JP2006315992A - Hydrate of dihydrochloride of aminoalcohol compound - Google Patents
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Abstract
Description
本発明は、アミノアルコール化合物の２塩酸塩の水和物に関する。 The present invention relates to a dihydrochloride hydrate of an amino alcohol compound.
式（３）
で示されるアミノアルコール化合物は、例えば医薬中間体として有用な化合物として知られている（例えば特許文献１参照。）。かかる式（３）で示されるアミノアルコール化合物は、その分子内にアミノ基やピリジン環を有するため、塩酸塩の形態を取り得るが、かかる式（３）で示されるアミノアルコール化合物の塩酸塩は、不可逆的な吸湿性を示すため、品質の安定性という点で、さらなる改善が望まれていた。
Formula (3)
Are known as compounds useful as, for example, pharmaceutical intermediates (see, for example, Patent Document 1). Since the amino alcohol compound represented by the formula (3) has an amino group or a pyridine ring in the molecule, it can take the form of hydrochloride, but the hydrochloride of the amino alcohol compound represented by the formula (3) is In order to show irreversible hygroscopicity, further improvement has been desired in terms of quality stability.
このような状況のもと、本発明者らは、不可逆的な吸湿性に乏しく、安定した品質で製造可能な、式（３）で示されるアミノアルコール化合物に代わり得る化合物を開発すべく検討したところ、式（３）で示されるアミノアルコール化合物の塩酸塩を水で処理することにより、新規な化合物である式（１）
で示されるアミノアルコール化合物の２塩酸塩の水和物が製造でき、かかる式（１）で示されるアミノアルコール化合物の２塩酸塩の水和物は、不可逆的な吸湿性に乏しく、安定した品質で製造可能であることを見出し、本発明に至った。
Under such circumstances, the present inventors have studied to develop a compound that can be substituted for the amino alcohol compound represented by the formula (3), which has poor irreversible hygroscopicity and can be produced with stable quality. However, by treating the hydrochloride of the amino alcohol compound represented by the formula (3) with water, a novel compound of the formula (1)
The dihydrochloride hydrate of the amino alcohol compound represented by the formula (1) can be produced, and the dihydrochloride hydrate of the amino alcohol compound represented by the formula (1) has poor irreversible hygroscopicity and stable quality. Thus, the present invention has been found.
すなわち本発明は、式（１）
（式中、Ｒは置換されていてもよいアリール基を１位の炭素原子上に有する低級アルキル基を表わす。ｎは０．５以上、１．５以下の正数を表わす。）
で示されるアミノアルコール化合物の２塩酸塩の水和物およびその製造方法を提供するものである。
(In the formula, R represents a lower alkyl group having an optionally substituted aryl group on the 1-position carbon atom. N represents a positive number of 0.5 or more and 1.5 or less.)
The hydrate of the dihydrochloride of the amino alcohol compound shown by these, and its manufacturing method are provided.
本発明の新規なアミノアルコール化合物の２塩酸塩の水和物は、不可逆的な吸湿性に乏しく、その品質の管理が容易であり、安定的に製造可能という点で、工業的な観点から有利な化合物となり得る。 The dihydrochloride hydrate of the novel amino alcohol compound of the present invention is advantageous from an industrial point of view in that it has poor irreversible hygroscopicity, easy quality control, and stable production. Compound.
式（１）
で示されるアミノアルコールの２塩酸塩の水和物（以下、水和物（１）と略記する。）の式中、Ｒ1は置換されていてもよいアリール基を１位の炭素原子上に有する低級アルキル基を表わす。 In the formula of the dihydrochloride hydrate of amino alcohol shown below (hereinafter abbreviated as hydrate (1)), R 1 represents an optionally substituted aryl group on the carbon atom at the 1-position. Represents a lower alkyl group.
置換されていてもよいアリール基としては、例えばフェニル基、１−ナフチル基、２−ナフチル基等およびこれらフェニル基、１−ナフチル基、２−ナフチル基等を構成する芳香環の水素原子が、例えば低級アルキル基、ハロゲン原子、低級アルコキシ基等で置換されたものが挙げられる。ここで低級アルキル基としては、例えば、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基等の炭素数１〜４のアルキル基が挙げられる。ハロゲン原子としては、例えばフッ素原子、塩素原子、臭素原子等が挙げられる。低級アルコキシ基としては、例えばメトキシ基、エトキシ基、ｎ−プロポキシ基、イソプロポキシ基、ｎ−ブトキシ基、イソブトキシ基、ｓｅｃ−ブトキシ基等の炭素数１〜４のアルコキシ基が挙げられる。 Examples of the optionally substituted aryl group include a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like, and a hydrogen atom of an aromatic ring constituting the phenyl group, 1-naphthyl group, 2-naphthyl group, and the like. Examples thereof include those substituted with a lower alkyl group, a halogen atom, a lower alkoxy group and the like. Here, examples of the lower alkyl group include alkyl groups having 1 to 4 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. Groups. Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. As a lower alkoxy group, C1-C4 alkoxy groups, such as a methoxy group, an ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, are mentioned, for example.
置換されていてもよいアリール基を１位の炭素原子上に有する低級アルキル基とは、例えばメチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基等の炭素数１〜４の低級アルキル基であって、該低級アルキル基の１位の炭素原子上に前記置換されていてもよいアリール基を有するものであり、例えばベンジル基、４−メトキシベンジル基、（１−ナフチル）メチル基、（２−ナフチル）メチル基、１−フェニルエチル基、１−（１−ナフチル）エチル基、１−（２−ナフチル）エチル基、ジフェニルメチル基、トリフェニルメチル基等が挙げられる。 Examples of the lower alkyl group having an optionally substituted aryl group on the 1-position carbon atom include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and a sec-butyl group. A lower alkyl group having 1 to 4 carbon atoms, such as a tert-butyl group, having the aryl group which may be substituted on the carbon atom at the 1-position of the lower alkyl group, such as a benzyl group 4-methoxybenzyl group, (1-naphthyl) methyl group, (2-naphthyl) methyl group, 1-phenylethyl group, 1- (1-naphthyl) ethyl group, 1- (2-naphthyl) ethyl group, diphenyl A methyl group, a triphenylmethyl group, etc. are mentioned.
また、水和物（１）の式中、ｎは０．５以上、１．５以下の正数を表わす。かかるｎは、水和物（１）の単結晶の調製が容易な場合には、調製した水和物（１）の単結晶をＸ線回折分析し、単位結晶格子中に含まれる無水物（１）と水分子とのモル比から求めることができ、また、水和物（１）の単結晶の調製が困難な場合には、例えば下式
に従い、算出することができる。なお、水和物（１）中の水分含量は、例えば通常のカール・フィッシャー水分計を用いるカール・フィッシャー法、水和物（１）を熱重量測定する方法等により定量することができる。例えば、塩酸塩（２）の分子量が、３０１．２１で、水和物（１）中の水分含量が４重量％の場合、ｎは、３０１．２１×（０．０４）／［１８．０２×（１−０．０４）］＝０．７となる。
In the formula of hydrate (1), n represents a positive number of 0.5 or more and 1.5 or less. When n is easy to prepare a single crystal of the hydrate (1), the single crystal of the prepared hydrate (1) is subjected to X-ray diffraction analysis, and the anhydride ( When it is difficult to prepare a single crystal of hydrate (1), it can be determined from the molar ratio between 1) and water molecules.
Can be calculated according to The water content in the hydrate (1) can be quantified by, for example, the Karl Fischer method using an ordinary Karl Fischer moisture meter, the method of thermogravimetrically measuring the hydrate (1), or the like. For example, when the molecular weight of the hydrochloride (2) is 301.21 and the water content in the hydrate (1) is 4% by weight, n is 301.21 × (0.04) / [18.02. X (1-0.04)] = 0.7.
かかる水和物（１）としては、例えば２−ベンジルアミノ−１−（２−ピリジル）エタノールの２塩酸塩の水和物、２−ベンジルアミノ−１−（３−ピリジル）エタノールの２塩酸塩の水和物、２−ベンジルアミノ−１−（４−ピリジル）エタノールの２塩酸塩の水和物、２−ベンジルアミノ−１−（６−クロロ−３−ピリジル）エタノールの２塩酸塩の水和物、２−ベンジルアミノ−１−（６−メチル−３−ピリジル）エタノールの２塩酸塩の水和物、２−（４−メトキシベンジルアミノ）−１−（３−ピリジル）エタノールの２塩酸塩の水和物、２−（１−フェニルエチルアミノ）−１−（３−ピリジル）エタノールの２塩酸塩の水和物、２−ジフェニルメチルアミノ−１−（３−ピリジル）エタノールの２塩酸塩の水和物、２−ジベンジルアミノ−１−（３−ピリジル）エタノールの２塩酸塩の水和物等が挙げられる。 Examples of the hydrate (1) include 2-benzylamino-1- (2-pyridyl) ethanol dihydrochloride, 2-benzylamino-1- (3-pyridyl) ethanol dihydrochloride. Hydrate of 2-benzylamino-1- (4-pyridyl) ethanol dihydrochloride, water of 2-benzylamino-1- (6-chloro-3-pyridyl) ethanol dihydrochloride 2-hydrate of 2-benzylamino-1- (6-methyl-3-pyridyl) ethanol, 2-hydrochloric acid of 2- (4-methoxybenzylamino) -1- (3-pyridyl) ethanol Salt hydrate, 2- (1-phenylethylamino) -1- (3-pyridyl) ethanol dihydrochloride, 2-diphenylmethylamino-1- (3-pyridyl) ethanol dihydrochloride Salt hydrate, 2-diben Arylamino-1- (3-pyridyl) hydrate of the dihydrochloride of ethanol.
かかる水和物（１）は不斉炭素原子を有するため、光学異性体が存在するが、本発明の水和物（１）は、光学活性体であってもよいし、ラセミ体であってもよい。 Since this hydrate (1) has an asymmetric carbon atom, an optical isomer exists, but the hydrate (1) of the present invention may be an optically active substance or a racemate. Also good.
かかる水和物（１）は、例えば（ｉ）式（２）
で示されるアミノアルコール化合物の２塩酸塩（以下、２塩酸塩（２）と略記する。）を水で処理する方法、（ｉｉ）式（３）
で示されるアミノアルコール化合物（以下、アミノアルコール化合物（３）と略記する。）を塩酸で処理する方法等により製造することができる。
Such hydrate (1) is, for example, (i) formula (2)
A method of treating a dihydrochloride salt of an amino alcohol compound represented by formula (hereinafter abbreviated as dihydrochloride salt (2)) with water, (ii) Formula (3)
Can be produced by a method such as treatment with hydrochloric acid (hereinafter abbreviated as amino alcohol compound (3)).
まず、（ｉ）２塩酸塩（２）を水で処理する方法について説明する。 First, (i) a method of treating dihydrochloride (2) with water will be described.
かかる塩酸塩（２）としては、例えば２−ベンジルアミノ−１−（２−ピリジル）エタノールの２塩酸塩、２−ベンジルアミノ−１−（３−ピリジル）エタノールの２塩酸塩、２−ベンジルアミノ−１−（４−ピリジル）エタノールの２塩酸塩、２−ベンジルアミノ−１−（６−クロロ−３−ピリジル）エタノールの２塩酸塩、２−ベンジルアミノ−１−（６−メチル−３−ピリジル）エタノールの２塩酸塩、２−（４−メトキシベンジルアミノ）−１−（３−ピリジル）エタノールの２塩酸塩、２−（１−フェニルエチルアミノ）−１−（３−ピリジル）エタノールの２塩酸塩、２−ジフェニルメチルアミノ−１−（３−ピリジル）エタノールの２塩酸塩、２−ジベンジルアミノ−１−（３−ピリジル）エタノールの２塩酸塩等が挙げられる。 Examples of the hydrochloride (2) include 2-benzylamino-1- (2-pyridyl) ethanol dihydrochloride, 2-benzylamino-1- (3-pyridyl) ethanol dihydrochloride, 2-benzylamino -1- (4-pyridyl) ethanol dihydrochloride, 2-benzylamino-1- (6-chloro-3-pyridyl) ethanol dihydrochloride, 2-benzylamino-1- (6-methyl-3- Of pyridyl) ethanol dihydrochloride, 2- (4-methoxybenzylamino) -1- (3-pyridyl) ethanol dihydrochloride, 2- (1-phenylethylamino) -1- (3-pyridyl) ethanol Dihydrochloride, 2-diphenylmethylamino-1- (3-pyridyl) ethanol dihydrochloride, 2-dibenzylamino-1- (3-pyridyl) ethanol dihydrochloride, etc. .
かかる塩酸塩（２）は、不斉炭素原子を有するため、光学異性体が存在するが、光学活性体を用いてもよいし、ラセミ体を用いてもよい。塩酸塩（２）の光学活性体を用いた場合には、水和物（１）の光学活性体が得られ、塩酸塩（２）のラセミ体を用いた場合には、水和物（１）のラセミ体が得られる。 Since this hydrochloride (2) has an asymmetric carbon atom, an optical isomer exists, but an optically active form may be used, or a racemic form may be used. When the optically active form of hydrochloride (2) is used, an optically active form of hydrate (1) is obtained, and when the racemate of hydrochloride (2) is used, hydrate (1 ) Is obtained.
塩酸塩（２）を水で処理する方法としては、塩酸塩（２）と水とを接触させればよく、例えば水分を含んだ気体と塩酸塩（２）とを接触させる方法、塩酸塩（２）と水を混合する方法等が挙げられる。 As a method for treating the hydrochloride (2) with water, the hydrochloride (2) may be brought into contact with water. For example, a method in which a gas containing moisture and the hydrochloride (2) are brought into contact with each other, hydrochloride ( 2) and water are mixed.
水分を含んだ気体と塩酸塩（２）とを接触させる方法における気体としては、例えば空気、窒素ガス、アルゴンガス、ヘリウムガス等が挙げられ、好ましくは空気または窒素ガスが挙げられる。水分を含んだ気体中の水分含量は、気体中の相対湿度換算で、通常４０〜９９％、好ましくは５０〜９０％である。塩酸塩（２）と水分を含んだ気体とを接触させる温度は、通常５〜９０℃、好ましくは２０〜８０℃である。 Examples of the gas in the method of bringing the moisture-containing gas into contact with the hydrochloride (2) include air, nitrogen gas, argon gas, and helium gas, and preferably air or nitrogen gas. The moisture content in the gas containing moisture is usually 40 to 99%, preferably 50 to 90% in terms of relative humidity in the gas. The temperature at which the hydrochloride (2) is brought into contact with the moisture-containing gas is usually 5 to 90 ° C, preferably 20 to 80 ° C.
かかる水分を含んだ気体と塩酸塩（２）との接触時間は、例えば該気体中の水分含量、該気体の通気量、該気体との接触面積等に応じて適宜決めればよい。 The contact time between the moisture-containing gas and the hydrochloride (2) may be appropriately determined according to, for example, the moisture content in the gas, the gas ventilation rate, the contact area with the gas, and the like.
塩酸塩（２）と水とを混合する方法における水の使用量は、塩酸塩（２）に対して、通常０．５モル倍以上、好ましくは１モル倍以上であり、その上限は特にないが、あまり多すぎると、水和物（１）が水に溶解し、その取り出しが煩雑になるため、実用的には、塩酸塩（２）に対して、５０モル倍以下である。 The amount of water used in the method of mixing the hydrochloride (2) and water is usually 0.5 mol times or more, preferably 1 mol times or more, and there is no particular upper limit for the hydrochloride (2). However, if the amount is too large, the hydrate (1) is dissolved in water, and the removal thereof becomes complicated, so that it is practically 50 moles or less with respect to the hydrochloride (2).
塩酸塩（２）と水とはそのまま混合してもよいし、溶媒の存在下に混合してもよい。溶媒としては、例えばｎ−ヘキサン、ｎ−ヘプタン、シクロヘキサン等の脂肪族炭化水素系溶媒、例えばトルエン、キシレン等の芳香族炭化水素系溶媒、例えばクロロベンゼン、ジクロロベンゼン、ジクロロメタン、クロロホルム等のハロゲン化炭化水素系溶媒、例えばメタノール、エタノール、２−プロパノール等のアルコール系溶媒、例えばジエチルエーテル、テトラヒドロフラン、１，２−ジメトキシエタン、メチルｔｅｒｔ−ブチルエーテル等のエーテル系溶媒、例えばアセトン、メチルイソブチルケトン等のケトン系溶媒、例えば酢酸エチル等のエステル系溶媒、例えばＮ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、１−メチル−２−ピロリジノン、１，３−ジメチル−２−イミダゾリジノン等のアミド系溶媒、例えばアセトニトリル等のニトリル系溶媒等の単独または混合溶媒が挙げられ、好ましくはアルコール系溶媒またはエーテル系溶媒が挙げられる。かかる溶媒を用いる場合のその使用量は、塩酸塩（２）に対して、通常０．５重量倍以上、好ましくは２重量倍以上であり、その上限は特にないが、あまり多すぎると容積効率が悪くなるため、実用的には３０重量倍以下である。 Hydrochloride (2) and water may be mixed as they are, or may be mixed in the presence of a solvent. Examples of the solvent include aliphatic hydrocarbon solvents such as n-hexane, n-heptane, and cyclohexane, aromatic hydrocarbon solvents such as toluene and xylene, and halogenated carbonization such as chlorobenzene, dichlorobenzene, dichloromethane, and chloroform. Hydrogen solvents such as alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and methyl tert-butyl ether, such as ketones such as acetone and methyl isobutyl ketone Solvents, ester solvents such as ethyl acetate, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone solvent For example, an alone or a mixed solvent of a nitrile solvent such as acetonitrile, preferably include alcohol solvents or ether solvents. When using such a solvent, the amount used is usually 0.5 times by weight or more, preferably 2 times by weight or more with respect to the hydrochloride (2), and there is no particular upper limit. Is practically 30 weight times or less.
塩酸塩（２）と水との混合順序は特に制限されず、例えば塩酸塩（２）に水を加えてもよいし、水に塩酸塩（２）を加えてもよい。また、かかる混合の際に、攪拌等を行ってもよい。かかる塩酸塩（２）と水との混合時間は、攪拌等の条件、水の活量等に応じて適宜決めればよい。 The mixing order of the hydrochloride (2) and water is not particularly limited. For example, water may be added to the hydrochloride (2), or the hydrochloride (2) may be added to water. Moreover, you may perform stirring etc. in the case of this mixing. The mixing time of the hydrochloride (2) and water may be appropriately determined according to conditions such as stirring, the activity of water, and the like.
混合温度は、通常−３０〜１００℃、好ましくは−１０〜８０℃である。 The mixing temperature is usually −30 to 100 ° C., preferably −10 to 80 ° C.
塩酸塩（２）と水とを、所定時間混合した後、例えば得られた混合物をそのままもしくは冷却処理した後、析出した結晶を濾取することにより、水和物（１）の結晶を取り出すことができる。また、例えば前記混合物を濃縮処理することにより、塩酸塩（１）を取り出すこともできる。 After the hydrochloride (2) and water are mixed for a predetermined time, for example, the obtained mixture is left as it is or cooled, and then the precipitated crystals are collected by filtration to take out the crystals of the hydrate (1). Can do. Moreover, hydrochloride (1) can also be taken out, for example by concentrating the said mixture.
取り出した塩酸塩水和物（１）は、例えば再結晶、カラムクロマトグラフィ等の通常の精製手段により、さらに精製してもよい。 The extracted hydrochloride hydrate (1) may be further purified by ordinary purification means such as recrystallization and column chromatography.
続いて、（ｉｉ）アミノアルコール化合物（３）を塩酸で処理する方法について説明する。 Subsequently, (ii) a method of treating the amino alcohol compound (3) with hydrochloric acid will be described.
かかるアミノアルコール化合物（３）としては、例えば２−ベンジルアミノ−１−（２−ピリジル）エタノール、２−ベンジルアミノ−１−（３−ピリジル）エタノール、２−ベンジルアミノ−１−（４−ピリジル）エタノール、２−ベンジルアミノ−１−（６−クロロ−３−ピリジル）エタノール、２−ベンジルアミノ−１−（６−メチル−３−ピリジル）エタノール、２−（４−メトキシベンジルアミノ）−１−（３−ピリジル）エタノール、２−（１−フェニルエチルアミノ）−１−（３−ピリジル）エタノール、２−ジフェニルメチルアミノ−１−（３−ピリジル）エタノール、２−ジベンジルアミノ−１−（３−ピリジル）エタノール等が挙げられる。 Examples of the amino alcohol compound (3) include 2-benzylamino-1- (2-pyridyl) ethanol, 2-benzylamino-1- (3-pyridyl) ethanol, 2-benzylamino-1- (4-pyridyl) ) Ethanol, 2-benzylamino-1- (6-chloro-3-pyridyl) ethanol, 2-benzylamino-1- (6-methyl-3-pyridyl) ethanol, 2- (4-methoxybenzylamino) -1 -(3-pyridyl) ethanol, 2- (1-phenylethylamino) -1- (3-pyridyl) ethanol, 2-diphenylmethylamino-1- (3-pyridyl) ethanol, 2-dibenzylamino-1- (3-pyridyl) ethanol and the like can be mentioned.
かかるアミノアルコール化合物（３）は、不斉炭素原子を有するため、光学異性体が存在するが、本発明には、光学活性体を用いてもよいし、ラセミ体を用いてもよい。アミノアルコール化合物（３）の光学活性体を用いた場合には、水和物（１）の光学活性体が得られ、アルコール化合物（３）のラセミ体を用いた場合には、水和物（１）のラセミ体が得られる。 Since this amino alcohol compound (3) has an asymmetric carbon atom, an optical isomer exists, but in the present invention, an optically active form or a racemic form may be used. When the optically active form of the amino alcohol compound (3) is used, an optically active form of the hydrate (1) is obtained, and when the racemic form of the alcohol compound (3) is used, the hydrate ( The racemate of 1) is obtained.
アミノアルコール化合物（３）を塩酸と反応させる際の塩酸の使用量は、アミノアルコール化合物（３）に対して、通常１．８モル倍以上であり、その上限は特にないが、あまり多すぎると経済的に不利になりやすいため、実用的には２０モル倍以下、好ましくは１０モル倍以下である。かかる塩酸の濃度は、通常５〜３７重量％、好ましくは１０〜３７重量％である。 The amount of hydrochloric acid used when reacting the amino alcohol compound (3) with hydrochloric acid is usually 1.8 mol times or more with respect to the amino alcohol compound (3), and there is no particular upper limit. Since it tends to be economically disadvantageous, it is practically 20 mole times or less, preferably 10 mole times or less. The concentration of hydrochloric acid is usually 5 to 37% by weight, preferably 10 to 37% by weight.
アミノアルコール化合物（３）と塩酸との反応は、通常溶媒の存在下に実施される。溶媒としては、例えばｎ−ヘキサン、ｎ−ヘプタン、シクロヘキサン等の脂肪族炭化水素系溶媒、例えばトルエン、キシレン等の芳香族炭化水素系溶媒、例えばクロロベンゼン、ジクロロベンゼン、ジクロロメタン、クロロホルム等のハロゲン化炭化水素系溶媒、例えばメタノール、エタノール、２−プロパノール等のアルコール系溶媒、例えばジエチルエーテル、テトラヒドロフラン、１，２−ジメトキシエタン、メチルｔｅｒｔ−ブチルエーテル等のエーテル系溶媒、例えばアセトン、メチルイソブチルケトン等のケトン系溶媒、例えば酢酸エチル等のエステル系溶媒、例えばＮ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、１−メチル−２−ピロリジノン、１，３−ジメチル−２−イミダゾリジノン等のアミド系溶媒、例えばアセトニトリル等のニトリル系溶媒、および水等の単独または混合溶媒が挙げられ、好ましくはアルコール系溶媒、エーテル系溶媒が挙げられる。かかる溶媒の使用量は、アミノアルコール化合物（３）に対して、通常０．５重量倍以上、好ましくは２重量倍以上であり、その上限は特にないが、あまり多すぎると容積効率が悪くなるため、実用的には３０重量倍以下である。 The reaction between the amino alcohol compound (3) and hydrochloric acid is usually carried out in the presence of a solvent. Examples of the solvent include aliphatic hydrocarbon solvents such as n-hexane, n-heptane, and cyclohexane, aromatic hydrocarbon solvents such as toluene and xylene, and halogenated carbonization such as chlorobenzene, dichlorobenzene, dichloromethane, and chloroform. Hydrogen solvents such as alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and methyl tert-butyl ether, such as ketones such as acetone and methyl isobutyl ketone Solvents, ester solvents such as ethyl acetate, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone solvent For example nitriles such as acetonitrile, and alone or a mixed solvent such as water and the like, preferably alcohol solvents, ether solvents. The amount of the solvent used is usually 0.5 times by weight or more, preferably 2 times by weight or more with respect to the amino alcohol compound (3), and there is no particular upper limit. Therefore, it is practically 30 weight times or less.
反応は、通常アミノアルコール化合物（３）、溶媒および塩酸を混合することにより実施され、その混合順序は特に制限されず、例えばアミノアルコール化合物（３）と溶媒の混合物に塩酸を加えてもよいし、塩酸と溶媒の混合物中にアミノアルコール化合物（３）を加えてもよい。アミノアルコール化合物（３）と塩酸との混合時間は、例えば塩酸濃度、溶媒の使用の有無、攪拌等の条件に応じて適宜決めればよい。 The reaction is usually carried out by mixing the amino alcohol compound (3), a solvent and hydrochloric acid, and the mixing order is not particularly limited. For example, hydrochloric acid may be added to the mixture of the amino alcohol compound (3) and the solvent. The amino alcohol compound (3) may be added to a mixture of hydrochloric acid and a solvent. The mixing time of the amino alcohol compound (3) and hydrochloric acid may be appropriately determined according to conditions such as hydrochloric acid concentration, presence / absence of use of a solvent, stirring, and the like.
反応温度は、通常−３０〜１００℃、好ましくは−１０〜８０℃である。 The reaction temperature is usually −30 to 100 ° C., preferably −10 to 80 ° C.
反応終了後、例えば得られた反応混合物を冷却して析出した結晶を濾取することにより、水和物（１）を取り出すことができる。また、例えば得られた反応混合物を濃縮して溶媒を除去することにより、水和物（１）を取り出すこともできる。 After completion of the reaction, for example, the hydrate (1) can be taken out by cooling the obtained reaction mixture and collecting the precipitated crystals by filtration. Further, for example, the hydrate (1) can be taken out by concentrating the obtained reaction mixture to remove the solvent.
取り出した塩酸塩水和物（１）は、例えば再結晶、カラムクロマトグラフィ等の通常の精製手段により、さらに精製してもよい。 The extracted hydrochloride hydrate (1) may be further purified by ordinary purification means such as recrystallization and column chromatography.
なお、２塩酸塩（２）は、例えばアミノアルコール化合物（３）と、塩化水素／ジエチルエーテル溶液等の塩化水素の有機溶媒溶液とを接触、混合することにより製造することができる。また、アミノアルコール化合物（３）は、例えば式（５）
で示される化合物を還元処理することにより製造することができる。
The dihydrochloride (2) can be produced, for example, by contacting and mixing an amino alcohol compound (3) and an organic solvent solution of hydrogen chloride such as a hydrogen chloride / diethyl ether solution. In addition, the amino alcohol compound (3) is represented by, for example, the formula (5)
It can manufacture by reducing the compound shown by these.
以下、実施例により本発明をさらに詳細に説明するが、本発明はこれら実施例に限定されない。なお、純度は、高速液体クロマトグラフィー（ＬＣ）法により分析した。 EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples. Purity was analyzed by high performance liquid chromatography (LC).
参考例１
Ｎ−ベンジル−２−ヒドロキシ−２−（３−ピリジル）アセトアミド１０ｇ、テトラヒドロフラン５０ｍＬおよび水素化ホウ素ナトリウム４．６８ｇの混合物に、内温５５〜６２℃で三フッ化ホウ素・ジエチルエーテル錯体２３．４ｇを２時間かけて滴下し、同温度で１時間４２分攪拌、反応させた。その後、内温４０℃まで冷却し、同温度で７．８重量％塩酸３８．６ｇを２０分かけて滴下した。その後、内温５０℃に昇温し、同温度で５３分攪拌、保持した後、酢酸エチル５０ｍＬを加え、２０重量％水酸化ナトリウム水溶液２５．８ｇを加えてｐＨ６．７に調整した。内温５５℃に昇温した後、分液処理し、有機層と水層を得た。水層は酢酸エチル３０ｍＬでさらに２回抽出処理し、得られた酢酸エチル層を先に得た有機層と合一した。合一後の有機層１６８ｇのうちの４２ｇを濃縮処理した。濃縮残渣にテトラヒドロフラン２５ｍＬを加えて濃縮処理し、２−ベンジルアミノ−１−（３−ピリジル）エタノール１．６ｇを含む濃縮残渣１２．７ｇを得た。収率：６７％。
Reference example 1
To a mixture of 10 g of N-benzyl-2-hydroxy-2- (3-pyridyl) acetamide, 50 mL of tetrahydrofuran and 4.68 g of sodium borohydride, 23.4 g of boron trifluoride / diethyl ether complex at an internal temperature of 55 to 62 ° C. Was added dropwise over 2 hours, and the mixture was stirred and reacted at the same temperature for 1 hour and 42 minutes. Thereafter, the internal temperature was cooled to 40 ° C., and 38.6 g of 7.8 wt% hydrochloric acid was added dropwise at the same temperature over 20 minutes. Thereafter, the temperature was raised to 50 ° C., and the mixture was stirred and maintained at the same temperature for 53 minutes. Then, 50 mL of ethyl acetate was added, and 25.8 g of a 20 wt% aqueous sodium hydroxide solution was added to adjust the pH to 6.7. After raising the internal temperature to 55 ° C., liquid separation treatment was performed to obtain an organic layer and an aqueous layer. The aqueous layer was further extracted twice with 30 mL of ethyl acetate, and the resulting ethyl acetate layer was combined with the previously obtained organic layer. 42 g of the combined organic layer 168 g was concentrated. The concentrated residue was concentrated by adding 25 mL of tetrahydrofuran to obtain 12.7 g of a concentrated residue containing 1.6 g of 2-benzylamino-1- (3-pyridyl) ethanol. Yield: 67%.
実施例１
前記参考例１で得た２−ベンジルアミノ−１−（３−ピリジル）エタノール１．６ｇを含む濃縮残渣１２．７ｇに、テトラヒドロフラン１２．５ｇおよびメタノール０．５ｇを加え、２−ベンジルアミノ−１−（３−ピリジル）エタノールを含む溶液を調製した。該液溶液のうちの５．１ｇを、３５重量％塩酸１．７ｇとテトラヒドロフラン２０ｍＬとの混合溶液中に、内温１〜２℃で、８分かけて滴下した後、種晶を加えて、同温度で３０分攪拌、保持した。これに、先に調製した２−ベンジルアミノ−１−（３−ピリジル）エタノールを含む溶液の残り２０．６ｇを、同温度で１時間１０分かけて滴下した後、同温度で１時間１５分攪拌、保持し、析出した結晶を濾取した。濾取した結晶をテトラヒドロフランで洗浄した後、乾燥させて、２−ベンジルアミノ−１−（３−ピリジル）エタノールの２塩酸塩の水和物２．２ｇを得た。水分含量から、０．９２水和物（ｎ＝０．９２）であることが分かった。純度：９７．２％（ＬＣ面積百分率値）。含量：９６．５重量％（０．９２水和物として）。収率：９５％。
Example 1
To 12.7 g of the concentrated residue containing 1.6 g of 2-benzylamino-1- (3-pyridyl) ethanol obtained in Reference Example 1, 12.5 g of tetrahydrofuran and 0.5 g of methanol were added, and 2-benzylamino-1 A solution containing-(3-pyridyl) ethanol was prepared. After dripping 5.1 g of the liquid solution into a mixed solution of 1.7 g of 35 wt% hydrochloric acid and 20 mL of tetrahydrofuran at an internal temperature of 1 to 2 ° C. over 8 minutes, seed crystals were added, The mixture was stirred and held at the same temperature for 30 minutes. To this, 20.6 g of the remaining solution containing 2-benzylamino-1- (3-pyridyl) ethanol prepared above was added dropwise at the same temperature over 1 hour and 10 minutes, and then at the same temperature for 1 hour and 15 minutes. The mixture was stirred and held, and the precipitated crystals were collected by filtration. The crystals collected by filtration were washed with tetrahydrofuran and then dried to obtain 2.2 g of 2-benzylamino-1- (3-pyridyl) ethanol dihydrochloride hydrate. From the water content, it was found to be 0.92 hydrate (n = 0.92). Purity: 97.2% (LC area percentage value). Content: 96.5% by weight (as 0.92 hydrate). Yield: 95%.
水分含量（カール・フィッシャー法）：５．２％
塩素含量（元素分析法）：２３．０％
Water content (Karl Fischer method): 5.2%
Chlorine content (elemental analysis method): 23.0%
１Ｈ−ＮＭＲスペクトルデータ（δ／ｐｐｍ，ＤＭＳＯ−ｄ６）
９．７６（ｂｒｓ，１Ｈ），９．６２（ｂｒｓ，１Ｈ），８．８８（ｄ，１Ｈ，Ｊ＝１．７Ｈｚ），８．８４（ｄｄ，１Ｈ，Ｊ＝１．１，５．５Ｈｚ），８．５２（ｄ，１Ｈ，Ｊ＝８．２Ｈｚ），８．０１（ｄｄ，１Ｈ，Ｊ＝５．５，８．２Ｈｚ），７．５−７．７（ｍ，２Ｈ），７．３−７．５（ｍ，３Ｈ），５．３７（ｄｄ，１Ｈ，Ｊ＝３．４，８．５Ｈｚ），４．１９（ｂｒｓ，２Ｈ），３．２８（ｍ，１Ｈ），３．１２（ｍ，１Ｈ）
1 H-NMR spectrum data (δ / ppm, DMSO-d 6 )
9.76 (brs, 1H), 9.62 (brs, 1H), 8.88 (d, 1H, J = 1.7 Hz), 8.84 (dd, 1H, J = 1.1, 5.5 Hz) ), 8.52 (d, 1H, J = 8.2 Hz), 8.01 (dd, 1H, J = 5.5, 8.2 Hz), 7.5-7.7 (m, 2H), 7 3-7.5 (m, 3H), 5.37 (dd, 1H, J = 3.4, 8.5 Hz), 4.19 (brs, 2H), 3.28 (m, 1H), 3 .12 (m, 1H)
参考例２
（２Ｒ）−Ｎ−ベンジル−２−ヒドロキシ−２−（３−ピリジル）アセトアミド０．９６ｇ、テトラヒドロフラン５ｍＬおよび水素化ホウ素ナトリウム０．４７ｇの混合物に、内温５〜１０℃で三フッ化ホウ素・ジエチルエーテル錯体２．３ｇを２８分かけて滴下した後、内温５０℃に昇温し、同温度で３時間攪拌、反応させた。その後、内温４０℃まで冷却し、同温度で７．８重量％塩酸３．９ｇを１０分かけて滴下した。その後、内温５０℃に昇温し、同温度で１時間攪拌、保持した後、酢酸エチル５ｍＬを加え、２０重量％水酸化ナトリウム水溶液２．５ｇを加えてｐＨ６．５に調整した。内温５５℃に昇温した後、分液処理し、有機層と水層を得た。水層は酢酸エチル３ｍＬでさらに２回抽出処理し、得られた酢酸エチル層を先に得た有機層と合一した。合一後の有機層を濃縮処理し、得られた濃縮残渣にテトラヒドロフラン２０ｍＬを加えてさらに濃縮処理し、（１Ｒ）−２−ベンジルアミノ−１−（３−ピリジル）エタノール０．６７ｇを含む有機層５．０ｇを得た。収率：７３％
Reference example 2
To a mixture of 0.92 g of (2R) -N-benzyl-2-hydroxy-2- (3-pyridyl) acetamide, 5 mL of tetrahydrofuran and 0.47 g of sodium borohydride, boron trifluoride. After 2.3 g of diethyl ether complex was added dropwise over 28 minutes, the temperature was raised to an internal temperature of 50 ° C., and the mixture was stirred and reacted at the same temperature for 3 hours. Thereafter, the internal temperature was cooled to 40 ° C., and 3.9 g of 7.8 wt% hydrochloric acid was added dropwise at the same temperature over 10 minutes. Thereafter, the temperature was raised to 50 ° C., and the mixture was stirred and maintained at the same temperature for 1 hour. Then, 5 mL of ethyl acetate was added, and 2.5 g of 20 wt% sodium hydroxide aqueous solution was added to adjust the pH to 6.5. After raising the internal temperature to 55 ° C., liquid separation treatment was performed to obtain an organic layer and an aqueous layer. The aqueous layer was further extracted twice with 3 mL of ethyl acetate, and the resulting ethyl acetate layer was combined with the previously obtained organic layer. The combined organic layer is concentrated, and 20 mL of tetrahydrofuran is added to the resulting concentrated residue, followed by further concentration, and an organic solution containing 0.67 g of (1R) -2-benzylamino-1- (3-pyridyl) ethanol. 5.0 g of layer was obtained. Yield: 73%
実施例２
前記参考例２で得た（１Ｒ）−２−ベンジルアミノ−１−（３−ピリジル）エタノール０．６７ｇを含む濃縮残渣５．０ｇに、テトラヒドロフラン５ｇおよびメタノール０．２ｇを加え、（１Ｒ）−２−ベンジルアミノ−１−（３−ピリジル）エタノールを含む溶液を調製した。該溶液のうちの２．０ｇを、３５重量％塩酸０．６９ｇとテトラヒドロフラン８ｍＬとの混合溶液中に、内温０〜５℃で１５分かけて滴下した後、種晶を加え、同温度で３０分保持した。これに、先に調製した（１Ｒ）−２−ベンジルアミノ−１−（３−ピリジル）エタノールを含む溶液の残りの８．２ｇを１時間かけて滴下した後、内温０〜５℃で１時間攪拌、保持し、析出した結晶を濾取した。濾取した結晶をテトラヒドロフランで洗浄した後、乾燥させて、（１Ｒ）−２−ベンジルアミノ−１−（３−ピリジル）エタノールの２塩酸塩の水和物０．９０ｇを得た。水分含量から、１．１水和物（ｎ＝１．１）であることが分かった。純度：９８．４％（ＬＣ面積百分率値）。含量：９８．６重量％（１．１水和物として）。収率：９６％。
Example 2
To 5.0 g of the concentrated residue containing 0.67 g of (1R) -2-benzylamino-1- (3-pyridyl) ethanol obtained in Reference Example 2, 5 g of tetrahydrofuran and 0.2 g of methanol were added, and (1R)- A solution containing 2-benzylamino-1- (3-pyridyl) ethanol was prepared. 2.0 g of the solution was dropped into a mixed solution of 0.69 g of 35 wt% hydrochloric acid and 8 mL of tetrahydrofuran at an internal temperature of 0 to 5 ° C. over 15 minutes, and then seed crystals were added. Hold for 30 minutes. To this, the remaining 8.2 g of the solution containing (1R) -2-benzylamino-1- (3-pyridyl) ethanol prepared above was added dropwise over 1 hour, and then 1 at an internal temperature of 0 to 5 ° C. The mixture was stirred and maintained for a time, and the precipitated crystals were collected by filtration. The crystal collected by filtration was washed with tetrahydrofuran and then dried to obtain 0.90 g of a hydrate of (1R) -2-benzylamino-1- (3-pyridyl) ethanol dihydrochloride. From the water content, it was found to be 1.1 hydrate (n = 1.1). Purity: 98.4% (LC area percentage value). Content: 98.6 wt% (as 1.1 hydrate). Yield: 96%.
水分含量（カール・フィッシャー法）：６．０％
光学純度（キラル高速液体クロマトグラフィー法）：１００％ｅｅ
Water content (Karl Fischer method): 6.0%
Optical purity (chiral high performance liquid chromatography method): 100% ee
１Ｈ−ＮＭＲスペクトルデータ（δ／ｐｐｍ，ＤＭＳＯ−ｄ６）
９．７７（ｂｒｓ，１Ｈ），９．６２（ｂｒｓ，１Ｈ），８．８８（ｄ，１Ｈ，Ｊ＝１．７Ｈｚ），８．８５（ｄｄ，１Ｈ，Ｊ＝１．０，５．６Ｈｚ），８．５２（ｄ，１Ｈ，Ｊ＝８．１Ｈｚ），８．０１（ｄｄ，１Ｈ，Ｊ＝５．６，８．１Ｈｚ），７．５−７．７（ｍ，２Ｈ），７．３−７．５（ｍ，３Ｈ），５．３７（ｄｄ，１Ｈ，Ｊ＝３．４，８．５Ｈｚ），４．１９（ｂｒｓ，２Ｈ），３．２８（ｍ，１Ｈ），３．１１（ｍ，１Ｈ）
1 H-NMR spectrum data (δ / ppm, DMSO-d 6 )
9.77 (brs, 1H), 9.62 (brs, 1H), 8.88 (d, 1H, J = 1.7 Hz), 8.85 (dd, 1H, J = 1.0, 5.6 Hz) ), 8.52 (d, 1H, J = 8.1 Hz), 8.01 (dd, 1H, J = 5.6, 8.1 Hz), 7.5-7.7 (m, 2H), 7 3-7.5 (m, 3H), 5.37 (dd, 1H, J = 3.4, 8.5 Hz), 4.19 (brs, 2H), 3.28 (m, 1H), 3 .11 (m, 1H)
参考例３
水分吸脱着測定装置（ＨＩＤＥＮ ＡＮＡＬＹＴＩＣＡＬ社製 ＩＧＡｓｏｒｐ）を用いて、前記実施例２で得られた（１Ｒ）−２−ベンジルアミノ−１−（３−ピリジル）エタノールの２塩酸塩の１．１水和物（ｎ＝１．１）３３．５ｍｇを、温度２５℃で相対湿度５％から相対湿度９５％まで１２時間以上かけて段階的に加湿した。さらに、同温度で相対湿度９５％から相対湿度０％まで３０時間以上かけて段階的に除湿した。測定後の試料重量は３３．５ｍｇであり、測定前の試料重量に対する吸湿量は０重量％であった。加湿および除湿の間の試料の重量変化を経時的に記録した結果を図１に示した。図１から、（１Ｒ）−２−ベンジルアミノ−１−（３−ピリジル）エタノールの２塩酸塩の水和物は不可逆的な吸湿性に乏しいことが分かる。
Reference example 3
1.1 water of dihydrochloride of (1R) -2-benzylamino-1- (3-pyridyl) ethanol obtained in Example 2 above using a moisture adsorption / desorption measuring device (IGAsorb manufactured by HIDEN ANALYTICAL) 33.5 mg of a Japanese product (n = 1.1) was humidified stepwise from a relative humidity of 5% to a relative humidity of 95% at a temperature of 25 ° C. over 12 hours. Further, dehumidification was performed stepwise from 95% relative humidity to 0% relative humidity over 30 hours at the same temperature. The sample weight after the measurement was 33.5 mg, and the moisture absorption relative to the sample weight before the measurement was 0% by weight. The results of recording the change in weight of the sample over time during humidification and dehumidification are shown in FIG. FIG. 1 shows that the hydrate of (1R) -2-benzylamino-1- (3-pyridyl) ethanol dihydrochloride is poor in irreversible hygroscopicity.
参考例４
（２Ｒ）−Ｎ−ベンジル−２−ヒドロキシ−２−（３−ピリジル）アセトアミド１ｇ、テトラヒドロフラン２２．５ｍＬおよび水素化ホウ素ナトリウム０．７５ｇの混合物に、内温２２℃で三フッ化ホウ素・ジエチルエーテル錯体３．５ｇを滴下し、内温６０℃に昇温、同温度で４時間１０分攪拌、反応させた。その後、内温５０℃まで冷却し、同温度で１０重量％塩化水素／メタノール溶液１４ｍＬを２３分かけて滴下した。その後、内温５８℃に昇温、同温度で１５分攪拌、保持した後、内温１℃まで冷却し、同温度で５０分攪拌、保持した。不溶分を濾別した後、水４５ｇおよび酢酸エチル３５ｍＬを加え、内温５０℃に昇温し、２０重量％水酸化ナトリウム水溶液９．５ｇを加え、ｐＨ９．５に調整後、分液処理し、有機層と水層を得た。水層は酢酸エチルで再度２回抽出処理し、得られた酢酸エチル層を先に得た有機層と合一した。合一した有機層を、内温５０℃で飽和食塩水で洗浄処理した後、濃縮処理し、濃縮残渣０．８９ｇを得た。濃縮残渣に、メタノール４ｇを加えた後、還流させた後、内温２１℃まで冷却した。その後、塩化水素／ジエチルエーテル溶液（塩化水素濃度：１ｍｏｌ／Ｌ）１ｍＬを加え、種晶を加えた後、さらに塩化水素／ジエチルエーテル溶液（塩化水素濃度：１ｍｏｌ／Ｌ）７ｍＬを滴下した。同温度で５分攪拌、保持し、テトラヒドロフラン１２ｍＬを滴下した後、内温２℃まで冷却した。同温度で１時間攪拌、保持した後、析出した結晶を濾取、洗浄、乾燥させ、（１Ｒ）−２−ベンジルアミノ−１−（３−ピリジル）エタノールの２塩酸塩０．９ｇを得た。
Reference example 4
(2R) -N-benzyl-2-hydroxy-2- (3-pyridyl) acetamide (1 g), tetrahydrofuran (22.5 mL) and sodium borohydride (0.75 g) in a mixture of boron trifluoride / diethyl ether at an internal temperature of 22 ° C. 3.5 g of the complex was added dropwise, the temperature was raised to an internal temperature of 60 ° C., and the mixture was stirred and reacted at the same temperature for 4 hours and 10 minutes. Thereafter, the internal temperature was cooled to 50 ° C., and 14 mL of a 10 wt% hydrogen chloride / methanol solution was added dropwise at the same temperature over 23 minutes. Thereafter, the temperature was raised to an internal temperature of 58 ° C., stirred and held at the same temperature for 15 minutes, then cooled to an internal temperature of 1 ° C., and stirred and held at the same temperature for 50 minutes. After insoluble matter was filtered off, 45 g of water and 35 mL of ethyl acetate were added, the temperature was raised to an internal temperature of 50 ° C., 9.5 g of a 20 wt% sodium hydroxide aqueous solution was added, and the pH was adjusted to 9.5, followed by liquid separation treatment. An organic layer and an aqueous layer were obtained. The aqueous layer was extracted twice again with ethyl acetate, and the resulting ethyl acetate layer was combined with the previously obtained organic layer. The combined organic layers were washed with saturated brine at an internal temperature of 50 ° C. and then concentrated to obtain 0.89 g of a concentrated residue. After adding 4 g of methanol to the concentrated residue, the mixture was refluxed and then cooled to an internal temperature of 21 ° C. Thereafter, 1 mL of a hydrogen chloride / diethyl ether solution (hydrogen chloride concentration: 1 mol / L) was added, seed crystals were added, and then 7 mL of a hydrogen chloride / diethyl ether solution (hydrogen chloride concentration: 1 mol / L) was added dropwise. The mixture was stirred and maintained at the same temperature for 5 minutes, and 12 mL of tetrahydrofuran was added dropwise, followed by cooling to an internal temperature of 2 ° C. After stirring and holding at the same temperature for 1 hour, the precipitated crystals were collected by filtration, washed and dried to obtain 0.9 g of (1R) -2-benzylamino-1- (3-pyridyl) ethanol dihydrochloride. .
比較例１
前記参考例４と同様に実施して得られた（１Ｒ）−２−ベンジルアミノ−１−（３−ピリジル）エタノールの２塩酸塩３３．１ｍｇを、水分吸脱着測定装置（ＨＩＤＥＮ ＡＮＡＬＹＴＩＣＡＬ社製 ＩＧＡｓｏｒｐ）を用いて、温度２５℃で相対湿度５％から相対湿度９５％まで１２時間以上かけて段階的に加湿した。さらに、同温度で相対湿度９５％から相対湿度０％まで３０時間以上かけて段階的に除湿した。測定後の試料重量は３４．５ｍｇであり、測定前の試料重量に対する吸湿量は４．２重量％であった。加湿および除湿の間の試料の重量変化を経時的に記録した結果を図２に示した。図２から、（１Ｒ）−２−ベンジルアミノ−１−（３−ピリジル）エタノールの２塩酸塩は不可逆的な吸湿性を示すことが分かる。
Comparative Example 1
33.1 mg of (1R) -2-benzylamino-1- (3-pyridyl) ethanol dihydrochloride obtained by carrying out in the same manner as in Reference Example 4 was added to a moisture adsorption / desorption measuring device (IGAsorb, manufactured by HIDEN ANALYTICAL). ) Was used in a stepwise manner over a period of 12 hours from a relative humidity of 5% to a relative humidity of 95% at a temperature of 25 ° C. Further, dehumidification was performed stepwise from 95% relative humidity to 0% relative humidity over 30 hours at the same temperature. The sample weight after the measurement was 34.5 mg, and the moisture absorption relative to the sample weight before the measurement was 4.2% by weight. The results of recording the change in weight of the sample over time during humidification and dehumidification are shown in FIG. FIG. 2 shows that (1R) -2-benzylamino-1- (3-pyridyl) ethanol dihydrochloride exhibits irreversible hygroscopicity.
参考例５
前記実施例２と同様に実施して得られた（１Ｒ）−２−ベンジルアミノ−１−（３−ピリジル）エタノールの２塩酸塩の０．９９水和物（ｎ＝０．９９）３７ｇ、Ｎ，Ｎ−ジメチルホルムアミド３５ｇ、テトラヒドロフラン３５ｇおよびトリエチルアミン２４ｇの混合物を２５℃で３０分攪拌した後、１−ヒドロキシベンゾトリアゾール・水和物１．８ｇ、Ｎ−エチル−Ｎ’−（３−ジメチルアミノプロピル）カルボジイミド・塩酸塩２７ｇおよびテトラヒドロフラン１５８ｇを加えた。この混合物に内温２５〜２７℃で（７−ベンジルオキシ−１Ｈ−インドール−３−イル）酢酸３６ｇおよびテトラヒドロフラン９０ｇの混合溶液を５０分かけて滴下し、同温度で２０時間１０分攪拌、反応させた。その後、内温２４℃で酢酸エチル２６４ｇおよび１０重量％食塩水１３２ｇを加え、攪拌、分液処理し、有機層を５重量％食塩水１３２ｇおよび２０重量％食塩水１３２ｇの順に攪拌、分液処理した後、酢酸エチルを加え、濃縮処理し、有機層２８１ｇを得た。得られた有機層に酢酸エチル１０４ｇを加え、内温４６℃まで昇温し、種晶を加え、同温度で３０分攪拌した後、内温１℃まで冷却した。この混合物に、内温１〜２５℃で、ｎ−ヘプタン３０２ｇを３時間５９分かけて滴下し、内温２５℃で４５分攪拌した後、内温０℃まで２時間３０分かけて冷却、同温度で１時間攪拌した。析出した結晶を濾取、洗浄、乾燥させ、Ｎ−ベンジル−２−［７−（ベンジルオキシ）−１Ｈ−インドール−３−イル］−Ｎ−［（２Ｒ）−２−ヒドロキシ−２−ピリジン−３−イルエチル］アセトアミド５１．３ｇ（純分）を得た。収率：９０％
Reference Example 5
37 g of (1R) -2-benzylamino-1- (3-pyridyl) ethanol dihydrochloride 0.99 hydrate (n = 0.99) obtained in the same manner as in Example 2; After stirring a mixture of 35 g of N, N-dimethylformamide, 35 g of tetrahydrofuran and 24 g of triethylamine at 25 ° C. for 30 minutes, 1.8 g of 1-hydroxybenzotriazole hydrate, N-ethyl-N ′-(3-dimethylamino 27 g of propyl) carbodiimide hydrochloride and 158 g of tetrahydrofuran were added. To this mixture, a mixed solution of 36 g of (7-benzyloxy-1H-indol-3-yl) acetic acid and 90 g of tetrahydrofuran was added dropwise over 50 minutes at an internal temperature of 25 to 27 ° C., and the mixture was stirred for 20 hours and 10 minutes at the same temperature. I let you. Thereafter, 264 g of ethyl acetate and 132 g of 10 wt% saline were added at an internal temperature of 24 ° C., and the mixture was stirred and separated. The organic layer was stirred and separated in the order of 132 g of 5 wt% saline and 132 g of 20 wt% saline. Then, ethyl acetate was added and concentrated to obtain 281 g of an organic layer. 104 g of ethyl acetate was added to the obtained organic layer, the temperature was raised to an internal temperature of 46 ° C., seed crystals were added, and the mixture was stirred at the same temperature for 30 minutes, and then cooled to an internal temperature of 1 ° C. To this mixture, 302 g of n-heptane was dropped over 3 hours and 59 minutes at an internal temperature of 1 to 25 ° C., stirred for 45 minutes at an internal temperature of 25 ° C., and then cooled to an internal temperature of 0 ° C. over 2 hours and 30 minutes. Stir at the same temperature for 1 hour. The precipitated crystals were collected by filtration, washed and dried, and N-benzyl-2- [7- (benzyloxy) -1H-indol-3-yl] -N-[(2R) -2-hydroxy-2-pyridine- 31.3 g (pure content) of 3-ylethyl] acetamide was obtained. Yield: 90%
水素化リチウムアルミニウム９．４ｇおよびテトラヒドロフラン１４４ｇの懸濁液を内温１０℃に冷却し、これに前記と同様にして得られたＮ−ベンジル−２−［７−（ベンジルオキシ）−１Ｈ−インドール−３−イル］−Ｎ−［（２Ｒ）−２−ヒドロキシ−２−ピリジン−３−イルエチル］アセトアミド２４ｇおよびテトラヒドロフラン８８ｇの混合溶液を同温度で１時間３８分かけて滴下し、同温度で５時間４５分攪拌、反応させた。その後、内温０℃まで冷却した。冷却後の反応混合物を、酢酸エチル６５ｇ中に、内温−１４〜−１℃で１時間２０分かけて滴下した。その後、内温４０℃まで昇温、同温度で１時間攪拌した。これに、内温２５℃で硫酸ナトリウム７８ｇおよび水７１ｇを加えて攪拌した後、不溶分を濾別した。得られた濾液に、内温４０℃で、トルエン２３４ｇ、水６８ｇおよび３５重量％塩酸２７ｇを加えた後、分液処理し、有機層と水層を得た。有機層はさらに３．６重量％塩酸２７ｇで抽出処理し、得られた水層を先に得た水層と合一した。合一後の水層に、トルエン１７５ｇおよびテトラヒドロフラン１８０ｇを加え、内温４０℃で１５重量％水酸化ナトリウム水溶液７４ｇを滴下してｐＨ６．８に調整した後、分液処理し、有機層と水層を得た。水層をさらにトルエン７０ｇで抽出処理し、得られたトルエン層を先に得た有機層と合一した。合一した有機層を２６１ｇとなるまで濃縮処理した。濃縮残液に、活性炭２．７ｇを加え、内温６５℃に昇温した。これに、ｎ−ヘプタン１４８ｇを加えた後、同温度で不溶物を濾別し、不溶物はトルエン１５．１ｇおよびｎ−ヘプタン１１．９ｇの混合液で洗浄した。得られた濾液および洗液を内温５０℃まで冷却し、種晶を加え、同温度で１時間１５分攪拌した。さらに、内温０℃まで２０時間１５分かけて冷却し、同温度でｎ−ヘプタン７４ｇを１時間３０分かけて滴下した。さらに、同温度で２時間攪拌、保持し、析出した結晶を濾取、洗浄、乾燥させ、（１Ｒ）−２−（ベンジル｛２−［７−（ベンジルオキシ）−１Ｈ−インドール−３−イル］エチル｝アミノ）−１−ピリジン−３−イルエタノール１８．３ｇ（純分）を得た。収率：７８％ A suspension of 9.4 g of lithium aluminum hydride and 144 g of tetrahydrofuran was cooled to an internal temperature of 10 ° C., and N-benzyl-2- [7- (benzyloxy) -1H-indole obtained in the same manner as above was added thereto. A mixed solution of 24 g of -3-yl] -N-[(2R) -2-hydroxy-2-pyridin-3-ylethyl] acetamide and 88 g of tetrahydrofuran was added dropwise at the same temperature over 1 hour and 38 minutes. The reaction was stirred for 45 minutes. Thereafter, the internal temperature was cooled to 0 ° C. The reaction mixture after cooling was dropped into 65 g of ethyl acetate at an internal temperature of -14 to -1 ° C over 1 hour and 20 minutes. Then, it heated up to 40 degreeC of internal temperature, and stirred at the same temperature for 1 hour. To this, 78 g of sodium sulfate and 71 g of water were added and stirred at an internal temperature of 25 ° C., and the insoluble matter was filtered off. To the obtained filtrate, 234 g of toluene, 68 g of water and 27 g of 35 wt% hydrochloric acid were added at an internal temperature of 40 ° C., followed by liquid separation treatment to obtain an organic layer and an aqueous layer. The organic layer was further extracted with 27 g of 3.6 wt% hydrochloric acid, and the resulting aqueous layer was combined with the previously obtained aqueous layer. To the combined aqueous layer, 175 g of toluene and 180 g of tetrahydrofuran were added, and 74 g of a 15% by weight aqueous sodium hydroxide solution was added dropwise at an internal temperature of 40 ° C. to adjust the pH to 6.8. A layer was obtained. The aqueous layer was further extracted with 70 g of toluene, and the obtained toluene layer was combined with the previously obtained organic layer. The combined organic layer was concentrated to 261 g. 2.7 g of activated carbon was added to the concentrated residue, and the temperature was raised to an internal temperature of 65 ° C. After adding 148 g of n-heptane to this, insoluble matter was filtered off at the same temperature, and the insoluble matter was washed with a mixed solution of 15.1 g of toluene and 11.9 g of n-heptane. The obtained filtrate and washings were cooled to an internal temperature of 50 ° C., seed crystals were added, and the mixture was stirred at the same temperature for 1 hour and 15 minutes. Furthermore, the internal temperature was cooled to 0 ° C. over 20 hours and 15 minutes, and 74 g of n-heptane was added dropwise over 1 hour and 30 minutes at the same temperature. Further, the mixture was stirred and maintained at the same temperature for 2 hours, and the precipitated crystals were collected by filtration, washed and dried to give (1R) -2- (benzyl {2- [7- (benzyloxy) -1H-indol-3-yl]. Ethyl} amino) -1-pyridin-3-ylethanol (18.3 g, pure) was obtained. Yield: 78%
Claims (3)
で示されるアミノアルコール化合物の２塩酸塩の水和物。 Formula (1)
A dihydrochloride hydrate of an amino alcohol compound represented by the formula:
で示されるアミノアルコール化合物の２塩酸塩を水で処理することを特徴とする式（１）
で示されるアミノアルコール化合物の２塩酸塩の水和物の製造方法。 Formula (2)
A dihydrochloride of an amino alcohol compound represented by the formula (1) is treated with water:
The manufacturing method of the hydrate of the dihydrochloride of the amino alcohol compound shown by these.
で示されるアミノアルコール化合物を塩酸で処理することを特徴とする式（１）
で示されるアミノアルコール化合物の２塩酸塩の水和物の製造方法。
Formula (3)
The amino alcohol compound represented by formula (1) is treated with hydrochloric acid.
The manufacturing method of the hydrate of the dihydrochloride of the amino alcohol compound shown by these.
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