TW202328077A - Hydrogenation synthesis method for preparing pyrazinecarboxylic acid derivative as fluorescent tracer - Google Patents
Hydrogenation synthesis method for preparing pyrazinecarboxylic acid derivative as fluorescent tracer Download PDFInfo
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Abstract
Description
本發明涉及用於製備在醫學診斷中用作螢光示蹤劑的3,6-二胺基-2,5-雙{N-[(1R)-1-羧酸-2-羥基乙基]胺基甲醯基}吡嗪的方法。The present invention relates to the preparation of 3,6-diamino-2,5-bis{N-[(1R)-1-carboxylic acid-2-hydroxyethyl] for use as a fluorescent tracer in medical diagnosis The carbamoyl}pyrazine method.
吡嗪類衍生物作為螢光示蹤劑在評估腎功能方面具有潛在的應用前景。作為一種極具臨床應用價值的螢光示蹤劑，3,6-二胺基-2,5-雙{N-[(1R)-1-羧基-2-羥基乙基]胺基甲醯基}吡嗪（下文中也稱作「式1的化合物」或「化合物1」）的研究得到了廣泛的關注，但是目前該化合物的合成路線報導極少。Pyrazine derivatives have potential applications as fluorescent tracers in the assessment of renal function. As a fluorescent tracer with great clinical application value, 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]aminoformyl The research on }pyrazine (hereinafter also referred to as "compound of formula 1" or "compound 1") has received extensive attention, but there are very few reports on the synthesis route of this compound.
2011年，Raghavan Rajagopalan等人對化合物1的合成進行了優化，減少了反應步驟（J. Med. Chem., 2011, 54, 5048-5058）。在該合成方法中，作為原料的3,6-二胺基吡嗪-2,5-二甲酸經醯胺化、鈀催化氫化等步驟得到化合物1： 然而，該路線的第2個步驟以氫氣作為氫源，在工業生產時不僅需要加壓而且反應時間長；而且氫氣是易燃易爆氣體，在工業化生產中存在極大的安全隱患。 In 2011, Raghavan Rajagopalan et al. optimized the synthesis of compound 1 and reduced the number of reaction steps (J. Med. Chem., 2011, 54, 5048-5058). In this synthesis method, 3,6-diaminopyrazine-2,5-dicarboxylic acid as a raw material is subjected to amidation, palladium-catalyzed hydrogenation and other steps to obtain compound 1: However, the second step of this route uses hydrogen as the hydrogen source, which not only requires pressurization but also takes a long time to react in industrial production; moreover, hydrogen is a flammable and explosive gas, which poses a great safety hazard in industrial production.
因此，仍然需要開發具有高安全性和高效益的適合3,6-二胺基-2,5-雙{N-[(1R)-1-羧基-2-羥基乙基]胺基甲醯基}吡嗪的工業化生產的方法。Therefore, there is still a need to develop a suitable 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl group with high safety and high efficiency. } The industrial production method of pyrazine.
本發明的目的在於克服現有技術中存在的問題，避免使用易燃易爆的氫氣，降低工業化生產中的安全隱患。The purpose of the present invention is to overcome the problems existing in the prior art, avoid the use of inflammable and explosive hydrogen, and reduce the potential safety hazards in industrial production.
本發明進一步的目的是：在實現與現有技術（例如Raghavan Rajagopalan等人， J. Med. Chem.，2011, 54, 5048-5058.）同等的化合物1的收率和品質的同時，縮短反應時間。這對於工業化生產具有重要意義。 A further object of the present invention is to shorten the reaction time while realizing the yield and quality of compound 1 equivalent to those of the prior art (such as Raghavan Rajagopalan et al., J. Med. Chem. , 2011, 54, 5048-5058.) . This is of great significance for industrial production.
通過提供本發明的適合化合物1的工業化生產的製備方法實現了以上目的。The above object is achieved by providing a preparation method suitable for the industrial production of Compound 1 of the present invention.
一般而言，本發明提供一種用於製備式1的3,6-二胺基-2,5-雙{N-[(1R)-1-羧基-2-羥基乙基]胺基甲醯基}吡嗪（下文中也稱為「化合物1」）的新方法，所述方法包括以下步驟： 使式5的化合物（下文中也稱為「化合物5」）與借氫試劑在溶劑中在適合的金屬催化劑的存在下進行借氫反應，以提供所述式1的3,6-二胺基-2,5-雙{N-[(1R)-1-羧基-2-羥基乙基]胺基甲醯基}吡嗪， 其中所述溶劑選自醇或醇水溶液。 In general, the present invention provides a method for the preparation of 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl } A new method for pyrazine (hereinafter also referred to as "compound 1"), said method comprising the following steps: A compound of formula 5 (hereinafter also referred to as "compound 5") is reacted with a hydrogen-borrowing reagent in a solvent in the presence of a suitable metal catalyst to provide the 3,6-diamine group of formula 1 -2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]aminoformyl}pyrazine, wherein the solvent is selected from alcohol or alcohol aqueous solution.
定義definition
除非在下文中另有定義，本文中所用的所有技術術語和科學術語的含義意圖與本領域技術人員通常所理解的相同。提及本文中使用的技術意圖指在本領域中通常所理解的技術，包括那些對本領域技術人員顯而易見的技術的變化或等效技術的替換。雖然相信以下術語對於本領域技術人員很好理解，但仍然闡述以下定義以更好地解釋本發明。Unless defined otherwise hereinafter, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including those variations of the techniques or substitutions of equivalent techniques that are obvious to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
如本文中所使用，術語「包括」、「包含」、「具有」、「含有」或「涉及」及其在本文中的其它變體形式為包含性的(inclusive)或開放式的，且不排除其它未列舉的元素或方法步驟，儘管其它未列舉的元素或方法步驟不一定存在(即，這些術語也涵蓋術語「基本上由……組成」和「由……組成」)。As used herein, the terms "comprises," "comprising," "has," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended, and do not Other unrecited elements or method steps are excluded although other unrecited elements or method steps are not necessarily present (ie, these terms also encompass the terms "consisting essentially of" and "consisting of").
如本文所使用，術語「借氫反應」，也被稱為氫轉移反應，是指利用金屬催化劑從相對惰性的有機化合物中脫氫形成金屬氫化物，同時使所述有機化合物活化並參與後續反應生成中間體，之後所述金屬氫化物再還原所述中間體以生成新產物。所述有機化合物被稱作「借氫試劑」。As used herein, the term "hydrogen borrowing reaction", also known as a hydrogen transfer reaction, refers to the use of a metal catalyst to dehydrogenate a relatively inert organic compound to form a metal hydride while simultaneously activating the organic compound and participating in a subsequent reaction An intermediate is formed, which is then reduced by the metal hydride to form a new product. Such organic compounds are referred to as "hydrogen borrowing agents".
如本文中所使用，術語「室溫」是指約20至25°C。As used herein, the term "room temperature" refers to about 20 to 25°C.
術語「約」是指在所述數值的±10%範圍內，較佳±5%範圍內，更佳±2%範圍內。The term "about" means within ±10%, preferably within ±5%, more preferably within ±2% of the stated value.
在第一方面，本發明提供製備式1的3,6-二胺基-2,5-雙{N-[(1R)-1-羧基-2-羥基乙基]胺基甲醯基}吡嗪的方法，其特徵在於，所述方法包括以下步驟： 使式5的化合物與借氫試劑在溶劑中在適合的金屬催化劑的存在下進行借氫反應，以提供所述式1的3,6-二胺基-2,5-雙{N-[(1R)-1-羧基-2-羥基乙基]胺基甲醯基}吡嗪， 其中所述溶劑包括醇或醇水溶液。 In a first aspect, the present invention provides for the preparation of 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl}pyridine The method for oxazine, is characterized in that, described method comprises the following steps: A compound of formula 5 is subjected to a hydrogen borrowing reaction with a hydrogen borrowing reagent in a solvent in the presence of a suitable metal catalyst to provide the 3,6-diamino-2,5-bis{N-[( 1R)-1-carboxy-2-hydroxyethyl]carbamoyl}pyrazine, wherein the solvent includes alcohol or an aqueous alcohol solution.
用於本發明的方法的借氫試劑較佳地是適於工業化生產的試劑。某些試劑的使用可能會帶來生產隱患，因此不是較佳的。例如，甲酸銨易於昇華，因而會造成堵塞管路的問題。The hydrogen-borrowing reagent used in the method of the present invention is preferably a reagent suitable for industrial production. The use of certain reagents may pose production hazards and is therefore not preferred. For example, ammonium formate is prone to sublimation, which can cause clogging problems.
在一些實施方案中，所述借氫試劑選自甲酸和鹼金屬甲酸鹽的組合、環己二烯和異丙醇。In some embodiments, the hydrogen-borrowing agent is selected from a combination of formic acid and an alkali metal formate, cyclohexadiene, and isopropanol.
在一些實施方案中，所述式5的化合物與所述借氫試劑的莫耳比為約1:2至1:20，較佳約1:2至1:10，例如約1:2.5、約1:4、約1:5、約1:6或約1:8。In some embodiments, the molar ratio of the compound of formula 5 to the hydrogen-borrowing agent is about 1:2 to 1:20, preferably about 1:2 to 1:10, such as about 1:2.5, about 1:4, about 1:5, about 1:6, or about 1:8.
在一些實施方案中，所述金屬催化劑為碳載鈀(Pd/C)。所述Pd/C催化劑中鈀的質量分數可以為約5至20%，較佳約10%。例如，所述Pd/C催化劑可以含有約50 w/w%的水。In some embodiments, the metal catalyst is palladium on carbon (Pd/C). The mass fraction of palladium in the Pd/C catalyst can be about 5 to 20%, preferably about 10%. For example, the Pd/C catalyst may contain about 50 w/w% water.
在一些實施方案中，所述式5的化合物與所述金屬催化劑的質量比為約10:1至10:3，較佳約10:2。In some embodiments, the mass ratio of the compound of formula 5 to the metal catalyst is about 10:1 to 10:3, preferably about 10:2.
在一些實施方案中，所述溶劑為醇。In some embodiments, the solvent is alcohol.
在另一些實施方案中，所述溶劑為醇水溶液。所述醇水溶液中醇與水的體積比可以為約1:10至10:1，較佳約1:8至8:1，更佳約4:1至8:1。In other embodiments, the solvent is an aqueous alcohol solution. The volume ratio of alcohol to water in the alcohol aqueous solution may be about 1:10 to 10:1, preferably about 1:8 to 8:1, more preferably about 4:1 to 8:1.
在一些上文所述的實施方案中，無論所述溶劑是否包括水，所述醇的量可以為所述式5的化合物的量的約4至40倍（v/w），例如約10、15、25、30或35倍（v/w）。In some of the above-described embodiments, whether the solvent includes water or not, the amount of the alcohol may be about 4 to 40 times (v/w) the amount of the compound of formula 5, such as about 10, 15, 25, 30 or 35 times (v/w).
所述醇可以選自甲醇、乙醇、異丙醇及其混合物，較佳為甲醇或乙醇，更佳為乙醇。The alcohol can be selected from methanol, ethanol, isopropanol and mixtures thereof, preferably methanol or ethanol, more preferably ethanol.
在一些實施方案中，所述借氫反應在約20°C至100°C，較佳約20°C至80°C的溫度下進行。在一些較佳的實施方案中，所述借氫反應在約50°C至70°C的溫度下進行。在一些較佳的實施方案中，所述借氫反應在室溫下進行。In some embodiments, the hydrogen borrowing reaction is carried out at a temperature of about 20°C to 100°C, preferably about 20°C to 80°C. In some preferred embodiments, the hydrogen borrowing reaction is performed at a temperature of about 50°C to 70°C. In some preferred embodiments, the hydrogen borrowing reaction is performed at room temperature.
在一些實施方案中，所述借氫反應進行約1至12小時，較佳約2至12小時，更佳約2小時、10小時或12小時，以完成所述式5的化合物向所述式1的化合物的轉化。In some embodiments, the hydrogen borrowing reaction is carried out for about 1 to 12 hours, preferably about 2 to 12 hours, more preferably about 2 hours, 10 hours or 12 hours, to complete the conversion of the compound of formula 5 to the formula 1. Transformation of Compounds.
在一些較佳的實施方案中，所述借氫反應在約70°C的溫度下進行約2小時，以完成所述式5的化合物向所述式1的化合物的轉化。In some preferred embodiments, the hydrogen borrowing reaction is carried out at a temperature of about 70° C. for about 2 hours to complete the conversion of the compound of formula 5 to the compound of formula 1.
可以通過例如薄層色譜法(TLC)檢測反應物中式5的化合物的殘留量來監測其向所述式1的化合物的轉化。The conversion to the compound of formula 1 can be monitored by detecting the residual amount of the compound of formula 5 in the reactant, eg, by thin layer chromatography (TLC).
所生成的式1的化合物可以通過以下步驟來分離和純化： （1）在所述借氫反應完成後，過濾反應混合物，並用醇水溶液洗滌濾餅至濾液為淺黃色，合併所得的濾液； （2）濃縮所述濾液，得到所述式I的化合物的粗品； （3）向所述式I的化合物的粗品加入適量乙腈或水並打漿適合的時間（例如約1至4小時）； （4）過濾，並將濾餅在適合的溫度（例如約40至45°C）下減壓乾燥，得到所述式I的化合物。 The compound of formula 1 generated can be separated and purified by the following steps: (1) After the hydrogen borrowing reaction is completed, filter the reaction mixture, and wash the filter cake with an aqueous alcohol solution until the filtrate is light yellow, and combine the obtained filtrate; (2) concentrating the filtrate to obtain the crude product of the compound of formula I; (3) adding an appropriate amount of acetonitrile or water to the crude product of the compound of formula I and beating for a suitable time (for example, about 1 to 4 hours); (4) filtering, and drying the filter cake under reduced pressure at a suitable temperature (for example, about 40 to 45°C) to obtain the compound of formula I.
步驟（1）中所述的醇水溶液可以是例如乙醇水溶液。所述乙醇水溶液的含水量可以為約25%至40% (v/v)，較佳約30%至36% (v/v)。The aqueous alcohol solution described in step (1) may be, for example, an aqueous ethanol solution. The water content of the aqueous ethanol solution may be about 25% to 40% (v/v), preferably about 30% to 36% (v/v).
在第二方面，本發明提供如上文第一方面所述的方法，其特徵在於，所述借氫試劑為甲酸以及鹼金屬甲酸鹽的組合。In a second aspect, the present invention provides the method as described in the first aspect above, wherein the hydrogen-borrowing reagent is a combination of formic acid and alkali metal formate.
在一些實施方案中，所述甲酸與所述鹼金屬甲酸鹽的莫耳比為約1:6至6:1，較佳約1:1至5:1，更佳約1:2至5:1。In some embodiments, the molar ratio of the formic acid to the alkali metal formate is about 1:6 to 6:1, preferably about 1:1 to 5:1, more preferably about 1:2 to 5 :1.
在一些實施方案中，所述式5的化合物與所述甲酸和所述鹼金屬甲酸鹽的總和的莫耳比為約1:2至1:20，例如約1:4至1:18、約1:6至1:16或約1:8至1:12。在一些較佳的實施方案中，所述莫耳比為約1:5至1:10，例如約1:6至1:8，更佳約1:6。In some embodiments, the molar ratio of the compound of formula 5 to the sum of the formic acid and the alkali metal formate is about 1:2 to 1:20, such as about 1:4 to 1:18, About 1:6 to 1:16 or about 1:8 to 1:12. In some preferred embodiments, the molar ratio is about 1:5 to 1:10, such as about 1:6 to 1:8, more preferably about 1:6.
在一些較佳的實施方案中，所述鹼金屬甲酸鹽為甲酸鈉或甲酸鉀，較佳甲酸鉀。In some preferred embodiments, the alkali metal formate is sodium formate or potassium formate, preferably potassium formate.
所述甲酸以及鹼金屬甲酸鹽的組合可以通過向反應體系中加入單獨的甲酸以及鹼金屬甲酸鹽或其混合物來得到，也可以經由過量的甲酸和適量的相應鹼金屬鹼在反應體系中反應而原位形成。所述鹼可以選自氫氧化鉀、氫氧化鈉、碳酸鉀、碳酸鈉、碳酸氫鉀和碳酸氫鈉及其任意組合。The combination of formic acid and alkali metal formate can be obtained by adding separate formic acid and alkali metal formate or a mixture thereof to the reaction system, or by adding an appropriate amount of formic acid and an appropriate amount of the corresponding alkali metal base in the reaction system. reaction to form in situ. The base may be selected from potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate and any combination thereof.
在一些較佳的實施方案中，所述溶劑為醇水溶液。所述醇水溶液中醇與水的體積比可以為約1:10至10:1，較佳約1:8至8:1，更佳約4:1至8:1。所述醇的量可以為所述式5的化合物的量的約10至40倍（v/w），較佳約10至35倍（v/w），例如15、25或30倍（v/w）。在一些較佳的實施方案中，所述醇選自甲醇、乙醇及其混合物，較佳為甲醇或乙醇，更佳為乙醇。In some preferred embodiments, the solvent is an aqueous alcohol solution. The volume ratio of alcohol to water in the alcohol aqueous solution may be about 1:10 to 10:1, preferably about 1:8 to 8:1, more preferably about 4:1 to 8:1. The amount of said alcohol can be about 10 to 40 times (v/w), preferably about 10 to 35 times (v/w), such as 15, 25 or 30 times (v/w) of the amount of the compound of formula 5 w). In some preferred embodiments, the alcohol is selected from methanol, ethanol and mixtures thereof, preferably methanol or ethanol, more preferably ethanol.
在一些實施方案中，所述借氫反應在約50°C至80°C，較佳在約50°C、約60°C或更佳約70°C的溫度下進行。In some embodiments, the hydrogen borrowing reaction is performed at a temperature of about 50°C to 80°C, preferably at about 50°C, about 60°C or more preferably about 70°C.
在一些實施方案中，所述借氫反應進行約2至12小時，較佳約2小時，以完成所述式5的化合物向所述式1的化合物的轉化。In some embodiments, the hydrogen borrowing reaction is performed for about 2 to 12 hours, preferably about 2 hours, to complete the conversion of the compound of formula 5 to the compound of formula 1.
所述方法可以實現與Raghavan Rajagopalan等人（J. Med. Chem.，2011, 54, 5048-5058）所報導的同等的化合物1的收率和品質。The method can achieve the same yield and quality of compound 1 as reported by Raghavan Rajagopalan et al. (J. Med. Chem., 2011, 54, 5048-5058).
在一些更佳的實施方案中，所述借氫反應在約70°C的溫度下進行約2小時，以完成所述式5的化合物向所述式1的化合物的轉化。In some more preferred embodiments, the hydrogen borrowing reaction is performed at a temperature of about 70° C. for about 2 hours to complete the conversion of the compound of formula 5 to the compound of formula 1.
在一些特別佳的實施方案中，本發明提供如上文所述的方法，其特徵在於，所述借氫試劑為莫耳比為約1:2至5:1的甲酸和甲酸鉀的組合； 所述式5的化合物與所述甲酸和所述甲酸鉀的總和的莫耳比為約1:5至1:10，更佳約1:6； 所述溶劑為甲醇或乙醇的水溶液，其中所述甲醇或乙醇與水的體積比為約4:1至8:1； 所述甲醇或乙醇的量為所述式5的化合物的量的約15至35倍（v/w）； 所述金屬催化劑為Pd/C，其中所述Pd/C催化劑中鈀的質量分數為約10%（例如，所述Pd/C催化劑含有約50 w/w%的水）； 所述式5的化合物與所述Pd/C催化劑的質量比為約10:2；並且 所述借氫反應在約50°C至70°C的溫度下進行約2至12小時，更佳約70°C的溫度下進行約2小時，以完成所述式5的化合物向所述式1的化合物的轉化。 In some particularly preferred embodiments, the present invention provides a method as described above, wherein the hydrogen-borrowing reagent is a combination of formic acid and potassium formate in a molar ratio of about 1:2 to 5:1; The molar ratio of the compound of the formula 5 to the sum of the formic acid and the potassium formate is about 1:5 to 1:10, more preferably about 1:6; The solvent is an aqueous solution of methanol or ethanol, wherein the volume ratio of the methanol or ethanol to water is about 4:1 to 8:1; The amount of methanol or ethanol is about 15 to 35 times (v/w) that of the compound of formula 5; The metal catalyst is Pd/C, wherein the mass fraction of palladium in the Pd/C catalyst is about 10% (for example, the Pd/C catalyst contains about 50 w/w% water); The mass ratio of the compound of the formula 5 to the Pd/C catalyst is about 10:2; and The hydrogen borrowing reaction is carried out at a temperature of about 50°C to 70°C for about 2 to 12 hours, more preferably at a temperature of about 70°C for about 2 hours, to complete the conversion of the compound of the formula 5 to the formula 1. Transformation of Compounds.
所生成的式1的化合物可以通過如上文第一方面所述的步驟來分離和純化。在一些實施方案中，該分離和純化過程還可以包括在合併的濾液中加入適量的酸（例如，與用於原位形成所述鹼金屬甲酸鹽的鹼金屬鹼相同的莫耳量）並混合的步驟。例如，當如上文所述原位形成所述甲酸以及鹼金屬甲酸鹽的組合時，可以向合併的濾液中加入與用於原位形成所述鹼金屬甲酸鹽的鹼金屬鹼相同莫耳量的酸。所述酸較佳為鹽酸。然後，將所得的混合物濃縮，得到所述式I的化合物的粗品。The resulting compound of formula 1 can be isolated and purified by the steps described in the first aspect above. In some embodiments, the isolation and purification process may also include adding an appropriate amount of acid (e.g., the same molar amount of alkali metal base used to form the alkali metal formate in situ) to the combined filtrate and Mixing steps. For example, when the combination of formic acid and alkali metal formate is formed in situ as described above, the same molar amount of alkali metal base used to form the alkali metal formate in situ can be added to the combined filtrate. amount of acid. The acid is preferably hydrochloric acid. Then, the resulting mixture was concentrated to obtain the crude compound of formula I.
在第三方面，本發明提供如上文第一方面所述的方法，其特徵在於，所述借氫試劑為環己二烯。In a third aspect, the present invention provides the method as described in the first aspect above, wherein the hydrogen-borrowing reagent is cyclohexadiene.
在一些實施方案中，所述式5的化合物與所述環己二烯的莫耳比為約1:2至1:5；較佳約1:2至1:3。In some embodiments, the molar ratio of the compound of formula 5 to the cyclohexadiene is about 1:2 to 1:5; preferably about 1:2 to 1:3.
在一些實施方案中，所述溶劑為醇，較佳為甲醇或乙醇，更佳為乙醇。In some embodiments, the solvent is alcohol, preferably methanol or ethanol, more preferably ethanol.
在一些實施方案中，所述醇的量為所述式5的化合物的量的約4至10倍（v/w），例如約4、約6或約8倍（v/w）。In some embodiments, the amount of the alcohol is about 4 to 10 times (v/w), such as about 4, about 6 or about 8 times (v/w) the amount of the compound of formula 5.
在一些實施方案中，所述借氫反應在室溫下進行約10至12小時，以完成所述式5的化合物向所述式1的化合物的轉化。In some embodiments, the hydrogen borrowing reaction is performed at room temperature for about 10 to 12 hours to complete the conversion of the compound of Formula 5 to the compound of Formula 1 .
在一些實施方案中，本發明提供如上文所述的方法，其特徵在於，所述借氫試劑為環己二烯； 所述式5的化合物與所述環己二烯的莫耳比為約1:2至1:3； 所述溶劑為甲醇或乙醇，並且所述甲醇或乙醇的量為所述式5的化合物的量的約4至6倍（v/w）； 所述金屬催化劑為Pd/C，其中所述Pd/C催化劑中鈀的質量分數為約10%（例如，所述Pd/C催化劑含有約50 w/w%的水）； 所述式5的化合物與所述Pd/C催化劑的質量比為約10:2；並且 所述借氫反應在室溫下進行約10至12小時，以完成所述式5的化合物向所述式1的化合物的轉化。 In some embodiments, the present invention provides a method as described above, wherein the hydrogen-borrowing reagent is cyclohexadiene; The molar ratio of the compound of the formula 5 to the cyclohexadiene is about 1:2 to 1:3; The solvent is methanol or ethanol, and the amount of the methanol or ethanol is about 4 to 6 times (v/w) the amount of the compound of formula 5; The metal catalyst is Pd/C, wherein the mass fraction of palladium in the Pd/C catalyst is about 10% (for example, the Pd/C catalyst contains about 50 w/w% water); The mass ratio of the compound of the formula 5 to the Pd/C catalyst is about 10:2; and The hydrogen borrowing reaction is carried out at room temperature for about 10 to 12 hours to complete the conversion of the compound of formula 5 to the compound of formula 1.
所生成的式1的化合物可以通過如上文第一方面所述的步驟來分離和純化。The resulting compound of formula 1 can be isolated and purified by the steps described in the first aspect above.
有益效果Beneficial effect
本發明的方法避免了使用易燃易爆的氫氣，大大降低了工業化生產中的安全隱患。本發明的方法還具有脫苄基反應進行徹底，基本無副反應的優點。而且，通過調整反應條件（例如，反應物的配比和反應溫度），本發明的方法在實現與Raghavan Rajagopalan等人（J. Med. Chem.，2011, 54, 5048-5058）所報導的同等的化合物1的收率和品質的同時，能夠將反應時間由Raghavan Rajagopalan等人報導的10多個小時縮短至約2小時或更少，從而大大縮短生產時間。本發明的方法還避免了在使用甲酸銨時由昇華所致的堵塞管路的問題。本發明的方法對設備要求不高，操作簡便，產率高，安全性和成本效益高，適於工業化生產，具有重要應用價值。The method of the invention avoids the use of inflammable and explosive hydrogen, and greatly reduces potential safety hazards in industrialized production. The method of the present invention also has the advantages that the debenzylation reaction is carried out completely and there is basically no side reaction. Moreover, by adjusting the reaction conditions (for example, the ratio of reactants and reaction temperature), the method of the present invention is equivalent to that reported by Raghavan Rajagopalan et al. (J. Med. Chem., 2011, 54, 5048-5058). While improving the yield and quality of compound 1, the reaction time can be shortened from more than 10 hours reported by Raghavan Rajagopalan et al. to about 2 hours or less, thereby greatly shortening the production time. The method of the present invention also avoids the problem of clogged lines caused by sublimation when ammonium formate is used. The method of the invention has low requirements on equipment, simple and convenient operation, high yield, high safety and cost-effectiveness, is suitable for industrial production, and has important application value.
實施例Example
以下結合實施例進一步描述本發明，但提供這些實施例並非意圖限制本發明的範圍。The present invention is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.
本發明實施例中未註明具體條件的實驗方法，通常為常規條件，或按照原料或商品製造廠商所建議的條件；未註明來源的試劑，通常為通過商業途徑可購得的常規試劑或者可以由已知的試劑通過常規方法製備得到。The experimental method that does not indicate specific condition in the embodiment of the present invention, is conventional condition usually, or according to the condition suggested by raw material or commodity manufacturer; Known reagents are prepared by conventional methods.
試劑及儀器1. HRMS 儀器型號：Agilent 1290 Q-TOF-6545A； 試劑：甲酸、三氟乙酸、乙腈、甲醇。 2. LC/MS 儀器：Waters 2767 Sample Manager 、Waters 515 HPLC Pump、Waters2489UV/Visible Detector 、Waters 3100 Mass Detector； 試劑：純化水、乙腈。 質譜是用LC-MS儀測定得到，離子化方式可為ESI或APCI。 薄層層析(TLC)使用煙臺黃海HSGF254或青島GF254矽膠板。使用的矽膠板採用的規格是0.15 mm～0.2 mm，用於薄層層析分離純化的矽膠板採用的規格是0.4 mm～0.5 mm。 柱層析一般使用煙臺黃海200-300目矽膠為載體。 各種起始原料和試劑來自市售或者是根據已知的方法合成，市售原料和試劑均不經進一步純化直接使用，除非另有指明。 Reagents and instruments 1. HRMS instrument model: Agilent 1290 Q-TOF-6545A; Reagents: formic acid, trifluoroacetic acid, acetonitrile, methanol. 2. LC/MS instruments: Waters 2767 Sample Manager, Waters 515 HPLC Pump, Waters2489UV/Visible Detector, Waters 3100 Mass Detector; Reagents: purified water, acetonitrile. The mass spectrum is measured by LC-MS instrument, and the ionization method can be ESI or APCI. Thin layer chromatography (TLC) used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The size of the silica gel plate used is 0.15 mm to 0.2 mm, and the size of the silica gel plate used for thin layer chromatography separation and purification is 0.4 mm to 0.5 mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier. Various starting materials and reagents were either commercially available or synthesized according to known methods, and commercially available materials and reagents were used without further purification unless otherwise indicated.
實施 例 1 ： 3,6- 二胺基 -2,5- 雙 {N-[(1R)-1- 羧基 -2- 羥基乙基 ] 胺基甲醯基 } 吡嗪的製備往250 mL反應瓶中加入20 mL純化水和0.56 g KOH，完全溶解後加入2.76g HCOOH和80mL乙醇，攪拌5 min後於室溫下加入5.00 g化合物5和1 g 10% Pd/C (含水50%)，在70 °C加熱回流2 h，TLC監測顯示反應完畢，趁熱用矽藻土濾除Pd/C。用乙醇水溶液（30 % H 2O，V/V）洗滌濾餅至濾液為淺黃色，合併濾液。向濾液中加入10 ml的1N鹽酸，攪拌15min後減壓濃縮至乾。將所得的固體用50 mL乙腈/水打漿2 h，然後過濾。將濾餅於40°C減壓乾燥12 h，得到2.19 g固體形式的標題化合物 (莫耳收率：65%)。 LC-MS：RT=3.02 min, [M-H]=370.9. HRMS：[M+H +]=373.1110. 1H NMR [500Hz, DMSO- d6] δ 8.47 (d, 2H), 6.78 (s, 4H), 4.47 (dt, 2H), 3.90 (dd, 2H), 3.76 (dd, 2H). Embodiment 1 : Preparation of 3,6- diamino -2,5- bis {N-[(1R)-1- carboxy -2- hydroxyethyl ] aminoformyl } pyrazine into 250 mL reaction flask 20 mL of purified water and 0.56 g KOH were added to the solution, and after complete dissolution, 2.76 g of HCOOH and 80 mL of ethanol were added. After stirring for 5 min, 5.00 g of compound 5 and 1 g of 10% Pd/C (50% water content) were added at room temperature. Heating to reflux at 70 °C for 2 h, TLC monitoring showed that the reaction was complete, and the Pd/C was filtered out with diatomaceous earth while it was still hot. The filter cake was washed with ethanol aqueous solution (30% H 2 O, V/V) until the filtrate was light yellow, and the filtrates were combined. Add 10 ml of 1N hydrochloric acid to the filtrate, stir for 15 min and concentrate to dryness under reduced pressure. The resulting solid was slurried with 50 mL of acetonitrile/water for 2 h, then filtered. The filter cake was dried under reduced pressure at 40° C. for 12 h to obtain 2.19 g of the title compound as a solid (molar yield: 65%). LC-MS: RT=3.02 min, [MH]=370.9. HRMS: [M+H + ]=373.1110. 1 H NMR [500Hz, DMSO- d6 ] δ 8.47 (d, 2H), 6.78 (s, 4H) , 4.47 (dt, 2H), 3.90 (dd, 2H), 3.76 (dd, 2H).
比較 例 1 ： 3,6- 二胺基 -2,5- 雙 {N-[(1R)-1- 羧基 -2- 羥基乙基 ] 胺基甲醯基 } 吡嗪的製備除了不加入KOH以外，重複實施例1的操作。 具體而言，往250 mL反應瓶中加入20 mL純化水，然後加入2.76g HCOOH和80mL乙醇，攪拌5 min後於室溫下加入5.00 g化合物5和1 g 10% Pd/C (含水50%)，在70 °C加熱回流2 h。TLC監測顯示目標化合物幾乎不可見，原料點有大量殘留。 Comparative Example 1 : The preparation of 3,6- diamino -2,5- bis {N-[(1R)-1- carboxy -2- hydroxyethyl ] aminoformyl } pyrazine except without adding KOH , repeat the operation of embodiment 1. Specifically, 20 mL of purified water was added to a 250 mL reaction flask, followed by 2.76 g of HCOOH and 80 mL of ethanol. After stirring for 5 min, 5.00 g of compound 5 and 1 g of 10% Pd/C (50% water content ), heated to reflux at 70 °C for 2 h. TLC monitoring showed that the target compound was almost invisible, and there was a large amount of residue at the raw material point.
實施 例 2 ： 3,6- 二胺基 -2,5- 雙 {N-[(1R)-1- 羧基 -2- 羥基乙基 ] 胺基甲醯基 } 吡嗪的製備往250mL反應瓶中加入20 mL純化水和2.23 g KOH，完全溶解後加入2.76 g HCOOH和160 mL乙醇，攪拌5 min後於室溫下加入5.00 g化合物5、1 g 10% Pd/C (含水50%)，在60°C加熱回流10 h，TLC監測顯示反應完畢，趁熱用矽藻土濾除Pd/C。用乙醇水溶液（30% H 2O，V/V）洗滌濾餅至濾液為淺黃色，合併濾液。向濾液中加入40 ml的1N鹽酸，攪拌15min後減壓濃縮至乾。將所得的固體用30 mL水打漿2 h，然後過濾。將濾餅於40°C減壓乾燥12 h，得到2.12 g固體形式的標題化合物（莫耳收率：63%）。 LC-MS：RT=3.02min, [M-H]=370.9. HRMS和 1H NMR資料同實施例1。 Embodiment 2 : Preparation of 3,6- diamino -2,5- bis {N-[(1R)-1- carboxy -2- hydroxyethyl ] aminoformyl } pyrazine into a 250mL reaction flask 20 mL of purified water and 2.23 g of KOH were added, and after complete dissolution, 2.76 g of HCOOH and 160 mL of ethanol were added. After stirring for 5 min, 5.00 g of compound 5 and 1 g of 10% Pd/C (50% water content) were added at room temperature. Heating to reflux at 60°C for 10 h, TLC monitoring showed that the reaction was complete, and the Pd/C was filtered out with diatomaceous earth while it was still hot. The filter cake was washed with ethanol aqueous solution (30% H 2 O, V/V) until the filtrate was light yellow, and the filtrates were combined. Add 40 ml of 1N hydrochloric acid to the filtrate, stir for 15 min and concentrate to dryness under reduced pressure. The resulting solid was slurried with 30 mL of water for 2 h, then filtered. The filter cake was dried under reduced pressure at 40°C for 12 h to obtain 2.12 g of the title compound as a solid (molar yield: 63%). LC-MS: RT=3.02min, [MH]=370.9. HRMS and 1 H NMR data are the same as in Example 1.
實施例 3 ： 3,6- 二胺基 -2,5- 雙 {N-[(1R)-1- 羧基 -2- 羥基乙基 ] 胺基甲醯基 } 吡嗪的製備往250 mL反應瓶中加入20 mL純化水和2.23g KOH，完全溶解後加入2.76 g HCOOH和80mL甲醇，攪拌5 min後於室溫下加入5.00 g化合物5、1 g 10% Pd/C (含水50%)，在50°C加熱回流12 h，TLC監測顯示反應完畢，趁熱用矽藻土濾除Pd/C。用乙醇水溶液（36% H 2O，V/V）洗滌濾餅至濾液為淺黃色，合併濾液。向濾液中加入40 ml的1N鹽酸，攪拌15 min後減壓濃縮至25 mL，然後過濾。將濾餅用50 mL水打漿2 h，然後過濾。將濾餅於40°C減壓乾燥12 h，得到1.85 g紅色固體形式的標題化合物（莫耳收率：55%）。 LC-MS：RT=3.02min, [M-H]=370.9. HRMS和 1H NMR資料同實施例1。 Embodiment 3 : Preparation of 3,6- diamino -2,5- bis {N-[(1R)-1- carboxy -2- hydroxyethyl ] aminoformyl } pyrazine into 250 mL reaction flask 20 mL of purified water and 2.23 g of KOH were added to it, and after complete dissolution, 2.76 g of HCOOH and 80 mL of methanol were added. After stirring for 5 min, 5.00 g of compound 5 and 1 g of 10% Pd/C (50% water content) were added at room temperature. Heated to reflux at 50°C for 12 h, TLC monitoring showed that the reaction was complete, and the Pd/C was filtered out with diatomaceous earth while it was still hot. The filter cake was washed with ethanol aqueous solution (36% H 2 O, V/V) until the filtrate was light yellow, and the filtrates were combined. Add 40 ml of 1N hydrochloric acid to the filtrate, stir for 15 min, concentrate under reduced pressure to 25 mL, and then filter. The filter cake was slurried with 50 mL of water for 2 h, and then filtered. The filter cake was dried under reduced pressure at 40°C for 12 h to obtain 1.85 g of the title compound as a red solid (molar yield: 55%). LC-MS: RT=3.02min, [MH]=370.9. HRMS and 1 H NMR data are the same as in Example 1.
實施例 4 ： 3,6- 二胺基 -2,5- 雙 {N-[(1R)-1- 羧基 -2- 羥基乙基 ] 胺基甲醯基 } 吡嗪的製備往250 mL反應瓶中加入20 mL乙醇和5.00 g化合物5、2 g環己二烯和1 g 10% Pd/C (含水50%)，於室溫下反應12 h，TLC監測顯示反應完畢，經矽藻土濾除Pd/C。用乙醇水溶液（36% H 2O，V/V）洗滌濾餅至濾液為淺黃色，合併濾液。將濾液濃縮至乾，用20 mL水打漿2 h，然後過濾。將濾餅於40°C減壓乾燥12 h，得2.20 g紅色固體形式的標題化合物（莫耳收率：65%）。 LC-MS：RT=3.02 min, [M-H]=370.9. HRMS和 1H NMR資料同實施例1。 Embodiment 4 : Preparation of 3,6- diamino -2,5- bis {N-[(1R)-1- carboxy -2- hydroxyethyl ] aminoformyl } pyrazine into 250 mL reaction flask Add 20 mL of ethanol and 5.00 g of compound 5, 2 g of cyclohexadiene and 1 g of 10% Pd/C (water content 50%), react at room temperature for 12 h, TLC monitoring shows that the reaction is complete, filter through diatomaceous earth Except Pd/C. The filter cake was washed with ethanol aqueous solution (36% H 2 O, V/V) until the filtrate was light yellow, and the filtrates were combined. The filtrate was concentrated to dryness, slurried with 20 mL of water for 2 h, and then filtered. The filter cake was dried under reduced pressure at 40°C for 12 h to obtain 2.20 g of the title compound as a red solid (molar yield: 65%). LC-MS: RT=3.02 min, [MH]=370.9. HRMS and 1 H NMR data are the same as in Example 1.
除本文中描述的實施方案外，根據前述描述，本發明的多種修改對本領域技術人員而言會是顯而易見的。這樣的修改也意圖落入所附申請專利範圍的範圍內。In addition to the embodiments described herein, various modifications of the invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.
本申請中所引用的各參考文獻(包括所有專利、專利申請、期刊文章、書籍及任何其它公開)均以其整體通過援引加入本文。Each reference cited in this application, including all patents, patent applications, journal articles, books, and any other publications, is hereby incorporated by reference in its entirety.
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- 2022-09-23 WO PCT/CN2022/120729 patent/WO2023046046A1/en active Search and Examination
- 2022-09-23 TW TW111136048A patent/TW202328077A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN118103355A (en) | 2024-05-28 |
| WO2023046046A1 (en) | 2023-03-30 |
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