JP2016153379A - Method for producing 1-(3-hydroxymethylpyridyl-2-)-2-phenyl-4-methylpiperazine - Google Patents
Method for producing 1-(3-hydroxymethylpyridyl-2-)-2-phenyl-4-methylpiperazine Download PDFInfo
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本発明は、１−（３−ヒドロキシメチルピリジル−２−）−２−フェニル−４−メチルピペラジンの新規な製造方法に関する。 The present invention relates to a novel process for producing 1- (3-hydroxymethylpyridyl-2-)-2-phenyl-4-methylpiperazine.
下記式（１）で示される１−（３−ヒドロキシメチルピリジル−２−）−２−フェニル−４−メチルピペラジン（以下、「ピリジンメタノール化合物」ともいう。）は医農薬中間体、電子材料等の重要な中間体である。 1- (3-Hydroxymethylpyridyl-2-)-2-phenyl-4-methylpiperazine (hereinafter, also referred to as “pyridinemethanol compound”) represented by the following formula (1) is a pharmaceutical / agrochemical intermediate, electronic material, etc. Is an important intermediate.
特に、抗精神薬として用いられているミルタザピン、即ち、下記式（２）で示される（１４ｂＲＳ）−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］ベンザゼピン（以下「ミルタザピン」ともいう。）の有用な中間体である。 In particular, mirtazapine used as an antipsychotic, that is, (14bRS) -1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a] represented by the following formula (2) It is a useful intermediate of pyrido [2,3-c] [2] benzazepine (hereinafter also referred to as “mirtazapine”).
従来、ピリジンメタノール化合物は、下記式（３）で示される１−（３−カルボキシピリジル−２−）−２−フェニル−４−メチルピペラジン（以下「ピリジンカルボン酸化合物」ともいう。）のカルボン酸を還元剤存在下で水酸基に変換後、後処理操作を行い、次いで、再結晶操作により精製し製造されている。 Conventionally, the pyridinemethanol compound is a carboxylic acid of 1- (3-carboxypyridyl-2-)-2-phenyl-4-methylpiperazine (hereinafter also referred to as “pyridinecarboxylic acid compound”) represented by the following formula (3). Is converted to a hydroxyl group in the presence of a reducing agent, followed by a post-treatment operation, and then purified by a recrystallization operation.
例えば、特許文献１には、ピリジンカルボン酸化合物を水素化リチウムアルミニウムにて還元し、反応終了後に水でクエンチし、生成した無機塩をろ過し、濾液を濃縮、最後にエーテルによる晶析によりピリジンメタノール化合物を取得する方法が述べられている。 For example, in Patent Document 1, a pyridinecarboxylic acid compound is reduced with lithium aluminum hydride, quenched with water after completion of the reaction, the produced inorganic salt is filtered, the filtrate is concentrated, and finally crystallization is performed by crystallization with ether. A method for obtaining a methanol compound is described.
また、特許文献２には、ピリジンカルボン酸化合物のカリウム塩をＴＨＦ中、水素化リチウムアルミニウムにて還元し、反応終了後に水でクエンチし、アルカリ水溶液で中和し、中和により生じた塩をろ過後、ＴＨＦを留去する。これにヘプタンを４８℃付近で加えて結晶を析出させ、０〜５℃で１時間冷却、ろ過し、ピリジンメタノール化合物を取得する方法が述べられている。 Patent Document 2 discloses that a potassium salt of a pyridinecarboxylic acid compound is reduced with lithium aluminum hydride in THF, quenched with water after completion of the reaction, neutralized with an alkaline aqueous solution, and a salt generated by neutralization is obtained. After filtration, the THF is distilled off. A method is described in which heptane is added to this at about 48 ° C. to precipitate crystals, cooled at 0 to 5 ° C. for 1 hour and filtered to obtain a pyridinemethanol compound.
しかしながら、特許文献１に記載の方法ではエーテルを用いていることから、その引火性のため、工業的な大量合成に用いるのは、極めて困難である。また、特許文献２に記載の方法は、ピリジンカルボン酸化合物の還元反応及び晶析を通して、収率が７０〜７９％程度であり、更なる収率向上の余地がある。また、本発明者等が特許文献２の追試実験を実施した結果、晶析時にヘプタンを用いているため、静電気によると思われるスケーリングが生じて、反応容器に結晶が多量に付着することで結晶を回収しにくいという欠点があることを確認した。 However, since ether is used in the method described in Patent Document 1, it is extremely difficult to use it for industrial mass synthesis because of its flammability. The method described in Patent Document 2 has a yield of about 70 to 79% through the reduction reaction and crystallization of the pyridinecarboxylic acid compound, and there is room for further yield improvement. In addition, as a result of the inventors performing a follow-up experiment of Patent Document 2, since heptane is used during crystallization, scaling that appears to be caused by static electricity occurs, and a large amount of crystals adhere to the reaction vessel. It has been confirmed that there is a drawback that it is difficult to recover.
さらに、取得したピリジンメタノール化合物及び該ピリジンメタノール化合物を用いて製造したミルタザピンについて高速液体クロマトグラフィーにより純度を分析したところ、ピリジンメタノール化合物中には引用文献１又は２に記載の方法では除去が困難であり、最終的にミルタザピンにも含まれてくる不純物（以下、「特定不純物」ともいう）が存在することが判明した。 Furthermore, when the purity of the obtained pyridinemethanol compound and mirtazapine produced using the pyridinemethanol compound was analyzed by high performance liquid chromatography, it was difficult to remove the pyridinemethanol compound by the method described in Reference 1 or 2. In the end, it has been found that there are impurities (hereinafter also referred to as “specific impurities”) that are also contained in mirtazapine.
従って、ミルタザピンの重要中間体であるピリジンメタノール化合物を安全で高純度、且つ高収率で製造できる製法の開発が求められている。 Therefore, development of a production method capable of producing a pyridinemethanol compound, which is an important intermediate of mirtazapine, in a safe, high-purity, and high-yield manner is required.
本発明は、前記従来技術の課題に鑑みてなされたものであり、ピリジンカルボン酸化合物からピリジンメタノール化合物を高純度且つ高収率で製造しうる方法を提供することを目的とする。 This invention is made | formed in view of the subject of the said prior art, and it aims at providing the method which can manufacture a pyridinemethanol compound with a high purity and a high yield from a pyridinecarboxylic acid compound.
本発明者らは、上記課題を解決するために、鋭意研究を重ねた結果、エステル系溶媒と炭化水素系溶媒との混合溶媒を用いて、粗ピリジンメタノール化合物の晶析を実施することにより、スケーリングを生じさせず、収率も向上させることができ、さらに特定不純物を大幅に低減でき、高純度のピリジンメタノール化合物を取得できることを見出した。 As a result of intensive studies to solve the above problems, the present inventors conducted a crystallization of a crude pyridinemethanol compound using a mixed solvent of an ester solvent and a hydrocarbon solvent, It was found that scaling can be prevented, the yield can be improved, specific impurities can be greatly reduced, and a high-purity pyridinemethanol compound can be obtained.
すなわち、本発明は、下記式（３） That is, the present invention provides the following formula (3)
で表わされるピリジンカルボン酸化合物の還元によって得られた式（１） Formula (1) obtained by reduction of a pyridinecarboxylic acid compound represented by
で表わされるピリジンメタノール化合物をエステル系溶媒と炭化水素系溶媒との混合溶媒を用いて晶析することを特徴とするピリジンメタノール化合物の製造方法である。 A pyridinemethanol compound represented by the following formula: crystallization using a mixed solvent of an ester solvent and a hydrocarbon solvent.
本発明によれば、工業的に安全に使用できる溶媒を用いて、ピリジンメタノール化合物の粗体から、特許文献１又は２に記載の方法よりも高収率でピリジンメタノール化合物を取得することができる。また、特許文献２に記載の方法で生じるスケーリングを抑制することができる。さらに、特許文献１又は２に記載の精製方法によっては低減が困難な特定不純物を低減することで、高純度のピリジンメタノール化合物を取得することができる。本発明により製造されたピリジンメタノール化合物を原料として製造されたミルタザピンは、特定不純物の含有量が極めて少なく、医薬品として好適に使用することができる。 According to the present invention, a pyridinemethanol compound can be obtained in a higher yield than the method described in Patent Document 1 or 2 from a crude pyridinemethanol compound using a solvent that can be used industrially safely. . Moreover, the scaling which arises with the method of patent document 2 can be suppressed. Furthermore, a high-purity pyridinemethanol compound can be obtained by reducing specific impurities that are difficult to reduce by the purification method described in Patent Document 1 or 2. Mirtazapine produced from the pyridinemethanol compound produced according to the present invention has a very small content of specific impurities and can be suitably used as a pharmaceutical product.
本発明は、ピリジンカルボン酸化合物を還元して得られたピリジンメタノール化合物をエステル系溶媒と炭化水素系溶媒との混合溶媒を用いて晶析する結晶化工程を含むことを特徴とするピリジンメタノール化合物の製造方法である。 The present invention includes a crystallization methanol compound comprising a crystallization step of crystallizing a pyridinemethanol compound obtained by reducing a pyridinecarboxylic acid compound using a mixed solvent of an ester solvent and a hydrocarbon solvent. It is a manufacturing method.
＜ピリジンメタノール化合物＞
下記式（１）
<Pyridine methanol compound>
Following formula (1)
で表わされるピリジンメタノール化合物は、下記式（３） A pyridinemethanol compound represented by the following formula (3)
で表わされるピリジンカルボン酸化合物を出発物質として使用し、有機溶媒中、還元剤によりカルボキシル基をヒドロキシル基へ変換することで得ることができる。 Can be obtained by converting a carboxyl group to a hydroxyl group with a reducing agent in an organic solvent using a pyridinecarboxylic acid compound represented by the formula:
ピリジンメタノール化合物を得るための出発物質であるピリジンカルボン酸化合物は公知の化合物であり、例えば、前述の特許文献１等に記載されている方法で製造することができる。具体的には、下記式（４） The pyridinecarboxylic acid compound, which is a starting material for obtaining the pyridinemethanol compound, is a known compound and can be produced, for example, by the method described in Patent Document 1 described above. Specifically, the following formula (4)
で表わされるピリジンシアノ化合物を水酸化カリウムを含むエタノール溶液中で反応させることにより製造することができる。 It can manufacture by making the pyridine cyano compound represented by these react in the ethanol solution containing potassium hydroxide.
ピリジンカルボン酸化合物を還元してピリジンメタノール化合物とする方法としては、特許文献１又は２等に記載されている公知の方法を用いることができる。具体的にはピリジンカルボン酸化合物を含む有機溶媒中に金属水素化物を添加し、還元する。 As a method for reducing the pyridinecarboxylic acid compound to obtain a pyridinemethanol compound, a known method described in Patent Document 1 or 2 can be used. Specifically, a metal hydride is added to an organic solvent containing a pyridinecarboxylic acid compound and reduced.
ピリジンカルボン酸化合物を還元するための金属水素化物としては、目的の反応を進行させるものであれば、公知の金属水素化物を制限無く使用することができる。例えば、水素化リチウムアルミニウム、ソジウムジヒドロビス（２−メトキシエトキシ）アルミネートがあげられる。これらの還元剤の中では、大量合成時の取扱い易さの観点より、ソジウムジヒドロビス（２−メトキシエトキシ）アルミネートが好ましい。 As the metal hydride for reducing the pyridinecarboxylic acid compound, a known metal hydride can be used without limitation as long as it allows the target reaction to proceed. Examples thereof include lithium aluminum hydride and sodium dihydrobis (2-methoxyethoxy) aluminate. Among these reducing agents, sodium dihydrobis (2-methoxyethoxy) aluminate is preferable from the viewpoint of easy handling during mass synthesis.
金属水素化物の量は、反応を速やかに進行させるために、ピリジンカルボン酸化合物１モルに対して１〜２０モルとするのが好ましく、１〜１０モルとするのがより好ましく、１〜５モルとするのが特に好ましい。 The amount of the metal hydride is preferably 1 to 20 mol, more preferably 1 to 10 mol, and more preferably 1 to 5 mol with respect to 1 mol of the pyridinecarboxylic acid compound so that the reaction proceeds rapidly. It is particularly preferable that
反応温度は、特に限定されないが、反応を速やかに進行させるために、１０〜５０℃が好ましく、１５〜４５℃がより好ましく、２０〜４０℃が特に好ましい。 Although reaction temperature is not specifically limited, In order to advance reaction rapidly, 10-50 degreeC is preferable, 15-45 degreeC is more preferable, and 20-40 degreeC is especially preferable.
反応時間は、液体クロマトグラフィー等によりピリジンメタノール化合物の生成割合を確認して決定すれば良い。用いる還元剤の当量数、反応温度等により反応性が異なるため、一概に言うことはできないが、通常、０．５〜１０時間、特に１〜６時間とするのが好適である。 The reaction time may be determined by confirming the production ratio of the pyridinemethanol compound by liquid chromatography or the like. Since the reactivity varies depending on the number of equivalents of the reducing agent to be used, the reaction temperature, and the like, it cannot be generally stated, but it is usually 0.5 to 10 hours, particularly 1 to 6 hours.
有機溶媒としては、例えば、テトラヒドロフラン、トルエン、これらの混合溶媒の使用が好適である。 As the organic solvent, for example, tetrahydrofuran, toluene, or a mixed solvent thereof is preferably used.
有機溶媒の量は、特に限定はないが、ピリジンカルボン酸化合物１質量部に対して１〜１０００質量部とするのが好ましく、２〜１００質量部とするのがより好ましく、３〜５０質量部とするのが特に好ましい。 The amount of the organic solvent is not particularly limited, but is preferably 1 to 1000 parts by weight, more preferably 2 to 100 parts by weight, and 3 to 50 parts by weight with respect to 1 part by weight of the pyridinecarboxylic acid compound. It is particularly preferable that
得られたピリジンメタノール化合物は、還元反応の反応溶液から公知の方法で後処理を実施し、分離すれば良い。例えば特許文献１に記載されている様に、反応終了の溶液に水を添加し、還元剤を分解し、生じた無機塩をろ過した後、溶媒を濃縮し、粗体のピリジンメタノール化合物を得ることができる。また、分解した還元剤と錯体を形成させ、分液操作により取り除くために、還元後の反応溶液に対し、ロッシェル塩水溶液あるいは酒石酸ナトリウム水溶液を滴下しても良い。該水溶液を滴下後、分液操作により有機層を取り出し、得られた有機層を濃縮し、ピリジンメタノール化合物の粗体を得ることができる。上記方法で分離されたピリジンメタノール化合物の粗体には、特定不純物が、通常、０．１％〜３．０％程度含まれる。 The obtained pyridinemethanol compound may be separated from the reaction solution of the reduction reaction by post-treatment by a known method. For example, as described in Patent Document 1, water is added to the reaction-terminated solution, the reducing agent is decomposed, the resulting inorganic salt is filtered, and then the solvent is concentrated to obtain a crude pyridinemethanol compound. be able to. Further, in order to form a complex with the decomposed reducing agent and remove it by a liquid separation operation, an aqueous Rochelle salt solution or an aqueous sodium tartrate solution may be added dropwise to the reaction solution after reduction. After dropping the aqueous solution, the organic layer is taken out by a liquid separation operation, and the obtained organic layer is concentrated to obtain a crude pyridinemethanol compound. The crude product of the pyridine methanol compound separated by the above method usually contains about 0.1% to 3.0% of specific impurities.
なお、特定不純物の濃度は、下記の実施例で説明する条件で高速液体クロマトグラフィー（ＨＰＬＣ）により測定した時の、全ピークの面積値の合計に対する特定不純物のピーク面積値の割合で示した値である。また、ピリジンメタノール化合物の純度も、上記と同様にしてＨＰＬＣで測定した時の、全ピークの面積値の合計に対するピリジンメタノール化合物のピーク面積値の割合として表すことができる。 The concentration of the specific impurity is a value represented by the ratio of the peak area value of the specific impurity to the total area value of all the peaks when measured by high performance liquid chromatography (HPLC) under the conditions described in the following examples. It is. The purity of the pyridinemethanol compound can also be expressed as the ratio of the peak area value of the pyridinemethanol compound to the sum of the area values of all peaks when measured by HPLC in the same manner as described above.
＜結晶化工程＞
得られたピリジンメタノール化合物はエステル系溶媒と炭化水素系溶媒との混合溶媒を用いて晶析することによって、精製されたピリジンメタノール化合物を製造する。
<Crystalling process>
The obtained pyridinemethanol compound is crystallized using a mixed solvent of an ester solvent and a hydrocarbon solvent to produce a purified pyridinemethanol compound.
具体的には、得られたピリジンメタノール化合物をエステル系溶媒に加熱溶解し、その後、炭化水素系溶媒を加えて結晶を析出させるのが好ましい。 Specifically, it is preferable to heat-dissolve the obtained pyridinemethanol compound in an ester solvent, and then add a hydrocarbon solvent to precipitate crystals.
エステル系溶媒としては、下記式（５） As ester solvent, following formula (5)
（式中、Ｒ１及びＲ２はアルキル基である。）
で示されるエステル系溶媒を用いることができる。前記式（５）で示されるエステル系溶媒において、Ｒ１のアルキル基としては特に限定されないが、一般的には炭素数１〜５のアルキル基が好ましい。またＲ２のアルキル基についても特に限定されないが、一般的には炭素数１〜６のアルキル基が好ましい。
(In the formula, R 1 and R 2 are alkyl groups.)
An ester solvent represented by can be used. In the ester solvent represented by the formula (5), the alkyl group for R 1 is not particularly limited, but in general, an alkyl group having 1 to 5 carbon atoms is preferable. Although there is no particular limitation on the alkyl groups of R 2, it is generally preferably an alkyl group having 1 to 6 carbon atoms.
上記式（５）で示されるエステル系溶媒のなかでも、エステル系溶媒として工業的な製造において汎用されている下記式（６） Among the ester solvents represented by the above formula (5), the following formula (6) widely used in industrial production as an ester solvent.
（式中、Ｒ３は炭素数１〜６のアルキル基である。）
で示されるエステル系溶媒を用いることが好ましい。
(In the formula, R 3 is an alkyl group having 1 to 6 carbon atoms.)
It is preferable to use an ester solvent represented by
前記式（６）で示されるエステル系溶媒において、Ｒ３のアルキル基として好適なアルキル基を例示すると、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、ｓｅｃ−ブチル基、イソブチル基、ｎ−ヘキシル基等を挙げることができる。これらの中でも不純物除去、収率向上の観点及び医薬品製造において汎用されている観点から、炭素数１〜４のアルキル基がより好ましく、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、イソブチル基が好ましい。 In the ester solvent represented by the formula (6), examples of suitable alkyl groups as the alkyl group for R 3 include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group. , Isobutyl group, n-hexyl group and the like. Among these, an alkyl group having 1 to 4 carbon atoms is more preferable from the viewpoint of removing impurities, improving yield, and a viewpoint commonly used in pharmaceutical production. A methyl group, ethyl group, n-propyl group, isopropyl group, n- A butyl group and an isobutyl group are preferable.
エステル系溶媒の量は、特に限定されるものではないが、ピリジンメタノール化合物の精製効果及び収率向上を考慮した場合、ピリジンメタノール化合物１質量部に対して、１〜３０質量部が好ましく、２〜２０質量部がより好ましく、３〜１０質量部が特に好ましい。 The amount of the ester solvent is not particularly limited, but when considering the purification effect of the pyridinemethanol compound and the yield improvement, 1 to 30 parts by mass is preferable with respect to 1 part by mass of the pyridinemethanol compound. -20 mass parts is more preferable, and 3-10 mass parts is especially preferable.
エステル系溶媒を加えた後、ピリジンメタノール化合物を加熱溶解させる温度は特に限定されるものではないが、ピリジンメタノール化合物が溶媒に完全に溶解し、且つ、加えるエステル溶媒の沸点以下が好ましい。具体的には５０℃〜７０℃で溶解させることが好ましい。 The temperature at which the pyridinemethanol compound is heated and dissolved after the ester solvent is added is not particularly limited, but the pyridinemethanol compound is completely dissolved in the solvent and is preferably not more than the boiling point of the ester solvent to be added. Specifically, it is preferable to dissolve at 50 ° C to 70 ° C.
ピリジンメタノール化合物にエステル系溶媒を加えて加熱溶解し、ピリジンメタノール化合物溶液とした後、炭化水素系溶媒を添加し、結晶を析出させ、ピリジンメタノール化合物を製造する。 An ester solvent is added to the pyridinemethanol compound and dissolved by heating to obtain a pyridinemethanol compound solution, and then a hydrocarbon solvent is added to precipitate crystals to produce a pyridinemethanol compound.
炭化水素系溶媒としてはｎ−ヘキサン、イソヘキサン、シクロヘキサン、ｎ−ペンタン、ヘプタン、イソオクタン、トルエン、キシレンを用いることができる。これらの中でも、不純物除去及び収率向上の観点より、ヘプタン、ｎ−ヘキサンを用いることが好ましい。 As the hydrocarbon solvent, n-hexane, isohexane, cyclohexane, n-pentane, heptane, isooctane, toluene and xylene can be used. Among these, heptane and n-hexane are preferably used from the viewpoint of impurity removal and yield improvement.
エステル系溶媒と炭化水素系溶媒の混合比率としては、特に限定はないが、ピリジンメタノール化合物の精製効果及び収率を考慮した場合、エステル系溶媒と炭化水素系溶媒を１：１〜１：１０の比率（質量比）で混合することが望ましく、エステル系溶媒と炭化水素系溶媒を１：１〜１：５の比率で混合することがより望ましく、エステル系溶媒と炭化水素系溶媒を１：１〜１：３の比率で混合することが特に望ましい。 The mixing ratio of the ester solvent and the hydrocarbon solvent is not particularly limited. However, in consideration of the purification effect and yield of the pyridinemethanol compound, the ester solvent and the hydrocarbon solvent are used in a ratio of 1: 1 to 1:10. The ester solvent and the hydrocarbon solvent are more desirably mixed at a ratio of 1: 1 to 1: 5, and the ester solvent and the hydrocarbon solvent are It is particularly desirable to mix at a ratio of 1-1: 3.
ピリジンメタノール化合物溶液への炭化水素系溶媒の添加は、ピリジンメタノール化合物溶液に炭化水素系溶媒を滴下することで行えば良い。炭化水素系溶媒は、ピリジンメタノール化合物溶液を温度４０℃以上に保ちながら滴下することが好ましい。炭化水素系溶媒の滴下により結晶が析出する。結晶の析出においては、炭化水素系溶媒の添加終了後、結晶が析出したスラリー溶液を冷却、熟成させることが望ましい。熟成温度としては、特に限定されるものではないが、−１５℃〜３５℃が好ましく、−１０℃〜３０℃がより好ましく、０℃〜２５℃が特に好ましい。 The addition of the hydrocarbon solvent to the pyridine methanol compound solution may be performed by dropping the hydrocarbon solvent into the pyridine methanol compound solution. The hydrocarbon solvent is preferably added dropwise while keeping the pyridine methanol compound solution at a temperature of 40 ° C. or higher. Crystals are precipitated by the dropwise addition of the hydrocarbon solvent. In the precipitation of crystals, it is desirable to cool and age the slurry solution in which the crystals have been deposited after the addition of the hydrocarbon solvent. The aging temperature is not particularly limited, but is preferably −15 ° C. to 35 ° C., more preferably −10 ° C. to 30 ° C., and particularly preferably 0 ° C. to 25 ° C.
また、スラリー溶液を熟成させる時間としては、収率向上及び操作効率の観点より、１時間〜２４時間が好ましく、１時間〜１０時間がより好ましく、１時間〜５時間が特に好ましい。 The time for aging the slurry solution is preferably 1 hour to 24 hours, more preferably 1 hour to 10 hours, and particularly preferably 1 hour to 5 hours from the viewpoint of yield improvement and operation efficiency.
その後、スラリー溶液をろ過し、洗浄を行う。ろ過温度は特に限定されるものではないが、−１５〜４５℃が好ましく、−１０〜３５℃がより好ましく、０〜２５℃が特に好ましい。 Thereafter, the slurry solution is filtered and washed. Although filtration temperature is not specifically limited, -15-45 degreeC is preferable, -10-35 degreeC is more preferable, and 0-25 degreeC is especially preferable.
洗浄溶媒としてはヘプタン或いはｎ−ヘキサン単独、ヘプタン或いはｎ−ヘキサンとエステル系溶媒の混合溶媒を用いて行うことができる。洗浄溶媒の温度は、−１５〜４５℃が好ましく、−１０〜３５℃がより好ましく、０〜２５℃が特に好ましい。洗浄溶媒の量は、特に限定されるものではないが、ピリジンメタノール化合物１質量部に対して、１〜３質量部であることが好ましい。 As the washing solvent, heptane or n-hexane alone, heptane or a mixed solvent of n-hexane and an ester solvent can be used. The temperature of the washing solvent is preferably -15 to 45 ° C, more preferably -10 to 35 ° C, and particularly preferably 0 to 25 ° C. Although the quantity of a washing | cleaning solvent is not specifically limited, It is preferable that it is 1-3 mass parts with respect to 1 mass part of pyridine methanol compounds.
ピリジンメタノール化合物はろ過後、０．５〜５ｋｐａの減圧下、４０〜５０℃で乾燥することが好ましい。 The pyridinemethanol compound is preferably dried at 40 to 50 ° C. under reduced pressure of 0.5 to 5 kpa after filtration.
かくして、晶析操作においてスケーリングを生じさせずに、高収率且つ、特定不純物の少ない高純度なピリジンメタノール化合物を得ることができる。 Thus, a high-purity pyridinemethanol compound with high yield and few specific impurities can be obtained without causing scaling in the crystallization operation.
得られたピリジンメタノール化合物を用いることにより、特定不純物の含有量が極めて少ないミルタザピンを製造することができる。ミルタザピンは、特許文献２等に記載の公知の方法で製造すればよい。 By using the obtained pyridinemethanol compound, mirtazapine with an extremely low content of specific impurities can be produced. Mirtazapine may be produced by a known method described in Patent Document 2 and the like.
以下、実施例を挙げて本発明を詳細に説明するが、本発明はこれらの実施例によって何等制限されることはない。なお、実施例及び比較例における各種測定および評価方法は以下の通りである。 EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited at all by these Examples. The various measurements and evaluation methods in the examples and comparative examples are as follows.
（ピリジンメタノール化合物及びミルタザピンの純度及び特定不純物の濃度評価）
製造したピリジンメタノール化合物及び該ピリジンメタノール化合物から製造したミルタザピンの純度及び特定不純物量は、高速液体クロマトグラフィー（ＨＰＬＣ）により測定した。ＨＰＬＣ測定に使用した装置、測定の条件は、下記の装置、条件を採用した。なお、該条件によるＨＰＬＣ分析では特定不純物は６つ検出され、ピリジンメタノール化合物の保持時間は７．５分付近、ミルタザピンの保持時間２５分付近であり、６つの特定不純物の保持時間はそれぞれ２分、２．４分、２．６分、３分、６．７分及び９．３分付近である（以下、保持時間２分付近のものを「特定不純物Ａ」、保持時間２．４分付近のものを「特定不純物Ｂ」、保持時間２．６分付近のものを「特定不純物Ｃ」、保持時間３分付近のものを「特定不純物Ｄ」、６．７分付近のものを「特定不純物Ｅ」、保持時間９．３分付近のものを「特定不純物Ｆ」ともいう。）。
(Purity of pyridine methanol compound and mirtazapine and concentration evaluation of specific impurities)
The purity and specific impurity amount of the produced pyridinemethanol compound and mirtazapine produced from the pyridinemethanol compound were measured by high performance liquid chromatography (HPLC). The following apparatus and conditions were employed as the apparatus used for HPLC measurement and the measurement conditions. In the HPLC analysis under these conditions, six specific impurities were detected, the retention time of pyridinemethanol compound was around 7.5 minutes, the retention time of mirtazapine was around 25 minutes, and the retention time of the six specific impurities was 2 minutes each. 2.4 minutes, 2.6 minutes, 3 minutes, 6.7 minutes, and 9.3 minutes (hereinafter referred to as “specific impurity A” with a retention time of about 2 minutes, and a retention time of about 2.4 minutes) "Specific impurity B", retention time around 2.6 minutes "specific impurity C", retention time around 3 minutes "specific impurity D", 6.7 minutes near "specific impurity" E ”, those having a retention time of around 9.3 minutes are also referred to as“ specific impurities F ”).
装置：ウォーターズ社製２６９５
検出器：紫外吸光光度計（ウォーターズ２４８９）
検出波長：２４０ｎｍ
カラム：内径４．６ｍｍ、長さ２５ｃｍのステンレス管に５μｍの液体クロマトグラフィー用オクタデシルシリカゲルが充填されたもの。
移動相及び送液方法：以下に示す移動相Ａ及びＢを用い、試料注入後の経過時間に従い、両者の混合比を下記表１に示す様に制御し、送液した。
移動相Ａ：ペンタンスルホン酸ナトリウム３ｇを水３０００ｍＬに溶解し、トリエチルアミン９ｍＬを加えた後、リン酸を加えてｐＨ２．５とした。
移動相Ｂ：ペンタンスルホン酸ナトリウム３ｇを水９００ｍＬに溶解し、トリエチルアミン９ｍＬを加えた後、リン酸を加えてｐＨ２．５とした。これにアセトニトリル１０５０ｍＬ及びメタノール１０５０ｍＬを加えた。
流量：毎分１．５ｍＬ
カラム温度：４０℃付近の一定温度
Apparatus: 2695 manufactured by Waters
Detector: UV spectrophotometer (Waters 2489)
Detection wavelength: 240 nm
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm packed with 5 μm of octadecyl silica gel for liquid chromatography.
Mobile phase and liquid feeding method: Using the following mobile phases A and B, the mixing ratio of both was controlled as shown in Table 1 according to the elapsed time after sample injection, and the liquid was fed.
Mobile phase A: 3 g of sodium pentanesulfonate was dissolved in 3000 mL of water, 9 mL of triethylamine was added, and phosphoric acid was added to adjust the pH to 2.5.
Mobile phase B: 3 g of sodium pentanesulfonate was dissolved in 900 mL of water, 9 mL of triethylamine was added, and phosphoric acid was added to adjust the pH to 2.5. To this was added 1050 mL of acetonitrile and 1050 mL of methanol.
Flow rate: 1.5 mL per minute
Column temperature: constant temperature around 40 ° C
実施例１（ピリジンメタノール化合物の製造）
撹拌翼、温度計を取り付けた１Ｌの三口フラスコ中でピリジンカルボン酸化合物６０ｇ、（２０１．８ｍｍｏｌ）をテトラヒドロフラン２７０ｍＬに懸濁し、１０℃に冷却した。窒素気流下にて７０％ソジウムジヒドロビス（２−メトキシエトキシ）アルミネートのトルエン溶液２４０ｇ（７０６．２ｍｍｏｌ）を滴下した後、４０℃で５時間反応させた。反応終了後、３５ｗｔ％ロッシェル塩溶液２７５ｍＬを加えた後、有機層と水層を分液した。有機層に２５ｗｔ％食塩水１２０ｍＬを加えて洗浄後、分液を行い、得られた有機層を減圧下、濃縮した。得られた残査にトルエン２４０ｍＬを加えた後、６０〜６５℃に加熱し、不溶物を濾別した。トルエン層を減圧濃縮した後にピリジンメタノール化合物の粗体５７ｇを得た。（粗収率９９％、特定不純物Ａ ０．２％、特定不純物Ｂ ０．１％、特定不純物Ｃ ０．２％、特定不純物Ｄ ０．２％、特定不純物Ｅ０．１％、特定不純物Ｆ ０．４％）。
Example 1 (Production of pyridine methanol compound)
In a 1 L three-necked flask equipped with a stirring blade and a thermometer, 60 g of pyridinecarboxylic acid compound (201.8 mmol) was suspended in 270 mL of tetrahydrofuran and cooled to 10 ° C. Under a nitrogen stream, 240 g (706.2 mmol) of a toluene solution of 70% sodium dihydrobis (2-methoxyethoxy) aluminate was dropped, and the mixture was reacted at 40 ° C. for 5 hours. After completion of the reaction, 275 mL of 35 wt% Rochelle salt solution was added, and then the organic layer and the aqueous layer were separated. The organic layer was washed by adding 120 mL of 25 wt% brine, and separated, and the resulting organic layer was concentrated under reduced pressure. After adding 240 mL of toluene to the obtained residue, it heated at 60-65 degreeC, and the insoluble matter was separated by filtration. After concentrating the toluene layer under reduced pressure, 57 g of crude pyridinemethanol compound was obtained. (Coarse yield 99%, specific impurity A 0.2%, specific impurity B 0.1%, specific impurity C 0.2%, specific impurity D 0.2%, specific impurity E 0.1%, specific impurity F 0 .4%).
ピリジンメタノール化合物の粗体に対し、酢酸イソプロピル４２０ｇを加え、６０℃に加熱し、該粗体を溶解させた後、ヘプタン４２０ｇを内温５０℃以上で滴下した。該溶液を５℃まで冷却をおこない、ピリジンメタノール化合物のスラリー液を５℃付近で２時間程熟成した。熟成後、該スラリー溶液をろ過し、得られた白色結晶を４０℃で５時間減圧乾燥し、白色結晶としてピリジンメタノール化合物５１．０ｇ（１８１．７ｍｏｌ）を得た（収率８９％、ＨＰＬＣ純度９９．９％、特定不純物Ａ 未検出、特定不純物Ｂ 未検出、特定不純物Ｃ 未検出、特定不純物Ｄ 未検出、特定不純物Ｅ 未検出、特定不純物Ｆ 未検出）。また、晶析時の反応容器壁面へのスケーリングは認められなかった。 To the crude pyridinemethanol compound, 420 g of isopropyl acetate was added and heated to 60 ° C. to dissolve the crude, and then 420 g of heptane was added dropwise at an internal temperature of 50 ° C. or higher. The solution was cooled to 5 ° C., and the pyridine methanol compound slurry was aged at about 5 ° C. for about 2 hours. After aging, the slurry solution was filtered, and the resulting white crystals were dried under reduced pressure at 40 ° C. for 5 hours to obtain 51.0 g (181.7 mol) of pyridinemethanol compound as white crystals (yield 89%, HPLC purity). 99.9%, specific impurity A not detected, specific impurity B not detected, specific impurity C not detected, specific impurity D not detected, specific impurity E not detected, specific impurity F not detected). In addition, scaling to the reaction vessel wall during crystallization was not observed.
実施例２〜１４（ピリジンメタノール化合物の製造）
実施例１に示した方法でピリジンカルボン酸化合物４５０ｇ（１．５１ｍｏｌ）より、ピリジンメタノール化合物の粗体４２８ｇを得た。（粗収率９９％、特定不純物Ａ ０．２％、特定不純物Ｂ ０．１％、特定不純物Ｃ ０．２％、特定不純物Ｄ ０．２％、特定不純物Ｅ０．１％、特定不純物Ｆ ０．４％）。
Examples 2 to 14 (Production of pyridine methanol compound)
By a method shown in Example 1, 428 g of a crude pyridinemethanol compound was obtained from 450 g (1.51 mol) of a pyridinecarboxylic acid compound. (Coarse yield 99%, specific impurity A 0.2%, specific impurity B 0.1%, specific impurity C 0.2%, specific impurity D 0.2%, specific impurity E 0.1%, specific impurity F 0 .4%).
該ピリジンメタノール化合物の粗体各２８．５ｇに対し、実施例１の晶析に使用する溶媒の種類及びその量を表２に示す様に変えた以外は実施例１と同様の方法でピリジンメタノール化合物を得た。 Pyridinemethanol was prepared in the same manner as in Example 1 except that the type and amount of the solvent used for crystallization in Example 1 were changed as shown in Table 2 for 28.5 g of the crude pyridinemethanol compound. A compound was obtained.
実施例１５
特許文献２に記載の方法に準じて、ピリジンメタノール化合物からミルタザピンを得た。
Example 15
Mirtazapine was obtained from a pyridinemethanol compound according to the method described in Patent Document 2.
撹拌翼、温度計を取り付けた２００ｍＬの三口フラスコに、濃硫酸２４ｇ（２４７ｍｍｏｌ）を加え、実施例１で得られたピリジンメタノール化合物 ７ｇ（２４．８ｍｍｏｌ）を徐々に加えて、４０℃で８時間反応した。反応終了後、０℃に冷却し、蒸留水５０ｍＬを滴下した。２５ｗｔ％水酸化ナトリウム水溶液６６．４ｇ（３９５ｍｍｏｌ）を０℃で滴下した後、活性炭０．３ｇを加え３０分間撹拌した。活性炭をろ過した後、ろ液にトルエン１５ｍＬ及び２５ｗｔ％水酸化ナトリウム水溶液１３．５ｇ（８５ｍｍｏｌ）を加えた後、トルエン層を分液した。トルエンを減圧下にて濃縮後、得られた残渣にトルエン１１ｍＬを加え、６０℃で加熱溶解し、ヘプタン１１ｍＬを滴下した。該溶液を冷却し、スラリー溶液とした後、０℃で２時間撹拌した後、ろ過をおこない、ろ物をトルエン７ｍＬ及びヘプタン７ｍＬの混合溶媒で洗浄した。得られたミルタザピンの湿体を６０℃で乾燥しミルタザピン５．３ｇ（１９．８ｍｍｏｌ）を得た（収率８０％、ＨＰＬＣ純度９９．８％、特定不純物Ａ 未検出、特定不純物Ｂ 未検出、特定不純物Ｃ 未検出、特定不純物Ｄ 未検出、特定不純物Ｅ 未検出、特定不純物Ｆ 未検出）。 To a 200 mL three-necked flask equipped with a stirring blade and a thermometer, 24 g (247 mmol) of concentrated sulfuric acid was added, 7 g (24.8 mmol) of the pyridinemethanol compound obtained in Example 1 was gradually added, and the mixture was heated at 40 ° C. for 8 hours. Reacted. After completion of the reaction, the reaction mixture was cooled to 0 ° C., and 50 mL of distilled water was added dropwise. After adding 66.4 g (395 mmol) of 25 wt% aqueous sodium hydroxide solution at 0 ° C., 0.3 g of activated carbon was added and stirred for 30 minutes. After the activated carbon was filtered, 15 mL of toluene and 13.5 g (85 mmol) of 25 wt% sodium hydroxide aqueous solution were added to the filtrate, and then the toluene layer was separated. After concentrating toluene under reduced pressure, 11 mL of toluene was added to the resulting residue, dissolved by heating at 60 ° C., and 11 mL of heptane was added dropwise. The solution was cooled to a slurry solution, and stirred at 0 ° C. for 2 hours, followed by filtration. The residue was washed with a mixed solvent of 7 mL of toluene and 7 mL of heptane. The obtained wet body of mirtazapine was dried at 60 ° C. to obtain 5.3 g (19.8 mmol) of mirtazapine (yield 80%, HPLC purity 99.8%, specific impurity A not detected, specific impurity B not detected, Specific impurity C not detected, specific impurity D not detected, specific impurity E not detected, specific impurity F not detected).
実施例１６
実施例１１で得られたピリジンメタノール化合物を用いた以外は実施例１５と同様の方法でミルタザピン５．４ｇ（２０．３ｍｍｏｌ）を得た（収率８２％、ＨＰＬＣ純度９９．７％、特定不純物Ａ 未検出、特定不純物Ｂ 未検出、特定不純物Ｃ 未検出、特定不純物Ｄ 未検出、特定不純物Ｅ 未検出、特定不純物Ｆ 未検出）。
Example 16
5.4 g (20.3 mmol) of mirtazapine was obtained in the same manner as in Example 15 except that the pyridinemethanol compound obtained in Example 11 was used (yield 82%, HPLC purity 99.7%, specific impurities). A not detected, specific impurity B not detected, specific impurity C not detected, specific impurity D not detected, specific impurity E not detected, specific impurity F not detected).
比較例１（特許文献１に記載された方法）
撹拌翼、温度計を取り付けた１Ｌの三口フラスコ中で、ピリジンカルボン酸化合物２０．３ｇ、（６８．３ｍｍｏｌ）を無水テトラヒドロフラン３００ｍＬに溶解し、１時間撹拌を続けながら、窒素気流下にて、還流した水素化リチウムアルミニウム２０．３ｇ（５３４．９ｍｍｏｌ）の６００ｍＬ無水テトラヒドロフランに徐々に加え、加熱還流下、４時間反応した。反応終了後、０℃まで冷却し、蒸留水８１．６ｍＬを序々に滴下した後、室温にて１時間撹拌し、析出した無機塩をろ過により分離した。ろ過物を減圧下、濃縮し、１８．２ｇのピリジンメタノール化合物の粗体を得た（粗収率９９％、特定不純物Ａ ０．３％、特定不純物Ｂ ０．２％、特定不純物Ｃ ０．２％、特定不純物Ｄ ０．２％、特定不純物Ｅ０．１％、特定不純物Ｆ ０．４％）。
Comparative Example 1 (Method described in Patent Document 1)
In a 1 L three-necked flask equipped with a stirring blade and a thermometer, 20.3 g of pyridinecarboxylic acid compound (68.3 mmol) was dissolved in 300 mL of anhydrous tetrahydrofuran and refluxed under a nitrogen stream while continuing stirring for 1 hour. The resulting mixture was gradually added to 20.3 g (534.9 mmol) of lithium aluminum hydride in 600 mL of anhydrous tetrahydrofuran, and reacted for 4 hours while heating under reflux. After completion of the reaction, the reaction mixture was cooled to 0 ° C., 81.6 mL of distilled water was gradually added dropwise, and the mixture was stirred at room temperature for 1 hour, and the precipitated inorganic salt was separated by filtration. The filtrate was concentrated under reduced pressure to obtain 18.2 g of a crude product of pyridinemethanol compound (crude yield 99%, specific impurity A 0.3%, specific impurity B 0.2%, specific impurity C 0. 2%, specific impurity D 0.2%, specific impurity E 0.1%, specific impurity F 0.4%).
該粗体に、ジエチルエーテル４００ｍＬを加えて、４０℃に加熱した後、５℃まで冷却して再結晶をおこない、ピリジンメタノール化合物１４．５ｇ（５１．１ｍｍｏｌ）を得た（収率７６％、ＨＰＬＣ純度９７．７％、特定不純物Ａ ０．２％、特定不純物Ｂ ０．１％、特定不純物Ｃ ０．１％、特定不純物Ｄ ０．１％、特定不純物Ｅ０．０６％、特定不純物Ｆ ０．２％）。晶析時の反応容器壁面へのスケーリングは認められなかった。 To the crude product, 400 mL of diethyl ether was added and heated to 40 ° C., then cooled to 5 ° C. and recrystallized to obtain 14.5 g (51.1 mmol) of a pyridinemethanol compound (yield 76%, HPLC purity 97.7%, specific impurity A 0.2%, specific impurity B 0.1%, specific impurity C 0.1%, specific impurity D 0.1%, specific impurity E 0.06%, specific impurity F 0 .2%). Scaling to the reaction vessel wall during crystallization was not observed.
比較例２
比較例１で得られたピリジンメタノール化合物を用いた以外は実施例１５と同様の方法でミルタザピン５．２ｇ（１９．６ｍｍｏｌ）を得た（収率７９％、ＨＰＬＣ純度９８．４％、特定不純物Ａ ０．１％、特定不純物Ｂ ０．０６％、特定不純物Ｃ ０．０６％、特定不純物Ｄ０．０４％、特定不純物Ｅ ０．０２％、特定不純物Ｆ ０．１％）。
Comparative Example 2
Mirtazapine 5.2g (19.6mmol) was obtained in the same manner as in Example 15 except that the pyridinemethanol compound obtained in Comparative Example 1 was used (yield 79%, HPLC purity 98.4%, specific impurities). A 0.1%, specific impurity B 0.06%, specific impurity C 0.06%, specific impurity D 0.04%, specific impurity E 0.02%, specific impurity F 0.1%).
比較例３（特許文献２に記載された方法）
ピリジンカルボン酸化合物のカリウム塩３６．４ｇ、（１０８．６ｍｍｏｌ）に無水テトラヒドロフラン８９ｇを添加し、テトラヒドロフラン溶液を得た。無水テトラヒドロフラン２３５ｇに水素化リチウムアルミニウム１２．５ｇ（３２９．３ ｍｍｏｌ）を溶解させた溶液に、２０〜３０℃で前記テトラヒドロフラン溶液を３０分間かけて滴下し、同温度で３時間３０分間攪拌した。反応終了後、２５℃で水１２．３ｇを滴下し、２０重量％水酸化ナトリウム水溶液１２．２ｇ、次いで水３８ｇを加えて２０〜２５℃で、１時間撹拌した。析出した結晶をろ過し、テトラヒドロフラン４５ｇで洗浄し、常圧下、１１０℃までの温度でテトラヒドロフラン及び水合わせて約３８０ｇを留去した後、ピリジンメタノール化合物の粗体３０ｇを含むＴＨＦ溶液８２ｇを得た（特定不純物Ａ ０．２％、特定不純物Ｂ ０．２％、特定不純物Ｃ ０．２％、特定不純物Ｄ ０．２％、特定不純物Ｅ０．１％、特定不純物Ｆ ０．４％）。
Comparative Example 3 (Method described in Patent Document 2)
89 g of anhydrous tetrahydrofuran was added to 36.4 g of potassium salt of pyridinecarboxylic acid compound (108.6 mmol) to obtain a tetrahydrofuran solution. To a solution of 12.5 g (329.3 mmol) of lithium aluminum hydride dissolved in 235 g of anhydrous tetrahydrofuran, the tetrahydrofuran solution was added dropwise at 20 to 30 ° C. over 30 minutes and stirred at the same temperature for 3 hours and 30 minutes. After completion of the reaction, 12.3 g of water was added dropwise at 25 ° C., 12.2 g of a 20 wt% sodium hydroxide aqueous solution and then 38 g of water were added, and the mixture was stirred at 20 to 25 ° C. for 1 hour. The precipitated crystals were filtered, washed with 45 g of tetrahydrofuran, and tetrahydrofuran and water were combined at a pressure up to 110 ° C. under atmospheric pressure to distill off about 380 g. Then, 82 g of a THF solution containing 30 g of a crude pyridinemethanol compound was obtained. (Specific impurity A 0.2%, specific impurity B 0.2%, specific impurity C 0.2%, specific impurity D 0.2%, specific impurity E 0.1%, specific impurity F 0.4%).
該粗体溶液に、ヘプタン４２ｇを攪拌しながら４８〜４９℃で３０分間かけて滴下した。０〜５℃に冷却後、１時間攪拌し、同温度でろ過し、トルエン４３ｇとヘプタン３４ｇの混合液で洗浄し、乾燥後、ピリジンメタノール化合物２１．５ｇ（７６．０ｍｍｏｌ）得た（収率７０％、ＨＰＬＣ純度９８．１％、特定不純物Ａ ０．１％、特定不純物Ｂ ０．１％、特定不純物Ｃ ０．２％、特定不純物Ｄ ０．２％、特定不純物Ｅ０．１％、特定不純物Ｆ ０．３％）。 To the crude solution, 42 g of heptane was added dropwise at 48 to 49 ° C. over 30 minutes with stirring. After cooling to 0-5 ° C., the mixture was stirred for 1 hour, filtered at the same temperature, washed with a mixed solution of 43 g of toluene and 34 g of heptane, and dried to obtain 21.5 g (76.0 mmol) of pyridinemethanol compound (yield) 70%, HPLC purity 98.1%, specific impurity A 0.1%, specific impurity B 0.1%, specific impurity C 0.2%, specific impurity D 0.2%, specific impurity E 0.1%, specific Impurity F 0.3%).
比較例４
比較例３で得られたピリジンメタノール化合物を用いた以外は実施例１５と同様の方法でミルタザピン５．３ｇ（２０．０ｍｍｏｌ）を得た（収率８１％、ＨＰＬＣ純度９９．３％、特定不純物Ａ ０．１％、特定不純物Ｂ ０．１％、特定不純物Ｃ ０．０８％、特定不純物Ｄ０．０６％、特定不純物Ｅ ０．０２％、特定不純物Ｆ ０．０５％）。
Comparative Example 4
Mirtazapine 5.3 g (20.0 mmol) was obtained in the same manner as in Example 15 except that the pyridinemethanol compound obtained in Comparative Example 3 was used (yield 81%, HPLC purity 99.3%, specific impurities). A 0.1%, specific impurity B 0.1%, specific impurity C 0.08%, specific impurity D 0.06%, specific impurity E 0.02%, specific impurity F 0.05%).
Claims (4)
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5942678B2 (en) * | 1975-04-05 | 1984-10-16 | アクゾ・エヌ・ヴエ− | Tetracyclic compounds and their production method |
| WO2001042240A1 (en) * | 1999-12-13 | 2001-06-14 | Sumika Fine Chemicals Co., Ltd. | Process for the preparation of a pyridinemethanol compound |
| CN1429819A (en) * | 2001-12-29 | 2003-07-16 | 中国科学院上海药物研究所 | Method of preparing anti-depression medicine Midanping |
| CN102432594A (en) * | 2011-11-28 | 2012-05-02 | 山东鲁药制药有限公司 | Preparation method of drug intermediate 1- (3-hydroxymethylpyridine-2-yl) -2-phenyl-4-methylpiperazine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5942678B2 (en) * | 1975-04-05 | 1984-10-16 | アクゾ・エヌ・ヴエ− | Tetracyclic compounds and their production method |
| WO2001042240A1 (en) * | 1999-12-13 | 2001-06-14 | Sumika Fine Chemicals Co., Ltd. | Process for the preparation of a pyridinemethanol compound |
| CN1429819A (en) * | 2001-12-29 | 2003-07-16 | 中国科学院上海药物研究所 | Method of preparing anti-depression medicine Midanping |
| CN102432594A (en) * | 2011-11-28 | 2012-05-02 | 山东鲁药制药有限公司 | Preparation method of drug intermediate 1- (3-hydroxymethylpyridine-2-yl) -2-phenyl-4-methylpiperazine |
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| プロセス化学, JPN6018031049, 2008, pages ２３７−２４５ * |
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