JP2019525946A - Method for producing hydronidone - Google Patents
Method for producing hydronidone Download PDFInfo
- Publication number
- JP2019525946A JP2019525946A JP2019507241A JP2019507241A JP2019525946A JP 2019525946 A JP2019525946 A JP 2019525946A JP 2019507241 A JP2019507241 A JP 2019507241A JP 2019507241 A JP2019507241 A JP 2019507241A JP 2019525946 A JP2019525946 A JP 2019525946A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- ethyl acetate
- crude product
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
Abstract
本発明は、操作が簡単で、反応条件が温和で、反応時間が短く、収率が高く、より安全で大規模生産に適する、ヒドロニドンの製造方法を提供する。本発明はアンモニア水で中間化合物の粗製品を処理することで、触媒に残った銅イオンの除去にも、産物の析出にも有利である。【選択図】なしThe present invention provides a method for producing hydridone that is simple in operation, mild in reaction conditions, short in reaction time, high in yield, safer and suitable for large-scale production. In the present invention, a crude product of an intermediate compound is treated with aqueous ammonia, which is advantageous for removing copper ions remaining in the catalyst and precipitating the product. [Selection figure] None
Description
本発明は、医薬の分野に関し、具体的に、銅触媒による炭素-ヘテロ原子カップリング反応およびその使用、具体的にヒドロニドンの製造方法に関する。 The present invention relates to the field of medicine, and in particular, to a copper-catalyzed carbon-heteroatom coupling reaction and use thereof, specifically to a method for producing hydronidone.
肝線維化は慢性肝疾患の進行における共通の病理的原因で、様々な慢性損傷が肝細胞の変性、壊死を起こし、線維結合組織が異常増殖して過剰沈着し、再生する肝細胞を包み、「偽小葉」を形成して肝臓の元の組織構造を破壊し、最終的に肝臓が結節状に、硬くなり、従って肝臓の機能が損傷し、ひいては完全に喪失し、肝硬変が生じる。
多くの慢性疾患、たとえば慢性ウイルス性肝炎、慢性アルコール中毒、胆汁鬱滞、先天性酵素欠損による代謝障害性疾患、長期間にわたる毒物や薬物との接触などが肝線維化につながる。肝線維化、肝硬変は肝疾患の患者の生活品質、医療費用の支出に影響する要因の一つである。肝保護薬の市場需要が年々増えている。現在、肝線維化の治療に使用できる薬物は少なく、患者および医者の安全で有効な薬物に対する需要が大きい。中国では、肝線維化治療薬の市場のシェアは約24億ドル、日本では、約19億ドルであると予測されている。今まで、世界では、肝線維化を適応症とする化学薬品がまだなく、早期のヒドロニドン（以下式I化合物と略する）に対する研究では、優れた薬理学的・毒理学的特性を有し、肝線維化および肝硬変を治療および予防する理想の経口投与薬物であることが示された。
Liver fibrosis is a common pathological cause in the progression of chronic liver disease, various chronic injuries cause hepatocyte degeneration and necrosis, fiber connective tissue overgrow and over-deposit, enveloping hepatocytes to regenerate, A “pseudolobule” is formed, destroying the original tissue structure of the liver, and eventually the liver becomes nodular and hard, thus damaging the liver's function and eventually being completely lost, resulting in cirrhosis.
Many chronic diseases, such as chronic viral hepatitis, chronic alcoholism, cholestasis, metabolic disorders due to congenital enzyme deficiencies, prolonged contact with poisons and drugs lead to liver fibrosis. Liver fibrosis and cirrhosis are one of the factors affecting the quality of life and medical expenses of patients with liver disease. The market demand for hepatoprotective drugs is increasing year by year. Currently, there are few drugs available for the treatment of liver fibrosis, and there is a great demand for safe and effective drugs for patients and doctors. In China, the market share of hepatic fibrosis treatment is estimated to be about $ 2.4 billion, and in Japan it is estimated to be about $ 1.9 billion. Until now, there are no chemicals in the world for indications of liver fibrosis, and early research on hydronidone (hereinafter abbreviated as formula I compound) has excellent pharmacological and toxicological properties. It has been shown to be the ideal orally administered drug to treat and prevent liver fibrosis and cirrhosis.
既存技術では、式I化合物の合成方法が公開され、2-アミノ-5-メチルピリジンを出発原料とし、Meをフェノール性ヒドロキシ基の保護基として使用し、その脱保護に使用される試薬が高価で、反応過程において劇毒の気体が発生しやすく、かつ汚水・廃棄物の処理が煩雑で、操作が複雑で、収率が低い（40％）。そして、既存技術においてヒドロニドンを製造する方法の多くはブロモフェノールのヒドロキシ基の保護に関わり、工業的過程では煩雑な反応工程を加える必要がある。
そのため、本分野では、操作が簡単で、反応条件が温和で、反応時間が短く、収率が高く、より安全で大規模生産に適する、ヒドロニドンの製造方法の研究・開発が切望されている。
In the existing technology, a method for synthesizing a compound of formula I is disclosed, and 2-amino-5-methylpyridine is used as a starting material, Me is used as a protecting group for a phenolic hydroxy group, and the reagent used for the deprotection is expensive. In the reaction process, toxic poison gas is likely to be generated, sewage / waste disposal is complicated, operation is complicated, and yield is low (40%). Many of the methods for producing hydronidone in the existing technology are related to protection of the hydroxy group of bromophenol, and it is necessary to add a complicated reaction step in an industrial process.
Therefore, research and development of a method for producing hydridone that is easy to operate, has mild reaction conditions, has a short reaction time, has a high yield, is safer, and is suitable for large-scale production is eagerly desired.
本発明の目的は、ヒドロニドンの製造方法およびその使用を提供することにある。
本発明の第一の側面では、式I化合物を製造する方法であって、
(1) 溶媒において、触媒の存在下で、2-ヒドロキシ-5-メチルピリジンをp-ブロモベンズアルデヒドと反応させ、式II化合物の粗製品を得る工程と、
(2) 前記式II化合物の粗製品をアンモニア水で洗浄し、精製された式II化合物を得る工程と、
(3) 精製された式II化合物をHBrと反応させ、前記式I化合物を得る工程と、
を含む方法を提供する。
もう一つの好適な例において、前記2-ヒドロキシ-5-メチルピリジンとp-ブロモベンズアルデヒドのモル比は1：1〜1：2（好ましくは1：1〜1：1.8、より好ましくは1：1〜1：1.5、最も好ましくは1：1〜1：1.3）である。
もう一つの好適な例において、前記方法は、さらに、以下の工程（4）を含む：
工程（3）で得られた式I化合物をエタノールおよび酢酸エチルの混合溶媒相と混合し、降温し、ろ過し、式I化合物の白色結晶の固体を得る。
もう一つの好適な例において、前記工程(4)では、前記式I化合物とエタノールおよび酢酸エチルの混合溶媒の質量比は1.5〜7.5、好ましくは2.5〜6.5、より好ましくは3〜4.5である。
もう一つの好適な例において、前記工程(4)では、前記エタノールと酢酸エチルの質量比は(0.8〜1.2):(5.8〜6.2)である。
もう一つの好適な例において、前記工程(1)では、前記溶媒はDMAC、DMF、またはこれらの組み合わせからなる群から選ばれる。
もう一つの好適な例において、前記工程(1)では、前記触媒は、CuI、CuSO4・5H2O、K2CO3、またはこれらの組み合わせからなる群から選ばれ、好ましくはCuIとK2CO3の混合物またはCuSO4・5H2OとK2CO3の混合物である。
もう一つの好適な例において、前記工程(1)では、前記溶媒はDMFで、かつ前記触媒はCuSO4・5H2OとK2CO3の混合物である。
もう一つの好適な例において、前記工程(1)では、前記CuIとK2CO3のモル比は1：50〜1：80、好ましくは1：55〜1：70である。
もう一つの好適な例において、前記工程(1)では、前記溶媒はDMACで、かつ前記触媒はCuIとK2CO3の混合物である。
もう一つの好適な例において、前記工程(1)では、加熱還流温度は130〜150℃、好ましくは135〜145℃である。
もう一つの好適な例において、前記工程(2)では、前記アンモニア水の濃度は15〜28wt％、好ましくは16〜25wt％、より好ましくは17〜20wt％である。
もう一つの好適な例において、前記工程（3）の前に、さらに、工程（2）で得られた生成された式II化合物を酢酸エチルおよび活性炭素と混合し、加熱して還流させ、ろ過し、降温して結晶を析出させる、工程（3-1）を含む。
もう一つの好適な例において、前記工程（3-1）では、前記酢酸エチルと式II化合物の粗製品の質量比は1.0〜10.0、好ましくは2.0〜8.0、より好ましくは3.0〜6.0である。
もう一つの好適な例において、前記工程（3-1）では、前記活性炭素と式II化合物の粗製品の質量比は0.01〜0.1、好ましくは0.025〜0.075、より好ましくは0.03〜0.06である。
もう一つの好適な例において、前記工程（3）では、前記式II化合物とHBrのモル比は1：5〜1：10で、好ましくは1：6〜1：8である。
The object of the present invention is to provide a process for the production of hydridone and its use.
In a first aspect of the present invention there is provided a process for producing a compound of formula I comprising
(1) reacting 2-hydroxy-5-methylpyridine with p-bromobenzaldehyde in a solvent in the presence of a catalyst to obtain a crude product of the formula II compound;
(2) washing the crude product of the formula II compound with aqueous ammonia to obtain a purified formula II compound;
(3) reacting the purified Formula II compound with HBr to obtain the Formula I compound;
A method comprising:
In another preferred example, the molar ratio of 2-hydroxy-5-methylpyridine to p-bromobenzaldehyde is 1: 1 to 1: 2 (preferably 1: 1 to 1: 1.8, more preferably 1: 1). ~ 1: 1.5, most preferably 1: 1-1: 1.3).
In another preferred example, the method further comprises the following step (4):
The compound of formula I obtained in step (3) is mixed with a mixed solvent phase of ethanol and ethyl acetate, cooled, and filtered to obtain a white crystalline solid of the compound of formula I.
In another preferred example, in the step (4), the mass ratio of the mixed solvent of the compound of formula I and ethanol and ethyl acetate is 1.5 to 7.5, preferably 2.5 to 6.5, more preferably 3 to 4.5.
In another preferred example, in the step (4), the mass ratio of ethanol to ethyl acetate is (0.8 to 1.2) :( 5.8 to 6.2).
In another preferred example, in the step (1), the solvent is selected from the group consisting of DMAC, DMF, or a combination thereof.
In another preferred example, in the step (1), the catalyst is selected from the group consisting of CuI, CuSO 4 .5H 2 O, K 2 CO 3 , or a combination thereof, preferably CuI and K 2. It is a mixture of CO 3 or a mixture of CuSO 4 .5H 2 O and K 2 CO 3 .
In another preferred example, in the step (1), the solvent is DMF, and the catalyst is a mixture of CuSO 4 .5H 2 O and K 2 CO 3 .
In another preferred example, in the step (1), the molar ratio of CuI to K 2 CO 3 is 1:50 to 1:80, preferably 1:55 to 1:70.
In another preferred example, in the step (1), the solvent is DMAC, and the catalyst is a mixture of CuI and K 2 CO 3 .
In another preferred example, in the step (1), the heating reflux temperature is 130 to 150 ° C, preferably 135 to 145 ° C.
In another preferred example, in the step (2), the concentration of the ammonia water is 15 to 28 wt%, preferably 16 to 25 wt%, more preferably 17 to 20 wt%.
In another preferred example, prior to step (3), the compound of formula II obtained in step (2) is further mixed with ethyl acetate and activated carbon, heated to reflux and filtered. And a step (3-1) in which the temperature is lowered to precipitate crystals.
In another preferred example, in the step (3-1), the mass ratio of the crude product of the ethyl acetate and the compound of formula II is 1.0 to 10.0, preferably 2.0 to 8.0, more preferably 3.0 to 6.0.
In another preferred example, in the step (3-1), the mass ratio of the crude product of the activated carbon and the compound of formula II is 0.01 to 0.1, preferably 0.025 to 0.075, more preferably 0.03 to 0.06.
In another preferred example, in the step (3), the molar ratio of the compound of formula II and HBr is 1: 5 to 1:10, preferably 1: 6 to 1: 8.
もちろん、本発明の範囲内において、本発明の上記の各技術特徴および下記（たとえば実施例）の具体的に記述された各技術特徴は互いに組合せ、新しい、または好適な技術方案を構成できることが理解される。紙数に限りがあるため、ここで逐一説明しない。 Of course, it is understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the specific technical features described below (for example, the embodiments) can be combined with each other to constitute a new or preferred technical scheme. Is done. Since there is a limit to the number of papers, it will not be explained here.
具体的な実施形態
本発明者は幅広く深く研究したところ、初めて意外に、収率が高く、反応条件が温和で、安全で効率的なヒドロニドンの製造方法を見出した。本発明はアンモニア水で式II化合物の粗製品を処理することで、触媒に残った銅イオンの除去にも、産物の析出にも有利である。これに基づき、本発明を完成させた。
Specific Embodiments As a result of extensive and extensive research, the present inventor has unexpectedly discovered for the first time a safe and efficient method for producing hydridone with a high yield, mild reaction conditions, and the like. By treating the crude product of the formula II compound with aqueous ammonia, the present invention is advantageous for removing copper ions remaining in the catalyst and precipitating the product. Based on this, the present invention was completed.
用語の説明
別途に定義しない限り、本明細書で用いられるすべての技術と科学の用語はいずれも本発明が属する分野の当業者が通常理解する意味と同様である。
本明細書で用いられるように、具体的に例示される数値で使用される場合、用語「約」とは当該値が例示される数値から1％以内で変わってもよい。たとえば、本明細書で用いられるように、「約100」という記述は99と101およびその間の全部の値（たとえば、99.1、99.2、99.3、99.4など）を含む。
本明細書で用いられるように、用語「含有」または「含む」は開放式、半閉鎖式および閉鎖式のものでもよい。言い換えれば、前記用語は「基本的に・・・で構成される」、または「・・・で構成される」も含む。
Explanation of Terms Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, when used in a specifically exemplified numerical value, the term “about” may vary within 1% of the numerical value in which the value is exemplified. For example, as used herein, the description “about 100” includes 99 and 101 and all values in between (eg, 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term “containing” or “including” may be open, semi-closed and closed. In other words, the term also includes "basically composed of ..." or "consists of ...".
本発明の主な利点は以下の通りである。
(1) 本発明はアンモニア水で式II化合物の粗製品を処理することで、触媒由来の残った銅イオンの除去にも、産物の析出にも有利である。
(2) 本発明の脱メチルの過程で既存技術においてよく使用される高価で、毒性が大きいBBr3の代わりにHBrを使用する。
(3) 本発明は、既存技術におけるブロモフェノールを保護する工程を省略し、操作がより簡単にある。
(4) 本発明の製造方法は、簡単で操作しやすく、反応条件が温和で、反応時間が短く、収率が高く、より安全で大規模生産に適する。
The main advantages of the present invention are as follows.
(1) By treating the crude product of the compound of formula II with aqueous ammonia, the present invention is advantageous for removing the copper ions remaining from the catalyst and for precipitating the product.
(2) Instead of the expensive and highly toxic BBr 3 often used in the existing technology in the demethylation process of the present invention, HBr is used.
(3) The present invention eliminates the step of protecting bromophenol in the existing technology and is easier to operate.
(4) The production method of the present invention is simple and easy to operate, mild reaction conditions, short reaction time, high yield, safer and suitable for large-scale production.
原料
本発明に使用される原料のリストは下記表1に示す。
以下、具体的な実施例によって、さらに本発明を説明する。これらの実施例は本発明を説明するために用いられるものだけで、本発明の範囲の制限にはならないと理解されるものである。以下の実施例において、具体的な条件が記載されていない実験方法は、通常、通常の条件、あるいはメーカーの薦めの条件で行われた。特に説明しない限り、百分率および部は重量百分率および重量部である。
以下、実施例で使用された実験材料および試薬は、特に説明しない限り、いずれも市販品として得られる。
Hereinafter, the present invention will be further described with reference to specific examples. It should be understood that these examples are only used to illustrate the invention and do not limit the scope of the invention. In the following examples, the experimental methods for which specific conditions are not described were usually performed under normal conditions or conditions recommended by the manufacturer. Unless stated otherwise, percentages and parts are percentages by weight and parts by weight.
Hereinafter, all the experimental materials and reagents used in the examples are obtained as commercial products unless otherwise specified.
実施例1-生産経路1：
1．式II化合物：N-(4-メトキシフェニル)-5-メチル-2-ピリドンの合成
上記原料の仕込み量および仕込み比は表2に示す。
表2
(2) 上記ろ液を縮合オートクレーブに戻して減圧で画分が出なくなるまで蒸留し、洗浄オートクレーブに入れ、55kgのアンモニア水(18wt％)および156 kgの水を入れ、撹拌して洗浄し、降温し、遠心ろ過し、母液が無色になるまできれいな水で洗浄した。ケーキを取り出し、皿に入れて自然乾燥し、式II化合物の粗製品55.4kgを調製した(2-ヒドロキシ-5-メチルピリジンで換算すると、収率は72％である)。
結果：紫外可視分光光度法によって検出したところ、Cu+が見られなかった。
2．式（II）化合物の粗製品の溶解脱色
脱溶媒精製オートクレーブに酢酸エチル(濃度≧99.0％)130kg、薬用活性炭素(サンプル液の吸収度が重クロム酸カリウム色度標準液の吸收度以下である)1.95kgおよび式II化合物の粗製品39kgを仕込み、撹拌しながら加熱還流し、1時間脱色し、冷めないうちにろ過し、ろ液を結晶反応オートクレーブに投入し、残渣を8kgの酢酸エチルで洗浄し、ろ過残渣を捨て、ろ液を合併し、脱溶媒し、冷却して結晶させた。ろ液が70％脱溶媒した後、撹拌しながらゆっくり結晶させ、0℃〜5℃に冷却し、3〜5時間撹拌し、遠心機に入れた。明らかに液の流れが止まるまで遠心ろ過し、精製された式II化合物を得たが、重量を測定し、皿に入れて自然乾燥し、得られた精製された式II化合物は31.2kgであった(純度99.66％、収率80％)。
3．式I化合物の調製：
N-(4-メトキシフェニル)-5-メチル-2-ピリドン(30kg)を反応オートクレーブに入れ、撹拌しながらゆっくり40wt％の臭化水素酸158kgを滴下し、滴下終了後、還流まで昇温させ、原料がなくなった時点をTCLプレートによる検出によってモニタリングした。冷却してpH=5〜6になるまで中和し、遠心ろ過し、ケーキを皿に入れて自然乾燥し、式I化合物の粗製品（収率：98％）を調製した。
(3-2) 懸濁精製：
上記工程(3-1)で得られた式I化合物の粗製品30kgを取り、エタノール(濃度95％、15kg)、酢酸エチル(濃度99％、90kg)を入れて懸濁させ、1h還流させ、10℃に降温し、遠心ろ過し、母液を回収し、ケーキを自然乾燥した。
精製脱色オートクレーブに純水900kgを入れ、撹拌し、水が沸騰するまで加熱し、さらに上記自然乾燥後のケーキ30kgを投入し、ケーキが完全に溶解した後、さらに活性炭素1.25kgを入れ、15分間還流させ、冷めないうちに加圧ろ過し、冷却して結晶し、25℃程度に降温し、同温度のままで2時間撹拌し、遠心ろ過し、ケーキを純水で2回洗浄して回転乾燥し、式I化合物の白色結晶の固体を得たが、60℃のオーブンで温度を制御して乾燥した後、式I化合物の完成品を得た(純度：99.92％、収率：90％)。
Example 1-Production path 1:
1． Synthesis of Formula II Compound: N- (4-Methoxyphenyl) -5-methyl-2-pyridone
Table 2 shows the charged amounts and charged ratios of the above raw materials.
Table 2
(2) Return the above filtrate to the condensation autoclave and distill under reduced pressure until no fraction is produced, put into a washing autoclave, add 55 kg of ammonia water (18 wt%) and 156 kg of water, stir and wash, The temperature was lowered, the solution was filtered by centrifugal filtration, and washed with clean water until the mother liquor became colorless. The cake was taken out, placed in a plate and air-dried to prepare 55.4 kg of a crude product of the compound of formula II (converted to 2-hydroxy-5-methylpyridine, the yield was 72%).
Results: Cu + was not found when detected by UV-Vis spectrophotometry.
2． Dissolve decolorization of crude product of formula (II) Compound 130 kg ethyl acetate (concentration ≧ 99.0%) in desolvation-purified autoclave, absorption of medicinal activated carbon (absorbance of sample solution is less than absorption of potassium dichromate standard solution) ) Charge 1.95 kg and 39 kg of the crude compound of formula II, heat to reflux with stirring, decolorize for 1 hour, filter without cooling, throw the filtrate into the crystal reaction autoclave, and residue with 8 kg of ethyl acetate. Washing, discarding the filtration residue, combining the filtrate, removing the solvent, cooling and crystallizing. After the solvent was removed from the filtrate by 70%, it was slowly crystallized with stirring, cooled to 0 ° C. to 5 ° C., stirred for 3 to 5 hours, and placed in a centrifuge. Centrifugal filtration was carried out until the liquid flow clearly stopped to obtain a purified formula II compound, which was weighed, placed in a dish and air-dried, and the obtained purified formula II compound was 31.2 kg. (Purity 99.66%, yield 80%).
3． Preparation of Formula I compounds:
Add N- (4-methoxyphenyl) -5-methyl-2-pyridone (30 kg) to the reaction autoclave and slowly add 158 kg of 40 wt% hydrobromic acid dropwise with stirring. The point at which the raw material was exhausted was monitored by detection with a TCL plate. The mixture was neutralized by cooling to pH = 5-6, centrifuged, and the cake was placed in a dish and air-dried to prepare a crude product of the compound of formula I (yield: 98%).
(3-2) Suspension purification:
Take 30 kg of the crude product of formula I compound obtained in the above step (3-1), suspend in ethanol (concentration 95%, 15 kg), ethyl acetate (concentration 99%, 90 kg), reflux for 1 h, The temperature was lowered to 10 ° C., centrifugal filtration was performed, the mother liquor was collected, and the cake was air-dried.
In a purified decolorization autoclave, 900 kg of pure water was stirred, heated until the water boiled, and further 30 kg of the above naturally dried cake was added. After the cake was completely dissolved, 1.25 kg of activated carbon was further added, Reflux for minutes, filter under pressure before cooling, cool and crystallize, cool to about 25 ° C, stir at the same temperature for 2 hours, centrifuge and wash the cake twice with pure water Spin-drying gave a white crystalline solid of the compound of formula I, but after drying by controlling the temperature in an oven at 60 ° C., a finished product of the compound of formula I was obtained (purity: 99.92%, yield: 90 %).
実施例2-生産経路2
1．式II化合物：N-(4-メトキシフェニル)-5-メチル-2-ピリドンの合成
表3
(2) 上記混合液を室温に降温して遠心ろ過し、減圧で画分が出なくなるまでろ液を蒸留し、120℃に降温し、156kgの水を含有する洗浄オートクレーブに入れ、56kgのアンモニア水(18wt％)を滴下し、撹拌して洗浄し、降温し、遠心ろ過し、ろ液が無色になるまできれいな水で洗浄した。ケーキを取り出し、皿に入れて自然乾燥し、式II化合物の粗製品を調製した。
2-ヒドロキシ-5-メチルピリジンで換算する収率は80%であった。
2．式（II）化合物の粗製品の溶解脱色
脱溶媒精製オートクレーブに酢酸エチル(濃度≧99.0％)170kg、薬用活性炭素(サンプル液の吸収度が重クロム酸カリウム色度標準液の吸收度以下である)2.75kgおよび式II化合物の粗製品55kgを仕込み、撹拌しながら加熱還流し、1時間脱色し、冷めないうちにろ過し、ろ液を結晶反応オートクレーブに投入し、残渣を酢酸エチル20kgで洗浄し、ろ過残渣を捨て、ろ液を合併し、脱溶媒し、冷却して結晶させた。ろ液が70％脱溶媒した後、撹拌しながらゆっくり結晶させ、0℃〜5℃に冷却し、3〜5時間撹拌し、遠心機に入れた。明らかに液の流れが止まるまで遠心ろ過し、精製された式II化合物を得たが、重量を測定し、皿に入れて自然乾燥し、得られた精製された式II化合物は含有量が99.64％であった。
3．式I化合物の調製：
N-(4-メトキシフェニル)-5-メチル-2-ピリドン(44kg)を反応オートクレーブに入れ、撹拌しながらゆっくり40wt％の臭化水素酸267kgを滴下し、滴下終了後、還流まで昇温させ、原料がなくなった時点をTCLプレートによる検出によってモニタリングした。冷却してpH=6になるまで中和し、遠心ろ過し、ケーキを皿に入れて自然乾燥し、式I化合物の粗製品を調製した。
(3-2) 懸濁精製：
上記工程(3-1)で得られた式I化合物の粗製品44kgを取り、0.5倍量のエタノール(濃度95％、22kg)、3倍量の酢酸エチル(濃度99％、132kg)を入れて懸濁させ、1h還流させ、10℃に降温し、遠心ろ過し、母液を回収し、ケーキを自然乾燥した。
精製脱色オートクレーブに純水900kgを入れ、撹拌し、水が沸騰するまで加熱し、さらに上記自然乾燥後のケーキ30 kgを投入し、ケーキが完全に溶解した後、さらに活性炭素1.5kgを入れ、15分間還流させ、冷めないうちに加圧ろ過し、冷却結晶オートクレーブに入れ、25℃程度に降温し、同温度のままで2時間撹拌し、遠心ろ過し、ケーキを純水で2回洗浄して回転乾燥し、式I化合物の白色結晶の固体を得たが、60℃のオーブンで温度を制御して乾燥した後、式I化合物の完成品24kgを得た(純度：99.98％、収率：80％)。
Example 2-Production path 2
1． Synthesis of Formula II Compound: N- (4-Methoxyphenyl) -5-methyl-2-pyridone
Table 3
(2) The temperature of the above mixture is lowered to room temperature, centrifuged, and the filtrate is distilled under reduced pressure until no fraction is produced.The temperature is lowered to 120 ° C., placed in a washing autoclave containing 156 kg of water, and 56 kg of ammonia. Water (18 wt%) was added dropwise, washed with stirring, cooled, centrifuged, and washed with clean water until the filtrate was colorless. The cake was taken out, placed in a dish and air dried to prepare a crude product of the formula II compound.
The yield in terms of 2-hydroxy-5-methylpyridine was 80%.
2． Dissolve decolorization of crude product of formula (II) Compound in desolvation-purified autoclave 170 kg ethyl acetate (concentration ≧ 99.0%), medicinal activated carbon (absorbance of sample solution is less than absorption of potassium dichromate color standard solution) ) 2.75 kg and 55 kg of the crude compound of formula II were charged, heated to reflux with stirring, decolored for 1 hour, filtered without cooling, the filtrate was put into a crystal reaction autoclave, and the residue was washed with 20 kg of ethyl acetate. The filtration residue was discarded, the filtrates were combined, desolvated, cooled and crystallized. After the solvent was removed from the filtrate by 70%, it was slowly crystallized with stirring, cooled to 0 ° C. to 5 ° C., stirred for 3 to 5 hours, and placed in a centrifuge. Centrifugal filtration was performed until the liquid flow clearly stopped to obtain a purified formula II compound, which was weighed, placed in a dish and air-dried, and the purified formula II compound obtained had a content of 99.64. %Met.
3． Preparation of Formula I compounds:
Add N- (4-methoxyphenyl) -5-methyl-2-pyridone (44 kg) to the reaction autoclave and slowly add 267 kg of 40 wt% hydrobromic acid while stirring. The point at which the raw material was exhausted was monitored by detection with a TCL plate. The mixture was neutralized by cooling to pH = 6, centrifuged, and the cake was placed in a dish and air-dried to prepare a crude product of the compound of formula I.
(3-2) Suspension purification:
Take 44 kg of the crude product of the formula I compound obtained in the above step (3-1), add 0.5 volume ethanol (concentration 95%, 22 kg), 3 volume ethyl acetate (concentration 99%, 132 kg). It was suspended, refluxed for 1 h, cooled to 10 ° C., centrifuged, the mother liquor was recovered, and the cake was air dried.
Put 900 kg of pure water in a purified decolorization autoclave, stir, heat until the water boils, and then add 30 kg of the cake after natural drying, and after the cake is completely dissolved, add 1.5 kg of activated carbon, Reflux for 15 minutes, filter under pressure before cooling, place in a cooled crystal autoclave, cool to about 25 ° C, stir at the same temperature for 2 hours, centrifuge and wash the cake twice with pure water And dried to obtain a white crystalline solid of the compound of formula I. After drying by controlling the temperature in an oven at 60 ° C., 24 kg of a finished product of the compound of formula I was obtained (purity: 99.98%, yield) : 80%).
比較例1
実施例1と同様で、異なるところは、式II化合物：N-(4-メトキシフェニル)-5-メチル-2-ピリドンの合成工程では、アンモニア水の代わりに水で洗浄したことにあり、その結果、調製された式II化合物の粗製品の収率は42％しかなかった。
結果：紫外可視分光光度法によって検出したところ、Cu+濃度が0.05μg/50mlであった。
Comparative Example 1
As in Example 1, the difference is that in the synthesis step of the compound of formula II: N- (4-methoxyphenyl) -5-methyl-2-pyridone, it was washed with water instead of ammonia water. As a result, the yield of the prepared crude product of the formula II compound was only 42%.
Result: As detected by UV-Vis spectrophotometry, the Cu + concentration was 0.05 μg / 50 ml.
このことから、アンモニア水で洗浄すると、銅イオンを有効に除去することができると同時に、得られる中間体の式II化合物の収率がより高く、産物の析出により有利であることがわかる。 From this, it can be seen that washing with aqueous ammonia can effectively remove copper ions, and at the same time, the yield of the resulting intermediate compound of formula II is higher and is more advantageous for precipitation of the product.
各文献がそれぞれ単独に引用されるように、本発明に係るすべての文献は本出願で参考として引用する。また、本発明の上記の内容を読み終わった後、当業者が本発明を各種の変動や修正をすることができるが、それらの等価の形態のものは本発明の請求の範囲に含まれることが理解されるはずである。 All documents according to the present invention are cited in this application as a reference, so that each document is individually cited. In addition, after reading the above contents of the present invention, those skilled in the art can make various changes and modifications to the present invention, and equivalent forms thereof are included in the scope of the claims of the present invention. Should be understood.
Claims (10)
(1) 溶媒において、触媒の存在下で、2-ヒドロキシ-5-メチルピリジンをp-ブロモベンズアルデヒドと反応させ、式II化合物の粗製品を得る工程と、
(2) 前記式II化合物の粗製品をアンモニア水で洗浄し、精製された式II化合物を得る工程と、
(3) 精製された式II化合物をHBrと反応させ、前記式I化合物を得る工程と、
含む方法。 A process for preparing a compound of formula I comprising:
(1) reacting 2-hydroxy-5-methylpyridine with p-bromobenzaldehyde in a solvent in the presence of a catalyst to obtain a crude product of the formula II compound;
(2) washing the crude product of the formula II compound with aqueous ammonia to obtain a purified formula II compound;
(3) reacting the purified Formula II compound with HBr to obtain the Formula I compound;
Including methods.
工程（3）で得られた式I化合物をエタノールおよび酢酸エチルの混合溶媒相と混合し、降温し、ろ過し、式I化合物の白色結晶の固体を得る。 The method according to claim 1, further comprising the following step (4):
The compound of formula I obtained in step (3) is mixed with a mixed solvent phase of ethanol and ethyl acetate, cooled, and filtered to obtain a white crystalline solid of the compound of formula I.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610642515.0A CN107698499A (en) | 2016-08-08 | 2016-08-08 | A kind of preparation method of oxycodone |
| CN201610642515.0 | 2016-08-08 | ||
| PCT/CN2017/095882 WO2018028508A1 (en) | 2016-08-08 | 2017-08-03 | Method for preparing hydronidone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2019525946A true JP2019525946A (en) | 2019-09-12 |
| JP6764999B2 JP6764999B2 (en) | 2020-10-07 |
Family
ID=61161577
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2019507241A Active JP6764999B2 (en) | 2016-08-08 | 2017-08-03 | How to make hydronidon |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP6764999B2 (en) |
| CN (3) | CN107698499A (en) |
| WO (1) | WO2018028508A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111004173A (en) * | 2019-12-31 | 2020-04-14 | 北京康蒂尼药业有限公司 | Preparation method of hydroxyl-niatone |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005515995A (en) * | 2001-12-06 | 2005-06-02 | エーザイ株式会社 | Pharmaceutical compositions and their use |
| JP2007510618A (en) * | 2003-11-14 | 2007-04-26 | シャンハイ ゲノミックス インク | Pyridone derivatives and their use |
| WO2007141200A1 (en) * | 2006-06-02 | 2007-12-13 | Janssen Pharmaceutica N.V. | Novel n-aryl and n-heteroaryl substituted pyridinone derivatives for use in mch-1 mediated diseases |
| CN101165051A (en) * | 2007-08-07 | 2008-04-23 | 中国科学院长春应用化学研究所 | Dendritic main body material and organic electroluminescence device prepared from the same |
| JP2010511666A (en) * | 2006-12-05 | 2010-04-15 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Novel substituted diaza-spiro-pyridinone derivatives for use in diseases mediated by MCH-1 |
| JP2010513292A (en) * | 2006-12-14 | 2010-04-30 | イーライ リリー アンド カンパニー | Novel MCH receptor antagonist |
| CN101723883A (en) * | 2008-10-24 | 2010-06-09 | 上海睿星基因技术有限公司 | Method for preparing oxycodone |
| CN102766041A (en) * | 2012-08-17 | 2012-11-07 | 济南大学 | Method for preparing intermediate of salicylic aldehyde derivatives |
| JP2016500661A (en) * | 2012-10-02 | 2016-01-14 | インターミューン， インコーポレイテッド | Antifibrotic pyridinone |
| JP2019507219A (en) * | 2016-02-01 | 2019-03-14 | スリーエム イノベイティブ プロパティズ カンパニー | Adhesive composition |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2726588C (en) * | 2008-06-03 | 2019-04-16 | Karl Kossen | Compounds and methods for treating inflammatory and fibrotic disorders |
-
2016
- 2016-08-08 CN CN201610642515.0A patent/CN107698499A/en active Pending
- 2016-08-08 CN CN202310048439.0A patent/CN116082225A/en active Pending
-
2017
- 2017-08-03 JP JP2019507241A patent/JP6764999B2/en active Active
- 2017-08-03 CN CN201780048603.0A patent/CN109563039A/en active Pending
- 2017-08-03 WO PCT/CN2017/095882 patent/WO2018028508A1/en active Application Filing
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005515995A (en) * | 2001-12-06 | 2005-06-02 | エーザイ株式会社 | Pharmaceutical compositions and their use |
| JP2007510618A (en) * | 2003-11-14 | 2007-04-26 | シャンハイ ゲノミックス インク | Pyridone derivatives and their use |
| WO2007141200A1 (en) * | 2006-06-02 | 2007-12-13 | Janssen Pharmaceutica N.V. | Novel n-aryl and n-heteroaryl substituted pyridinone derivatives for use in mch-1 mediated diseases |
| JP2010511666A (en) * | 2006-12-05 | 2010-04-15 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Novel substituted diaza-spiro-pyridinone derivatives for use in diseases mediated by MCH-1 |
| JP2010513292A (en) * | 2006-12-14 | 2010-04-30 | イーライ リリー アンド カンパニー | Novel MCH receptor antagonist |
| CN101165051A (en) * | 2007-08-07 | 2008-04-23 | 中国科学院长春应用化学研究所 | Dendritic main body material and organic electroluminescence device prepared from the same |
| CN101723883A (en) * | 2008-10-24 | 2010-06-09 | 上海睿星基因技术有限公司 | Method for preparing oxycodone |
| CN102766041A (en) * | 2012-08-17 | 2012-11-07 | 济南大学 | Method for preparing intermediate of salicylic aldehyde derivatives |
| JP2016500661A (en) * | 2012-10-02 | 2016-01-14 | インターミューン， インコーポレイテッド | Antifibrotic pyridinone |
| JP2019507219A (en) * | 2016-02-01 | 2019-03-14 | スリーエム イノベイティブ プロパティズ カンパニー | Adhesive composition |
Non-Patent Citations (2)
| Title |
|---|
| GREENE, T. W. ET AL., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, THIRD EDITION, JPN6020001737, 1999, pages 249 - 257, ISSN: 0004196432 * |
| 化学実験法, JPN6020001738, 21 July 1976 (1976-07-21), pages 83, ISSN: 0004196433 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109563039A (en) | 2019-04-02 |
| CN107698499A (en) | 2018-02-16 |
| CN116082225A (en) | 2023-05-09 |
| JP6764999B2 (en) | 2020-10-07 |
| WO2018028508A1 (en) | 2018-02-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104230803B (en) | Preparation method of hydroxychloroquine sulfate | |
| CN106256824B (en) | Preparation method of high-purity delafloxacin meglumine salt | |
| CN105254544A (en) | Preparing method for bisphenol S | |
| CN106905319B (en) | Preparation method of substituted benzenesulfonyl kuhseng butane or hydrochloride thereof | |
| JP6764999B2 (en) | How to make hydronidon | |
| JPH10505084A (en) | Method for producing tetrabromobisphenol-A by reducing formation of methyl bromide | |
| JP6764998B2 (en) | How to make hydronidon | |
| WO2020215835A1 (en) | Method for purifying haloperidol | |
| JP2008231062A (en) | Preparation method of mirtazapine | |
| CN102382072A (en) | Method for refining D-cycloserine | |
| CN104418810A (en) | New synthetic route of levosimendan | |
| EP0421046A1 (en) | Process for producing highly pure 3,3',4,4' - biphenyltetra- carboxylic acid or dianhydride thereof | |
| CN111004173A (en) | Preparation method of hydroxyl-niatone | |
| CN104650048B (en) | Purification method of olmesartan medoxomil condensation compound | |
| CN110483270B (en) | Preparation method for efficient green synthesis of fenofibric acid | |
| RU2192470C2 (en) | Method of fusidic acid preparing | |
| CN109422679B (en) | Purification of bedaquiline and preparation method of stable crystal form | |
| CN107652269A (en) | Methanesulfonic acid fluorine imatinib purification of intermediate method | |
| JP2010059068A (en) | Method of producing pioglitazone | |
| CN106496191B (en) | A kind of preparation method of S-pantoprazole sodium | |
| CN100491341C (en) | Separating and purifying method for N-methyl-2-(4-phenoxy phenoxy)-2-chloroacetamide | |
| CN104086533A (en) | Refinement method of esomeprazole | |
| CN117624009A (en) | Continuous synthesis method of JAK inhibitor drug heterocyclic intermediate | |
| CN115850305A (en) | Refining method of high-purity Kribolol | |
| TWI535659B (en) | The purification method of alkali-metal sulfate compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190405 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20200123 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200128 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20200427 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20200629 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200727 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20200818 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200914 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6764999 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |