JP2009524606A - Method for the synthesis of acratonium napadisylate and its analogues - Google Patents
Method for the synthesis of acratonium napadisylate and its analogues Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
Abstract
本発明は下式(Ｖ)化合物の合成方法について述べたものである。
【化１】
そのうち、Ｒ１〜Ｒ７の相違はそれぞれ水素、Ｃ１〜４のアルキル基による。ｎは１〜４の整数から選んだ。特に“ワンポット合成法”を採用している。本発明は他にも乳酸を原料としてコリン類薬物アクラトニウムナパジシル酸塩及びその類似化合物の合成方法を提示している。この方法は原材料が得やすく、生産コストが比較的低く、同時に技術要求が低く、制御しやすく、大規模生産に向いている。The present invention describes a method for synthesizing the compound of the following formula (V).
[Chemical 1]
Among them, hydrogen differences R1~R7 respectively, by an alkyl group of C 1 to 4. n was selected from an integer of 1 to 4. In particular, the “one-pot synthesis method” is adopted. The present invention also provides a method for synthesizing the cholinergic drug acratonium napadisylate and its similar compounds using lactic acid as a raw material. This method is easy to obtain raw materials, has a relatively low production cost, has low technical requirements, is easy to control, and is suitable for large-scale production.
Description
［技術分野］
本発明は、下式(Ｖ)化合物の合成方法、特に“ワンポット合成”を採用した化合物Ｖの合成方法に関するものである。本発明は他に下式(Ｉ)のコリン類薬物活性化成分のアクラトニウムナパジシル酸塩及びその類似化合物の合成、特にアクラトニウムナパジシル酸塩の合成方法に関するもので、薬学化学分野に属する。
[Technical field]
The present invention relates to a method for synthesizing a compound of the following formula (V), particularly to a method for synthesizing a compound V employing “one-pot synthesis”. The present invention also relates to the synthesis of actinium napadisylate and its similar compounds, which are choline compounds activating components of the following formula (I), and in particular to a method for synthesizing acratonium napadisylate. Belonging to.
［背景技術］
コリン類薬品活性化成分アクラトニウムナパジシル酸塩及びその類似化合物は、一種の平滑筋及び消化器運動機能増強薬で、胃腸及び胆管の興奮作用があり、胃幽門前庭部への作用は強く、消化器官のほかの部位への作用は胃より弱い。他にも、胆管末端の運動亢進、胆嚢内圧上昇、胆汁十二指腸排泄を促進することができる。迷走神経及びモルヒネによる運動機能低下状態に対しても増強作用があり、健常者だけでなく、慢性胃炎或いは術後患者に対しても胃内容物排出作用を促進することができる。消化器官機能異常、例えば悪心や嘔吐、食欲不振、腹部膨満感、慢性胃炎、胆管運動障害、消化器術後等の治療に使われる。現在、臨床で使用されている薬物は主にアクラトニウムナパジシル酸塩で、化学結合式は下記の通りである（Ｉａ）：
[Background technology]
Actinium napadisylate and its similar compounds, which are cholinergic chemical activation components, are a kind of smooth muscle and gastrointestinal motility enhancer, and have a gastrointestinal and bile duct excitability, and strong action on the gastropyloric antrum. The action on other parts of the digestive tract is weaker than that of the stomach. In addition, it is possible to promote increased bile duct movement, increased pressure in the gallbladder, and excretion of bile duodenum. It also has an enhancing effect on the state of motor function decline due to the vagus nerve and morphine, and can promote the gastric emptying action not only for healthy subjects but also for chronic gastritis or postoperative patients. It is used to treat gastrointestinal dysfunction, such as nausea and vomiting, loss of appetite, abdominal bloating, chronic gastritis, bile duct dysfunction, and post-digestive surgery. Currently, the drugs in clinical use are mainly acratonium napadisylate, and the chemical bonding formula is as follows (Ia):
［発明の開示］
［発明が解決しようとする課題］
現有のアクラトニウムナパジシル酸塩及び類似化合物の合成技術では、原料獲得、原料合成の難度が高い上に中間生成物の単離や精製が難しく、設備要求や生産コストも比較的高いため、大規模生産には向いていなかった。
[Disclosure of the Invention]
[Problems to be solved by the invention]
In the existing synthesis technology of acratonium napadisilate and similar compounds, it is difficult to acquire and synthesize raw materials, and it is difficult to isolate and purify intermediate products, and the equipment requirements and production costs are relatively high. It was not suitable for large-scale production.
本発明の主旨は大規模生産に適したアクラトニウムナパジシル酸塩と類似化合物の生産方法を提供することである。 The gist of the present invention is to provide a method for producing acratonium napadisilate and similar compounds suitable for large-scale production.
［課題を解決するための手段］
本発明の技術プロトコルは以下の通り：
本発明は化合物Ｖを生成する方法を提示する。化合物ＩＩは以下の方法によって得ることができる：
（１）化合物ＩＩと塩化アセチルａをエステル化し、化合物ＩＩＩを得る。
[Means for solving problems]
The technical protocol of the present invention is as follows:
The present invention presents a method of producing compound V. Compound II can be obtained by the following method:
(1) Compound II and acetyl chloride a are esterified to obtain compound III.
本発明の優先プロトコルとして、上記の方法のように“ワンポット合成”によって、措置（１）〜（３）を同一の反応容器にて行うことである。 As a priority protocol of the present invention, measures (1) to (3) are performed in the same reaction vessel by “one-pot synthesis” as in the above method.
また、本発明は化合物Ｉの生成方法を提示する。化合物Ｉは化合物ＩＩより以下の方法にて生成できる。
（１）化合物ＩＩと塩化アセチルａをエステル化し化合物ＩＩＩを得る。
The present invention also presents a method for producing Compound I. Compound I can be produced from compound II by the following method.
(1) Compound II and acetyl chloride a are esterified to obtain compound III.
本発明の優先プロトコルとして、上記の化合物Ｉの生成方法として“ワンポット合成”を採用し、措置（１）〜（３）は同一の反応容器にて行う。生成された化合物Vを更に１、５−ナフタレンジスルホン酸デアルキル脂ｃと反応させ化合物Iを得る。 As a priority protocol of the present invention, “one-pot synthesis” is adopted as a method for producing the above compound I, and measures (1) to (3) are carried out in the same reaction vessel. The resulting compound V is further reacted with 1,5-naphthalenedisulfonic acid dealkyl fat c to obtain compound I.
上記の方法のでは、措置（１）と（２）は溶剤がある状態でもない状態でも行うことができる。有機溶剤は非プロトン性溶媒、例えばベンジン、トルエンあるいはエーテル類溶剤（例えばジエチルエーテル）などのうち一種あるいは多種を優先的に使用する。また、本発明では措置（１）と（２）は溶媒がない状態で行うものとしている。 In the above method, the measures (1) and (2) can be performed with or without a solvent. As the organic solvent, one or more aprotic solvents such as benzine, toluene or ether solvents (for example, diethyl ether) are preferentially used. In the present invention, the measures (1) and (2) are performed in the absence of a solvent.
そして、措置（１）と（２）の反応時間と温度には、特別な要求はない。例えば、措置（１）のエステルかは通常０〜１００℃で１〜８時間という条件で行い、措置（２）のアルキル化は通常２０〜８０℃で２〜６時間の条件で行う。 And there is no special requirement for the reaction time and temperature of measures (1) and (2). For example, the ester of the measure (1) is usually performed at 0 to 100 ° C. for 1 to 8 hours, and the alkylation of the measure (2) is usually performed at 20 to 80 ° C. for 2 to 6 hours.
上記の方法では、措置（３）の有機溶剤は、アセトニトリル、ジエチルエーテル、ベンジン、アセトン、クロロホルム等のうち一つか多数を使用する。また、縛酸剤としては第三級アミン、トリエチルアミン、Ｎ、Ｎ-ジメチルホルムアミド、ピリジンのうち一つか多数を使う。 In the above method, the organic solvent of the measure (3) uses one or many of acetonitrile, diethyl ether, benzine, acetone, chloroform and the like. In addition, as a binding acid agent, one or many of tertiary amine, triethylamine, N, N-dimethylformamide and pyridine are used.
また、措置（３）のエステル化では、優先的に−１０〜３０℃で０．５〜６時間行う。反応終了後に、純化、分離、乾燥と濃縮を行った後、比較的高純度の化合物Vを得ることができる。 Further, the esterification in the measure (3) is preferentially carried out at −10 to 30 ° C. for 0.5 to 6 hours. After completion of the reaction, purification, separation, drying and concentration are performed, and then a relatively high purity compound V can be obtained.
本発明の具体的な施行方法として、上記の方法の中でＲ１、Ｒ６、Ｒ７を水素、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ８はアルキル基、ｎを２とし、化合物Iは下記結合式の化合物Ｉａである。 As a specific enforcement method of the present invention, among the above methods, R1, R6, R7 are hydrogen, R2, R3, R4, R5, R8 are alkyl groups, n is 2, and compound I is a compound of the following bond formula Ia.
［発明の効果］
現有のアクラトニウムナパジシル酸塩及びその類似化合物の合成技術と比べ、本発明の反応原料は廉価で入手しやすく、特に本発明のアクラトニウムナパジシル酸塩とその類似化合物の反応原料となる乳酸は原料が豊富の上、廉価で入手しやすい。本発明の最も突出している特徴は原材料（化合物ＩＩ）から中間生成物（化合物V）の合成過程にある。“ワンポット合成”或いは“一釜法”によって行われ、すべての反応家庭を同一の反応容器で行うことができ、純化措置や反応設備を節約でき、収率を向上させ、生産コストを大幅に削減できる。また、本発明の合成方法の反応条件温度等は制御しやすく操作も容易で大規模な生産に向いている。
[The invention's effect]
Compared with the existing synthesizing technology of acratonium napadisylate and its similar compounds, the reaction raw material of the present invention is inexpensive and easy to obtain. Lactic acid is abundant in raw materials and is inexpensive and easy to obtain. The most prominent feature of the present invention lies in the process of synthesizing the intermediate product (Compound V) from the raw material (Compound II). Performed by “one pot synthesis” or “one pot method”, all reaction households can be carried out in the same reaction vessel, saving purification measures and reaction equipment, improving yields and greatly reducing production costs it can. Further, the reaction condition temperature of the synthesis method of the present invention is easy to control and easy to operate, and is suitable for large-scale production.
［発明を実施するための最良の形態］
以下の生成例を通して本発明の詳細な説明を行う。生成例は本発明の内容と主旨に限定されるものではない。
[Best Mode for Carrying Out the Invention]
The present invention will be described in detail through the following generation examples. The generation example is not limited to the contents and the gist of the present invention.
（生成例１）：２−アセトキシメチルプロパノール（化合物Ｖａ）の生成 (Production Example 1): Production of 2-acetoxymethylpropanol (Compound Va)
（生成例２）：２アセトキシメチルプロパノール（化合物Ｖａ）の生成
２００ｇ（９０％）（２．０ｍｏｌ）の乳酸を反応容器に入れ、攪拌しながら塩化アセチル２８２ｇ（３．６ｍｏｌ）を滴定し、２０〜３０℃で４時間反応させ、反応終了後反応液を減圧蒸留し、余剰の塩化アセチルを蒸発させる。蒸留後α−アセトキシメチルを得る。３５７ｇ（３．０ｍｏｌ）の塩化チオニルを滴定し、加熱回流で４時間反応させた後、減圧蒸留で余剰の塩化チオニルを蒸発させ、２−アセトキシメチルプロパノールクロライドを得る。冷却しつつ１３４ｇ（１．５ｍｏｌ）のＮ、Ｎ-ジメチルアミノエタノール、１１０ｇ（１．５ｍｏｌ）ジメチルホルムアミドと１０００ｍｌのベンジンを上記の反応容器に入れ、５〜１０℃で攪拌しつつ２時間反応させ、濾過し、濾過液を％ＮａＯＨ溶液で洗浄する。有機層は無水硫酸ナトリウムで乾燥、濾過しベンジン層を蒸留したのち、減圧蒸留し化合物Ｖａを得る（２３６ｇ、収率５８．１％）。
(Production Example 2): Production of 2 acetoxymethylpropanol (Compound Va) 200 g (90%) (2.0 mol) of lactic acid was placed in a reaction vessel, and 282 g (3.6 mol) of acetyl chloride was titrated while stirring. The reaction is carried out at -30 ° C for 4 hours, and after completion of the reaction, the reaction solution is distilled under reduced pressure to evaporate excess acetyl chloride. Α-Acetoxymethyl is obtained after distillation. 357 g (3.0 mol) of thionyl chloride is titrated and reacted for 4 hours by heating circulation, and then excess thionyl chloride is evaporated by distillation under reduced pressure to obtain 2-acetoxymethylpropanol chloride. While cooling, 134 g (1.5 mol) of N, N-dimethylaminoethanol, 110 g (1.5 mol) of dimethylformamide and 1000 ml of benzine were placed in the above reaction vessel and allowed to react for 2 hours while stirring at 5 to 10 ° C. Filter and wash the filtrate with% NaOH solution. The organic layer is dried over anhydrous sodium sulfate and filtered, and the benzine layer is distilled, followed by distillation under reduced pressure to obtain Compound Va (236 g, yield 58.1%).
（生成例３）：２−アセトキシメチルプロパノール（化合物Ｖａ）の生成
生成例１と同様の方法を行い、その中で１１９ｇ（１．５ｍｏｌ）ピリジン、１０００ｍｌクロロホルムをそれぞれ生成例１のトリエチルアミン、ジエチルエーテルと置き換え、化合物Ｖａを得る（２２９ｇ、収率５６．３％）。
(Production Example 3): Production of 2-acetoxymethylpropanol (Compound Va) The same method as in Production Example 1 was performed, in which 119 g (1.5 mol) pyridine and 1000 ml chloroform were produced, respectively. Triethylamine and diethyl ether of Production Example 1 To give compound Va (229 g, 56.3% yield).
（生成例４）アクラトニウムナパジシル酸塩（化合物Ia）の生成
１００ｇ（０．３１６ｍｏｌ）の１，５−ジメチルナパジシル酸塩と８００ｍｌのイソプロピルアルコールを反応容器に入れ、攪拌しつつ１３０ｇ（０．６３４ｍｏｌ）の２−アセトキシメチルプロパノール（化合物Ｖａ）を加え、５０〜６０℃まで加熱し１時間攪拌し、反応終了後熱を取り、濾過し１７０ｇのアクラトニウムナパジシル酸塩（化合物Ｉａ）を得る。収率７４．５％、融点１９１〜１９２℃。構造（Ｃ３０Ｈ４６Ｎ２Ｏ１４Ｓ２）、理論値（％）Ｃ４９．８５，Ｈ６．４２，Ｎ３．８８;実測値（％）Ｃ４９．８４，Ｈ６．４４，Ｎ３．８８；1Ｈ−ＮＭＲ（Ｄ２Ｏ）：１．３５０（３Ｈ，ｄ，ＣＨＣＨ３）， ２．０４６（３Ｈ，ｓ，ＣＯＣＨ３），３．０１１（３Ｈ，ｓ，ＮＣＨ３），３．５４７（２Ｈ，ｔ，ＮＣＨ２ＣＨ２），４．４１２（２Ｈ，ｔ，ＮＣＨ２ＣＨ２），４．９７６（１Ｈ，ｑ，ＣＨＣＨ３），７．６７５〜８．７９８（Ａｒ−Ｈ）。１３Ｃ−ＮＭＲ（Ｄ２Ｏ）:１５．８６５（ＣＨＣＨ３），２０．１０１（ＣＯＣＨ３），５３．７５０（ＮＣＨ３），５９．２５８（ＮＣＨ２ＣＨ２），６４．３９７（ＮＣＨ２ＣＨ２），６９．４４８（ＣＨＣＨ３），
１２６．３４８〜１３９．２５１（−Ｃ＝），１７２．０２５（ＯＣＯＣＨＣＨ３），１７３．４４０（ＯＣＯＣＨ３）。ＩＲ（ｃｍ−１）: ３０３６，２９８４，１７５８，１７３３，１４９１，１４５６，１３８０，１２４７，１２０１，１１０６，１０３３，８０３。ＭＳ（ＥＩ）ｍ／ｚ：２２２，１２７，１１５，５８，４２。
(Production Example 4) Production of acratonium napadisylate (Compound Ia) 100 g (0.316 mol) of 1,5-dimethylnapadisylate and 800 ml of isopropyl alcohol were placed in a reaction vessel and stirred while stirring 130 g. (0.634 mol) of 2-acetoxymethylpropanol (Compound Va) was added, heated to 50-60 ° C. and stirred for 1 hour. After completion of the reaction, the heat was removed, filtered, and 170 g of akratonium napadisylate (compound) Ia) is obtained. Yield 74.5%, mp 191-192 ° C. Structure (C 30 H 46 N 2 O 14 S 2), the theoretical value (%) C49.85, H6.42, N3.88 ; Found (%) C49.84, H6.44, N3.88 ; 1 H -NMR (D 2 O): 1.350 (3H, d, CHCH 3), 2.046 (3H, s, COCH 3), 3.011 (3H, s, NCH 3), 3.547 (2H, t, NCH 2 CH 2), 4.412 (2H, t, NCH 2 CH 2), 4.976 (1H, q, CHCH 3), 7.675~8.798 (Ar-H). 13C-NMR (D2O): 15.865 (CHCH 3), 20.101 (COCH 3), 53.750 (NCH 3), 59.258 (NCH 2 CH 2), 64.397 (NCH 2 CH 2) , 69.448 (CHCH 3 ),
126.348~139.251 (-C =), 172.025 ( OCOCHCH 3), 173.440 (OCOCH 3). IR (cm-1): 3036, 2984, 1758, 1733, 1491, 1456, 1380, 1247, 1201, 1106, 1033, 803. MS (EI) m / z: 222, 127, 115, 58, 42.
（生成例５）アクラトニウムナパジシル酸塩（化合物Ia）の生成
１００ｇ（０．３１６ｍｏｌ）１，５−メチルナパジシル酸塩と９００ｍｌアセトンを反応容器に入れ、攪拌しつつ１３０ｇ（０．６３４ｍｏｌ）２−アセトキシメチルプロパノール（化合物Ｖａ）を入れ、５０〜６０℃まで加熱し、１時間攪拌した後、熱を取って濾過し、１６７ｇのアクラトニウムナパジシル酸塩（化合物Ｉａ）を得る。収率７３．１％、融点１９１〜１９２℃。
(Production Example 5) Production of akratonium napadisylate (Compound Ia) 100 g (0.316 mol) 1,5-methylnapadisylate and 900 ml acetone were placed in a reaction vessel and stirred with 130 g (0.634 mol) 2 -Acetoxymethylpropanol (Compound Va) is added, heated to 50-60 ° C, stirred for 1 hour, then filtered by taking heat to obtain 167 g of Acratonium napadisylate (Compound Ia). Yield 73.1%, mp 191-192 ° C.
（生成例６）：２−アセトプロピルプロパノール（化合物Ｖｂ）の生成
２００ｇ（９０％）（２．０ｍｏｌ）の乳酸を反応容器に入れ、攪拌しつつ３３２．８ｇ（３．６ｍｏｌ）のプロピオン酸クロライドを滴定した後、２０〜３０℃で４時間反応させる。反応後減圧蒸留し、余剰のプロピオン酸クロライドを蒸発させ、α−アセトプロピルを得る。３５７ｇ（３．０ｍｏｌ）塩化チオニルを滴定した後、加熱回流で４時間反応させた後、余剰な塩化チオニルを蒸発させ、２−アセトプロピオン酸クロライドを得る。冷却しつつ１３４ｇ（１．５ｍｏｌ）Ｎ，Ｎ-ジメチルアミノエタノール、１５２ｇ（１．５ｍｏｌ）トリエチルアミンと１０００ｍｌジエチルエーテルを上記の反応容器に加え、５〜１０℃で２時間反応させた後、濾過し、濾過液を１％ＮａＯＨ溶液で洗浄する。有機層は無水硫酸ナトリウムで乾燥、濾過しジエチルエーテル層を蒸留した後、減圧蒸留し、化合物Ｖｂを得る（２６５ｇ、収率６１．０％）。
(Production Example 6): Production of 2-acetopropylpropanol (Compound Vb) 200 g (90%) (2.0 mol) of lactic acid was placed in a reaction vessel and stirred with 332.8 g (3.6 mol) of propionic acid chloride. Is allowed to react at 20-30 ° C. for 4 hours. After the reaction, the reaction mixture is distilled under reduced pressure to evaporate excess propionic acid chloride to obtain α-acetopropyl. After titration of 357 g (3.0 mol) thionyl chloride, the reaction was carried out for 4 hours by heating circulation, and then excess thionyl chloride was evaporated to obtain 2-acetopropionic acid chloride. While cooling, 134 g (1.5 mol) N, N-dimethylaminoethanol, 152 g (1.5 mol) triethylamine and 1000 ml diethyl ether were added to the above reaction vessel, reacted at 5 to 10 ° C. for 2 hours, and then filtered. The filtrate is washed with 1% NaOH solution. The organic layer is dried over anhydrous sodium sulfate and filtered, and the diethyl ether layer is distilled, followed by distillation under reduced pressure to obtain compound Vb (265 g, yield 61.0%).
（生成例７）：マロトニウムナパジシル酸塩（化合物Ｉｂ）の生成
１００ｇ（０．３１６ｍｏｌ）１，５−ジメチルナパジシル酸塩と８００ｍｌイソプロピルアルコールを反応容器に入れ、攪拌しつつ１３８ｇ（０．６３４ｍｏｌ）２−アセトプロピルプロパノール（化合物Ｖｂ）を加え、５０〜６０℃まで加熱し１時間攪拌後、熱を取り、１７６ｇのマロトニウムナパジシル酸塩（化合物Ｉｂ）を得る。収率：７５．６％、融点１２０〜１２２℃。構造（Ｃ３１Ｈ４８Ｎ２Ｏ１４Ｓ２）、理論値（％）：Ｃ５０．５３，Ｈ６．５７，Ｎ３．８０、実測値（％）：Ｃ５０．４６，Ｈ６．４９，Ｎ３．７２。
(Production Example 7): Production of malotonium napadisylate (Compound Ib) 100 g (0.316 mol) 1,5-dimethylnapadisylate and 800 ml isopropyl alcohol were placed in a reaction vessel and stirred with 138 g ( 0.634 mol) 2-acetopropylpropanol (Compound Vb) is added, heated to 50-60 ° C., stirred for 1 hour, and then heated to obtain 176 g of malotonium napadisylate (Compound Ib). Yield: 75.6%, melting point 120-122 ° C. Structure (C 31 H 48 N 2 O 14 S 2), the theoretical value (%): C50.53, H6.57, N3.80, Found (%): C50.46, H6.49, N3.72.
（生成例８）：ブチトニウムナパジシル酸塩（化合物Ｉｃ）の生成
上記の生成方法例における塩化アセチル或いはプロピオン酸クロライドをブチリルクロリドに置き換え、ブチトニウムナパジシル酸塩（化合物Ｉｃ）を得る。
(Production Example 8): Production of Butynium Napadisylate (Compound Ic) Acetyl chloride or propionic acid chloride in the above production method example was replaced with butyryl chloride, and butytonium napadisylate (Compound Ic) was replaced. obtain.
生成例を用いて本発明を詳しく説明した。上記の描写と実施例は本発明の例に過ぎない。本発明の目的と範囲の中で、本領域技術者は本発明の代行プロトコルや改善プロトコルを設計することができ、本発明の保護範囲内にそれらは属する。 The present invention has been described in detail using generation examples. The above depictions and examples are merely examples of the invention. Within the purpose and scope of the present invention, a domain engineer can design proxy protocols and improved protocols of the present invention, which fall within the protection scope of the present invention.
Claims (10)
（１）化合物ＩＩと塩化アセチルａによるエステル化反応によって化合物ＩＩＩを得る。
(1) Compound III is obtained by esterification reaction between Compound II and acetyl chloride a.
（１）化合物ＩＩと塩化アセチルａのエステル化反応により、化合物ＩＩＩを得る。
(1) Compound III is obtained by esterification of compound II and acetyl chloride a.
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| CN200610145695.8 | 2006-11-24 | ||
| PCT/CN2007/070948 WO2008061466A1 (en) | 2006-11-24 | 2007-10-24 | Synthetic methods of aclatonium napadisilate and analogs thereof |
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| CN110386878B (en) * | 2018-04-20 | 2022-04-22 | 扬子江药业集团有限公司 | Industrial preparation method of diethyl cholamine napadisylate |
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| JPS5018413A (en) * | 1973-06-20 | 1975-02-26 | ||
| JPH01104085A (en) * | 1987-07-15 | 1989-04-21 | Zambon Group Spa | Phosphonic acid derivative and enanthioselective manufacture |
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| JPS5414092B1 (en) * | 1970-12-28 | 1979-06-05 | ||
| DE2425983C3 (en) * | 1973-06-12 | 1978-09-14 | Toyama Chemical Co. Ltd., Tokio | Sulphonic acid salts of acylcholines, processes for their preparation and pharmaceutical compositions containing them |
| DE2546845A1 (en) * | 1975-10-18 | 1977-04-28 | Basf Ag | Herbicidal (iso)quinolyloxy-alkanoic acid derivs. - prepd. e.g. by reacting hydroxy-(iso)quinoline cpds. with halo-alkanamides |
| JPS58180463A (en) * | 1982-04-19 | 1983-10-21 | Toyama Chem Co Ltd | Preparation of bischolinedisulfonate |
| CN100475773C (en) * | 2006-11-24 | 2009-04-08 | 李晓祥 | Synthesis method of naphthalene disulfonic acid aclatonium and similar compound thereof |
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| JPS5018413A (en) * | 1973-06-20 | 1975-02-26 | ||
| JPH01104085A (en) * | 1987-07-15 | 1989-04-21 | Zambon Group Spa | Phosphonic acid derivative and enanthioselective manufacture |
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| JP5007309B2 (en) | 2012-08-22 |
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