JP2020007243A - Method for producing phenylpiperazine pyridine methyl acetate - Google Patents
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本願は、１，２，３，４，１０，１４ｂ−ヘキサヒドロ−２−メチル−ピラジノ〔２，１−a〕ピリド〔２，３−c〕〔２〕ベンザセピン（一般名「ミルタザピン」）の製造方法に関する。 The present application relates to the production of 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino [2,1-a] pyrido [2,3-c] [2] benzacepin (generic name: mirtazapine) About the method.
ミルタザピンの製造方法として、特許文献１には、２−（４−メチル−2−フェニル−１−ピペラジニル）−３−ピリジンメタノール（本明細書において、２−（４−メチル−2−フェニル−１−ピペラジニル）−３−ピリジンメタノールを単にピリジンメタノール（II）もしくはピリジンメタノールと示すことがある）を濃硫酸中で反応を行ない、生成物からミルタザピンの結晶を得る方法が開示されている。 As a method for producing mirtazapine, Patent Document 1 discloses 2- (4-methyl-2-phenyl-1-piperazinyl) -3-pyridinemethanol (in this specification, 2- (4-methyl-2-phenyl-1). -Piperazinyl) -3-pyridinemethanol (sometimes simply referred to as pyridinemethanol (II) or pyridinemethanol) in concentrated sulfuric acid to obtain mirtazapine crystals from the product.
特許文献２および特許文献３には、ピリジンメタノール（II）と濃硫酸を用いて反応を行ない、得られたミルタザピンの粗体からミルタザピンの結晶を得る方法が記載されている。 Patent Literatures 2 and 3 disclose a method in which a reaction is performed using pyridine methanol (II) and concentrated sulfuric acid to obtain mirtazapine crystals from the obtained crude mirtazapine.
特許文献１におけるミルタザピンの製造方法は、濃硫酸とピリジンメタノール（II）とを反応させて得られるミルタザピンを含む反応混合物をクロロホルム溶媒抽出、油水分液、溶媒濃縮を行ない、得られたミルタザピンの粗体を石油エーテルなどで再結晶を行なう方法である。当該の方法では、ミルタザピンのメタノール不溶分が多く、ミルタザピンの品質として満足できるものではなかった。 In the method for producing mirtazapine in Patent Document 1, a reaction mixture containing mirtazapine obtained by reacting concentrated sulfuric acid with pyridinemethanol (II) is subjected to chloroform solvent extraction, an oil-water solution, and solvent concentration to obtain a crude mirtazapine. In this method, the body is recrystallized with petroleum ether. In this method, mirtazapine had a large amount of methanol-insoluble components, and was not satisfactory as a quality of mirtazapine.
特許文献２におけるミルタザピンの製造方法はピリジンメタノール（II）を用いて、ミルタザピンの反応混合物をトルエン溶媒抽出、油水分液、溶媒濃縮を行ない、次いで、メタノールなどのアルコールを加えて活性炭処理を行なった後、水を加えて晶析を行ないミルタザピンを得る方法である。当該の方法では、得られるミルタザピンとメタノール溶媒とを、一定比率で混合溶解し、ミルタザピンのメタノール溶液に浮遊する不純物（濁り成分）であるミルタザピンのメタノール不溶物の除去効果が必ずしも十分ではない。 In the method for producing mirtazapine in Patent Document 2, a reaction mixture of mirtazapine was subjected to toluene solvent extraction, an oil-water solution, and solvent concentration using pyridine methanol (II), and then an alcohol such as methanol was added thereto to perform an activated carbon treatment. Thereafter, water is added for crystallization to obtain mirtazapine. In this method, the obtained mirtazapine and the methanol solvent are mixed and dissolved at a fixed ratio, and the effect of removing the methanol-insoluble matter of mirtazapine, which is an impurity (turbid component) suspended in the methanol solution of mirtazapine, is not necessarily sufficient.
特許文献３におけるミルタザピンの製造方法は、濃硫酸とピリジンメタノール（II）を反応させてえられるミルタザピンを含む反応混合物をトルエン溶媒抽出、油水分液を行ない、次いで、ヘプタンを加えて晶析してミルタザピンの粗体を得、この粗体をメタノールなどのアルコール溶媒中で活性炭処理を行なった後、溶媒濃縮して、プロパノールなどのアルコールとヘプタンの混合溶媒、あるいはプロパノールなどのアルコール水の溶媒を用い、再結晶を行なってミルタザピンを得る方法である。当該再結晶方法では、ミルタザピンのメタノール不溶物の除去効果が小さく、ミルタザピンの品質が必ずしも満足のいくものではないこと、および再結晶によるミルタザピンのロスを招くという問題がある。 In the method for producing mirtazapine in Patent Document 3, a reaction mixture containing mirtazapine obtained by reacting concentrated sulfuric acid and pyridinemethanol (II) is subjected to toluene solvent extraction, an oily water solution, and crystallization by adding heptane. A crude product of mirtazapine is obtained, the crude product is subjected to activated carbon treatment in an alcohol solvent such as methanol, and then the solvent is concentrated, and a mixed solvent of alcohol and heptane such as propanol or a solvent of alcohol water such as propanol is used. And recrystallization to obtain mirtazapine. The recrystallization method has a problem that the effect of mirtazapine to remove methanol insolubles is small, the quality of mirtazapine is not always satisfactory, and the loss of mirtazapine due to recrystallization is caused.
本願は、上記課題を解決する方法を提供するものであって、ミルタザピンの品質を向上できるミルタザピンの製造方法を提供する。 The present application provides a method for solving the above-described problem, and provides a method for producing mirtazapine that can improve the quality of mirtazapine.
本発明の製造方法及び化合物は、以下の態様を包含する。
１．有機溶媒中で、２−（４−メチル−2−フェニル−１−ピペラジニル）−３−ピリジンメタノールと無水酢酸とを反応させることを特徴とする〔２−（４−メチル−2−フェニルピペラジン−1−イル）ピリジン−３−イル〕メチルアセテートの製造方法。
２．前記反応により生成する〔２−（４−メチル−2−フェニルピペラジン−1−イル）ピリジン−３−イル〕メチルアセテートを含む有機溶媒溶液を中和して晶析母液を調製し、当該晶析母液から〔２−（４−メチル−2−フェニルピペラジン−1−イル）ピリジン−３−イル〕メチルアセテートを晶析する前項１に記載の製造方法。
３．有機溶媒が、水と不混和性の有機溶媒であり、晶析母液の調製が、中和した有機溶媒溶液の濃縮あるいは当該有機溶媒溶液に貧溶媒を添加するか、あるいはその両方で行われる前項２に記載の製造方法。
４．有機溶媒が、水と混和性の有機溶媒であり、晶析母液の調製が、中和した有機溶媒溶液の濃縮あるいは当該有機溶媒溶液に貧溶媒を添加するか、あるいはその両方で行われる前項２に記載の製造方法。
５．貧溶媒が水である前項４に記載の製造方法。
６．貧溶媒がヘキサンまたはヘプタンである請求項３に記載の製造方法。
７．有機溶媒が、脂肪族溶媒である、前項１、２、３または６に記載の製造方法。
８．脂肪族溶媒が、シクロヘキサンおよびメチルシクロヘキサンから選択される少なくとも１種である、前項７に記載の製造方法。
９．有機溶媒が、芳香族溶媒である、前項１，２、３または６に記載の製造方法。
１０．芳香族溶媒がトルエン、エチルベンゼン、キシレンから選択される少なくとも１種である、前項９に記載の製造方法。
１１．有機溶媒が、アセトンである前項１，２、４または５に記載の製造方法。
１２．有機溶媒が、メチルエチルケトンおよびメチルイソブチルケトンから選択される少なくとも１種である、前項１，２、３、または６に記載の製造方法。
１３．晶析母液に含まれる溶媒が、シクロヘキサンまたはメチルシクロヘキサンからなる単一溶媒である前項８に記載の製造方法。
１４．前項１〜１３のいずれか一項に記載の方法により〔２−（４−メチル−2−フェニルピペラジン−1−イル）ピリジン−３−イル〕メチルアセテートを得る工程、及び
〔２−（４−メチル−2−フェニルピペラジン−1−イル）ピリジン−３−イル〕メチルアセテートを濃硫酸中で反応させる工程を含む、１，２，３，４，１０，１４ｂ−ヘキサヒドロ−２−メチル−ピラジノ〔２，１−a〕ピリド〔２，３−c〕〔２〕ベンザセピンの製造方法。
１５．式（１）：
の〔２−（４−メチル−2−フェニルピペラジン−1−イル）ピリジン−３−イル〕メチルアセテート。
The production method and the compound of the present invention include the following embodiments.
1. Characterized in that 2- (4-methyl-2-phenyl-1-piperazinyl) -3-pyridinemethanol is reacted with acetic anhydride in an organic solvent [2- (4-methyl-2-phenylpiperazine- 1-yl) pyridin-3-yl] methyl acetate.
2. An organic solvent solution containing [2- (4-methyl-2-phenylpiperazin-1-yl) pyridin-3-yl] methyl acetate produced by the above reaction is neutralized to prepare a mother liquor for crystallization. 2. The production method according to the above item 1, wherein [2- (4-methyl-2-phenylpiperazin-1-yl) pyridin-3-yl] methyl acetate is crystallized from the mother liquor.
3. The organic solvent is an organic solvent immiscible with water, and the preparation of the crystallization mother liquor is performed by concentrating the neutralized organic solvent solution or adding a poor solvent to the organic solvent solution, or both. 3. The production method according to 2.
4. The organic solvent is an organic solvent that is miscible with water, and the preparation of the crystallization mother liquor is performed by concentrating the neutralized organic solvent solution, adding a poor solvent to the organic solvent solution, or both. The production method described in 1.
5. Item 5. The production method according to Item 4, wherein the poor solvent is water.
6. The method according to claim 3, wherein the poor solvent is hexane or heptane.
7. 7. The production method according to the above 1, 2, 3, or 6, wherein the organic solvent is an aliphatic solvent.
8. 8. The production method according to the above item 7, wherein the aliphatic solvent is at least one selected from cyclohexane and methylcyclohexane.
9. 7. The production method according to the above 1, 2, 3 or 6, wherein the organic solvent is an aromatic solvent.
10. 10. The production method according to the above item 9, wherein the aromatic solvent is at least one selected from toluene, ethylbenzene, and xylene.
11. 6. The production method according to the above 1, 2, 4 or 5, wherein the organic solvent is acetone.
12. 7. The production method according to the above 1, 2, 3, or 6, wherein the organic solvent is at least one selected from methyl ethyl ketone and methyl isobutyl ketone.
13. 9. The method according to the above item 8, wherein the solvent contained in the crystallization mother liquor is a single solvent consisting of cyclohexane or methylcyclohexane.
14． A step of obtaining [2- (4-methyl-2-phenylpiperazin-1-yl) pyridin-3-yl] methyl acetate by the method described in any one of the above items 1 to 13, and [2- (4- Methyl-2-phenylpiperazin-1-yl) pyridin-3-yl] methyl acetate in concentrated sulfuric acid, comprising 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino [ 2,1-a] pyrido [2,3-c] [2] benzacepin production method.
15. Equation (1):
[2- (4-Methyl-2-phenylpiperazin-1-yl) pyridin-3-yl] methyl acetate.
本発明の製造方法によれば、〔２−（４−メチル−2−フェニルピペラジン−1−イル）ピリジン−３−イル〕メチルアセテート（本明細書において、前述の式（I）で示される〔２−（４−メチル−2−フェニルピペラジン−1−イル）ピリジン−３−イル〕メチルアセテートを単にピリジンメチルアセテート（I）と示すこともある）を合成し、これを、濃硫酸中で反応させミルタザピンを製造することにより、ミルタザピンに含まれるメタノール不溶分を抑制でき、従来の方法とは異なり、高い品質のミルタザピンが得られる。また、ミルタザピンの精製操作を省略できるなど、特に工業スケールでの経済性に優れる。 According to the production method of the present invention, [2- (4-methyl-2-phenylpiperazin-1-yl) pyridin-3-yl] methyl acetate (in the present specification, represented by the aforementioned formula (I) [ 2- (4-methyl-2-phenylpiperazin-1-yl) pyridin-3-yl] methylacetate may be simply referred to as pyridinemethylacetate (I)) and reacted in concentrated sulfuric acid. By producing mirtazapine, the insoluble content of methanol contained in mirtazapine can be suppressed, and unlike the conventional method, high quality mirtazapine can be obtained. In addition, the process of purifying mirtazapine can be omitted.
いくつかの態様を例示して本発明について説明する。
〔１〕アセチル化
The present invention will be described with reference to some embodiments.
[1] Acetylation
〔２−（４−メチル−2−フェニルピペラジン−1−イル）ピリジン−３−イル〕メチルアセテート（I）は２−（４−メチル−2−フェニル−１−ピペラジニル）−３−ピリジンメタノール（II）と無水酢酸との反応によって得られる。 [2- (4-Methyl-2-phenylpiperazin-1-yl) pyridin-3-yl] methyl acetate (I) is 2- (4-methyl-2-phenyl-1-piperazinyl) -3-pyridinemethanol ( It is obtained by the reaction of II) with acetic anhydride.
有機溶媒としては、水と不混和性の有機溶媒あるいは水と混和性の有機溶媒が使用できる。本発明において、「水と不混和性の有機溶媒」とは、常温（２５℃）で水に完全に混ざらず油水分離する有機溶媒を示す。一方、本発明において、「水と混和性の有機溶媒」とは、常温（２５℃）で水に完全に混ざり合い油水分離しない有機溶媒を示す。水と不混和性の有機溶媒としては、シクロヘキサン、メチルシクロヘキサンなどの脂肪族溶媒（例えば、炭素数５〜８の脂肪族溶媒）、トルエン、エチルベンゼン、キシレンなどの芳香族溶媒（例えば、炭素数６〜９の芳香族炭化水素溶媒）等が挙げられる。メチルエチルケトン、メチルイソブチルケトンなどのケトン溶媒（例えば、アルキル部分の炭素数が合計１〜３であるジアルキルケトン（アルキルカルボニルアルカン））等が挙げられる。水と混和性の有機溶媒としては、アセトン等が挙げられる。これらの有機溶媒は、１種単独で又は２種以上を組み合わせて用いることができる。 As the organic solvent, an organic solvent immiscible with water or an organic solvent miscible with water can be used. In the present invention, “water-immiscible organic solvent” refers to an organic solvent that does not completely mix with water at normal temperature (25 ° C.) and separates into oil and water. On the other hand, in the present invention, the “water-miscible organic solvent” refers to an organic solvent which is completely mixed with water at normal temperature (25 ° C.) and does not separate oil and water. Examples of the organic solvent immiscible with water include aliphatic solvents such as cyclohexane and methylcyclohexane (for example, aliphatic solvents having 5 to 8 carbon atoms), and aromatic solvents such as toluene, ethylbenzene, and xylene (for example, those having 6 carbon atoms). To 9 aromatic hydrocarbon solvents). Examples thereof include ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone (for example, dialkyl ketone (alkylcarbonylalkane) having a total of 1 to 3 carbon atoms in the alkyl portion). Acetone etc. are mentioned as an organic solvent miscible with water. These organic solvents can be used alone or in combination of two or more.
有機溶媒の使用量は、アセトン溶媒を除き、２−（４−メチル−2−フェニル−１−ピペラジニル）−３−ピリジンメタノール（II）１重量部当たり、０．８〜５重量部の範囲が好ましく、より好ましくは１〜３重量部の範囲である。アセトン溶媒を用いる場合は、２−（４−メチル−2−フェニル−１−ピペラジニル）−３−ピリジンメタノール（II）１重量部当たり、０．８〜３重量部が好ましく、より好ましくは１〜１．５重量部の範囲が好ましい。 Except for the acetone solvent, the amount of the organic solvent used ranges from 0.8 to 5 parts by weight per 1 part by weight of 2- (4-methyl-2-phenyl-1-piperazinyl) -3-pyridinemethanol (II). Preferably, it is more preferably in the range of 1 to 3 parts by weight. When using an acetone solvent, the amount is preferably 0.8 to 3 parts by weight, more preferably 1 to 2 parts by weight, per part by weight of 2- (4-methyl-2-phenyl-1-piperazinyl) -3-pyridinemethanol (II). A range of 1.5 parts by weight is preferred.
無水酢酸の使用量としては、２−（４−メチル−2−フェニル−１−ピペラジニル）−３−ピリジンメタノール（II）１モル当たり、１．０〜１．５モルの範囲が好ましく、より好ましくは１．１〜１．３モルの範囲である。 The amount of acetic anhydride to be used is preferably in the range of 1.0 to 1.5 mol, more preferably 1 mol of 2- (4-methyl-2-phenyl-1-piperazinyl) -3-pyridinemethanol (II). Ranges from 1.1 to 1.3 moles.
無水酢酸の添加方法は、特に制限はないが、２−（４−メチル−2−フェニル−１−ピペラジニル）−３−ピリジンメタノール（II）と有機溶媒との混合液に、一挙に加える方法、連続的に滴下する方法、又は、間欠的に滴下する方法いずれの添加方法を用いでも良い。 The method of adding acetic anhydride is not particularly limited, but a method of adding it at once to a mixture of 2- (4-methyl-2-phenyl-1-piperazinyl) -3-pyridinemethanol (II) and an organic solvent, Either a continuous dropping method or an intermittent dropping method may be used.
無水酢酸の添加温度は用いる有機溶媒の物性によって異なるが、１０〜８０℃の範囲が好ましく、５０〜８０℃の範囲がより好ましい。無水酢酸の添加時間は特に制限はないが、通常、０．５〜６時間程度である。反応を完結させるために保温が行なわれ、保温時間は、好ましくは３〜１０時間程度である。保温の際の温度は、５０〜１００℃の範囲が好ましく、５５〜８０℃の範囲がより好ましい。 The temperature at which acetic anhydride is added depends on the physical properties of the organic solvent used, but is preferably in the range of 10 to 80C, more preferably in the range of 50 to 80C. The addition time of acetic anhydride is not particularly limited, but is usually about 0.5 to 6 hours. Warming is performed to complete the reaction, and the warming time is preferably about 3 to 10 hours. The temperature at the time of heat retention is preferably in the range of 50 to 100 ° C, more preferably in the range of 55 to 80 ° C.
〔２〕中和
本発明の好ましい実施形態において、上述した方法で得られたピリジンメチルアセテート（I）の反応混合物に水を加えた後、副生した酸のアルカリ中和処理が行われる。反応にアセトン溶媒を用いた場合には中和処理後に、そのまま晶析母液として晶析工程に付される。
[2] Neutralization In a preferred embodiment of the present invention, after water is added to the reaction mixture of pyridine methyl acetate (I) obtained by the above-described method, an alkali neutralization treatment of an acid produced as a by-product is performed. When an acetone solvent is used for the reaction, after the neutralization treatment, it is directly subjected to a crystallization step as a crystallization mother liquor.
反応混合物に加える水量は、アセトン溶媒を用いる場合を除き、特に制限はない。反応でアセトン溶媒を用いた場合には、加える水量はアセトン溶媒１重量部当たり、１〜３重量部程度である。ピリジンメチルアセテート（I）の加水分解を抑制する観点から、水の添加温度は３５℃以下が好ましい。 The amount of water added to the reaction mixture is not particularly limited, except when using an acetone solvent. When an acetone solvent is used in the reaction, the amount of water to be added is about 1 to 3 parts by weight per 1 part by weight of the acetone solvent. From the viewpoint of suppressing the hydrolysis of pyridine methyl acetate (I), the water addition temperature is preferably 35 ° C. or lower.
中和に用いるアルカリの種類は、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウムなどである。特にアルカリの形態に制限はないが、通常は水溶液が好ましく用いられる。これらのアルカリは、１種単独で又は２種以上を組み合わせて用いることができる。 The kind of alkali used for neutralization is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like. The form of the alkali is not particularly limited, but usually an aqueous solution is preferably used. These alkalis can be used alone or in combination of two or more.
中和におけるpHはピリジンメチルアセテート（I）の収率低下および加水分解を抑制する観点から、ｐＨは７．５〜９．０の範囲が好ましく、より好ましくはｐＨ８．０〜８．６の範囲である。中和温度は、３５℃以下が好ましく、通常、２０〜３０℃程度である。 The pH in the neutralization is preferably in the range of 7.5 to 9.0, more preferably in the range of pH 8.0 to 8.6, from the viewpoint of reducing the yield of pyridine methyl acetate (I) and suppressing hydrolysis. It is. The neutralization temperature is preferably 35 ° C or lower, and is usually about 20 to 30 ° C.
〔３〕水洗
本工程は反応溶媒に水と不混和性の有機溶媒（脂肪族溶媒、芳香族溶媒、メチルエチルケトン、メチルイソブチルケトン）を用いた場合のみ行なわれ、ケトン系溶媒のうちアセトンを用いた場合は、水洗処理は行わずに晶析工程で水を加えて晶析が行われる。
[3] Water washing This step is performed only when an organic solvent (aliphatic solvent, aromatic solvent, methyl ethyl ketone, methyl isobutyl ketone) that is immiscible with water is used as a reaction solvent, and acetone is used among ketone solvents. In this case, crystallization is performed by adding water in the crystallization step without performing the water washing treatment.
水洗したピリジンメチルアセテート（I）を含む、水と不混和性の有機溶媒溶液と水の混合液は、通常、４０〜６５℃程度まで加熱して水層部を分液し、さらに水を加えて水洗を行われる。 A water-immiscible organic solvent solution containing water-immiscible pyridine methyl acetate (I) and a mixture of water are usually heated to about 40 to 65 ° C. to separate the aqueous layer, and then water is added. Washing with water.
〔４〕脱水および溶媒濃縮
上記で得られたピリジンメチルアセテート（I）の有機溶媒溶液のうち、脂肪族溶媒（例えば、シクロヘキサンまたはメチルシクロヘキサン）の溶液の場合には、そのまま晶析に用いても良いが、通常、脱水を行なった後、晶析が行われる。脱水を行なう温度は、溶媒の沸点によって異なるが、溶媒が還流状態にあれば良く、還流時間は０．５〜２時間程度である。
芳香族溶媒（例えば、トルエン、エチルベンゼンまたはキシレン）の溶液およびケトン溶媒（例えば、メチルエチルケトンまたはメチルイソブチルケトン）の溶液の場合には、そのまま晶析に用いた場合は溶媒に対するピリジンメチルアセテート（I）の溶解度が高いため、収率の低下などを招くことから、混合液に含まれ有機溶媒の留去（溶媒濃縮）することが好ましい。濃縮後の溶媒濃度としては、１５〜２５重量％の範囲が好ましく、通常、濃縮液中の溶媒含有濃度の分析を行ない溶媒濃度の調整を行なう。濃縮液からの結晶を析出しつつ、収率も高める観点から、濃縮後の溶媒濃度を上記範囲とすることが好ましい。濃縮温度は４０〜６０℃が好ましく、減圧度は３〜１０kPa程度が好ましい。
[4] Dehydration and solvent concentration In the organic solvent solution of pyridine methyl acetate (I) obtained above, in the case of a solution of an aliphatic solvent (for example, cyclohexane or methylcyclohexane), it can be used for crystallization as it is. Although good, crystallization is usually performed after dehydration. The temperature at which dehydration is performed depends on the boiling point of the solvent, but it is sufficient that the solvent is in a reflux state, and the reflux time is about 0.5 to 2 hours.
In the case of a solution of an aromatic solvent (for example, toluene, ethylbenzene or xylene) and a solution of a ketone solvent (for example, methyl ethyl ketone or methyl isobutyl ketone), when pyridine methyl acetate (I) is used for crystallization as it is, Since the solubility is high and the yield is reduced, it is preferable to distill off the organic solvent (solvent concentration) contained in the mixed solution. The concentration of the solvent after the concentration is preferably in the range of 15 to 25% by weight. Usually, the concentration of the solvent in the concentrated solution is analyzed to adjust the concentration of the solvent. From the viewpoint of increasing the yield while precipitating the crystals from the concentrated solution, it is preferable that the solvent concentration after the concentration be within the above range. The concentration temperature is preferably 40 to 60 ° C, and the degree of reduced pressure is preferably about 3 to 10 kPa.
〔５〕晶析工程
晶析母液を徐々に冷却することによりミルタザピンを析出させることができる。例えば、脂肪族溶媒の溶液や濃縮した芳香族溶媒の溶液に貧溶媒を加えて晶析母液を調製することができる。前記アセチル化工程に水と不混和性の溶媒を用いた場合、貧溶媒としては、通常、ヘキサンまたはｎ−ヘプタンが用いられる。これらの貧溶媒は、１種単独で又は２種以上を組み合わせて用いることができる。
脂肪族溶媒の溶液から晶析母液を調製する場合、晶析母液中の貧溶媒含有量は、２０〜５０重量％が好ましく、より好ましくは３０〜４０重量％程度である。
晶析母液を構成する溶媒の量は、ピリジンメタノール（II）１重量当たり、２〜１０重量部が好ましい。
[5] Crystallization Step Mirtazapine can be precipitated by gradually cooling the crystallized mother liquor. For example, a crystallization mother liquor can be prepared by adding a poor solvent to an aliphatic solvent solution or a concentrated aromatic solvent solution. When a water-immiscible solvent is used in the acetylation step, hexane or n-heptane is usually used as the poor solvent. These poor solvents can be used alone or in combination of two or more.
When the crystallization mother liquor is prepared from a solution of an aliphatic solvent, the content of the poor solvent in the crystallization mother liquor is preferably 20 to 50% by weight, more preferably about 30 to 40% by weight.
The amount of the solvent constituting the crystallization mother liquor is preferably 2 to 10 parts by weight per 1 part by weight of pyridinemethanol (II).
使用量は、脱水混合物の場合は、ピリジンメタノール（II）１重量当たり、２〜１０重量部、アセトン溶媒混合物の場合には、ピリジンメタノール（II）１重量当たり、３〜３０重量が好ましく、より好ましくは５〜１５重量部程度である。貧溶媒を加える温度は好ましくは３０〜６０℃程度である。 The amount used is preferably 2 to 10 parts by weight per pyridine methanol (II) in the case of a dehydrated mixture, and 3 to 30 parts by weight per pyridine methanol (II) in an acetone solvent mixture. It is preferably about 5 to 15 parts by weight. The temperature at which the poor solvent is added is preferably about 30 to 60 ° C.
芳香族溶媒の溶液から晶析母液を調製する場合、晶析母液中の貧溶媒含有量は、７０〜９０重量％が好ましく、より好ましくは７５〜８５重量％程度である。 When the crystallization mother liquor is prepared from a solution of an aromatic solvent, the content of the poor solvent in the crystallization mother liquor is preferably from 70 to 90% by weight, more preferably about 75 to 85% by weight.
水と混和性の有機溶媒（例えば、アセトン）を用いた場合は、水を貧溶媒として添加して晶析母液が調製される。この場合の晶析母液中の貧溶媒である水の含有量は、９０〜７５％が好ましく、より好ましくは８０〜８５重量％程度である。晶析母液を構成する有機溶媒の量は、ピリジンメタノール（II）１重量当たり、３〜３０重量が好ましく、より好ましくは５〜１５重量部程度である。 When an organic solvent miscible with water (eg, acetone) is used, water is added as a poor solvent to prepare a crystallization mother liquor. In this case, the content of water as a poor solvent in the crystallization mother liquor is preferably 90 to 75%, more preferably about 80 to 85% by weight. The amount of the organic solvent constituting the crystallization mother liquor is preferably 3 to 30 parts by weight, more preferably about 5 to 15 parts by weight, per 1 part of pyridine methanol (II).
晶析母液の調製の際に貧溶媒を加える温度は３０〜６０℃程度である。晶析は種晶を接種して行われる。 The temperature at which the poor solvent is added during the preparation of the crystallization mother liquor is about 30 to 60 ° C. Crystallization is performed by inoculating seed crystals.
種晶の接種温度は、水と不混和性の有機溶媒を使用した場合は、通常、３０〜３５℃あり、水と混和性の有機溶媒を使用した場合は、通常、０〜５℃程度ある。結晶の熟成時間は、水と不混和性の有機溶媒を使用した場合は、接種温度と同温度で、通常、２〜７時間程度行われ、水と混和性の容器溶媒を使用した場合は、接種温度と同温度で、通常、１２〜２０時間程度行われる。 The seed crystal inoculation temperature is usually 30 to 35 ° C. when an organic solvent immiscible with water is used, and is usually about 0 to 5 ° C. when an organic solvent immiscible with water is used. . The ripening time of the crystal is usually about 2 to 7 hours at the same temperature as the inoculation temperature when an organic solvent immiscible with water is used, and when a water-miscible container solvent is used, It is usually carried out at the same temperature as the inoculation temperature for about 12 to 20 hours.
熟成されたピリジンメチルアセテート（I）の懸濁溶液は、徐々に冷却することにより、容器壁面への結晶付着が抑制され、さらにはピリジンメチルアセテート（I）の結晶をさらに析出させる。冷却温度は５〜−１０℃程度、より好ましくは０〜-１０℃まで徐々に冷却することにより、ピリジンメチルアセテート（I）の結晶をさらに析出させる。
冷却後は、同温度で１時間以上保温することが好ましい。
析出した結晶を、濾過等によって母液から分離し、洗浄することにより、目的とするピリジンメチルアセテート（I）の湿潤結晶を得ることができる。
The cooled suspension of the aged pyridine methyl acetate (I) is gradually cooled to suppress the adhesion of crystals to the vessel wall, and further precipitate the crystals of pyridine methyl acetate (I). The pyridine methyl acetate (I) crystal is further precipitated by gradually cooling to a cooling temperature of about 5 to -10 ° C, more preferably 0 to -10 ° C.
After cooling, it is preferable to keep the temperature at the same temperature for 1 hour or more.
The precipitated crystals are separated from the mother liquor by filtration or the like, and washed to obtain the desired wet crystals of pyridine methyl acetate (I).
湿潤結晶の乾燥は、通常、減圧下で加熱して行われ、乾燥温度は、好ましくは、２０〜６５℃の範囲、より好ましくは３０〜５０℃の範囲で行われる。乾燥温度が７０℃以上では結晶が融解するため好ましくない。 Drying of the wet crystals is usually performed by heating under reduced pressure, and the drying temperature is preferably in the range of 20 to 65 ° C, more preferably in the range of 30 to 50 ° C. If the drying temperature is 70 ° C. or higher, the crystals melt, which is not preferable.
かかる方法で得られた〔２−（４−メチル−2−フェニルピペラジン−1−イル）ピリジン−３−イル〕メチルアセテートは、濃硫酸中で脱水閉環反応に供して１，２，３，４，１０，１４ｂ−ヘキサヒドロ−２−メチル−ピラジノ〔２，１−a〕ピリド〔２，３−c〕〔２〕ベンザセピン（IV）を製造することができる。 [2- (4-Methyl-2-phenylpiperazin-1-yl) pyridin-3-yl] methyl acetate obtained by this method is subjected to a dehydration ring-closure reaction in concentrated sulfuric acid to give 1,2,3,4. , 10,14b-Hexahydro-2-methyl-pyrazino [2,1-a] pyrido [2,3-c] [2] benzacepin (IV).
上記脱水閉環反応は、自体公知の方法で行うことができる。
本発明の化合物が、光学異性体、立体異性体、位置異性体、回転異性体等の異性体を有する場合、そうでないことが明らかでない限り、いずれの異性体も、異性体の混合物も本発明化合物に包含される。同様に本発明の方法における原料化合物が、光学異性体、立体異性体、位置異性体、回転異性体等の異性体を有する場合、そうでないことが明らかでない限り、いずれの異性体も、当該異性体の混合物を用いた方法も本発明に包含される。同様に、本発明の方法には、そうでないことが明らかでない限り、反応中間体及び／又は反応生成物がいずれかの異性体又は異性体の混合物である方法が包含される。
The above dehydration ring closure reaction can be performed by a method known per se.
When the compound of the present invention has isomers such as optical isomers, stereoisomers, positional isomers, rotamers, etc., unless otherwise apparent, any isomers or mixtures of isomers are used in the present invention. Included in the compound. Similarly, when the raw material compound in the method of the present invention has isomers such as optical isomers, stereoisomers, positional isomers, rotamers, etc. Methods using mixtures of bodies are also encompassed by the present invention. Similarly, the methods of the present invention include those where the reaction intermediate and / or reaction product is any isomer or mixture of isomers, unless otherwise indicated.
以下、実施例等により本発明をさらに詳しく説明するが、本発明はこれらの例によって限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples and the like, but the present invention is not limited to these Examples.
〔ピリジンメチルアセテートの製造〕
温度計、攪拌装置、冷却管を備えた容器中に、シクロヘキサン５４．０重量部、２−（４−メチル−2−フェニルピペラジニル）−３−ピリジンメタノール４５．０重量部を仕込み、次いで、撹拌下に７０℃まで加熱し、無水酢酸（１８．６）重量部を６５〜７５℃の範囲で３時間をかけて滴下し、次いで、同温度で約５時間保温してピリジンメチルアセテート（I）の反応液を得た。その後、３５℃に冷却し、反応液中にシクロヘキサン１３．５重量部を仕込み、その後、水４５．０重量部を３５℃以下で滴下した。次いで、２５％水酸化ナトリウム水溶液を用い反応混合液を中和し、ｐH８．３に調整した。その後、６０℃まで加熱し、分液して水層を除去した。次いで、撹拌下に水３５．０重量部を仕込み、約６０℃で０．５時間撹拌し、同温度で分液して水層を除去した。その後、８３℃まで加熱し、溶媒の還流温度で１時間をかけで脱水を行った後、約３５℃まで冷却し、３５〜３０℃で混合液中にｎ−ヘプタン４５．０重量部を仕込み、次いで、約３５℃で種晶を加えて結晶を析出させ、同温度で６時間保温した。その後、約−５℃まで徐々に冷却し、同温度で１時間保温した後濾過し、氷冷ｎ−ヘプタンで洗浄し、４０℃／１ｋＰａで乾燥を行なって、ピリジンメチルアセテート（I）の結晶４８．１重量部（収率９３．０％）を得た。この結晶を液体クロマトグラフィーで分析した。
(Production of pyridine methyl acetate)
In a vessel equipped with a thermometer, a stirrer, and a condenser, 54.0 parts by weight of cyclohexane and 45.0 parts by weight of 2- (4-methyl-2-phenylpiperazinyl) -3-pyridinemethanol were charged. Then, the mixture was heated to 70 ° C. with stirring, acetic anhydride (18.6) parts by weight was added dropwise over a period of 3 hours in the range of 65 to 75 ° C., and then kept at the same temperature for about 5 hours to obtain pyridine methyl acetate ( The reaction solution of I) was obtained. Thereafter, the mixture was cooled to 35 ° C., 13.5 parts by weight of cyclohexane was charged into the reaction liquid, and 45.0 parts by weight of water was added dropwise at 35 ° C. or lower. Next, the reaction mixture was neutralized with a 25% aqueous sodium hydroxide solution and adjusted to pH 8.3. Thereafter, the mixture was heated to 60 ° C., and liquid separation was performed to remove an aqueous layer. Next, 35.0 parts by weight of water was charged with stirring, the mixture was stirred at about 60 ° C. for 0.5 hour, and liquid separation was performed at the same temperature to remove an aqueous layer. Thereafter, the mixture is heated to 83 ° C., dehydrated at the reflux temperature of the solvent for 1 hour, cooled to about 35 ° C., and charged with 45.0 parts by weight of n-heptane at 35 to 30 ° C. Then, seed crystals were added at about 35 ° C. to precipitate crystals, and the mixture was kept at the same temperature for 6 hours. Thereafter, the mixture was gradually cooled to about −5 ° C., kept at the same temperature for 1 hour, filtered, washed with ice-cooled n-heptane, and dried at 40 ° C./1 kPa to obtain a crystal of pyridine methyl acetate (I). 48.1 parts by weight (yield 93.0%) were obtained. The crystals were analyzed by liquid chromatography.
〔ピリジンメチルアセテートの製造〕
シクロヘキサンの代わりにメチルシクロヘキサン１１２．５重量部を用い、貧溶媒ｎ−ヘプタンを用いず、接種温度および保温温度３０℃、濾過温度０℃とした以外は実施例１と同様の操作を行ない、ピリジンメチルアセテート（I）の結晶４６．２重量部（収率８９．３％）を得た。純度９９．６％
(Production of pyridine methyl acetate)
The same operation as in Example 1 was carried out except that 112.5 parts by weight of methylcyclohexane was used instead of cyclohexane, the poor solvent n-heptane was not used, the inoculation temperature and the incubation temperature were 30 ° C., and the filtration temperature was 0 ° C. 46.2 parts by weight of crystals of methyl acetate (I) were obtained (yield: 89.3%). 99.6% purity
〔ピリジンメチルアセテートの製造〕
溶媒をシクロヘキサンの代わりにトルエンを用い、反応から水洗分液操作まで実施例１と同様の操作を行ない、その後、６０〜５０℃の範囲で減圧濃縮してトルエン約５０重量部を留去した。（濃縮液中のトルエン含有量２２．６重量％）、その後、約３５℃まで冷却し、濃縮混合液中にｎ−ヘプタン５４．０重量部を３５〜３０℃の範囲内で滴下し、その後、約３０℃で種晶を加えて結晶を析出させ、同温度で２時間保温した。その後、約０℃まで徐々に冷却し、同温度で１時間保温した。その後、０℃まで冷却して濾過し、氷冷ｎ−ヘプタンで洗浄し、５０℃／１ｋＰａで乾燥を行なって、ピリジンメチルアセテート（I）の結晶４６．２重量部（収率８９．４％）を得た。
(Production of pyridine methyl acetate)
Using toluene as the solvent in place of cyclohexane, the same operation as in Example 1 was performed from the reaction to the washing and separation operation with water, followed by concentration under reduced pressure in the range of 60 to 50 ° C. to distill off about 50 parts by weight of toluene. (Toluene content in concentrate: 22.6% by weight) Then, the mixture was cooled to about 35 ° C, and 54.0 parts by weight of n-heptane was dropped into the concentrated mixture within the range of 35 to 30 ° C, and thereafter At about 30 ° C., seed crystals were added to precipitate crystals, and the mixture was kept at the same temperature for 2 hours. Thereafter, the mixture was gradually cooled to about 0 ° C. and kept at the same temperature for 1 hour. Thereafter, the mixture was cooled to 0 ° C., filtered, washed with ice-cooled n-heptane, and dried at 50 ° C./1 kPa to obtain 46.2 parts by weight of pyridine methyl acetate (I) crystals (yield: 89.4%). ) Got.
〔ピリジンメチルアセテートの製造〕
溶媒をシクロヘキサンの代わりにメチルイソブチルケトンを用い、反応から水洗分液操作まで実施例１と同様の操作を行ない、その後、６０〜５０℃の範囲で減圧濃縮してメチルイソブチルケトン約４８重量部を留去（濃縮液中のメチルイソブチルケトン含有量１６．３重量％）およびｎ−ヘプタン１３５．０重量部を用いて結晶析出させた以外は実施例３と同様の操作を行ない、ピリジンメチルアセテート（I）の結晶４６．５重量部（収率８９．９％）を得た。
(Production of pyridine methyl acetate)
Using methyl isobutyl ketone as the solvent instead of cyclohexane, the same operation as in Example 1 was performed from the reaction to the washing and separation operation with water, and then concentrated under reduced pressure in the range of 60 to 50 ° C. to obtain about 48 parts by weight of methyl isobutyl ketone. The same operation as in Example 3 was carried out except for distilling off (the content of methyl isobutyl ketone in the concentrated liquid was 16.3% by weight) and crystallizing out using 135.0 parts by weight of n-heptane, to give pyridine methyl acetate ( 46.5 parts by weight of the crystal of I) were obtained (yield: 89.9%).
〔ピリジンメチルアセテートの製造〕
溶媒をシクロヘキサンの代わりにアセトン４５．０重量部、無水酢酸２０．４重量を用い、５０〜５５℃で１２時間で保温した以外は、実施例１と同様の操作を行なった。その後、３５℃に冷却し、同温度で水４５．０重量部を加え、２５％水酸化ナトリウム水溶液を用い反応混合液を中和し、ｐH８．０に調整した。次いで、３５〜３０℃で水９０．０重量部を加え、約５℃まで冷却し、同温度で種晶を加え、１２時間保温して結晶を析出させ、濾過し、５％アセトン水６７．５重量で洗浄し、５０℃／１ｋＰａで乾燥を行なって、ピリジンメチルアセテート（I）の結晶４５．７重量部（収率８８．４％）を得た。
(Production of pyridine methyl acetate)
The same operation as in Example 1 was performed, except that 45.0 parts by weight of acetone and 20.4 parts by weight of acetic anhydride were used instead of cyclohexane and the temperature was kept at 50 to 55 ° C. for 12 hours. Thereafter, the mixture was cooled to 35 ° C., 45.0 parts by weight of water was added at the same temperature, and the reaction mixture was neutralized with a 25% aqueous sodium hydroxide solution to adjust the pH to 8.0. Next, 90.0 parts by weight of water was added at 35 to 30 ° C., the mixture was cooled to about 5 ° C., seed crystals were added at the same temperature, and the mixture was kept warm for 12 hours to precipitate crystals, filtered and filtered. The mixture was washed with 5 parts by weight and dried at 50 ° C./1 kPa to obtain 45.7 parts by weight of pyridine methyl acetate (I) crystals (yield: 88.4%).
〔ミルタザピン（IV）の製造〕
（製造例１）
温度計、攪拌装置、冷却管を備えた容器中に、９６．３％濃硫酸 １４７．４重量部を仕込み、撹拌下に１５℃まで冷却し、実施例1で得た〔２−（４−メチル−2−フェニルピペラジン−1−イル）ピリジン−３−イル〕メチルアセテート４７．１重量部（ピリジンメタノール換算４１．０重量部）を３５℃以下で２時間かけて徐々に仕込んだ。次いで、５５℃まで加熱し、同温度で５時間保温した。その後、１０℃以下に冷却して水１４０．０重量部を３５℃以下で滴下した。次いで、同温度の範囲で２５％水酸化ナトリウム水溶液で中和を行ない、ｐＨ約７．１に調整した後、トルエン２８７．０重量部を加え、６０℃まで加熱し、同温度で約１時間保温した。次いで、水層部を分液除去し、ミルタザピンのトルエン溶液３９５．２重量部を得た。
[Production of mirtazapine (IV)]
(Production Example 1)
147.3 parts by weight of 96.3% concentrated sulfuric acid was charged into a vessel equipped with a thermometer, a stirrer, and a cooling pipe, and cooled to 15 ° C. with stirring, to obtain the compound obtained in Example 1 [2- (4- Methyl-2-phenylpiperazin-1-yl) pyridin-3-yl] methyl acetate 47.1 parts by weight (41.0 parts by weight in terms of pyridine methanol) was gradually charged at 35 ° C. or lower over 2 hours. Next, the mixture was heated to 55 ° C. and kept at the same temperature for 5 hours. Thereafter, the mixture was cooled to 10 ° C or lower, and 140.0 parts by weight of water was added dropwise at 35 ° C or lower. Next, neutralization is performed with a 25% aqueous sodium hydroxide solution in the same temperature range, the pH is adjusted to about 7.1, 287.0 parts by weight of toluene are added, the mixture is heated to 60 ° C., and is heated at the same temperature for about 1 hour. Insulated. Next, the aqueous layer was separated and removed to obtain 395.2 parts by weight of a toluene solution of mirtazapine.
〔ミルタザピン（IV）の製造〕
製造例１で得たミルタザピンのトルエン溶液１９２．８重量部を用い、６０〜５０℃の範囲で減圧濃縮してトルエンを約１５２．７重量部を留去し、次いで、メタノール７９．２重量部仕込んだ。その後、約５０℃で減圧濃縮してメタノールを約４３．０重量部を留去した後、メタノール４１．２重量部を仕込んだ。その後、５℃まで冷却し、活性炭３．０重量部を仕込み、同温度で１時間保温して活性炭を濾過し、ミルタザピンを含むトルエン、メタノールの混合液を得た。（混合液中のトルエン含有量９．７重量％）次いで、約５５℃に加熱した後、水２００．０重量部を５５〜５０℃で約１時間をかけて滴下した。その後、約５０〜４７℃で種晶を接種して結晶を析出させ、次いで、２５℃まで約３時間をかけて冷却し、同温度で１時間保温した後、約２時間をかけて５℃まで冷却し、同温度で約１時間保温して濾過し、１９％メタノール水溶液２４．８重量部で洗浄し、６０℃／１ｋＰａで乾燥を行なって、ミルタザピン（IV）の結晶１６．１重量部を得た。混合液中の有機溶媒は、ガスクロマトグラフィー分析、結晶は液体クロマトグラフィー分析および濁度試験装置で濁度（メタノール不溶分）を測定した。
[Production of mirtazapine (IV)]
Using 192.8 parts by weight of a toluene solution of mirtazapine obtained in Production Example 1, the mixture was concentrated under reduced pressure in the range of 60 to 50 ° C. to distill off about 152.7 parts by weight of toluene, and then 79.2 parts by weight of methanol I charged. Thereafter, the mixture was concentrated under reduced pressure at about 50 ° C. to distill off about 43.0 parts by weight of methanol, and then 41.2 parts by weight of methanol was charged. Thereafter, the mixture was cooled to 5 ° C., charged with 3.0 parts by weight of activated carbon, kept at the same temperature for 1 hour, and the activated carbon was filtered to obtain a mixture of toluene and methanol containing mirtazapine. (Toluene content in the mixture: 9.7% by weight) Then, after heating to about 55 ° C, 200.0 parts by weight of water was added dropwise at 55 to 50 ° C over about 1 hour. Thereafter, seed crystals are inoculated at about 50 to 47 ° C. to precipitate crystals, then cooled to 25 ° C. over about 3 hours, kept at the same temperature for 1 hour, and then kept at 5 ° C. for about 2 hours. After cooling at the same temperature for about 1 hour, the mixture was filtered, washed with 24.8 parts by weight of a 19% aqueous methanol solution, and dried at 60 ° C./1 kPa to obtain 16.1 parts by weight of mirtazapine (IV) crystals. I got The organic solvent in the mixture was analyzed by gas chromatography, and the crystals were analyzed by liquid chromatography and the turbidity (methanol insoluble content) was measured by a turbidity test device.
〔ミルタザピン（IV）の製造〕
溶媒の減圧濃縮でのトルエン留去量１４１．０重量部、メタノール留去量４１．０重量部を行ない、メタノール活性炭濾過後のミルタザピンを含むトルエン、メタノールの混合液（混合液中のトルエン含有量１５．９重量％）を得た以外は、実施例６と同様の操作を行ない、ミルタザピン（IV）の結晶１５．１重量部を得た。混合液中の有機溶媒は、ガスクロマトグラフィー分析、結晶は液体クロマトグラフィー分析および濁度試験装置で濁度（メタノール不溶分）を測定した。
[Production of mirtazapine (IV)]
After distilling off 141.0 parts by weight of toluene and 41.0 parts by weight of methanol by concentration of the solvent under reduced pressure, a mixed liquid of toluene and methanol containing mirtazapine after filtration with methanol activated carbon (toluene content in the mixed liquid) (15.9% by weight), and 15.1 parts by weight of mirtazapine (IV) crystals were obtained in the same manner as in Example 6. The organic solvent in the mixture was analyzed by gas chromatography, and the crystals were analyzed by liquid chromatography and the turbidity (methanol insoluble content) was measured by a turbidity test device.
〔ミルタザピン（IV）の製造〕
（製造例２）
〔２−（４−メチル−2−フェニルピペラジン−1−イル）ピリジン−３−イル〕メチルアセテートの代わりに、２−（４−メチル−2−フェニル−１−ピペラジニル）−３−ピリジンメタノール４１．０重量部を用いた以外は製造例１と同様の操作を行ない、ミルタザピンのトルエン溶液３９１．４重量部を得た。
[Production of mirtazapine (IV)]
(Production Example 2)
Instead of [2- (4-methyl-2-phenylpiperazin-1-yl) pyridin-3-yl] methyl acetate, 2- (4-methyl-2-phenyl-1-piperazinyl) -3-pyridinemethanol 41 The same operation as in Production Example 1 was performed except that 0.0 parts by weight was used, to obtain 391.4 parts by weight of a toluene solution of mirtazapine.
〔ミルタザピン（IV）の製造〕
（製造例２）で得たミルタザピンのトルエン溶液１９０．９重量部[ピリジンメタノール（II）換算２０．０重量部相当]を用い、溶媒の減圧濃縮でのトルエン留去量１５４．６重量部、メタノール留去量４０．０重量部を行ない、メタノール活性炭濾過後のミルタザピンを含むトルエン、メタノールの混合液（混合液中のトルエン含有量９．７重量％）を得た以外は、実施例６と同様の操作を行ない、ミルタザピン（IV）の結晶１６．０重量部を得た。混合液中の有機溶媒は、ガスクロマトグラフィー分析、結晶は液体クロマトグラフィー分析および濁度試験装置で濁度（メタノール不溶分）を測定した。
[Production of mirtazapine (IV)]
Using 190.9 parts by weight of a toluene solution of mirtazapine obtained in (Production Example 2) [equivalent to 20.0 parts by weight in terms of pyridinemethanol (II)], 154.6 parts by weight of toluene distilled off under reduced pressure of the solvent, Example 6 was repeated except that methanol was distilled off at 40.0 parts by weight to obtain a mixed solution of toluene and methanol containing mirtazapine after filtration with methanol activated carbon (toluene content in the mixed solution: 9.7% by weight). The same operation was carried out to obtain 16.0 parts by weight of mirtazapine (IV) crystals. The organic solvent in the mixture was analyzed by gas chromatography, and the crystals were analyzed by liquid chromatography and turbidity (methanol insolubles) by a turbidity test device.
〔ミルタザピン（IV）の製造〕
（製造例２）で得たミルタザピンのトルエン溶液１９０．９重量部[ピリジンメタノール（II）換算２０．０重量部相当]を用い、溶媒の減圧濃縮でのトルエン留去量１５８．９重量部、メタノール留去量４２．５重量部を行ない、メタノール活性炭濾過後のミルタザピンを含むトルエン、メタノールの混合液（混合液中のトルエン含有量１３．９重量％）を得た以外は、実施例６と同様の操作を行ない、ミルタザピン（IV）の結晶１５．４重量部を得た。混合液中の有機溶媒は、ガスクロマトグラフィー分析、結晶は液体クロマトグラフィー分析および濁度試験装置で濁度（メタノール不溶分）を測定した。
[Production of mirtazapine (IV)]
Using 190.9 parts by weight of a toluene solution of mirtazapine obtained in (Production Example 2) [equivalent to 20.0 parts by weight in terms of pyridinemethanol (II)], 158.9 parts by weight of toluene distilled off under reduced pressure of the solvent, Example 6 was repeated except that methanol was distilled off at 42.5 parts by weight to obtain a mixture of toluene and methanol containing mirtazapine after filtration with methanol activated carbon (toluene content in the mixture: 13.9% by weight). The same operation was performed to obtain 15.4 parts by weight of mirtazapine (IV) crystals. The organic solvent in the mixture was analyzed by gas chromatography, and the crystals were analyzed by liquid chromatography and the turbidity (methanol insoluble content) was measured by a turbidity test device.
〔ミルタザピン（IV）の再結晶精製〕
温度計、攪拌装置、冷却管を備えた容器中に、比較例１で得たミルタザピン（IV）５.０重量部を用い、イソプロピルアルコール４．５重量部を仕込み、撹拌下に７５〜８０℃で溶解させた後、約７５〜６０℃でｎ−ヘプタン４４．２重量を滴下した。次いで、５０℃まで冷却し、種晶を接種して結晶を析出させ、同温度で１時間保温した。その後、５℃まで約３時間をかけて冷却し、同温度で１時間保温して濾過し、６０℃／１ｋＰａで乾燥を行なって、ミルタザピン（IV）の結晶４．０重量部を得た。この結晶を液体クロマトグラフィー分析および濁度試験装置で濁度（メタノール不溶分）を測定した。
[Recrystallization purification of mirtazapine (IV)]
Using 5.0 parts by weight of mirtazapine (IV) obtained in Comparative Example 1 and 4.5 parts by weight of isopropyl alcohol in a container equipped with a thermometer, a stirrer, and a cooling tube, and stirring at 75 to 80 ° C. Then, 44.2 weight of n-heptane was added dropwise at about 75 to 60 ° C. Next, the mixture was cooled to 50 ° C., seed crystals were inoculated to precipitate crystals, and the mixture was kept at the same temperature for 1 hour. Thereafter, the mixture was cooled to 5 ° C. over about 3 hours, kept at the same temperature for 1 hour, filtered, and dried at 60 ° C./1 kPa to obtain 4.0 parts by weight of mirtazapine (IV) crystals. The turbidity (methanol-insoluble content) of the crystals was measured by liquid chromatography analysis and a turbidity test device.
〔ミルタザピン（IV）の再結晶精製〕
比較例２で得たミルタザピン５.０重量部用い、イソプロピルアルコール１１．８重量部を仕込み、撹拌下に７５〜８０℃で溶解させた後、約７５〜６０℃でｎ−ヘプタン１０２．６重量を滴下した。次いで、２０℃まで冷却し、種晶を接種して結晶を析出させ、同温度で１時間保温した。その後、５℃まで約１時間をかけて冷却し、同温度で１時間保温して濾過し、６０℃／１ｋＰａで乾燥を行なって、ミルタザピン（IV）の結晶２．６重量部を得た。この結晶を液体クロマトグラフィー分析および濁度試験装置で濁度（メタノール不溶分）を測定した。
[Recrystallization purification of mirtazapine (IV)]
Using 5.0 parts by weight of mirtazapine obtained in Comparative Example 2, 11.8 parts by weight of isopropyl alcohol was charged and dissolved at 75 to 80 ° C. with stirring, and then 102.6 parts by weight of n-heptane at about 75 to 60 ° C. Was added dropwise. Then, the mixture was cooled to 20 ° C., seed crystals were inoculated to precipitate crystals, and the mixture was kept at the same temperature for 1 hour. Thereafter, the mixture was cooled to 5 ° C. over about 1 hour, kept at the same temperature for 1 hour, filtered, and dried at 60 ° C./1 kPa to obtain 2.6 parts by weight of mirtazapine (IV) crystals. The turbidity (methanol-insoluble content) of the crystals was measured by liquid chromatography analysis and a turbidity test device.
〔ミルタザピン（IV）の再結晶精製〕
比較例２で得たミルタザピン５.０重量部用い、イソプロピルアルコール１５．７重量部を仕込み、撹拌下に７５〜８０℃で溶解させた後、約７５〜６５℃で水４０．０重量を約１時間をかけて滴下し、結晶を析出させた。次いで、６０℃まで冷却し、同温度で１時間保温した。その後、５℃まで約３時間をかけて冷却し、同温度で１時間保温して濾過し、６０℃／１ｋＰａで乾燥を行なって、ミルタザピン（IV）の結晶２．８重量部を得た。この結晶を液体クロマトグラフィー分析および濁度試験装置で濁度（メタノール不溶分）を測定した。
[Recrystallization purification of mirtazapine (IV)]
Using 5.0 parts by weight of mirtazapine obtained in Comparative Example 2, 15.7 parts by weight of isopropyl alcohol was charged and dissolved at 75 to 80 ° C. with stirring, and then 40.0 parts by weight of water at about 75 to 65 ° C. The solution was added dropwise over 1 hour to precipitate crystals. Next, it was cooled to 60 ° C. and kept at the same temperature for 1 hour. Thereafter, the mixture was cooled to 5 ° C. over about 3 hours, kept at the same temperature for 1 hour, filtered, and dried at 60 ° C./1 kPa to obtain 2.8 parts by weight of mirtazapine (IV) crystals. The turbidity (methanol-insoluble content) of the crystals was measured by liquid chromatography analysis and a turbidity test device.
実施例１〜５についてはピリジンメチルアセテート（I）の反応および晶析に用いた溶媒の種類、晶析溶媒中の含有量、溶媒の合計量、および実施例６〜７および比較例１〜５について、ミルタザピンの反応に用いた原料の種類、晶析で用いた溶媒の種類、溶媒の合計量、ミルタザピン（IV）の収率、不純物の含有量、濁度（メタノール不溶分）実施例６〜７についてはピリジンメチルアセテート（I）を用いたミルタザピン（IV）の製造例、比較例１〜２についてはピリジンメタノール（II）を製造例、比較例３〜５についてはミルタザピン（IV）の再結晶精製の製造例を表１〜２にまとめて示す。 About Examples 1-5, the kind of the solvent used for the reaction and crystallization of pyridine methyl acetate (I), the content in the crystallization solvent, the total amount of the solvent, and Examples 6-7 and Comparative Examples 1-5 About the kind of raw materials used in the reaction of mirtazapine, the kind of solvent used in the crystallization, the total amount of the solvent, the yield of mirtazapine (IV), the content of impurities, and the turbidity (methanol-insoluble matter). 7 is a production example of mirtazapine (IV) using pyridine methyl acetate (I), Comparative Examples 1 and 2 are production examples of pyridine methanol (II), and Comparative Examples 3 to 5 are recrystallization of mirtazapine (IV). Production examples of purification are shown in Tables 1 and 2.
混合物中の有機溶媒（トルエン）含有量の測定は、ガスクロマトグラフィー（島津製作所社製：ＧＣ２０１０型）によって測定した。
〔有機溶媒含有量の測定 ガスクロマトグラフィー条件〕
カラム：ＤＢ−６２４（内径０．５３mｍ、膜厚３．０μｍ×７５ｍ）
検出方法：FID、注入口温度：２４０℃、検出器：２７０℃
水素圧：７０kPa、空気圧：７０kPa、キャリヤーガス流量：窒素 ５ml／分
注入量：１．０μl、スプリット比：１：２０
カラム温度：６０℃／２分間→２３０℃（１５℃／分）→２３０℃／１０分間保持
溶媒含有量の分析方法：内部標準法 （内部標準物質 クロルベンゼン）
試料溶解溶媒種：１，３−ジメチル−２−イミダゾリジノン
The content of the organic solvent (toluene) in the mixture was measured by gas chromatography (GC2010, manufactured by Shimadzu Corporation).
[Measurement of organic solvent content gas chromatography conditions]
Column: DB-624 (0.53 mm inner diameter, 3.0 μm × 75 m film thickness)
Detection method: FID, inlet temperature: 240 ° C, detector: 270 ° C
Hydrogen pressure: 70 kPa, air pressure: 70 kPa, carrier gas flow rate: nitrogen 5 ml / min, injection volume: 1.0 μl, split ratio: 1:20
Column temperature: 60 ° C / 2 minutes → 230 ° C (15 ° C / min) → Hold at 230 ° C / 10 minutes Solvent content analysis method: Internal standard method (Internal standard substance chlorobenzene)
Sample dissolution solvent type: 1,3-dimethyl-2-imidazolidinone
純度および不純物含有量の測定は、高速液体クロマトグラフィー（島津製作所社製：ＬＣ２０Ａ型）によって測定した。ミルタザピンの濁度の測定はＤｅｎｓｉＣＨＥＫ ｐｌｕｓ（ｂｉｏＭｅｒｉｅｕｘ社製）によって測定した。 The purity and impurity content were measured by high performance liquid chromatography (manufactured by Shimadzu Corporation: Model LC20A). The turbidity of mirtazapine was measured by DensiCHEK plus (manufactured by bioMerieux).
〔純度および不純物含有量の測定 高速液体クロマトグラフィー条件〕
カラム：Ｃ１８（５μｍ、４．６ｍｍ×２５ｃｍ）
検出波長：２２０ｎｍ、カラム温度：３０℃、注入量：５μｌ、
移動層：Ａ液 ０．０１モル％／Ｌ 炭酸水素アンモニウム水
Ｂ液 アセトニトリル
移動層グラジエント：Ｂ液 １０→９０％／２５分間、９０％／１０分間保持
[Measurement of purity and impurity content High-performance liquid chromatography conditions]
Column: C18 (5 μm, 4.6 mm × 25 cm)
Detection wavelength: 220 nm, column temperature: 30 ° C., injection volume: 5 μl,
Moving layer: Solution A 0.01 mol% / L ammonium bicarbonate water
Solution B Acetonitrile Moving layer gradient: Solution B 10 → 90% / 25 minutes, 90% / 10 minutes hold
〔ミルタザピンの濁度（メタノール不溶分）の測定条件〕
ミルタザピン１．５ｇをメタノール溶媒１０ｍｌに溶解させ１２時間放置後に測定した。
[Measurement conditions of turbidity of mirtazapine (methanol-insoluble matter)]
1.5 g of mirtazapine was dissolved in 10 ml of a methanol solvent, and measured after standing for 12 hours.
なお、表１中溶媒合計量（重量部）はピリジンメタノール（II）１重量部当たりの重量部、溶媒中の溶媒含有量は良溶媒と貧溶媒に対する良溶媒の重量パーセント、収率は（モル％）はピリジンメタノール（II）１モルに対するモルパーセント、純度はピリジンメチルアセテート（I）の面積百分率パーセントを表す。また、表２中、実施例６〜７の収率（モル％）はピリジンメチルアセテート（I）に対するモルパーセント、比較例１〜２の収率（モル％）はピリジンメタノール（II）に対するモルパーセント、比較例３〜５の収率（モル％＊）は再結晶で用いたミルタザピンに対するモルパーセントを表す、不純物含有量（％）はミルタザピンに含有する不純物合計の面積百分率パーセント、濁度(MeF)はミルタザピンのメタノール不溶分（濁度）の単位を表す。また、図１は、ミルタザピンのメタノール溶解液の性状を表す。 In Table 1, the total amount (parts by weight) of the solvent is parts by weight per 1 part by weight of pyridinemethanol (II), the solvent content in the solvent is the weight percentage of the good solvent relative to the good solvent and the poor solvent, %) Is the mole percentage based on 1 mole of pyridine methanol (II), and the purity is the area percentage percentage of pyridine methyl acetate (I). In Table 2, the yields (mol%) of Examples 6 to 7 are mole percentages based on pyridine methyl acetate (I), and the yields (mol%) of Comparative Examples 1 and 2 are mole percentages based on pyridine methanol (II). The yields (mol% *) of Comparative Examples 3 to 5 represent the mole percentage based on mirtazapine used in the recrystallization. The impurity content (%) is the area percentage percentage of the total impurities contained in mirtazapine, and the turbidity (MeF). Represents a unit of methanol-insoluble matter (turbidity) of mirtazapine. FIG. 1 shows the properties of a methanol solution of mirtazapine.
本発明の方法によれば、ミルタザピンの製造において、従来の方法とは異なり、効率、品質および収率がよく、特に工業スケールでの作業性および経済性に優れ、ミルタザピンの製造には極めて有利な方法を提供できる。 According to the method of the present invention, in the production of mirtazapine, unlike the conventional method, efficiency, quality and yield are good, workability and economic efficiency are particularly excellent on an industrial scale, and the production of mirtazapine is extremely advantageous. We can provide a method.
Claims (15)
〔２−（４−メチル−2−フェニルピペラジン−1−イル）ピリジン−３−イル〕メチルアセテートを濃硫酸中で反応させる工程を含む、１，２，３，４，１０，１４ｂ−ヘキサヒドロ−２−メチル−ピラジノ〔２，１−a〕ピリド〔２，３−c〕〔２〕ベンザセピンの製造方法。 A process for obtaining [2- (4-methyl-2-phenylpiperazin-1-yl) pyridin-3-yl] methyl acetate by the method according to any one of claims 1 to 13, and [2- (4 -Methyl-2-phenylpiperazin-1-yl) pyridin-3-yl] methyl acetate in concentrated sulfuric acid, comprising 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino [2,1-a] pyrido [2,3-c] [2] benzacepin production method.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US4217452A (en) * | 1974-02-09 | 1980-08-12 | Akzona Incorporated | Synthesis for the preparation of tetracyclic compounds |
| JP2008231062A (en) * | 2007-03-22 | 2008-10-02 | Sumitomo Chemical Co Ltd | Preparation method of mirtazapine |
| JP2013112744A (en) * | 2011-11-29 | 2013-06-10 | Dic Corp | (meth)acrylic acid derivative, composition and cured product of the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4217452A (en) * | 1974-02-09 | 1980-08-12 | Akzona Incorporated | Synthesis for the preparation of tetracyclic compounds |
| JP2008231062A (en) * | 2007-03-22 | 2008-10-02 | Sumitomo Chemical Co Ltd | Preparation method of mirtazapine |
| JP2013112744A (en) * | 2011-11-29 | 2013-06-10 | Dic Corp | (meth)acrylic acid derivative, composition and cured product of the same |
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