TWI481612B - Preparation process of (6r)-tetrahydrobiopterin hydrochloride - Google Patents

Preparation process of (6r)-tetrahydrobiopterin hydrochloride Download PDF

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TWI481612B
TWI481612B TW099135243A TW99135243A TWI481612B TW I481612 B TWI481612 B TW I481612B TW 099135243 A TW099135243 A TW 099135243A TW 99135243 A TW99135243 A TW 99135243A TW I481612 B TWI481612 B TW I481612B
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preparation
solvent
biopterin
tetrahydrobiopterin
hydrogenation reaction
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TW201215613A (en
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Zhen Wang
Dongbing Zhao
Weida Wang
Jingbo Lan
Jingsong You
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Innopharmax Inc
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Description

(6 R )-四氫生物喋呤鹽酸鹽的製備方法Method for preparing (6 R )-tetrahydrobiopterin hydrochloride

本發明係關於一種(6R)-四氫生物喋呤鹽酸鹽的製備方法。This invention relates to a process for the preparation of a (6R)-tetrahydrobiopterin hydrochloride.

(6R)-四氫生物喋呤(簡稱BH4)是生物體自身產生的一種輔酶,屬於天然喋呤家族。喋呤係以氧化和還原形態存在於生物體中,但其中只有還原態的(6R)-5,6,7,8-四氫生物喋呤具有生物活性,其為苯丙胺酸羥化酶的輔酶。缺乏BH4不但會出現高苯丙胺酸血症,還會影響多種神經遞質的形成,使患者出現抽搐、癱瘓等一系列不同於苯丙酮尿症患者的神經系統症狀。(6R)-Tetrahydrobiopterin (BH4) is a coenzyme produced by the organism itself and belongs to the natural ape family. The lanthanide is present in the organism in oxidized and reduced form, but only the reduced (6R)-5,6,7,8-tetrahydrobiopterin is biologically active, which is a coenzyme of phenylalanine hydroxylase. . Lack of BH4 will not only cause hyperphenylalaninemia, but also affect the formation of a variety of neurotransmitters, causing patients with a series of nervous system symptoms different from phenylketonuria.

(6R )-四氫生物喋呤之製備,通常係先將L -生物喋呤(簡稱BH2)藉由氫化反應後得到RS 兩種非對映異構體混合物,再藉由多次重結晶而獲得。US 2006/0142573提供一種工業化大規模製備L -生物喋呤的方法。US 4,713,454則揭示一種在鉑系金屬催化劑存在下及使用有機鹼(例如,胺類,包括一級胺、二級胺、三級胺、及四級胺)調控反應基質為鹼性之條件下,將L -生物喋呤進行高壓氫化反應以製備(6R )-四氫生物喋呤的方法。於該案中,特別強調使用無機鹼控制pH值,會降低產品的非對映比(asymmetric ratio)R/S值。Preparation of (6 R )-tetrahydrobiopterin, usually by first hydrogenating L -biopterin (abbreviated as BH2) to obtain a mixture of two diastereomers of R and S , and then by multiple times Obtained by recrystallization. US 2006/0142573 provides an industrialized method for the large scale preparation of L -biopterin. US 4,713,454 discloses a condition in which the reaction substrate is basic in the presence of a platinum-based metal catalyst and using an organic base (eg, an amine, including a primary amine, a secondary amine, a tertiary amine, and a quaternary amine) The method of preparing a (6 R )-tetrahydrobiopterin by performing a high pressure hydrogenation reaction of L -biopterin. In this case, special emphasis was placed on the use of inorganic bases to control the pH, which would reduce the product's asymmetric ratio R/S value.

在本領域中,仍有需要對現有(6R )-四氫生物喋呤之製備進行改良,特別是提高操作的簡便性,以降低生產成本,利於工業化生產。In the present art, there remains a need for existing (6 R) - Preparation of tetrahydrobiopterin make improvements, in particular to improve the ease of operation, to reduce production costs, suitable for industrial production.

本發明首次提出在L -生物喋呤的氫化反應中利用氫氧化鉀及磷酸二氫鉀調整反應基質的酸鹼值,以製備出(6R)-四氫生物喋呤鹽酸鹽的技術方案。本發明之方法使用氫氧化鉀及磷酸二氫鉀,屬於無機鹼,具有容易移除而能簡化操作流程之優點,且又非可預期地發現,本發明之方法尚可容許溶劑體積之大幅減少下,維持等同的產物回收率,具有穩定產物回收率的效果,從而在固定容積生產槽中增加單位生產效率,增加操作簡便性,有助於工業化大規模製備(6R)-四氫生物喋呤鹽酸鹽。The present invention proposes for the first time to adjust the pH value of the reaction substrate by using potassium hydroxide and potassium dihydrogen phosphate in the hydrogenation reaction of L -biopterin to prepare a technical solution of (6R)-tetrahydrobiopterin hydrochloride. The method of the present invention uses potassium hydroxide and potassium dihydrogen phosphate, which are inorganic bases, have the advantages of easy removal and can simplify the operation process, and it is unexpectedly found that the method of the present invention can still allow a large reduction in solvent volume. The same product recovery rate is maintained, and the product recovery rate is stabilized, thereby increasing the unit production efficiency in the fixed volume production tank, increasing the operation simplicity, and facilitating industrial large-scale preparation of (6R)-tetrahydrobiopterin. Hydrochloride.

因此,在一方面,本發明係提供一種(6R)-四氫生物喋呤鹽酸鹽的製備方法,其包括將L-生物喋呤在鉑系金屬催化劑存在下於含有溶劑、氫氧化鉀及磷酸二氫鉀的鹼性基質中進行氫化反應,其中氫氧化鉀及磷酸二氫鉀控制該鹼性基質的pH在約10至約13之範圍內,以產生(6R)-四氫生物喋呤鹽酸鹽。Accordingly, in one aspect, the present invention provides a process for the preparation of (6R)-tetrahydrobiopterin hydrochloride, which comprises reacting L-biopterin in the presence of a platinum-based metal catalyst in a solvent, potassium hydroxide, and Hydrogenation is carried out in an alkaline matrix of potassium dihydrogen phosphate, wherein potassium hydroxide and potassium dihydrogen phosphate control the pH of the basic substrate in the range of from about 10 to about 13 to produce (6R)-tetrahydrobiopterin Hydrochloride.

特定而言,本發明之方法的L -生物喋呤與溶劑的比例在約1:10至約1:1000之範圍(w/v),更特定的是在約1:30至約1:100之範圍(w/v)。非可預期的是,在如此大幅度變動的比例範圍內,本發明之方法可維持實質上等同的(6R)-四氫生物喋呤鹽酸鹽回收率,具有穩定產物回收率的效果,從而增加單位生產效率。In particular, the ratio of L -biopterin to solvent of the method of the invention is in the range of from about 1:10 to about 1:1000 (w/v), more specifically from about 1:30 to about 1:100. The range (w/v). Unexpectedly, the method of the present invention maintains substantially equivalent (6R)-tetrahydrobiopterin hydrochloride recovery over a range of such large variations, with the effect of stabilizing product recovery, thereby Increase unit production efficiency.

較佳地,本發明之方法進一步包括去除催化劑、酸化、去除溶劑及/或再結晶等步驟。Preferably, the method of the present invention further comprises the steps of removing the catalyst, acidifying, removing the solvent, and/or recrystallizing.

下文中將詳細描述本發明的各種具體實施例。本發明的其他特徵將藉由下列有關各種具體實施例的詳細說明以及申請專利範圍而清楚呈現。Various specific embodiments of the invention are described in detail below. Other features of the present invention will be apparent from the following detailed description of various embodiments.

相信在本發明所屬技術領域中具通常知識者在不需進一步說明之情況下可根據此處的描述利用本發明至其最廣範圍。因此,下列描述應被當作例示之目的而非以任何方式作為本發明之範圍的限制。It is believed that those skilled in the art of the invention can <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Accordingly, the following description is to be considered as illustrative and not restrictive

除非另有說明,否則此處使用之全部技術和科學名詞與本發明所屬技術領域之技藝人士通常所瞭解的意義相同。All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to the invention.

此處所使用的冠詞「一」係指該冠詞的一或一個以上(即,至少一個)的文法受詞。The article "a" as used herein refers to one or more (ie, at least one) grammatical terms of the article.

本發明之方法係用於製備(6R)-四氫生物喋呤鹽酸鹽,其包括將L-生物喋呤在鉑系金屬催化劑存在下於含有溶劑、氫氧化鉀及磷酸二氫鉀的鹼性基質中進行氫化反應,其中氫氧化鉀及磷酸二氫鉀控制該鹼性基質的pH在約10至約13之範圍內,以產生(6R)-四氫生物喋呤鹽酸鹽。The method of the present invention is for preparing (6R)-tetrahydrobiopterin hydrochloride, which comprises using L-biopterin in the presence of a platinum-based metal catalyst in a base containing a solvent, potassium hydroxide and potassium dihydrogen phosphate. The hydrogenation reaction is carried out in a substrate in which potassium hydroxide and potassium dihydrogen phosphate control the pH of the basic substrate in the range of from about 10 to about 13 to produce (6R)-tetrahydrobiopterin hydrochloride.

本發明之製備方法可以如下反應式表示:The preparation method of the present invention can be represented by the following reaction formula:

根據本發明進行之氫化反應係指將氫氣加成到具有雙鍵或多重鍵之分子的化學反應,因而使得L -生物喋呤氫化而形成(6R)-四氫生物喋呤。The hydrogenation reaction carried out according to the present invention refers to a chemical reaction in which hydrogen is added to a molecule having a double bond or a multiple bond, thereby hydrogenating L -biopteryrene to form a (6R)-tetrahydrobiopterin.

本發明進行之氫化反應係在氫氧化鉀及磷酸二氫鉀控制pH於約10至約13之鹼性反應基質中進行,更佳為控制pH於約11至約12。一般情況下,有機鹼是分子中含有胺基的有機化合物,例如,胺類化合物;相較之下,本發明使用氫氧化鉀及磷酸二氫鉀,不含胺基,屬於無機鹼。The hydrogenation reaction carried out according to the present invention is carried out in an alkaline reaction substrate in which potassium hydroxide and potassium dihydrogen phosphate are controlled to have a pH of from about 10 to about 13, more preferably from about 11 to about 12. In general, the organic base is an organic compound having an amine group in the molecule, for example, an amine compound; in contrast, the present invention uses potassium hydroxide and potassium dihydrogen phosphate, does not contain an amine group, and is an inorganic base.

本發明方法中之鉑系金屬催化劑可為任何本領域中所習知者,其包括但不限於鉑黑、二氧化鉑、鉑/碳或鉑/氧化鋁,較佳為鉑黑或二氧化鉑。於本發明方法中,鉑系金屬催化劑可回收並重複多次使用,且該經回收的催化劑不會降低氫化產品的產率。The platinum group metal catalyst in the process of the invention may be any of those known in the art including, but not limited to, platinum black, platinum dioxide, platinum/carbon or platinum/alumina, preferably platinum black or platinum dioxide. . In the process of the present invention, the platinum group metal catalyst can be recovered and reused multiple times, and the recovered catalyst does not reduce the yield of the hydrogenated product.

本發明中之氫化反應可於氫氣壓力為約1至約10 MPa下進行,較佳為約1至約6 MPa,最佳為約2至約4 MPa;反應溫度為約0至約40℃,較佳為約10至約30℃;反應時間為約20至約50小時,較佳為約25至約40小時。The hydrogenation reaction in the present invention can be carried out at a hydrogen pressure of from about 1 to about 10 MPa, preferably from about 1 to about 6 MPa, most preferably from about 2 to about 4 MPa; and the reaction temperature is from about 0 to about 40 ° C, Preferably, it is from about 10 to about 30 ° C; and the reaction time is from about 20 to about 50 hours, preferably from about 25 to about 40 hours.

本發明進行氫化反應的溶劑,可為任何本領域中所習知者,其包括但不限於水、醇或其組合;其較佳為水。相關文獻如US 4,649,197。The solvent for carrying out the hydrogenation reaction of the present invention may be any of those known in the art including, but not limited to, water, alcohol or a combination thereof; it is preferably water. Related literature is for example US 4,649,197.

根據本發明之方法,進行氫化反應的鉑系金屬催化物、L-生物喋呤與溶劑之比例為本發明領域之技藝人士可依其自身之知識及/或其所需自行調整的。鉑系金屬與L-生物喋呤之重量比通常為約1%至約30%,較佳為約10%至約20%。鉑系金屬催化劑與溶劑之比例(w:v)為約1:100至約1:2000;較佳為約1:200至約1:1000;最佳為約1:300至約1:500。相關文獻如US 4,595,752。According to the process of the present invention, the ratio of the platinum group metal catalyst, L-biopteryrene and solvent which are subjected to the hydrogenation reaction can be adjusted by the person skilled in the art according to his own knowledge and/or its needs. The weight ratio of the platinum group metal to the L-biopterin is usually from about 1% to about 30%, preferably from about 10% to about 20%. The ratio of platinum metal catalyst to solvent (w:v) is from about 1:100 to about 1:2000; preferably from about 1:200 to about 1:1000; most preferably from about 1:300 to about 1:500. Related literature is for example US 4,595,752.

特定而言,根據本發明之方法,進行氫化反應的L -生物喋呤與溶劑的比例在約1:10至約1:1000之範圍(w/v),更特定的是在約1:30至約1:100之範圍(w/v)。非可預期的是,在如此大幅度變動的比例範圍下,本發明之方法可維持實質上等同的(6R)-四氫生物喋呤鹽酸鹽回收率,也就是相互比較的回收率之間的差距不超過5%,更佳係不超過3%。因此,本發明之方法可用於穩定產物回收率,從而在固定容積生產槽中增加單位生產效率,增加操作簡便性,有助於工業化大規模製備(6R)-四氫生物喋呤。In particular, according to the process of the present invention, the ratio of L -biopterin to solvent for the hydrogenation reaction is in the range of from about 1:10 to about 1:1000 (w/v), more specifically at about 1:30. To the range of about 1:100 (w/v). Unexpectedly, the method of the present invention maintains substantially equivalent (6R)-tetrahydrobiopterin hydrochloride recovery rates, i.e., between each other, in the range of such large variations. The gap is no more than 5%, and better than 3%. Therefore, the method of the present invention can be used to stabilize product recovery, thereby increasing unit production efficiency in a fixed volume production tank, increasing operational simplicity, and facilitating industrial large-scale preparation of (6R)-tetrahydrobiopterin.

根據本發明之方法,其進一步包括去除催化劑、酸化、去除溶劑及/或再結晶之步驟。According to the method of the present invention, it further comprises the steps of removing the catalyst, acidifying, removing the solvent, and/or recrystallizing.

於本發明方法中,可藉由任何習知方法除去氫化反應中的催化劑,其包括但不限於過濾法,如常壓過濾法或減壓過濾法,或者離心分離法。相關文獻如US 4,649,197。In the process of the present invention, the catalyst in the hydrogenation reaction can be removed by any conventional method including, but not limited to, filtration, such as atmospheric filtration or reduced pressure filtration, or centrifugation. Related literature is for example US 4,649,197.

在除去催化劑後,可添加無機酸或有機酸進行酸化,其中該無機酸可為但不限定為鹽酸或硫酸;而該有機酸可為但不限定為富馬酸或酒石酸。有機酸酸化產品之pH值為約0至約6,其較佳為約2至約5,無機酸酸化產品之pH值為約0至約3,其較佳為約1。After the catalyst is removed, an inorganic acid or an organic acid may be added for acidification, wherein the inorganic acid may be, but not limited to, hydrochloric acid or sulfuric acid; and the organic acid may be, but not limited to, fumaric acid or tartaric acid. The organic acid acidified product has a pH of from about 0 to about 6, preferably from about 2 to about 5, and the mineral acidified product has a pH of from about 0 to about 3, preferably about 1.

另於本發明方法中,可藉由任何習知方法除去溶劑,其包括但不限於加溫或不加溫的條件下進行常壓蒸餾或減壓蒸餾。In addition, in the process of the present invention, the solvent may be removed by any conventional method including, but not limited to, atmospheric distillation or vacuum distillation under conditions of heating or no heating.

接著,可進一步使用溶劑溶解產物,包括但不限於醇類、醇類水溶液或酸類水溶液及醇類的混合液,其中較佳之醇類為甲醇、乙醇或異丙醇,較佳之酸為鹽酸、硫酸、酒石酸或富馬酸。醇類水溶液之水及醇類的混合體積比例為約1:10至約1:40,較佳為約1:20至約1:30;酸類水溶液及醇類的混合體積比例為約1:10至約1:40,其中酸類水溶液之水及酸類的混合體積比例為約1:0.02至約1:1。Then, the solvent may be further used to dissolve the product, including but not limited to an alcohol, an aqueous alcohol solution or a mixture of an aqueous acid solution and an alcohol. The preferred alcohol is methanol, ethanol or isopropanol. Preferably, the acid is hydrochloric acid or sulfuric acid. , tartaric acid or fumaric acid. The mixed volume ratio of water and alcohol of the aqueous alcohol solution is from about 1:10 to about 1:40, preferably from about 1:20 to about 1:30; the mixing volume ratio of the aqueous acid solution and the alcohol is about 1:10. Up to about 1:40, wherein the mixed volume ratio of water and acid of the aqueous acid solution is from about 1:0.02 to about 1:1.

本發明方法可視需要進一步將獲自步驟(6)之產物進行至少一次重結晶,進而獲得高純度的(6R)-四氫生物喋呤鹽酸鹽。The process of the present invention may further recrystallize the product obtained from the step (6) at least once, thereby obtaining a high purity (6R)-tetrahydrobiopterin hydrochloride.

本發明所謂高純度之(6R)-四氫生物喋呤鹽酸鹽係指(6R)-四氫生物喋呤鹽酸鹽之鏡像異構物過量(enantiomeric excess;e.e)百分率大於約99%,較佳為大於約99.5%。可由下式求得鏡像異構物過量百分率:The so-called high purity (6R)-tetrahydrobiopterin hydrochloride of the present invention means that the percentage of enantiomeric excess (ee) of (6R)-tetrahydrobiopterin hydrochloride is greater than about 99%. It is preferably greater than about 99.5%. The percentage of image isomer excess can be determined by the following formula:

其中[R]為主要異構物產物的量,[S]為次要異構物產物的量。Where [R] is the amount of the major isomer product and [S] is the amount of the minor isomer product.

本發明中之重結晶可選擇以單一溶劑(如重複步驟(5)及(6))或混合溶劑的方式進行。混合溶劑一般由兩種能以任何比例混溶的溶劑組成,其中一種溶劑對產物的溶解度較大,稱為良溶劑;另一種溶劑則對產物的溶解度很小,稱為不良溶劑。操作時先將欲結晶物質溶於良溶劑中,再於其中滴加不良溶劑,放置冷卻並待結晶析出。相關文獻如US 2006/0035900The recrystallization in the present invention can be carried out in the form of a single solvent (e.g., repeating steps (5) and (6)) or a mixed solvent. The mixed solvent generally consists of two solvents which are miscible in any ratio. One of the solvents has a high solubility to the product and is called a good solvent; the other solvent has a small solubility to the product, which is called a poor solvent. In the operation, the substance to be crystallized is first dissolved in a good solvent, and then a poor solvent is added dropwise thereto, left to cool and crystallized. Related literature such as US 2006/0035900

進行重結晶所使用之良溶劑包括但不限於水、無機酸、有機酸或其混合物,其中該無機酸可為但不限定為鹽酸或硫酸;而該有機酸可為但不限定為富馬酸或酒石酸。根據本發明,較佳之良溶劑為水、鹽酸或其混合物。相關文獻如US 2006/0035900。The good solvent used for recrystallization includes, but is not limited to, water, inorganic acid, organic acid or a mixture thereof, wherein the inorganic acid may be, but not limited to, hydrochloric acid or sulfuric acid; and the organic acid may be, but not limited to, fumaric acid. Or tartaric acid. According to the invention, preferred solvents are water, hydrochloric acid or mixtures thereof. Related literature is for example US 2006/0035900.

進行重結晶所使用之不良溶劑包括但不限於醇類或醚類,其中該醇類可為但不限定為甲醇、乙醇或異丙醇等;而該醚類可為但不限定為四氫呋喃或二氧六環等。根據本發明,較佳之不良溶劑為甲醇、乙醇或四氫呋喃。相關文獻如US 2006/0035900,chemistry letters,1984,735-738。The poor solvent used for the recrystallization includes, but is not limited to, an alcohol or an ether, wherein the alcohol may be, but not limited to, methanol, ethanol or isopropanol; and the ether may be, but not limited to, tetrahydrofuran or Oxyhexane, etc. According to the present invention, a preferred poor solvent is methanol, ethanol or tetrahydrofuran. Related literature is for example US 2006/0035900, chemistry letters, 1984, 735-738.

於本發明之方法中,不同重結晶之條件可為相同或相異。於本發明之一較佳實施態樣中,重結晶係進行兩次,其中良溶劑與所欲重結晶(6R)-四氫生物喋呤鹽酸鹽產物的比例為約1:1至約20:1(v:w),較佳為約3:1至約10:1;而第一次重結晶所使用之良溶劑與不良溶劑的體積比為約1:1至約1:10,較佳為約1:1至約1:3;第二次重結晶所使用之良溶劑與不良溶劑的體積比為約10:1至約10:20,較佳為約10:5至約10:15。於第一次及第二次重結晶操作中,除良溶劑與不良溶劑之比例差別較大之外,其他操作條件皆相同。In the process of the invention, the conditions of the different recrystallizations may be the same or different. In a preferred embodiment of the invention, the recrystallization is carried out twice, wherein the ratio of the good solvent to the desired recrystallized (6R)-tetrahydrobiopterin hydrochloride product is from about 1:1 to about 20 : 1 (v: w), preferably from about 3:1 to about 10:1; and the volume ratio of the good solvent to the poor solvent used in the first recrystallization is from about 1:1 to about 1:10, Preferably, the ratio of the good solvent to the poor solvent used in the second recrystallization is from about 10:1 to about 10:20, preferably from about 10:5 to about 10: 15. In the first and second recrystallization operations, the other operating conditions were the same except that the ratio of the good solvent to the poor solvent was large.

於進行重結晶時,可視需要加入一定量的(6R)-四氫生物喋呤鹽酸鹽晶種。該晶種可為任何鏡像異構物過量百分率大於99%的(6R)-四氫生物喋呤鹽酸鹽結晶。When recrystallization is carried out, a certain amount of (6R)-tetrahydrobiopterin hydrochloride seed crystal may be added as needed. The seed crystal may be any (6R)-tetrahydrobiopterin hydrochloride crystal having an excess percentage of any mirror image isomer greater than 99%.

本發明之方法係使用氫氧化鉀及磷酸二氫鉀控制氫化反應之反應基質的pH值,可經由簡單後處理即可將其以無機鹽之形式去除,以增加(6R)-四氫生物喋呤鹽酸鹽在藥物使用上之安全性。且本發明方法中之鉑系金屬催化劑可輕易地回收並重複使用,以降低生產成本。又,本發明之方法可容許大幅度變動的L -生物喋呤與溶劑的比例而仍能維持等動的產物回收率,具有穩定產物回收率的效果,從而在固定容積生產槽中增加單位生產效率,增加操作簡便性,有助於工業化大規模製備(6R)-四氫生物喋呤。The method of the invention uses potassium hydroxide and potassium dihydrogen phosphate to control the pH of the reaction substrate of the hydrogenation reaction, which can be removed as an inorganic salt by simple post-treatment to increase (6R)-tetrahydrobiopterin. The safety of guanidine hydrochloride in drug use. Moreover, the platinum group metal catalyst in the method of the present invention can be easily recovered and reused to reduce the production cost. Moreover, the method of the present invention can tolerate a greatly varying ratio of L -biopterin to solvent while still maintaining an isotropic product recovery rate, and has the effect of stabilizing product recovery, thereby increasing unit production in a fixed volume production tank. Efficiency, increased ease of operation, and industrialization of large-scale preparation of (6R)-tetrahydrobiopterin.

以下將提出實例來更具體地說明本發明,其目的僅供參考而非限制。The invention is hereinafter described in more detail by way of example only, and not by way of limitation.

實施例1Example 1

0.05 g二氧化鉑加入到50 mL的水中,攪拌下加入0.5 g L-生物喋呤,以氫氧化鉀和磷酸二氫鉀調pH值為11.5,混合液轉入高壓釜中,充入4.0 MPa的氫氣,14 ℃下反應50小時後濾掉催化劑,加入濃鹽酸調pH=1後減壓蒸餾除去水,所得固體用HPLC分析測得(6R):(6S)=5.1:1,加入20 mL乙醇溶解產品,將不溶的無機鹽過濾除去,濾液減壓除去溶劑,加入2.5 mL 3M鹽酸溶解,滴加5 mL無水乙醇,加入晶種,在0 ℃下放置使晶體析出,抽濾,得到的白色固體加入1.5 mL 3M鹽酸溶解,向溶液中緩慢滴加1.5 mL無水乙醇後在0 ℃下放置6 h緩慢析出晶體,抽濾,乾燥,得到(6R)-四氫生物喋呤鹽酸鹽白色晶體0.27 g,純度>99.5%,ee值>99.5%,回收率41%。Add 0.05 g of platinum dioxide to 50 mL of water, add 0.5 g of L-biopterin with stirring, adjust the pH to 11.5 with potassium hydroxide and potassium dihydrogen phosphate, and transfer the mixture to the autoclave and charge 4.0 MPa. The hydrogen gas was reacted at 14 ° C for 50 hours, and then the catalyst was filtered off. After adding concentrated hydrochloric acid to adjust pH = 1, the water was distilled off under reduced pressure, and the obtained solid was analyzed by HPLC (6R): (6S) = 5.1:1, and 20 mL was added. Ethanol dissolved in the product, the insoluble inorganic salt was removed by filtration, the filtrate was removed under reduced pressure, dissolved in 2.5 mL of 3M hydrochloric acid, 5 mL of absolute ethanol was added dropwise, seed crystals were added, and the crystals were allowed to stand at 0 ° C to precipitate crystals. The white solid was dissolved in 1.5 mL of 3M hydrochloric acid, and 1.5 mL of absolute ethanol was slowly added dropwise to the solution, and the crystal was slowly precipitated at 0 ° C for 6 h, and the crystals were gradually filtered off, and dried to obtain (6R)-tetrahydrobiopterin hydrochloride white. The crystal was 0.27 g, the purity was >99.5%, the ee value was >99.5%, and the recovery was 41%.

實施例2Example 2

1 g二氧化鉑加入到1000 mL的水中,攪拌下加入10 g L-生物喋呤,以氫氧化鉀、磷酸二氫鉀調節pH值為11.5,混合液轉入高壓釜中,充入4.0 MPa的氫氣,14 ℃下反應50小時後濾掉催化劑,加入濃鹽酸調節pH=1後減壓蒸餾除去水,所得固體用HPLC分析測得(6R):(6S)=4.2:1,400 mL乙醇溶解產品,將不溶的無機鹽過濾除去,濾液減壓除去溶劑,加入3M鹽酸80 mL溶解,滴加160 mL無水乙醇後,加入晶種,在4 ℃下放置使晶體析出,抽濾後得到的白色固體加入3M鹽酸50 mL溶解後,向溶液中緩慢滴加40 mL無水乙醇後在4 ℃下放置6 h緩慢析出晶體,抽濾,乾燥,得到(6R)-四氫生物喋呤鹽酸鹽白色晶體3.96 g,純度>99.8%,ee值>99.8%,收率30%。1 g of platinum dioxide was added to 1000 mL of water, 10 g of L-biopterin was added with stirring, and the pH was adjusted to 11.5 with potassium hydroxide and potassium dihydrogen phosphate. The mixture was transferred to an autoclave and charged with 4.0 MPa. The hydrogen gas was reacted at 14 ° C for 50 hours, then the catalyst was filtered off, concentrated hydrochloric acid was added to adjust pH = 1, and the water was distilled off under reduced pressure. The obtained solid was analyzed by HPLC (6R): (6S) = 4.2:1, 400 mL of ethanol dissolved product The insoluble inorganic salt was removed by filtration, the filtrate was removed under reduced pressure, and dissolved in 80 mL of 3M hydrochloric acid. After dropwise addition of 160 mL of anhydrous ethanol, seed crystals were added, and the crystals were allowed to stand at 4 ° C to precipitate a crystal. After adding 3 mL of hydrochloric acid to dissolve 50 mL, 40 mL of absolute ethanol was slowly added dropwise to the solution, and the crystal was slowly precipitated at 4 ° C for 6 h, and the crystals were gradually filtered off, and dried to obtain white crystals of (6R)-tetrahydrobiopterin hydrochloride. 3.96 g, purity >99.8%, ee value >99.8%, yield 30%.

實施例3Example 3

已經使用一次的二氧化鉑0.12 g加入到100 mL的水中,攪拌下加入1.0 g L-生物喋呤,以氫氧化鉀、磷酸二氫鉀調節pH值為11.5,混合液轉入高壓釜中,充入4.0 MPa的氫氣,14 ℃下反應50小時後濾掉催化劑,加入濃鹽酸調節pH=1後減壓蒸餾除去水,所得固體用HPLC分析測得(6R):(6S)=4.5:1,400 mL乙醇溶解產品,將不溶的無機鹽過濾除去,濾液減壓除去溶劑,加入3M鹽酸6 mL溶解,滴加12 mL無水乙醇後,在4 ℃下放置使晶體析出,抽濾後得到的白色固體加入3M鹽酸4 mL溶解後,向溶液中緩慢滴加3 mL無水乙醇後在4 ℃下放置6 h緩慢析出晶體,抽濾,乾燥,得到(6R)-四氫生物喋呤鹽酸鹽白色晶體0.45 g,純度>99.8%,ee值>99.8%,回收率34%。0.12 g of platinum dioxide has been used once to add 100 mL of water, 1.0 g of L-biopterin is added with stirring, the pH is adjusted to 11.5 with potassium hydroxide and potassium dihydrogen phosphate, and the mixture is transferred to an autoclave. After charging with 4.0 MPa of hydrogen, reacting at 14 ° C for 50 hours, filtering off the catalyst, adding concentrated hydrochloric acid to adjust pH = 1 and then distilling off the water under reduced pressure, and the obtained solid was analyzed by HPLC analysis (6R): (6S) = 4.5:1,400 The product was dissolved in mL ethanol, and the insoluble inorganic salt was removed by filtration. The filtrate was removed under reduced pressure, and dissolved in 6 mL of 3M hydrochloric acid. After dropwise addition of 12 mL of anhydrous ethanol, the crystals were allowed to stand at 4 ° C to precipitate crystals. After adding 3 mL of 3M hydrochloric acid to dissolve, 3 mL of absolute ethanol was slowly added dropwise to the solution, and the crystal was gradually precipitated at 4 ° C for 6 h, and the crystal was gradually precipitated, suction filtered, and dried to obtain white crystal of (6R)-tetrahydrobiopterin hydrochloride. 0.45 g, purity >99.8%, ee value >99.8%, recovery rate 34%.

實施例4Example 4

已經使用兩次的二氧化鉑0.06 g加入到50 mL的水中,攪拌下加入0.5 g L-生物喋呤,以氫氧化鉀、磷酸二氫鉀調節pH值為11.5,混合液轉入高壓釜中,充入4.0 MPa的氫氣,14 ℃下反應50小時後濾掉催化劑,加入濃鹽酸調節pH=1後減壓蒸餾除去水,所得固體用HPLC分析測得(6R):(6S)=4.5:1,400 mL乙醇溶解產品,將不溶的無機鹽過濾除去,濾液減壓除去溶劑,加入3M鹽酸2.5 mL溶解,滴加5 mL無水乙醇後,在4 ℃下放置使晶體析出,抽濾後得到的白色固體加入3M鹽酸1.5 mL溶解後,向溶液中緩慢滴加1 mL無水乙醇後在4 ℃下放置6 h緩慢析出晶體,抽濾,乾燥,得到(6R)-四氫生物喋呤鹽酸鹽白色晶體0.23 g,純度>99.5%,ee值>99.5%,回收率35%。0.06 g of platinum dioxide has been used twice into 50 mL of water, 0.5 g of L-biopterin is added with stirring, the pH is adjusted to 11.5 with potassium hydroxide and potassium dihydrogen phosphate, and the mixture is transferred to an autoclave. After charging with 4.0 MPa of hydrogen, the reaction was carried out at 14 ° C for 50 hours, the catalyst was filtered off, concentrated hydrochloric acid was added to adjust pH = 1, and the water was distilled off under reduced pressure. The obtained solid was analyzed by HPLC (6R): (6S) = 4.5: 1,400 mL of ethanol was dissolved in the product, and the insoluble inorganic salt was removed by filtration. The filtrate was removed under reduced pressure, dissolved in 2.5 mL of 3M hydrochloric acid, and 5 mL of anhydrous ethanol was added dropwise, and then crystals were allowed to stand at 4 ° C to precipitate crystals. After solid solution was added to 1.5 mL of 3M hydrochloric acid, 1 mL of absolute ethanol was slowly added dropwise to the solution, and the crystal was gradually precipitated at 4 ° C for 6 h, and the crystal was precipitated by suction filtration to obtain (6R)-tetrahydrobiopterin hydrochloride white. The crystal was 0.23 g, the purity was >99.5%, the ee value was >99.5%, and the recovery was 35%.

實例5Example 5

將0.1 g之二氧化鉑分別加入30至100 ml之水中(如表1),於攪拌下加入1g L-生物喋呤,再加入氫氧化鉀及磷酸二氫鉀調整pH值至11.4。將混合溶液置入高壓釜中,並在4.0 MPa之氫氣壓力及14℃下反應50小時。於反應後,將溶液中之催化劑濾除,再加入濃鹽酸以調整濾液之pH至1,接著將濾液減壓蒸餾以去除水而得到一固體,所得固體依前載實施例以HPLC分析其6R:6S反應率並以相同步驟進行重結晶後計算其純品收率。表1顯示相關反應率與純品收率。0.1 g of platinum dioxide was added to 30 to 100 ml of water (as shown in Table 1), and 1 g of L-biopterin was added with stirring, and then potassium hydroxide and potassium dihydrogen phosphate were added to adjust the pH to 11.4. The mixed solution was placed in an autoclave and reacted under a hydrogen pressure of 4.0 MPa at 14 ° C for 50 hours. After the reaction, the catalyst in the solution is filtered off, and concentrated hydrochloric acid is added to adjust the pH of the filtrate to 1, and then the filtrate is distilled under reduced pressure to remove water to obtain a solid, and the obtained solid is analyzed by HPLC according to the preceding example. : 6S reaction rate and recrystallization in the same step to calculate the pure yield. Table 1 shows the relevant reaction rates and pure product yields.

如表1所示,依據本發明之方法,同樣使用1 g的L-生物喋呤,在溶劑體積從30至100 ml的變動範圍內,均維持幾乎等同的(6R)-四氫生物喋呤鹽酸鹽回收率(29-32%),具有穩定產物回收率的效果,從而在固定容積生產槽中增加單位生產效率,增加操作簡便性,有助於工業化大規模製備(6R)-四氫生物喋呤。As shown in Table 1, according to the method of the present invention, 1 g of L-biopterin was also used, and almost equivalent (6R)-tetrahydrobiopterin was maintained over a range of solvent volumes ranging from 30 to 100 ml. The hydrochloride recovery rate (29-32%) has the effect of stabilizing product recovery, which increases the unit production efficiency in the fixed volume production tank, increases the operation simplicity, and contributes to the industrial large-scale preparation of (6R)-tetrahydrogen. Biological paralysis.

熟知技藝之人士將可在不背離本發明精神之下,根據實施例進行改變和修改。要注意的是,本發明並不受限於說明書中實施例所揭露之範圍,而涵蓋於其他根據申請範圍內揭露之所有變化之形式。Those skilled in the art will be able to make changes and modifications in accordance with the embodiments without departing from the spirit of the invention. It is to be understood that the invention is not to be limited by the scope of the embodiments disclosed herein,

Claims (11)

一種(6R)-四氫生物喋呤鹽酸鹽的製備方法,其包括將L-生物喋呤在鉑系金屬催化劑存在下於含有溶劑、氫氧化鉀及磷酸二氫鉀的鹼性基質中進行氫化反應,其中氫氧化鉀及磷酸二氫鉀控制該鹼性基質的pH在10至13之範圍內,以及添加鹽酸進行酸化,以產生(6R)-四氫生物喋呤鹽酸鹽。 A method for preparing (6R)-tetrahydrobiopterin hydrochloride, which comprises carrying out L-biopterin in an alkaline matrix containing a solvent, potassium hydroxide and potassium dihydrogen phosphate in the presence of a platinum-based metal catalyst A hydrogenation reaction in which potassium hydroxide and potassium dihydrogen phosphate control the pH of the basic substrate in the range of 10 to 13, and acidification is carried out by adding hydrochloric acid to produce (6R)-tetrahydrobiopterin hydrochloride. 根據申請專利範圍第1項之製備方法,其中該溶劑係選自由水、醇及其組合所組成之群。 The preparation method according to Item 1, wherein the solvent is selected from the group consisting of water, alcohol, and a combination thereof. 根據申請專利範圍第1項之製備方法,其中氫化反應係在氫氣壓力為1至10MPa下進行。 The production method according to the first aspect of the patent application, wherein the hydrogenation reaction is carried out at a hydrogen pressure of from 1 to 10 MPa. 根據申請專利範圍第1項之製備方法,其中該氫化反應之溫度為0至40℃。 The preparation method according to the first aspect of the invention, wherein the temperature of the hydrogenation reaction is from 0 to 40 °C. 根據申請專利範圍第1項之製備方法,其中該氫化反應之時間為20至50小時。 The preparation method according to the first aspect of the patent application, wherein the hydrogenation reaction is carried out for 20 to 50 hours. 根據申請專利範圍第1項之製備方法,其中L -生物喋呤與該溶劑的比例在1:10至1:1000之範圍(w/v)。The preparation method according to claim 1, wherein the ratio of the L -biopterin to the solvent is in the range of 1:10 to 1:1000 (w/v). 根據申請專利範圍第6項之製備方法,其中L -生物喋呤與該溶劑的比例在1:30至1:100之範圍(w/v)。The preparation method according to claim 6, wherein the ratio of the L -biopterin to the solvent is in the range of 1:30 to 1:100 (w/v). 根據申請專利範圍第1至7項中任一項之製備方法,其可用於穩定(6R)-四氫生物喋呤鹽酸鹽之回收率,從而增加單位生產效率。 The preparation method according to any one of claims 1 to 7, which can be used for stabilizing the recovery rate of (6R)-tetrahydrobiopterin hydrochloride, thereby increasing unit production efficiency. 根據申請專利範圍第1至7項中任一項之製備方法,其進一步包括在L-生物喋呤的氫化反應後,以過濾方式移除催化劑。 The preparation method according to any one of claims 1 to 7, which further comprises removing the catalyst by filtration after hydrogenation of the L-biopterin. 根據申請專利範圍第9項之製備方法,其進一步包括在減壓下除去溶劑之濃縮步驟,以獲得濃縮產物。 The preparation method according to claim 9 of the patent application, which further comprises a concentration step of removing the solvent under reduced pressure to obtain a concentrated product. 根據申請專利範圍第10項之製備方法,其進一步包括將該濃縮產物予以再結晶。 The preparation method according to claim 10, further comprising recrystallizing the concentrated product.
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Citations (3)

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Publication number Priority date Publication date Assignee Title
US4595752A (en) * 1984-02-23 1986-06-17 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Process for preparing 5,6,7,8-tetrahydro-6-(L-erythro-1',2'-dihydroxypropyl)pterin
US4713454A (en) * 1985-01-28 1987-12-15 Shiratori Pharmaceutical Co., Ltd. Preparation process of (6R)-tetrahydro-L-biopterin
WO2009088979A1 (en) * 2008-01-07 2009-07-16 Biomarin Pharmaceutical Inc. Method of synthesizing tetrahydrobiopterin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4595752A (en) * 1984-02-23 1986-06-17 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Process for preparing 5,6,7,8-tetrahydro-6-(L-erythro-1',2'-dihydroxypropyl)pterin
US4713454A (en) * 1985-01-28 1987-12-15 Shiratori Pharmaceutical Co., Ltd. Preparation process of (6R)-tetrahydro-L-biopterin
WO2009088979A1 (en) * 2008-01-07 2009-07-16 Biomarin Pharmaceutical Inc. Method of synthesizing tetrahydrobiopterin

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