフリー体を得る第三工程；及び

A third step of obtaining a compound represented by formula (III) or a free form thereof from a compound represented by formula (IV); and

式（ＩＩＩ）で表される化合物又はそのフリー体と、式（ＩＩ）で表される化合物とを反応させ、式（Ｉ）で表される化合物を得る第四工程を含む、

A fourth step of reacting a compound represented by formula (III) or a free form thereof with a compound represented by formula (II) to obtain a compound represented by formula (I),

式（Ｉ）で表される化合物の製造方法であって、

A method for preparing a compound of formula (I), comprising the steps of:

以下の（１）、（２）及び（３）から選択される少なくとも１つの工程を含む、前記製造方法：
（１）前記第一工程が、Ｎ-メチルモルホリン、モルホリン、トリエチルアミン、ピリジン、ジイソプロピルエチルアミン及びジイソプロピルアミンからなる群より選択される塩基、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（ＥＤＣＩ・ＨＣｌ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（ＥＤＣＩ）、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド（ＤＣＣ）、Ｎ，Ｎ’－ジイソプロピルカルボジイミド（ＤＩＣ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウムクロリド（ＤＭＴ－ＭＭ）、Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロリン酸塩（ＨＡＴＵ）、Ｏ－（ベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロリン酸塩（ＨＢＴＵ）、Ｏ－（１Ｈ－６－クロロベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロリン酸塩（ＨＣＴＵ）、Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムテトラフルオロホウ酸塩（ＴＡＴＵ）、Ｏ－（ベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムテトラフルオロホウ酸塩（ＴＢＴＵ）、｛｛［（１－シアノ－２－エトキシ－２－オキソエチリデン）アミノ］オキシ｝－４－モルホリノメチレン｝ジメチルアンモニウムヘキサフルオロリン酸塩（ＣＯＭＵ）、Ｏ－［（エトキシカルボニル）シアノメチレンアミノ］－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロリン酸塩（ＨＯＴＵ）、１Ｈ－ベンゾトリアゾール－１－イルオキシトリピロリジノホスホ二ウムヘキサフルオロリン酸塩（ＰｙＢＯＰ）、１Ｈ－ベンゾトリアゾール－１－イルオキシトリス（ジメチルアミノ）ホスホニウムヘキサフルオロリン酸塩（ＢＯＰ）、及びブロモトリピロリジノホスホ二ウムヘキサフルオロリン酸塩（ＰｙＢｒｏＰ）からなる群より選択される縮合剤、並びに触媒量の、１－ヒドロキシベンゾトリアゾール一水和物、１－ヒドロキシベンゾトリアゾール、Ｎ－ヒドロキシスクシンイミド、４－ジメチルアミノピリジン、シアノ(ヒドロキシイミノ)酢酸エチル、６－クロロ－１－ヒドロキシベンゾトリアゾール及び１－ヒドロキシ－７－アザベンゾトリアゾールからなる群より選択される補助触媒の存在下、式（ＶＩＩ）で表される化合物と、式（ＶＩ）で表される化合物とを反応させ、式（Ｖ）で表される化合物を得ることを含む工程であり、
（２）前記第二工程が、ジメチル硫酸、ジエチル硫酸、トリフルオロメタンスルホン酸メチル、ｐ-トルエンスルホン酸メチル、ヨウ化エチル及びヨウ化メチルからなる群より選択されるアルキル化剤（特に、ジメチル硫酸、トリフルオロメタンスルホン酸メチル、ｐ-トルエンスルホン酸メチル及びヨウ化メチルからなる群より選択されるメチル化剤）、トリフルオロメタンスルホン酸、メタンスルホン酸、硫酸、又はトリフルオロ酢酸の存在下、式（Ｖ）で表される化合物に、水素化ホウ素ナトリウム及び水素化ホウ素カリウムから選択される還元剤を作用させ、式（ＩＶ）で表される化合物を得ることを含む工程であり、そして
（３）前記第三工程が、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸水素カリウム、水酸化ナトリウム、水酸化カリウム及び水酸化リチウムからなる群より選択される塩基、活性炭、並びに塩化鉄（ＩＩＩ）六水和物の存在下、式（ＩＶ）で表される化合物に、ヒドラジン一水和物を作用させ、式（ＩＩＩ）で表される化合物又はそのフリー体を得ることを含む工程である。

The production method includes at least one step selected from the following steps (1), (2), and (3):
(1) The first step is carried out using a base selected from the group consisting of N-methylmorpholine, morpholine, triethylamine, pyridine, diisopropylethylamine, and diisopropylamine, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), O-(7- O-(azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(1H-6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HCTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), Methyluronium tetrafluoroborate (TBTU), {{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethylene}dimethylammonium hexafluorophosphate (COMU), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium hexafluorophosphate (HOTU), 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), and bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP), and in the presence of a catalytic amount of a co-catalyst selected from the group consisting of 1-hydroxybenzotriazole monohydrate, 1-hydroxybenzotriazole, N-hydroxysuccinimide, 4-dimethylaminopyridine, ethyl cyano(hydroxyimino)acetate, 6-chloro-1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole, to obtain a compound represented by formula (V),
(2) the second step comprises reacting a compound represented by formula (V) with a reducing agent selected from sodium borohydride and potassium borohydride in the presence of an alkylating agent selected from the group consisting of dimethyl sulfate, diethyl sulfate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, ethyl iodide, and methyl iodide (particularly, a methylating agent selected from the group consisting of dimethyl sulfate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, and methyl iodide), trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, or trifluoroacetic acid to obtain a compound represented by formula (IV); and (3) the third step comprises reacting a compound represented by formula (IV) with hydrazine monohydrate in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide, activated carbon, and iron (III) chloride hexahydrate to obtain a compound represented by formula (III) or a free form thereof.

<2> The manufacturing method according to <1>, comprising the step (1).
<3> The manufacturing method described in <1>, which includes the step (2).
<4> The manufacturing method described in <1>, which includes the step (3).
<5> The manufacturing method according to <1>, comprising the steps (2) and (3).
<6> The manufacturing method according to <1>, comprising the steps (1), (2) and (3).
<7> The method according to any one of <1>, <2> and <6>, wherein in the step (1), the base is N-methylmorpholine, the condensing agent is EDCI.HCl, the co-catalyst is 1-hydroxybenzotriazole monohydrate, and the amount of the co-catalyst used is 0.04 to 0.06 mol per 1 mol of the compound represented by formula (IV).
<8> The method according to any one of <1>, <2>, <6> and <7>, wherein in the step (1), the compound represented by formula (VII) is added after the addition of the base.
<9> The method according to any one of <1>, <3>, <5> and <6>, wherein in the step (2), sodium borohydride is allowed to act on the compound represented by formula (V) in the presence of dimethyl sulfate.
<10> The method according to any one of <1>, <4>, <5> and <6>, wherein in the step (3), 1.3 to 2.0 mol of hydrazine monohydrate is reacted with 1 mol of the compound represented by formula (IV) in the presence of potassium carbonate, activated carbon, and iron(III) chloride hexahydrate.
<11> The method according to any one of <1>, <4>, <5>, <6> and <10>, further comprising adding hydrochloric acid in the step (3) to precipitate the compound represented by formula (III).
<12> The method according to any one of <1>, <4>, <5>, <6> and <10>, further comprising precipitating a free form of the compound represented by formula (III) without adding hydrochloric acid in the step (3).

<13> The method comprises reacting a compound represented by formula (VII) with a compound represented by formula (VI) in the presence of a base selected from the group consisting of N-methylmorpholine, morpholine, triethylamine, pyridine, diisopropylethylamine, and diisopropylamine, a condensing agent selected from the group consisting of EDCI.HCl, EDCI, DCC, DIC, DMT-MM, HATU, HBTU, HCTU, TATU, TBTU, COMU, HOTU, PyBOP, BOP, and PyBroP, and a catalytic amount of a cocatalyst selected from the group consisting of 1-hydroxybenzotriazole monohydrate, 1-hydroxybenzotriazole, N-hydroxysuccinimide, 4-dimethylaminopyridine, ethyl cyano(hydroxyimino)acetate, 6-chloro-1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole,

式（Ｖ）で表される化合物の製造方法。

A process for producing a compound represented by formula (V).

＜１４＞塩基がＮ-メチルモルホリンであり、縮合剤がＥＤＣＩ・ＨＣｌであり、補助触媒が１－ヒドロキシベンゾトリアゾール一水和物であり、前記補助触媒の使用量が、式（ＩＶ）で表される化合物１モルに対して、０．０４～０．０６モルである、＜１３＞に記載の製造方法。
＜１５＞ジメチル硫酸、ジエチル硫酸、トリフルオロメタンスルホン酸メチル、ｐ-トルエンスルホン酸メチル、ヨウ化エチル及びヨウ化メチルからなる群より選択されるアルキル化剤（特に、ジメチル硫酸、トリフルオロメタンスルホン酸メチル、ｐ-トルエンスルホン酸メチル及びヨウ化メチルからなる群より選択されるメチル化剤）、トリフルオロメタンスルホン酸、メタンスルホン酸、硫酸、又はトリフルオロ酢酸の存在下、式（Ｖ）で表される化合物に、

<14> The production method according to <13>, wherein the base is N-methylmorpholine, the condensing agent is EDCI.HCl, the co-catalyst is 1-hydroxybenzotriazole monohydrate, and the amount of the co-catalyst used is 0.04 to 0.06 mol per 1 mol of the compound represented by formula (IV).
<15> A method of reacting a compound represented by formula (V) with an alkylating agent selected from the group consisting of dimethyl sulfate, diethyl sulfate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, ethyl iodide, and methyl iodide (particularly, a methylating agent selected from the group consisting of dimethyl sulfate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, and methyl iodide), trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, or trifluoroacetic acid,

水素化ホウ素ナトリウム及び水素化ホウ素カリウムから選択される還元剤を作用させることを含む、式（ＩＶ）で表される化合物の製造方法。

A method for producing a compound represented by formula (IV), comprising reacting with a reducing agent selected from sodium borohydride and potassium borohydride.

＜１６＞ジメチル硫酸の存在下、式（Ｖ）で表される化合物に、水素化ホウ素ナトリウムを作用させることを含む、＜１５＞に記載の製造方法。
＜１７＞炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸水素カリウム、水酸化ナトリウム、水酸化カリウム及び水酸化リチウムからなる群より選択される塩基、活性炭、並びに塩化鉄（ＩＩＩ）六水和物の存在下、式（ＩＶ）で表される化合物に、

<16> The production method according to <15>, comprising reacting a compound represented by formula (V) with sodium borohydride in the presence of dimethyl sulfate.
<17> A compound represented by formula (IV) is reacted in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide, activated carbon, and iron (III) chloride hexahydrate,

ヒドラジン一水和物を作用させることを含む、式（ＩＩＩ）で表される化合物又はそのフリー体の製造方法。

A method for producing a compound represented by formula (III) or a free form thereof, comprising reacting with hydrazine monohydrate.

＜１８＞炭酸カリウム、活性炭、及び塩化鉄（ＩＩＩ）六水和物の存在下、式（ＩＶ）で表される化合物１モルに対して、１．３～２．０モルのヒドラジン一水和物を作用させることを含む、＜１７＞に記載の製造方法。
＜１９＞塩酸を添加して、式（ＩＩＩ）で表される化合物を析出させることを含む、＜１７＞又は＜１８＞に記載の製造方法。
＜２０＞塩酸を添加することなく、式（ＩＩＩ）で表される化合物のフリー体を析出させることを含む、＜１７＞又は＜１８＞に記載の製造方法。

<18> The production method according to <17>, comprising reacting 1.3 to 2.0 mol of hydrazine monohydrate with 1 mol of the compound represented by formula (IV) in the presence of potassium carbonate, activated carbon, and iron (III) chloride hexahydrate.
<19> The production method according to <17> or <18>, comprising adding hydrochloric acid to precipitate the compound represented by formula (III).
<20> The production method according to <17> or <18>, comprising precipitating a free form of the compound represented by formula (III) without adding hydrochloric acid.

The present invention provides a method for producing mirabegron or its production intermediates that is safe, efficient, and/or economical.

Hereinafter, an embodiment of the method for producing mirabegron or a production intermediate thereof according to the present invention will be described.
<Method of manufacturing mirabegron>
One embodiment of the present invention comprises reacting a compound represented by formula (VII) (i.e., (R)-mandelic acid) with a compound represented by formula (VI) (i.e., 4-nitrophenethylamine monohydrochloride);
A first step of obtaining a compound represented by formula (V) (i.e., (2R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide);
A second step of obtaining a compound represented by formula (IV) (i.e., (1R)-2-[(4-nitrophenethyl)amino]-1-phenylethan-1-ol monohydrochloride) from a compound represented by formula (V);
A method for producing a compound represented by formula (I), comprising: a third step of obtaining a compound represented by formula (III) (i.e., (1R)-2-[(4-aminophenethyl)amino]-1-phenylethan-1-ol dihydrochloride) or a free form thereof (i.e., (1R)-2-[(4-aminophenethyl)amino]-1-phenylethan-1-ol) from a compound represented by formula (IV); and a fourth step of reacting a compound represented by formula (III) or a free form thereof with a compound represented by formula (II) (i.e., 2-amino-1,3-thiazol-5-ylacetic acid) to obtain a compound represented by formula (I) (i.e., mirabegron),
The production method includes at least one step selected from the following steps (1), (2), and (3):
(1) the first step is a step comprising reacting a compound represented by formula (VII) with a compound represented by formula (VI) in the presence of a base selected from the group consisting of N-methylmorpholine, morpholine, triethylamine, pyridine, diisopropylethylamine, and diisopropylamine, a condensing agent selected from the group consisting of EDCI.HCl, EDCI, DCC, DIC, DMT-MM, HATU, HBTU, HCTU, TATU, TBTU, COMU, HOTU, PyBOP, BOP, and PyBroP, and a catalytic amount of a co-catalyst selected from the group consisting of 1-hydroxybenzotriazole monohydrate, 1-hydroxybenzotriazole, N-hydroxysuccinimide, 4-dimethylaminopyridine, ethyl cyano(hydroxyimino)acetate, 6-chloro-1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole, to obtain a compound represented by formula (V);
(2) the second step is a step comprising reacting a compound represented by formula (V) with a reducing agent selected from sodium borohydride and potassium borohydride in the presence of an alkylating agent selected from the group consisting of dimethyl sulfate, diethyl sulfate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, ethyl iodide, and methyl iodide (particularly, a methylating agent selected from the group consisting of dimethyl sulfate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, and methyl iodide), trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, or trifluoroacetic acid to obtain a compound represented by formula (IV); and (3) the third step is a step comprising reacting a compound represented by formula (IV) with hydrazine monohydrate in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide, activated carbon, and iron (III) chloride hexahydrate to obtain a compound represented by formula (III) or a free form thereof.

In one embodiment, the steps to which the steps (1), (2), or (3) are not applied may be carried out by applying a method known per se or a method equivalent thereto, for example, as described in Patent Documents 1 or 2.
The method for producing mirabegron according to the present invention, in one embodiment, comprises at least one step selected from the step (1), the step (2), and the step (3); in another embodiment, comprises two steps selected from the step (1), the step (2), and the step (3) (e.g., the step (1) and the step (2); the step (2) and the step (3); or the step (1) and the step (3)); and in yet another embodiment, comprises all of the step (1), the step (2), and the step (3).

<First step>
The first step is a step of reacting a compound represented by formula (VII) with a compound represented by formula (VI) to obtain a compound represented by formula (V).
In one embodiment, the first step is preferably a step including: (1) reacting a compound represented by formula (VII) with a compound represented by formula (VI) in the presence of a base selected from the group consisting of N-methylmorpholine, morpholine, triethylamine, pyridine, diisopropylethylamine, and diisopropylamine, a condensing agent selected from the group consisting of EDCI.HCl, EDCI, DCC, DIC, DMT-MM, HATU, HBTU, HCTU, TATU, TBTU, COMU, HOTU, PyBOP, BOP, and PyBroP, and a catalytic amount of a co-catalyst selected from the group consisting of 1-hydroxybenzotriazole monohydrate, 1-hydroxybenzotriazole, N-hydroxysuccinimide, 4-dimethylaminopyridine, ethyl cyano(hydroxyimino)acetate, 6-chloro-1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole, to obtain a compound represented by formula (V).

In this specification,
EDCI.HCl stands for 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride;
EDCI stands for 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;
DCC stands for N,N'-dicyclohexylcarbodiimide;
DIC stands for N,N'-diisopropylcarbodiimide;
DMT-MM represents 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride;
HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;
HBTU stands for O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;
HCTU represents O-(1H-6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;
TATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate;
TBTU stands for O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate;
COMU stands for {{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethylene}dimethylammonium hexafluorophosphate;
HOTU stands for O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium hexafluorophosphate;
PyBOP stands for 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate;
BOP stands for 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, and PyBroP stands for bromotripyrrolidinophosphonium hexafluorophosphate.

In the first step, in the conventional method, it is necessary to use about 1 mole or more of a relatively expensive and explosive auxiliary catalyst such as 1-hydroxybenzotriazole (sometimes abbreviated as HOBt) per mole of the raw material compound (e.g., the compound represented by formula (IV)). By adopting the above step (1), however, it is possible to reduce the amount of catalyst used (0.01 to 1 mole, preferably 0.04 to 0.06 mole, more preferably 0.05 mole per mole of the raw material compound (e.g., the compound represented by formula (IV))), and the target compound can be obtained in a yield roughly equivalent to that of the conventional method, thereby providing a manufacturing method that is safe and economical.

The reaction of the compound represented by formula (VII) with the compound represented by formula (VI) in the above step (1) is usually carried out in a solvent using 0.8 to 1.2 moles, preferably 0.88 to 1.12 moles, of the compound represented by formula (VII) per mole of the compound represented by formula (VI).
Examples of the solvent include ethanol, methanol, isopropanol, water, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, and mixed solvents thereof. Among these, ethanol, methanol, water, and mixed solvents thereof are preferred, and ethanol, water, and mixed solvents thereof are particularly preferred.
Examples of the auxiliary catalyst include 1-hydroxybenzotriazole monohydrate, 1-hydroxybenzotriazole, N-hydroxysuccinimide, 4-dimethylaminopyridine, ethyl cyano(hydroxyimino)acetate, 6-chloro-1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole. Among these, 1-hydroxybenzotriazole monohydrate or 1-hydroxybenzotriazole is preferred, and 1-hydroxybenzotriazole monohydrate is particularly preferred.
The amount of the solvent used in the reaction may usually be 2 to 10 vol., preferably 6 vol., based on the weight of the compound represented by formula (VI). In this specification, "X vol. based on the weight" means "XL per kg" or "X mL per g."

The amount of the condensing agent used in the reaction may usually be 1 to 1.5 moles, preferably 1.12 moles, per mole of the compound represented by formula (VI).
The amount of the base used in the reaction may usually be 1 to 2.5 moles, preferably 2.2 moles, per mole of the compound represented by formula (VI).
The reaction temperature may usually be from 0 to 80°C, preferably from 30 to 40°C.
The reaction time varies depending on the relative amounts of reactants used, the reaction temperature, concentrations, etc., but can usually be from 2 to 18 hours.
In the above step (1), it is preferable that the base is N-methylmorpholine, the condensing agent is EDCI.HCl, and the co-catalyst is 1-hydroxybenzotriazole monohydrate.
In the above step (1), it is preferable to add the compound represented by formula (VII) after the addition of the base, which can suppress solidification of the reaction solution and enable the product to be obtained in a higher yield.

The compound represented by formula (VII), the compound represented by formula (VI), the solvent, the base, the condensing agent and the auxiliary catalyst are each a known compound and can be produced according to a known method or commercially available.

The compound represented by formula (V) obtained in the first step can be subjected to the second step with or without isolation, but it is preferable to isolate the compound represented by formula (V) and then subject the compound to the second step. That is, in one embodiment, the first step includes a step of isolating the compound represented by formula (V).
The compound represented by formula (V) can be isolated by a method known per se, for example, by filtering the precipitated crystals, washing the filtered crystals with a washing liquid such as water, and drying them. The drying can be performed, for example, by drying under reduced pressure, preferably by vacuum drying at 70°C.

One aspect of the first step is a method for producing a compound represented by formula (V), which is a useful intermediate for the production of mirabegron. Therefore, specific examples and preferred embodiments thereof are the same as those of the first step.
In one embodiment, a method for producing a compound represented by formula (V), which is a useful intermediate for the production of mirabegron, comprises reacting a compound represented by formula (VII) with a compound represented by formula (VI) in the presence of a base selected from the group consisting of N-methylmorpholine, morpholine, triethylamine, pyridine, diisopropylethylamine, and diisopropylamine, a condensing agent selected from the group consisting of EDCI.HCl, EDCI, DCC, DIC, DMT-MM, HATU, HBTU, HCTU, TATU, TBTU, COMU, HOTU, PyBOP, BOP, and PyBroP, and a catalytic amount of a co-catalyst selected from the group consisting of 1-hydroxybenzotriazole monohydrate, 1-hydroxybenzotriazole, N-hydroxysuccinimide, 4-dimethylaminopyridine, ethyl cyano(hydroxyimino)acetate, 6-chloro-1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole.
In another embodiment, in the method for producing the compound represented by formula (V), the base is N-methylmorpholine, the condensing agent is EDCI.HCl, the co-catalyst is 1-hydroxybenzotriazole monohydrate, and the amount of the co-catalyst used is 0.04 to 0.06 mol per 1 mol of the compound represented by formula (IV).

<Second step>
The second step is a step of obtaining a compound represented by formula (IV) from a compound represented by formula (V).
In one embodiment, the second step is preferably a step comprising: (2) reacting a compound represented by formula (V) with a reducing agent selected from sodium borohydride and potassium borohydride in the presence of an alkylating agent selected from the group consisting of dimethyl sulfate, diethyl sulfate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, ethyl iodide, and methyl iodide (particularly, a methylating agent selected from the group consisting of dimethyl sulfate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, and methyl iodide), trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, or trifluoroacetic acid, to obtain a compound represented by formula (IV).

In the second step, in the conventional method, borane reduction using sodium borohydride and boron trifluoride tetrahydrofuran complex is applied, which generates hydrogen fluoride, which is corrosive to glass and the like, and therefore requires corrosion-resistant equipment. However, by adopting the above step (2), it is possible to eliminate the generation of hydrogen fluoride, making it possible to use general-purpose equipment, and since dimethyl sulfate is an inexpensive methylating agent in particular, it is possible to provide a manufacturing method that is safe and economical.

The conversion reaction from the compound represented by formula (V) to the compound represented by formula (IV) in the above step (2) is usually carried out in a solvent by reacting 1.5 to 3.5 mol, preferably 2 mol, of a reducing agent with respect to 1 mol of the compound represented by formula (V) in the presence of 1.5 to 3.5 mol, preferably 2 mol, of a methylating agent, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, or trifluoroacetic acid with respect to 1 mol of the compound represented by formula (V).
Examples of the solvent include tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dioxolane, 1,3-dimethyl-2-imidazolidinone, and mixed solvents thereof. Among them, 2-methyltetrahydrofuran, 1,3-dimethyl-2-imidazolidinone, and tetrahydrofuran are preferred, and tetrahydrofuran is particularly preferred.
The amount of the solvent used in the reaction may usually be 4 to 10 vol., preferably 8 vol., based on the weight of the compound represented by formula (V).
The reaction temperature may usually be 45 to 70°C, preferably 48 to 52°C.
The reaction time varies depending on the relative amounts of reactants used, the reaction temperature, concentrations, etc., but can usually be from 2 to 8 hours.
As the alkylating agent used in the reaction, dimethyl sulfate or diethyl sulfate is preferable since it is relatively inexpensive and gives a good production yield of the target compound of the reaction, and dimethyl sulfate is particularly preferable.
In the above step (2), it is preferable to react the compound represented by formula (V) with sodium borohydride as a reducing agent in the presence of dimethyl sulfate.

The solvent, methylating agent, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, trifluoroacetic acid, and reducing agent are each a known compound, and therefore can be produced according to a known method or obtained commercially.

The compound represented by formula (IV) obtained in the second step can be subjected to the third step with or without isolation, but it is preferable to isolate the compound represented by formula (IV) and then subject the compound to the third step. That is, in one embodiment, the second step includes a step of isolating the compound represented by formula (IV).
The compound represented by formula (IV) can be isolated by a method known per se. For example, after the completion of the reaction, hydrochloric acid, methanol and water are added, and the mixture is extracted with ethyl acetate or the like. In the extraction with ethyl acetate, it is preferable to adjust the pH of the aqueous layer to 8.0 to 11.0, preferably 9.0 to 10.0, and extraction with ethyl acetate heated to 40 to 60° C., preferably 50° C., is preferable because it can enhance the extraction efficiency. By adjusting the pH of the aqueous layer to the above range, it is possible to suppress the precipitation of inorganic substances and enhance the extraction efficiency. For the adjustment of the pH, inorganic salts such as potassium carbonate, potassium hydroxide, sodium hydroxide, or sodium carbonate can be used, and potassium carbonate is preferable.
The compound represented by formula (IV) extracted as described above can be obtained by concentrating the extract to precipitate crystals, filtering the precipitated crystals, washing the filtered crystals with a washing liquid such as ice-cooled isopropanol, and drying them. The drying can be performed, for example, by applying reduced pressure drying, and preferably by applying vacuum drying.

One aspect of the second step is a method for producing a compound represented by formula (IV), which is a useful intermediate for the production of mirabegron. Therefore, specific examples and preferred embodiments thereof are the same as those of the second step.
In one embodiment, a method for producing a compound represented by formula (IV), which is a useful intermediate for the production of mirabegron, comprises reacting a compound represented by formula (V) with a reducing agent selected from sodium borohydride and potassium borohydride in the presence of an alkylating agent selected from the group consisting of dimethyl sulfate, diethyl sulfate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, ethyl iodide, and methyl iodide (particularly, a methylating agent selected from the group consisting of dimethyl sulfate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, and methyl iodide), trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, or trifluoroacetic acid.
In another embodiment, the method for producing the compound represented by formula (IV) comprises reacting a compound represented by formula (V) with sodium borohydride in the presence of dimethyl sulfate.

<Third process>
The third step is a step of obtaining a compound represented by formula (III) or a free form thereof from a compound represented by formula (IV).
In one embodiment, the third step is preferably a step comprising: (3) reacting hydrazine monohydrate with a compound represented by formula (IV) in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide, activated carbon, and iron (III) chloride hexahydrate, to obtain a compound represented by formula (III) or a free form thereof.

In the third step, the conventional method disclosed in Patent Document 1 requires the use of expensive and highly toxic palladium and explosive hydrogen gas, and the conventional method disclosed in Patent Document 2 requires the use of an excessive amount of explosive hydrazine monohydrate. By adopting the above step (3), however, it is possible to avoid the use of palladium and hydrogen gas, and also to significantly reduce the amount of hydrazine monohydrate used, thereby providing a manufacturing method that is safe and economical.

The conversion reaction from the compound represented by formula (IV) to the compound represented by formula (III) or a free form thereof in the above step (3) is usually carried out in a solvent in the presence of 0.8 to 1.2 mol, preferably 0.88 to 1.12 mol, more preferably 1.0 mol, of a base per mol of the compound represented by formula (IV), 0.05 to 0.2 mol, preferably 0.05 mol, of iron(III) chloride hexahydrate, and 1 to 5 g, preferably 3 g, of activated carbon per 10 g of the compound represented by formula (IV), and in the presence of 1.3 to 7.6 mol, preferably 1.3 to 2.0 mol, more preferably 1.5 to 2.0 mol, particularly preferably 1.6 mol, of hydrazine monohydrate per mol of the compound represented by formula (IV).
Examples of the solvent include methanol, ethanol, isopropanol, and mixtures thereof, and among these, methanol is preferred.
The amount of the solvent used in the reaction may usually be 6 to 12 vol., preferably 8 vol., based on the weight of the compound represented by formula (IV).
The reaction temperature may usually be from 50 to 70°C, preferably from 62 to 68°C.
The reaction time varies depending on the relative amounts of reactants used, the reaction temperature, concentrations, etc., but can usually be 2 to 6 hours.
The base used in the reaction is preferably potassium carbonate, sodium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, and particularly preferably potassium carbonate.
In the above step (3), it is preferable to react 1.3 to 2.0 mol of hydrazine monohydrate with 1 mol of the compound represented by formula (IV) in the presence of potassium carbonate, activated carbon, and iron (III) chloride hexahydrate.
In the above step (3), when obtaining a compound represented by formula (III), it is preferable to add hydrochloric acid to the reaction solution to precipitate the compound represented by formula (III). In this specification, the hydrochloric acid has a hydrogen chloride concentration of 30 mass% or more, preferably 33 mass% or more, and more preferably 35 mass% or more, based on the total mass of hydrochloric acid, although its concentration is not particularly limited as long as it can precipitate the compound represented by formula (III).
In addition, in the above step (3), when obtaining the free form of the compound represented by formula (III), it is preferable to precipitate the free form of the compound represented by formula (III) without adding hydrochloric acid. In particular, when producing the free form of the compound represented by formula (III), the amount of organic solvent used can be significantly reduced by crystallizing the free form of the compound represented by formula (III) from methanol and water, which are reaction solutions, without adding hydrochloric acid, and the production of by-products can be suppressed, and the target product with higher purity can be obtained.

The solvent, base, activated carbon, iron(III) chloride hexahydrate, and hydrazine monohydrate are each a known compound and can be produced according to a known method or obtained commercially.

The compound represented by formula (III) or its free form obtained in the third step can be subjected to the fourth step with or without isolation, but it is preferable to isolate the compound represented by formula (III) or its free form and then subject the compound to the fourth step. That is, in one embodiment, the third step includes a step of isolating the compound represented by formula (III) or its free form.
The compound represented by formula (III) or its free form can be isolated by a method known per se, for example, by dissolving the compound represented by formula (III) or its free form obtained by the reaction in a solvent such as ethyl acetate and isopropanol, adding hydrochloric acid to the solution to precipitate crystals of the compound represented by formula (III), filtering the precipitated crystals, washing the filtered crystals with a washing liquid such as ice-cooled isopropanol, and drying. The drying can be performed, for example, by applying reduced pressure drying, preferably vacuum drying.
On the other hand, the free form of the compound represented by formula (III) can be isolated, for example, by precipitating the crystals of the free form of the compound represented by formula (III) obtained by the reaction from water and methanol, filtering the precipitated crystals, washing the filtered crystals with a washing liquid such as water, and drying them. The drying can be, for example, reduced pressure drying, and preferably vacuum drying.

One aspect of the third step is a method for producing a compound represented by formula (III) or its free form, which is a useful intermediate for the production of mirabegron. Therefore, specific examples and preferred embodiments thereof are the same as those of the third step.
In one embodiment, a method for producing the compound represented by formula (III) or its free form, which is a useful production intermediate of mirabegron, comprises reacting the compound represented by formula (IV) with hydrazine monohydrate in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide, activated carbon, and iron (III) chloride hexahydrate.
In another embodiment, the method for producing the compound represented by formula (III) or a free form thereof comprises reacting 1.3 to 2.0 mol of hydrazine monohydrate with 1 mol of the compound represented by formula (IV) in the presence of potassium carbonate, activated carbon, and iron (III) chloride hexahydrate.

<Fourth step>
The fourth step is a step of reacting the compound represented by formula (III) or its free form with the compound represented by formula (II) to obtain the compound represented by formula (I) (i.e., mirabegron).
When the compound obtained in the third step is a free form of the compound represented by formula (III), in the fourth step, it is preferable to add hydrochloric acid to convert the secondary amine moiety of the free form into a hydrochloride (monohydrochloride, compound of formula (III-I)) and then react it with the compound represented by formula (II). Even when such steps are taken, by obtaining the free form of the compound represented by formula (III) in the third step, it is possible to obtain a target product of higher purity with suppressed production of by-products, and therefore the compound represented by formula (I) can be produced more efficiently.

第四工程には、それ自体公知の方法を適用することができ、例えば、ＥＤＣＩ・ＨＣｌ、ＥＤＣＩ、ＤＣＣ、ＤＩＣ、ＤＭＴ－ＭＭ、ＨＡＴＵ、ＨＢＴＵ、ＴＡＴＵ、ＴＢＴＵ、ＣＯＭＵ、ＨＯＴＵ、ＰｙＢＯＰ、ＢＯＰ及びＰｙＢｒｏＰからなる群より選択される縮合剤の存在下、式（ＩＩＩ）で表される化合物若しくはそのフリー体、又は式（ＩＩＩ－Ｉ）で表される化合物と、式（ＩＩ）で表される化合物とを反応させ、式（Ｉ）で表される化合物を得ることを含む方法を適用することができる。
反応は、通常、溶媒中で、式（ＩＩＩ）で表される化合物若しくはそのフリー体、又は式（ＩＩＩ－Ｉ）で表される化合物１モルに対し、式（ＩＩ）で表される化合物０．８～１．２モル、好ましくは０．８８～１．１２モル、より好ましくは０．９０～１．００モル用いて行われる。
前記溶媒としては、エタノール、メタノール、イソプロパノール、水、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジクロロメタン、及びそれらの混合溶媒等が例示され、中でも水が好ましい。
反応に使用される溶媒の量は、通常、式（ＩＩＩ）で表される化合物若しくはそのフリー体、又は式（ＩＩＩ－Ｉ）で表される化合物の重量に対し、６～２０ｖｏｌ．、好ましくは１７ｖｏｌ．であり得る。

In the fourth step, a method known per se can be applied. For example, a method including reacting a compound represented by formula (III) or a free form thereof, or a compound represented by formula (III-I) with a compound represented by formula (II) in the presence of a condensing agent selected from the group consisting of EDCI.HCl, EDCI, DCC, DIC, DMT-MM, HATU, HBTU, TATU, TBTU, COMU, HOTU, PyBOP, BOP, and PyBroP to obtain a compound represented by formula (I).
The reaction is usually carried out in a solvent using 0.8 to 1.2 moles, preferably 0.88 to 1.12 moles, more preferably 0.90 to 1.00 moles of the compound represented by formula (II) per mole of the compound represented by formula (III) or its free form, or the compound represented by formula (III-I).
Examples of the solvent include ethanol, methanol, isopropanol, water, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, and mixed solvents thereof, and among these, water is preferable.
The amount of the solvent used in the reaction may usually be 6 to 20 vol., preferably 17 vol., based on the weight of the compound represented by formula (III) or its free form, or the compound represented by formula (III-I).

The amount of the condensing agent used in the reaction may usually be 0.9 to 1.2 moles, preferably 1.10 moles, per mole of the compound represented by formula (III) or its free form, or the compound represented by formula (III-I).
The reaction temperature may usually be from 0 to 80°C, preferably from 20 to 30°C.
The reaction time varies depending on the relative amounts of reactants used, the reaction temperature, concentrations, etc., but can usually be from 1 to 18 hours.
The pH during the reaction is preferably 4.5 to 5.5, and more preferably 4.8 to 5.2.
In the above reaction, the condensing agent is preferably EDCI.HCl.

The solvent and the condensing agent are each a known compound and can be produced according to a known method or obtained commercially.

The compound represented by formula (I) obtained in the fourth step can be isolated by a method known per se. For example, the compound represented by formula (I) obtained by the reaction can be dissolved by heating in a mixed solvent of ethanol and water, followed by cooling to precipitate crystals of the compound represented by formula (I), and the precipitated crystals can be collected by filtration, washed with a washing solution such as water, and then dried. The drying can be carried out, for example, by drying under reduced pressure. The volume ratio of the mixed solution is preferably 1 to 2 liters of ethanol per 1 liter of water, and more preferably 1.2 to 1.8 liters.

The present invention will be further explained below with reference to examples, but the present invention is not limited to these.

Example 1
Preparation of (2R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (compound represented by formula (V)) 4-nitrophenethylamine monohydrochloride (30.00 g, 148.04 mmol), ethanol (180 mL), water (15 mL), (R)-mandelic acid (22.98 g, 151.03 mmol) and N-methylmorpholine (32.94 g, 325.65 mmol) were added with 1-hydroxybenzotriazole monohydrate (1.14 g, 7.44 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31.80 g, 165.88 mmol) and stirred at 33° C. for 3 hours. Water (168 mL) was added dropwise to the reaction solution at 33° C. over 30 minutes, and then seed crystals (2 mg) were added and stirred at the same temperature for 2 hours. Water (540 mL) was added dropwise over 2 hours, then cooled to 20°C and stirred at the same temperature overnight. The crystals were filtered and washed twice with water (150 mL). They were dried in vacuum at 75°C to obtain (2R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (39.01 g, 129.89 mmol, yield 87.74%) as pale yellow crystals.
^1H -NMR(DMSO-d6, 400MHz) δ(ppm)=2.87(2H, t, J=6.8Hz), 3.27-3.49(2H, m), 4.85(1H, d, J=4.4Hz), 6.14(1H, d, J=4.0Hz), 7.25-7.31(5H, m), 7.40(2H, d, J=8.8Hz), 8.05-8.09(3H, m)

Example 2
Preparation of (1R)-2-[(4-nitrophenethyl)amino]-1-phenylethan-1-ol monohydrochloride (compound represented by formula (IV)) A mixture of tetrahydrofuran (240 mL), (2R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (30.00 g, 99.89 mmol), and sodium borohydride (7.53 g, 200.00 mmol) was cooled, and dimethyl sulfate (25.20 g, 199.8 mmol) was added dropwise at 10°C or less, while taking care not to generate foam. The mixture was then heated to 50°C and stirred for 4 hours. The reaction mixture was cooled, and methanol (22.3 mL, 549.84 mmol) and concentrated hydrochloric acid (34.3 mL, 399.63 mmol) were added at 10°C or less. After stirring at 65°C for 1 hour, water (60 mL) was added, and the mixture was concentrated under reduced pressure to 94 mL. Water (219 mL) and 30% potassium carbonate aqueous solution (159 mL) were added, and the pH was adjusted to 9.0-10.0, followed by extraction with ethyl acetate (300 mL) at 50°C. The aqueous layer was extracted again with ethyl acetate (300 mL), and the combined organic layers were washed with water (150 mL), then concentrated under reduced pressure to 84 mL. Isopropanol (302 mL) was added, and the mixture was concentrated under reduced pressure again to 84 mL. Isopropanol (218 mL) was added to the concentrated solution, which was dissolved at 55°C, and concentrated hydrochloric acid (8.7 mL, 101.36 mmol) was added to crystallize, and the mixture was stirred at the same temperature for 1 hour, and then stirred at 10°C or less for 2 hours. The crystals were filtered and washed twice with ice-cold isopropanol (60 mL). The obtained crystals were dried in vacuum to obtain (1R)-2-[(4-nitrophenethyl)amino]-1-phenylethan-1-ol monohydrochloride (30.47 g, 94.39 mmol, yield 94.49%).
^1H -NMR(DMSO-d6, 400MHz) δ(ppm)=3.04(1H, m), 3.14-3.28(5H, m), 4.99-5.03(1H, m), 6.22(1H, d, J=3.6Hz), 7.32-7.34(1H, m), 7.37-7.40(4H, m), 7.57(2H, d, J=8.8Hz), 8.22(2H, d, J=9.2Hz), 9.07(1H, br), 9.41(1H, br)

Example 3
Preparation of (1R)-2-[(4-aminophenethyl)amino]-1-phenylethan-1-ol dihydrochloride (compound represented by formula (III)) The atmosphere of a mixture of methanol (224 mL), (1R)-2-[(4-nitrophenethyl)amino]-1-phenylethan-1-ol monohydrochloride (28.00 g, 86.74 mmol), activated carbon (8.40 g), and potassium carbonate (11.99 g, 86.75 mmol) was replaced with nitrogen under reduced pressure. After adding iron(III) chloride hexahydrate (1.17 g, 4.32 mmol), the atmosphere was replaced with nitrogen under reduced pressure and the temperature was raised to 65°C. After stirring at the same temperature for 30 minutes, hydrazine monohydrate (6.95 g, 138.72 mmol) was added dropwise over 1 hour. The mixture was then stirred at 65°C for 4 hours. Ethyl acetate (224 mL) was added to the reaction mixture, cooled to 25°C, stirred at the same temperature for 1 hour, and the solid matter was removed by filtration. The filtration residue was washed with a mixture of ethyl acetate (70 mL) and methanol (70 mL), and the obtained filtrate was concentrated under reduced pressure to 56 mL. Isopropanol (280 mL) was added to the concentrated solution, and the solution was concentrated under reduced pressure to 56 mL. Isopropanol (278 mL) was added to the concentrated solution, and the solution was heated to 65°C to dissolve the precipitated crystals. Concentrated hydrochloric acid (14.9 mL, 173.60 mmol) was added to crystallize the solution, and the solution was stirred at 10°C or less for 4 hours. The crystals were filtered and washed with ice-cooled isopropanol (140 mL). The obtained crystals were dried in vacuum to obtain (1R)-2-[(4-aminophenethyl)amino]-1-phenylethan-1-ol dihydrochloride (28.39 g, 86.22 mmol, yield 99.39%).
^1H -NMR(DMSO-d6, 400MHz) δ(ppm)=2.93(3H, m), 3.13(3H, m), 5.02(1H, d, J=7.6Hz),6.20(1H, br) 6.97（2H, d, J=8.4Hz）, 7.14（2H, d, J=8.4Hz）, 7.31（1H, m）, 7.39(4H, m), 8.50（2H, br）, 8.89(1H, br), 9.32(1H, br)

Example 4
Preparation of Mirabegron (Compound represented by formula (I)) A mixture of water (170 mL), (2-amino-thiazol-4-yl)acetic acid (4.80 g, 30.34 mmol) and (1R)-2-[(4-aminophenethyl)amino]-1-phenylethan-1-ol dihydrochloride (10.0 g, 30.37 mmol) was added with 4N aqueous sodium hydroxide to adjust the pH to 4.5-5.5. Then, a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.40 g, 33.38 mmol) in water (10 mL) was prepared and gradually added to the reaction mixture at 25-30°C and stirred at the same temperature for 1 hour. Concentrated hydrochloric acid (1.9 mL) and water (10 mL) were added, followed by stirring for 1 hour. A mixture of water (41 mL) and 4N aqueous sodium hydroxide (18.9 mL) was added until the pH reached 9.0-10.0, causing crystallization. The crystals were filtered and washed with water (126 mL) to obtain crude wet crystals of 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide). Water (38.2 mL) and ethanol (38.2 mL) were added to the crude wet crystals, and the mixture was heated to about 80°C for dissolution, cooled, and then 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide) (62 mg) was added at 65°C. The mixture was then cooled to 20°C. The crystals were filtered and washed with water (50 mL). The obtained crystals were dried in vacuum at 40° C. to obtain 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide) (9.49 g, 23.93 mmol, yield 78.80%).
^1H -NMR(DMSO-d6, 400MHz) δ(ppm)=1.60(1H, brs), 2.62-2.65(4H, m), 2.70-2.80(2H, m), 3.44(2H, s), 4.59(1H, s), 5.23(1H, s), 6.29(1H, s), 6.90(2H, s), 7.11(2H, d, J=8.4Hz), 7.21(1H, m), 7.29(4H, m), 7.49(2H, d, J=8.8Hz), 10.00(1H, s)

Example 5
Preparation of (2R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (compound represented by formula (V)) To a mixture of 4-nitrophenethylamine monohydrochloride (30.00 g, 148.05 mmol), ethanol (180 mL), 1-hydroxybenzotriazole monohydrate (1.13 g, 7.40 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32.35 g, 168.77 mmol), N-methylmorpholine (32.94 g, 325.70 mmol) was added at 10° C. or lower, and then (R)-mandelic acid (25.68 g, 168.77 mmol) was added. The mixture was stirred at 10° C. or lower for 30 minutes, and then at 33° C. for 3 hours. Water (168 mL) was added dropwise to the reaction solution over 30 minutes at 33°C, and then seed crystals (26 mg) were added and stirred at the same temperature overnight. Water (540 mL) was added dropwise over 2 hours, and the mixture was cooled to 20°C and stirred at the same temperature for 2 hours. The crystals were filtered and washed twice with water (150 mL). The crystals were dried in vacuum at 70°C to obtain (2R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (41.39 g, 137.82 mmol, yield 93.09%) as pale yellow crystals.
1H-NMR(DMSO-d6, 400MHz) δ(ppm)=2.87(2H, t, J=6.8Hz), 3.27-3.49(2H, m), 4.85(1H, d, J=4.4Hz), 6.14(1H, d, J=4.0Hz), 7.25-7.31(5H, m), 7.40(2H, d, J=8.8Hz), 8.05-8.09(3H, m)

Example 6
Preparation of (1R)-2-[(4-nitrophenethyl)amino]-1-phenylethan-1-ol monohydrochloride (compound represented by formula (IV)) A mixture of tetrahydrofuran (280 mL), (2R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (35.00 g, 116.55 mmol), and sodium borohydride (8.82 g, 233.09 mmol) was cooled, and dimethyl sulfate (29.40 g, 233.09 mmol) was added dropwise at 10°C or less, while taking care not to generate foam. The mixture was then heated to 50°C and stirred for 4 hours. The reaction mixture was cooled, and methanol (26.0 mL, 641.00 mmol) and concentrated hydrochloric acid (40.0 mL, 466.18 mmol) were added at 10°C or less. After stirring at 65°C for 30 minutes, water (70 mL) was added, and the mixture was concentrated under reduced pressure to 110 mL. Water (256 mL) and 30% aqueous potassium carbonate solution (241.48 g) were added, and the pH was adjusted to 9.0-10.0, followed by extraction with ethyl acetate (350 mL) at 50°C. The aqueous layer was extracted again with ethyl acetate (350 mL), and the combined organic layers were washed with water (175 mL), then concentrated under reduced pressure to 98 mL. Ethyl acetate (346 mL) was added, and the mixture was concentrated under reduced pressure to 133 mL. Isopropanol (224 mL) was added to the concentrated solution, which was dissolved at 35°C, and concentrated hydrochloric acid (10.2 mL, 122.37 mmol) was added at 25°C to crystallize, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at 10°C or less for 1 hour. The crystals were filtered and washed with ice-cooled isopropanol (140 mL). The obtained crystals were dried in vacuum to obtain (1R)-2-[(4-nitrophenethyl)amino]-1-phenylethan-1-ol monohydrochloride (35.36 g, 109.54 mmol, yield 93.99%).
1H-NMR(DMSO-d6, 400MHz) δ(ppm)=3.04(1H, m), 3.14-3.28(5H, m), 4.99-5.03(1H, m), 6.22(1H, d, J=3.6Hz), 7.32-7.34(1H, m), 7.37-7.40(4H, m), 7.57(2H, d, J=8.8Hz), 8.22(2H, d, J=9.2Hz), 9.07(1H, br), 9.41(1H, br)

Example 7
Preparation of (1R)-2-[(4-aminophenethyl)amino]-1-phenylethan-1-ol (free form of the compound represented by formula (III)) The atmosphere of a mixture of methanol (280 mL), (1R)-2-[(4-nitrophenethyl)amino]-1-phenylethan-1-ol monohydrochloride (35.00 g, 108.42 mmol), activated carbon (7.00 g), and potassium carbonate (14.99 g, 108.42 mmol) was replaced with nitrogen under reduced pressure. After adding iron(III) chloride hexahydrate (1.47 g, 5.42 mmol), the atmosphere was replaced with nitrogen under reduced pressure and the temperature was raised to 65°C. After stirring at the same temperature for 30 minutes, hydrazine monohydrate (8.68 g, 173.25 mmol) was added dropwise over 1 hour. Then, the mixture was stirred at 65°C for 3 hours. The reaction mixture was cooled to 25°C, and the solid matter was removed by filtration. The residue was washed with methanol (140 mL), and the filtrate was concentrated under reduced pressure to 245 mL. Water (420 mL) was added dropwise to the concentrated solution at 42°C over 1 hour, and then seed crystals (116 mg) were added and stirred overnight. Water (315 mL) was added over 2 hours, and the mixture was stirred at 10°C or less for 4 hours. The crystals were filtered and washed with ice-cooled water (140 mL). The crystals were dried in vacuum at 50°C to give (1R)-2-[(4-aminophenethyl)amino]-1-phenylethan-1-ol (23.67 g, 92.33 mmol, yield 85.15%).
1H-NMR(DMSO-d6, 400MHz) δ(ppm)=2.50(2H, overlapped), 2.61-2.69(4H, m), 4.60(1H, dd, J=7.6Hz, 5.2Hz), 4.81(2H, br), 5.24(1H, br), 6.46（2H, d, J=8.0Hz）, 6.83（2H, d, J=8.8Hz）, 7.22（1H, m）, 7.30(4H, m)

Example 8
Preparation of Mirabegron (Compound represented by formula (I)) A mixture of water (374 mL), (2-amino-thiazol-4-yl)acetic acid (13.57 g, 85.82 mmol) and (1R)-2-[(4-aminophenethyl)amino]-1-phenylethan-1-ol (22.00 g, 85.82 mmol) was added with concentrated hydrochloric acid to adjust the pH to 5.0. Then, a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18.10 g, 94.40 mmol) in water (22 mL) was prepared and gradually added to the reaction mixture at 25-30°C and stirred at the same temperature for 1 hour. A mixture of concentrated hydrochloric acid (7.4 mL) and water (28 mL) was added and stirred for 1 hour. A mixture of water (117 mL) and 4N aqueous sodium hydroxide solution (53.7 mL) was added until the pH reached 9.0-10.0, causing crystallization. The crystals were filtered and washed with water (276 mL) to obtain crude wet crystals of 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide). Water (66 mL) and ethanol (105.6 mL) were added to the crude wet crystals, and the mixture was heated to about 75°C for dissolution, cooled, and then 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide) (138 mg) was added at 65°C. The mixture was then cooled to 20°C. The crystals were filtered and washed with water (110 mL). The obtained crystals were dried in vacuum at 50° C. to obtain 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide) (28.9 g, 72.88 mmol, yield 84.92%).
1H-NMR(DMSO-d6, 400MHz) δ(ppm)=1.60(1H, brs), 2.62-2.65(4H, m), 2.70-2.80(2H,m), 3.44(2H, s), 4.59(1H, s), 5.23(1H, s), 6.29(1H, s), 6.90(2H, s), 7.11(2H, d, J=8.4Hz), 7.21(1H, m), 7.29(4H, m), 7.49(2H, d, J=8.8Hz), 10.00(1H, s)

The present invention provides a method for producing mirabegron or its production intermediates that is safe, efficient, and/or economical.

Claims (20)

Reacting a compound represented by formula (VII) with a compound represented by formula (VI),

A first step of obtaining a compound represented by formula (V);

A second step of obtaining a compound represented by formula (IV) from a compound represented by formula (V);

A third step of obtaining a compound represented by formula (III) or a free form thereof from a compound represented by formula (IV); and

A fourth step of reacting a compound represented by formula (III) or a free form thereof with a compound represented by formula (II) to obtain a compound represented by formula (I),

A method for preparing a compound of formula (I), comprising the steps of:

The production method includes at least one step selected from the following steps (1), (2), and (3):
(1) the first step is a step comprising reacting a compound represented by formula (VII) with a compound represented by formula (VI) in the presence of a base selected from the group consisting of N-methylmorpholine, morpholine, triethylamine, pyridine, diisopropylethylamine, and diisopropylamine, a condensing agent selected from the group consisting of EDCI.HCl, EDCI, DCC, DIC, DMT-MM, HATU, HBTU, HCTU, TATU, TBTU, COMU, HOTU, PyBOP, BOP, and PyBroP, and a catalytic amount of a co-catalyst selected from the group consisting of 1-hydroxybenzotriazole monohydrate, 1-hydroxybenzotriazole, N-hydroxysuccinimide, 4-dimethylaminopyridine, ethyl cyano(hydroxyimino)acetate, 6-chloro-1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole, to obtain a compound represented by formula (V);
(2) the second step comprises reacting a compound represented by formula (V) with a reducing agent selected from sodium borohydride and potassium borohydride in the presence of an alkylating agent selected from the group consisting of dimethyl sulfate, diethyl sulfate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, ethyl iodide, and methyl iodide, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, or trifluoroacetic acid to obtain a compound represented by formula (IV); and (3) the third step comprises reacting a compound represented by formula (IV) with hydrazine monohydrate in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide, activated carbon, and iron (III) chloride hexahydrate to obtain a compound represented by formula (III) or a free form thereof. The manufacturing method according to claim 1, comprising the step (1). The manufacturing method according to claim 1, comprising step (2). The manufacturing method according to claim 1, comprising the step (3). The manufacturing method according to claim 1, comprising steps (2) and (3). The manufacturing method according to claim 1, comprising steps (1), (2) and (3). The method according to claim 1 or 2, wherein in step (1), the base is N-methylmorpholine, the condensing agent is EDCI.HCl, the co-catalyst is 1-hydroxybenzotriazole monohydrate, and the amount of the co-catalyst used is 0.04 to 0.06 moles per mole of the compound represented by formula (IV). The method according to claim 1 or 2, wherein in step (1), a compound represented by formula (VII) is added after the addition of the base. The method according to claim 1 or 3, wherein in step (2), the compound represented by formula (V) is reacted with sodium borohydride in the presence of dimethyl sulfate. The method according to claim 1 or 4, wherein in step (3), 1.3 to 2.0 moles of hydrazine monohydrate is reacted with 1 mole of the compound represented by formula (IV) in the presence of potassium carbonate, activated carbon, and iron (III) chloride hexahydrate. The method according to claim 1 or 4, further comprising adding hydrochloric acid in step (3) to precipitate the compound represented by formula (III). The method according to claim 1 or 4, further comprising precipitating the free form of the compound represented by formula (III) without adding hydrochloric acid in step (3). reacting a compound represented by formula (VII) with a compound represented by formula (VI) in the presence of a base selected from the group consisting of N-methylmorpholine, morpholine, triethylamine, pyridine, diisopropylethylamine, and diisopropylamine, a condensing agent selected from the group consisting of EDCI.HCl, EDCI, DCC, DIC, DMT-MM, HATU, HBTU, HCTU, TATU, TBTU, COMU, HOTU, PyBOP, BOP, and PyBroP, and a catalytic amount of a co-catalyst selected from the group consisting of 1-hydroxybenzotriazole monohydrate, 1-hydroxybenzotriazole, N-hydroxysuccinimide, 4-dimethylaminopyridine, ethyl cyano(hydroxyimino)acetate, 6-chloro-1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole.

A process for producing a compound represented by formula (V).

The method according to claim 13, wherein the base is N-methylmorpholine, the condensing agent is EDCI.HCl, the co-catalyst is 1-hydroxybenzotriazole monohydrate, and the amount of the co-catalyst used is 0.04 to 0.06 moles per mole of the compound represented by formula (IV). In the presence of a methylating agent selected from the group consisting of dimethyl sulfate, diethyl sulfate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, ethyl iodide and methyl iodide, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, or trifluoroacetic acid, a compound represented by formula (V) is

A method for producing a compound represented by formula (IV), comprising reacting with a reducing agent selected from sodium borohydride and potassium borohydride.

The method according to claim 15, which comprises reacting a compound represented by formula (V) with sodium borohydride in the presence of dimethyl sulfate. A compound represented by formula (IV) is reacted in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide, activated carbon and iron (III) chloride hexahydrate,

A method for producing a compound represented by formula (III) or a free form thereof, comprising reacting with hydrazine monohydrate.

The method according to claim 17, which comprises reacting 1.3 to 2.0 moles of hydrazine monohydrate with 1 mole of the compound represented by formula (IV) in the presence of potassium carbonate, activated carbon, and iron (III) chloride hexahydrate. The method according to claim 17 or 18, which comprises adding hydrochloric acid to precipitate the compound represented by formula (III). The method according to claim 17 or 18, which comprises precipitating the free form of the compound represented by formula (III) without adding hydrochloric acid.