JP6764998B2 - How to make hydronidon - Google Patents
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- JP6764998B2 JP6764998B2 JP2019507219A JP2019507219A JP6764998B2 JP 6764998 B2 JP6764998 B2 JP 6764998B2 JP 2019507219 A JP2019507219 A JP 2019507219A JP 2019507219 A JP2019507219 A JP 2019507219A JP 6764998 B2 JP6764998 B2 JP 6764998B2
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- 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
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- C07D213/64—One oxygen atom attached in position 2 or 6
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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, specifically to a copper-catalyzed carbon-heteroatom coupling reaction and its use, and specifically to a method for producing hydronidon.
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。 Liver fibrosis is a common pathological cause in the progression of chronic liver disease, with various chronic injuries causing degeneration and necrosis of hepatocytes, overgrowth of fibrous connective tissue, overdeposition, and wrapping of regenerating hepatocytes. It forms "pseudolobules" and destroys the original tissue structure of the liver, eventually causing the liver to become nodular and stiff, thus impairing liver function and thus complete loss, resulting in cirrhosis.
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。
中国特許（CN2003000968）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％）。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。 A Chinese patent (CN2003000968) discloses a method for synthesizing a compound of formula I, using 2-amino-5-methylpyridine as a starting material and Me as a protecting group for a phenolic hydroxy group, which is used for deprotection thereof. Reagents are expensive, toxic gases are likely to be generated during the reaction process, sewage / waste treatment is complicated, operations are complicated, and yields are low (40%). Many of the methods for producing hydronidon in the existing technology involve the protection of the hydroxy group of bromophenol, and it is necessary to add a complicated reaction step in the industrial process.
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。 Therefore, in this field, research and development of a method for producing hydronidon, which 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 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）溶媒中、触媒の存在下で、２−ヒドロキシ−５−メチルピリジンをｐ−ブロモアニソールと混合して式ＩＩ化合物の粗生成物を得る工程と、
（２）式ＩＩ化合物の粗生成物を酢酸エチルおよび活性炭素と混合し、還流温度に加熱し、ろ過し、降温して結晶を析出させ、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、前記工程（１）では、２−ヒドロキシ−５−メチルピリジンとｐ−ブロモアニソールのモル比は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、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、工程（４）を含む。
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、エタノール、酢酸エチルの質量比は（１．８〜２．２）：（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、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、Ｋ２ＣＯ３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、Ｋ２ＣＯ３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）の前に、さらに、工程（１）で得られた式ＩＩ化合物をアンモニア水と混合し、撹拌して洗浄する、工程（２−１）を含む。
もう一つの好適な例において、前記工程（２−１）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（２）では、前記酢酸エチルと式ＩＩ化合物の粗生成物の質量比は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（２）では、前記活性炭素と式ＩＩ化合物の粗生成物の質量比は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、前記精製された式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。
An object of the present invention is to provide a method for producing hydronidon and its use.
A first aspect of the present invention is a method of producing a Formula I compound.
(1) A step of mixing 2-hydroxy-5-methylpyridine with p-bromoanisole in a solvent in the presence of a catalyst to obtain a crude product of the formula II compound.
(2) A step of mixing the crude product of the formula II compound with ethyl acetate and activated carbon, heating to a reflux temperature, filtering, lowering the temperature to precipitate crystals, and obtaining a purified formula II compound.
(3) A step of reacting the purified Formula II compound with HBr to obtain the Formula I compound, and
Provide a method including.
In another preferred example, in step (1), the molar ratio of 2-hydroxy-5-methylpyridine to p-bromoanisole was 1: 1 to 1: 2 (preferably 1: 1 to 1: 1. 8, more preferably 1: 1 to 1: 1.5, most preferably 1: 1 to 1: 1.3).
In another preferred example, the method further mixes the Formula I compound obtained in step (3) with ethanol and ethyl acetate, cools and filters to give a solid white crystal of the Formula I compound. , Including step (4).
In another preferred example, in step (4), the mass ratio of the Formula I compound, ethanol, ethyl acetate was (1.8-2.2) :( 0.8-1.2) :( 5). It is 0.8 to 6.2).
In another preferred example, in step (1), the solvent is selected from the group consisting of DMAC, DMF, or a combination thereof.
In another preferred embodiment, in the step (1), wherein the catalyst is selected CuI, CuSO 4 · 5H 2 O , from K 2 CO 3, K 2 CO 3 or combinations thereof, preferably is a mixture or a mixture of CuSO 4 · 5H 2 O, K 2 CO 3 and of K 2 CO 3 CuI and K 2 CO 3.
In another preferred embodiment, the step (1), wherein the solvent is DMF, and the catalyst is a mixture of CuSO 4 · 5H 2 O, K 2 CO 3 and K 2 CO 3.
In another preferred embodiment, the step (1), the molar ratio of the CuI and K 2 CO 3 1: 50 to 1: 80, preferably 1: 55-1: 70.
In another preferred embodiment, the step (1), wherein the solvent is DMAC, and the catalyst is a mixture of CuI and K 2 CO 3.
In another preferred example, in step (1), the heating reflux temperature is 130-150 ° C, preferably 135-145 ° C.
In another preferred example, prior to step (2), step (2-1) of further mixing the Formula II compound obtained in step (1) with aqueous ammonia, stirring and washing is performed. Including.
In another preferred example, in the step (2-1), the concentration of the aqueous ammonia is 15 to 28 wt%, preferably 16 to 25 wt%, more preferably 17 to 20 wt%.
In another preferred example, in step (2), the mass ratio of the crude product of the ethyl acetate to the Formula II compound was 1.0 to 10.0, preferably 2.0 to 8.0, more preferably. Is 3.0 to 6.0.
In another preferred example, in step (2), the mass ratio of the crude product of the activated carbon to the Formula II compound is 0.01-0.1, preferably 0.025-0.075, more preferably. Is 0.03 to 0.06.
In another preferred example, in step (3), the molar ratio of the purified Formula II compound to 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, within the scope of the present invention, it is understood that the above technical features of the present invention and the specifically described technical features below (eg, Examples) can be combined with each other to form a new or suitable technical plan. Will be done. Since the number of papers is limited, I will not explain them one by one 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、酢酸エチルと活性炭素で中間体の式II化合物を溶解脱色して精製を行い、単に再結成を行うより効率が高く、短時間で得られる中間体の化合物の収率が高く、脱色効果が良い。これに基づき、本発明を完成させた。
Specific Embodiment As a result of extensive and deep research, the present inventor has found, for the first time, a safe and efficient method for producing hydronidon, which has a surprisingly high yield and mild reaction conditions. In the present invention, the intermediate compound of Formula II is dissolved and decolorized with ethyl acetate and activated carbon for purification, which is more efficient than simply reforming, and the yield of the intermediate compound obtained in a short time is high. Good decolorizing effect. Based on this, the present invention has been 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。
Terminology Unless otherwise defined, all technical and scientific terms used herein are similar to those commonly understood by those skilled in the art to which this invention belongs.
As used herein, when used in a specifically exemplified number, the term "about" may vary within 1% of the value 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 "contains" or "contains" may be open, semi-closed and closed. In other words, the term also includes "basically composed of ..." or "consisting of ...".
本発明の主な利点は以下の通りである。
(1) 本発明は、酢酸エチルと活性炭素で中間体の式II化合物を溶解脱色して精製を行い、単に再結成を行うより効率が高く、短時間で得られる中間体の化合物の収率が高く、脱色効果が良い。
(2) 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。
(3) 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。
(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) In the present invention, the yield of the intermediate compound obtained in a short time is higher than that of simply reforming by dissolving and decolorizing the intermediate formula II compound with ethyl acetate and activated carbon for purification. Is high and the decolorizing effect is good.
(2) The present invention omits the step of protecting bromophenol in the existing technology, and the operation is simpler.
(3) HBr is used in place of the expensive and highly toxic BBr 3 , which is often used in existing techniques in the process of demethylation of the present invention.
(4) The production method of the present invention is simple and easy to operate, the reaction conditions are mild, the reaction time is short, the yield is high, it is 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、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。
Raw Materials A list of raw materials used in the present invention is shown in Table 1 below.
Hereinafter, the experimental materials and reagents used in the examples are all obtained as commercially available 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１５６ｋｇ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化合物の粗生成物を調製した。
２−ヒドロキシ−５−メチルピリジンで換算する収率は７２％であった。
２．式（ＩＩ）化合物の粗生成物の溶解脱色
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収度以下である）１．９５ｋｇおよび式ＩＩ化合物の粗生成物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化合物の粗生成物（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化合物の粗生成物２９ｋｇを取り、エタノール（濃度９５％、１４．５ｋｇ）、酢酸エチル（濃度９９％、８７ｋｇ）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 route 1:
1. 1. Formula II compound: Synthesis of N- (4-methoxyphenyl) -5-methyl-2-pyridone
Table 2 shows the amount and ratio of the raw materials charged.
Table 2
(2) The above filtrate is returned to the condensed autoclave, distilled under reduced pressure until no fraction is produced, placed in the washing autoclave, 55 kg of ammonia water (18 wt%) and 156 kg of water are added, stirred and washed, and the temperature is lowered. Then, it was centrifuged and washed with clean water until the mother liquor became colorless. The cake was removed, placed in a dish and air dried to prepare a crude product of Formula II compound.
The yield converted with 2-hydroxy-5-methylpyridine was 72%.
2. Dissolution and decolorization of the crude product of the compound of formula (II) Desolvent purification Autoclave with 130 kg of ethyl acetate (concentration ≥99.0%), medicated activated carbon (absorption of sample solution is absorption of potassium bicarbonate chromaticity standard solution) 1.95 kg and 39 kg of a crude product of the formula II compound were charged, heated and refluxed with stirring, decolorized for 1 hour, filtered before cooling, and the filtrate was put into a crystal reaction autoclave to remove the residue. The mixture was washed with 8 kg of ethyl acetate, the filtration residue was discarded, the filtrate was mixed, the solvent was removed, and the mixture was cooled and crystallized. After 70% of the filtrate was desolvated, the mixture 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 apparently the flow of the liquid 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 weighed 31.2 kg. There was (purity 99.66%, yield 80%).
3. 3. Preparation of Formula I compound:
N- (4-Methoxyphenyl) -5-methyl-2-pyridone (30 kg) was placed in a reaction autoclave, and 158 kg of 40 wt% hydrobromic acid was slowly added dropwise with stirring, and the temperature was raised to reflux after completion of the addition. The time when the raw material was exhausted was monitored by detection with a TCL plate. The cake was cooled to neutralize to pH = 5-6, centrifuged, and the cake was placed in a dish and air-dried to prepare a crude product of Formula I compound (yield: 98%).
(3-2) Suspension purification:
Take 29 kg of the crude product of the formula I compound obtained in the above step (3-1), add ethanol (concentration 95%, 14.5 kg) and ethyl acetate (concentration 99%, 87 kg), suspend it, and suspend it for 1 h. The cake was refluxed, cooled to 10 ° C., centrifuged, the mother liquor was collected, and the cake was air-dried.
Put 900 kg of pure water in a purified and decolorized autoclave, stir, heat until the water boils, add 30 kg of the naturally dried cake, and after the cake is completely dissolved, add 1.25 kg of activated carbon. Refrigerate for 15 minutes, filter under pressure before cooling, cool to crystallize, lower to about 25 ° C, stir for 2 hours at the same temperature, centrifuge, and wash the cake twice with pure water. The mixture was spin-dried to obtain a solid white crystal of the formula I compound. After drying in an oven at 60 ° C. at a controlled temperature, a finished product of the formula I compound was obtained (purity: 99.92%, yield). Rate: 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化合物の粗生成物を調製した。
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）化合物の粗生成物の溶解脱色
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収度以下である）２．７５ｋｇおよび式ＩＩ化合物の粗生成物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化合物の粗生成物を調製した。
（３−２）懸濁精製：
上記工程（３−１）で得られた式Ｉ化合物の粗生成物４４ｋｇを取り、エタノール（濃度９５％、２２ｋｇ）、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１．５ｋｇ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化合物の完成品を得た（純度：９９．９８％、収率：９０％）。
Example 2-Production route 2
1. 1. Formula II compound: Synthesis of N- (4-methoxyphenyl) -5-methyl-2-pyridone
Table 3
(2) The above mixed solution is cooled to room temperature, centrifuged, the filtrate is distilled under reduced pressure until no fraction is produced, the temperature is lowered to 120 ° C., and the mixture is 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 became colorless. The cake was removed, placed in a dish and air dried to prepare a crude product of Formula II compound.
The yield converted with 2-hydroxy-5-methylpyridine was 80%.
2. Dissolution and decolorization of the crude product of the compound of formula (II) 170 kg of ethyl acetate (concentration ≥99.0%) in a desolvated purified autoclave, medicated activated carbon (absorption of sample solution is absorption of potassium bicarbonate chromaticity standard solution) (The following) 2.75 kg and 55 kg of the crude product of the formula II compound were charged, heated and refluxed with stirring, decolorized for 1 hour, filtered before cooling, and the filtrate was put into a crystal reaction autoclave to remove the residue. The mixture was washed with 20 kg of ethyl acetate, the filtration residue was discarded, the filtrate was mixed, the solvent was removed, and the mixture was cooled and crystallized. After 70% of the filtrate was desolvated, the mixture 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 apparently the flow of the liquid 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 had a content of 99. It was .64%.
3. 3. Preparation of Formula I compound:
N- (4-Methoxyphenyl) -5-methyl-2-pyridone (44 kg) was placed in a reaction autoclave, and 267 kg of 40 wt% hydrobromic acid was slowly added dropwise with stirring, and the temperature was raised to reflux after completion of the addition. The time when the raw material was exhausted was monitored by detection with a TCL plate. The cake was cooled, neutralized to pH = 6, centrifuged, and the cake was placed in a dish and air dried to prepare a crude product of Formula I compound.
(3-2) Suspension purification:
Take 44 kg of the crude product of the formula I compound obtained in the above step (3-1), add ethanol (concentration 95%, 22 kg) and ethyl acetate (concentration 99%, 132 kg), suspend and reflux for 1 h. The temperature was lowered to 10 ° C., centrifugation was performed, the mother liquor was collected, and the cake was air-dried.
Put 900 kg of pure water in a purified decolorized autoclave, stir, heat until the water boils, add 30 kg of the naturally dried cake, and after the cake is completely dissolved, add 1.5 kg of activated carbon. Refrigerate for 15 minutes, filter under pressure before cooling, place in a cooled crystal autoclave, lower the temperature to about 25 ° C., stir for 2 hours at the same temperature, centrifuge, and wash the cake twice with pure water. The mixture was spin-dried to obtain a solid white crystal of the formula I compound. After drying in an oven at 60 ° C. at a controlled temperature, a finished product of the formula I compound was obtained (purity: 99.98%, yield). Rate: 90%).
比較例１
実施例１と同様で、異なるところは式ＩＩ化合物の粗生成物を溶解脱色する工程では、酢酸エチルの代わりにエタノールを使用したことで、得られた精製された式ＩＩ化合物は１６．３ｋｇで、収率は４２％であった。
このように、本発明は、酢酸エチルと活性炭素で中間体の式ＩＩ化合物を溶解脱色して精製を行い、単に再結成を行うより効率が高く、短時間で得られる中間体の化合物の収率が高く、脱色効果が良い。
Comparative Example 1
The same as in Example 1, the difference is that in the step of dissolving and decolorizing the crude product of the formula II compound, ethanol was used instead of ethyl acetate, and the obtained purified formula II compound weighed 16.3 kg. The yield was 42%.
As described above, the present invention is more efficient than simply dissolving and decolorizing the intermediate formula II compound with ethyl acetate and activated carbon to purify the compound, and simply reforming the compound, and the yield of the intermediate compound is obtained in a short time. The rate is high and the decolorization effect is good.
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 relating to the present invention are cited as references in this application, just as each document is cited independently. In addition, after reading the above contents of the present invention, those skilled in the art can make various variations and modifications to the present invention, but those equivalent forms are included in the claims of the present invention. Should be understood.
Claims (10)
（１）溶媒中、触媒の存在下で、２−ヒドロキシ−５−メチルピリジンをｐ−ブロモアニソールと混合して式ＩＩ化合物の粗生成物を得る工程と、
（ＩＩ）
（２）式ＩＩ化合物の粗生成物を酢酸エチルおよび活性炭素と混合し、還流温度に加熱し、ろ過し、降温して結晶を析出させ、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、
を含み、
前記工程（２）では、前記活性炭素と式ＩＩ化合物の粗生成物の質量比は０．０１〜０．１である、方法。 A method for producing a compound of formula I.
(1) A step of mixing 2-hydroxy-5-methylpyridine with p-bromoanisole in a solvent in the presence of a catalyst to obtain a crude product of the formula II compound.
(II)
(2) A step of mixing the crude product of the formula II compound with ethyl acetate and activated carbon, heating to a reflux temperature, filtering, lowering the temperature to precipitate crystals, and obtaining a purified formula II compound.
(3) A step of reacting the purified Formula II compound with HBr to obtain the Formula I compound, and
Including
In the step (2), the mass ratio of the active carbon to the crude product of the formula II compound is 0.01 to 0.1 .
The method according to claim 1, wherein in the step (3), the molar ratio of the purified Formula II compound to HBr is 1: 5 to 1:10.
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