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JP7576921B2 - Method for producing O-substituted hydroxylamine derivatives - Google Patents

Method for producing O-substituted hydroxylamine derivatives Download PDF

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JP7576921B2
JP7576921B2 JP2020059567A JP2020059567A JP7576921B2 JP 7576921 B2 JP7576921 B2 JP 7576921B2 JP 2020059567 A JP2020059567 A JP 2020059567A JP 2020059567 A JP2020059567 A JP 2020059567A JP 7576921 B2 JP7576921 B2 JP 7576921B2
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substituted hydroxylamine
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裕基 坪井
康行 長井
隆洋 増田
彩 砂川
智子 立元
洋樹 一條
修 小林
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Sagami Chemical Research Institute
Tosoh Corp
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Description

本発明は、O-置換ヒドロキシルアミン誘導体の製造方法に関する。 The present invention relates to a method for producing O-substituted hydroxylamine derivatives.

O-置換ヒドロキシルアミン誘導体は、アセトアルデヒドやホルムアルデヒド等のアルデヒド類と化学的に反応して、効率良く捕獲・無害化することができ、アルデヒド類の捕捉剤(以下、「アルデヒド捕捉剤」ということもある。)の有効成分として有用である(例えば、特許文献1参照)。 O-substituted hydroxylamine derivatives can efficiently capture and detoxify aldehydes such as acetaldehyde and formaldehyde by chemically reacting with them, and are useful as active ingredients in aldehyde scavengers (hereinafter sometimes referred to as "aldehyde scavengers") (see, for example, Patent Document 1).

O-置換ヒドロキシルアミン誘導体は、α位に(1,3-ジオキソイソインドリン-2-イル)オキシ基を有するカルボン酸エステルを酸加水分解する方法で製造することができ、O-置換ヒドロキシルアミン誘導体と酸との塩が得られる(例えば、特許文献2又は3参照)。 O-substituted hydroxylamine derivatives can be produced by acid hydrolysis of a carboxylic acid ester having a (1,3-dioxoisoindolin-2-yl)oxy group at the α-position, to obtain a salt of the O-substituted hydroxylamine derivative with an acid (see, for example, Patent Documents 2 and 3).

国際公開第2018/124208号パンフレットInternational Publication No. 2018/124208 国際公開第99/49864号パンフレットInternational Publication No. 99/49864 国際公開第98/14447号パンフレットInternational Publication No. 98/14447

上記の方法で製造したO-置換ヒドロキシルアミン誘導体は、いずれも酸との塩を形成している。アルデヒド捕捉剤として用いるためには、O-置換ヒドロキシルアミン誘導体を水に溶解させた後に塩基で中和することが好ましいが、中和によってO-置換ヒドロキシルアミン誘導体の水溶液中に酸の塩を含むことになり、純度の面で課題がある。本発明の目的は、上記の課題を鑑みてなされたものであり、O-置換ヒドロキシルアミン誘導体の水溶液を高純度に製造する方法を提供するものである。 The O-substituted hydroxylamine derivatives produced by the above methods all form salts with acids. To use them as aldehyde scavengers, it is preferable to dissolve the O-substituted hydroxylamine derivatives in water and then neutralize them with a base; however, neutralization results in the aqueous solution of the O-substituted hydroxylamine derivative containing an acid salt, which poses a problem in terms of purity. The object of the present invention was made in view of the above problems, and is to provide a method for producing an aqueous solution of an O-substituted hydroxylamine derivative with high purity.

本発明者らは、上記の課題を解決するために鋭意検討を重ねた結果、特定のO-置換ヒドロキシルアミン誘導体を純度良く効率的に得る製造方法を見出し、本発明を完成するに至った。 As a result of extensive research into solving the above problems, the inventors discovered a method for efficiently obtaining specific O-substituted hydroxylamine derivatives with high purity, and thus completed the present invention.

すなわち、本発明は、一般式(2) That is, the present invention relates to a compound represented by the general formula (2)

(式中、Rは水素原子、又は炭素数1~4のアルキル基を表す。Rは炭素数1~4のアルキル基を表す。)
で示される化合物を加水分解して、一般式(1)
(In the formula, R 1 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. R 2 represents an alkyl group having 1 to 4 carbon atoms.)
to hydrolyze a compound represented by the general formula (1)

(式中、Rは前記と同じ意味を表す。)
で示されるO-置換ヒドロキシルアミン誘導体を製造する方法において、
a)前記一般式(2)の化合物をスルホン酸と接触させる工程と、
b)工程a)で得られた前記一般式(1)の化合物とスルホン酸の反応物を第2族元素に接触させる工程と、
c)工程b)で生成したスルホン酸塩を除去する工程と、
を含むO-置換ヒドロキシルアミン誘導体の製造方法に関する。
(In the formula, R1 has the same meaning as above.)
A method for producing an O-substituted hydroxylamine derivative represented by
a) contacting the compound of general formula (2) with a sulfonic acid;
b) contacting the reaction product of the compound of general formula (1) and sulfonic acid obtained in step a) with a Group 2 element;
c) removing the sulfonate produced in step b);
The present invention relates to a method for producing an O-substituted hydroxylamine derivative comprising the steps of:

一般に、低級アルキルエステルは酸に安定であることから、エステル部位を有する一般式(2)の化合物を酸性条件下で加水分解するには、加熱条件下で反応を実施することが好ましい。一方、反応温度が高過ぎると目的物が分解し、収率が低下する場合がある。 In general, lower alkyl esters are stable to acids, so to hydrolyze a compound of general formula (2) having an ester moiety under acidic conditions, it is preferable to carry out the reaction under heated conditions. On the other hand, if the reaction temperature is too high, the target product may decompose, resulting in a reduced yield.

したがって、工程a)は60~120℃の範囲から選ばれる反応温度で実施することが好ましく、70~110℃の範囲から選ばれる反応温度で実施することがさらに好ましい。 Therefore, step a) is preferably carried out at a reaction temperature selected from the range of 60 to 120°C, and more preferably at a reaction temperature selected from the range of 70 to 110°C.

一般式(1)の化合物は、いわゆるアミノ酸であり、スルホン酸存在下ではスルホン酸塩として存在する。そのため、反応に使用するスルホン酸の一部はスルホン酸塩形成に消費される。 The compound of general formula (1) is a so-called amino acid, and exists as a sulfonate salt in the presence of sulfonic acid. Therefore, a portion of the sulfonic acid used in the reaction is consumed in the formation of the sulfonate salt.

したがって、工程a)で使用するスルホン酸の量は、原料である一般式(2)の化合物の量に対して0.6モル当量以上であることが好ましく、1.2モル当量以上であることが、目的物の収率が良くなる点でさらに好ましい。 Therefore, the amount of sulfonic acid used in step a) is preferably 0.6 molar equivalents or more relative to the amount of the compound of general formula (2) used as the raw material, and more preferably 1.2 molar equivalents or more in terms of improving the yield of the target product.

使用するスルホン酸としては、硫酸等の無機硫黄オキソ酸類、メタンスルホン酸、トリフルオロメタンスルホン酸、トシル酸、ベンゼンスルホン酸、10-カンファー-スルホン酸等の有機スルホン酸類を例示することができ、安価である点で硫酸が好ましい。 Examples of sulfonic acids that can be used include inorganic sulfur oxoacids such as sulfuric acid, and organic sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, tosylic acid, benzenesulfonic acid, and 10-camphorsulfonic acid, with sulfuric acid being preferred because it is inexpensive.

使用するスルホン酸の濃度に特に制限はなく、高濃度のスルホン酸をそのまま使用しても良く、適宜水で希釈してから使用しても良い。 There is no particular limit to the concentration of sulfonic acid used, and high-concentration sulfonic acid may be used as is, or it may be diluted with water as appropriate before use.

一般式(2)の化合物をスルホン酸と接触させる方法に特に制限はなく、例えば、機械的スターラーを使用して混合すれば良い。また、スルホン酸を直接添加等して使用しても良く、反応系中にスルホン酸を発生させて接触させても良い。系中でスルホン酸を発生させる方法としては特に制限はなく、例えば、三酸化硫黄と水とを反応させて硫酸を発生させる方法等を用いれば良い。 There is no particular limitation on the method for contacting the compound of general formula (2) with sulfonic acid, and for example, mixing may be performed using a mechanical stirrer. Sulfonic acid may also be used by directly adding it, or it may be generated in the reaction system and then contacted. There is no particular limitation on the method for generating sulfonic acid in the system, and for example, a method of generating sulfuric acid by reacting sulfur trioxide with water may be used.

工程a)の反応後には、一般式(2)の化合物のフタルイミドが加水分解されて生じたフタル酸が固体として析出する。目的とする一般式(1)の化合物のスルホン酸塩を純度良く得るために、不要なフタル酸を除去すること)が好ましい。除去は、例えば、ろ過による方法が例示される。ろ過は、例えば、自然ろ過、減圧ろ過、遠心ろ過などから、反応スケール等に合わせて適宜選択して実施すれば良い。効率が良く、時間が短縮できる点で、減圧ろ過や遠心ろ過が好ましい。 After the reaction in step a), the phthalimide of the compound of general formula (2) is hydrolyzed and the resulting phthalic acid precipitates as a solid. In order to obtain the desired sulfonate of the compound of general formula (1) with high purity, it is preferable to remove unnecessary phthalic acid). For example, the removal can be performed by filtration. The filtration can be performed by, for example, natural filtration, reduced pressure filtration, centrifugal filtration, etc., appropriately selected according to the reaction scale, etc. Reduced pressure filtration and centrifugal filtration are preferable because they are efficient and can shorten the time.

工程a)の反応後のろ過でろ液として得られた一般式(1)の化合物とスルホン酸の反応液を第2族元素と接触させる(工程b)方法に特に制限はなく、例えば、機械的スターラーを使用して混合すれば良い。 There are no particular limitations on the method for contacting the reaction solution of the compound of general formula (1) and sulfonic acid obtained as the filtrate by filtration after the reaction in step a) with a Group 2 element (step b), and for example, mixing may be performed using a mechanical stirrer.

工程b)で用いる第2族元素は塩として使用することが好ましく、スルホン酸塩が難溶性であれば特に制限はなく、例えば、Be、Mg,Ca,Sr,Ba及びRaの塩が挙げられ、特にCaの塩が好ましい。第2族元素の塩としては、炭酸塩、炭酸水素塩及び水酸化物が挙げられ、安価である点で水酸化カルシウムが好ましい。 The Group 2 element used in step b) is preferably used as a salt, and there are no particular limitations as long as the sulfonate is sparingly soluble. Examples of the salt include salts of Be, Mg, Ca, Sr, Ba, and Ra, with Ca salts being particularly preferred. Examples of salts of Group 2 elements include carbonates, hydrogen carbonates, and hydroxides, with calcium hydroxide being preferred because it is inexpensive.

用いる第2族元素の塩の量に特に制限はないが、工程a)で用いたスルホン酸に対して1.0モル当量以上であることが好ましい。 There is no particular restriction on the amount of the salt of the Group 2 element used, but it is preferable that it be 1.0 molar equivalent or more relative to the sulfonic acid used in step a).

工程b)の反応後には、スルホン酸が第2族元素の塩によって中和されて生じたスルホン酸塩が固体として析出する。目的とする一般式(1)の化合物を純度良く得るために、不要なスルホン酸塩を除去すること(工程c)が好ましい。除去は、例えば、ろ過による方法が例示される。ろ過は、例えば、自然ろ過、減圧ろ過、遠心ろ過などから、反応スケール等に合わせて適宜選択して実施すれば良い。効率が良く、時間が短縮できる点で、減圧ろ過や遠心ろ過が好ましい。 After the reaction in step b), the sulfonic acid is neutralized with the salt of the Group 2 element to produce a sulfonate salt, which precipitates as a solid. In order to obtain the desired compound of general formula (1) with a high purity, it is preferable to remove unnecessary sulfonate salts (step c). For example, the removal can be performed by filtration. The filtration can be performed by, for example, natural filtration, reduced pressure filtration, centrifugal filtration, etc., appropriately selected according to the reaction scale, etc. Reduced pressure filtration and centrifugal filtration are preferred because they are efficient and can shorten the time.

一般式(2)の化合物のフタルイミドが加水分解されて生じるフタル酸は、工程a)の後に除去しても良いし、工程c)でスルホン酸塩とともに除去しても良い。除去は、例えば、ろ過による方法が例示される。ろ過は、例えば、自然ろ過、減圧ろ過、遠心ろ過などから、反応スケール等に合わせて適宜選択して実施すれば良い。効率が良く、時間が短縮できる点で、減圧ろ過や遠心ろ過が好ましい。 The phthalic acid generated by hydrolysis of the phthalimide of the compound of general formula (2) may be removed after step a) or may be removed together with the sulfonate in step c). The removal may be performed, for example, by filtration. The filtration may be performed by a method appropriately selected from natural filtration, reduced pressure filtration, centrifugal filtration, etc. according to the reaction scale, etc. Reduced pressure filtration and centrifugal filtration are preferred because they are efficient and can shorten the time.

本発明における反応は、溶媒中で実施することができる。好適な溶媒としては、水、アミド溶媒、エーテル溶媒、ニトリル溶媒、芳香族溶媒が挙げられる。 The reaction in the present invention can be carried out in a solvent. Suitable solvents include water, amide solvents, ether solvents, nitrile solvents, and aromatic solvents.

次に、一般式(1)及び(2)における置換基の定義について説明する。 Next, the definitions of the substituents in general formulas (1) and (2) will be explained.

一般式(1)及び(2)において、Rは水素原子、又は炭素数1~4のアルキル基を表し、該アルキル基は、直鎖状アルキル基又は分岐状アルキル基のいずれであっても良く、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、sec-ブチル基、又はtert-ブチル基であり、好ましくはメチル基又はエチル基である。製造方法において、Rは、好ましくは水素原子、メチル基、又はエチル基である。 In general formulae (1) and (2), R 1 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, which may be a linear or branched alkyl group, and is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, and is preferably a methyl group or an ethyl group. In the production method, R 1 is preferably a hydrogen atom, a methyl group, or an ethyl group.

一般式(2)において、Rは炭素数1~4のアルキル基を表し、該アルキル基は、直鎖状アルキル基又は分岐状アルキル基のいずれであっても良く、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、sec-ブチル基、又はtert-ブチル基であり、好ましくはメチル基、エチル基、又はtert-ブチル基である。製造方法において、Rは、好ましくはメチル基又はエチル基である。 In the general formula (2), R2 represents an alkyl group having 1 to 4 carbon atoms, which may be either a linear or branched alkyl group, and is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, and is preferably a methyl group, an ethyl group, or a tert-butyl group. In the production method, R2 is preferably a methyl group or an ethyl group.

本発明の製造方法により収率良く製造できるO-置換ヒドロキシルアミン誘導体は、有害なアルデヒド類を速やかに、かつ持続的に捕捉するアルデヒド捕捉剤の有効成分として有用であり、人々の生活環境を改善することができる。 The O-substituted hydroxylamine derivatives that can be produced in high yields using the production method of the present invention are useful as active ingredients in aldehyde scavengers that quickly and sustainably capture harmful aldehydes, and can improve people's living environments.

以下、本発明についてさらに詳細に説明するが、本発明はこれら実施例により何ら限定して解釈されるものではない。また、実施例及び比較例を表1にまとめて記載した。実施例に記載の収量は、アミノオキシ酢酸を4-ニトロベンズアルデヒドと反応させて誘導体化した後、液体クロマトグラフィー(島津製作所製 LC-2030C Plus)により算出した。硫酸イオン及び塩化物イオンについてはイオンクロマトグラフィー(東ソー製 IC-2010)により算出した。 The present invention will be described in more detail below, but the present invention should not be construed as being limited in any way by these examples. Examples and comparative examples are summarized in Table 1. The yields described in the examples were calculated by liquid chromatography (Shimadzu Corporation, LC-2030C Plus) after aminooxyacetic acid was reacted with 4-nitrobenzaldehyde to form a derivative. Sulfate ions and chloride ions were calculated by ion chromatography (Tosoh Corporation, IC-2010).

実施例1
2-[(1,3-ジオキソイソインドリン-2-イル)オキシ]酢酸エチル(2.49g,10mmol)に、1.2M硫酸(10mL)を加え、75℃で4時間撹拌した。反応終了後、反応液を室温まで放冷し、析出した固体をろ別した。ろ液に水酸化カルシウム(0.89g,12mmol)を加え、析出した固体をろ別し、アミノオキシ酢酸水溶液(2.25wt%,34.3g,収率85%)を得た。アミノオキシ酢酸水溶液に含まれる硫酸イオンをイオンクロマトグラフィーで算出した(0.19wt%)。アミノオキシ酢酸濃度が1wt%になるまで希釈したところ、硫酸イオン濃度は0.084wt%であった。
Example 1
1.2M sulfuric acid (10mL) was added to ethyl 2-[(1,3-dioxoisoindolin-2-yl)oxy]acetate (2.49g, 10mmol) and stirred at 75°C for 4 hours. After the reaction was completed, the reaction solution was allowed to cool to room temperature and the precipitated solid was filtered off. Calcium hydroxide (0.89g, 12mmol) was added to the filtrate and the precipitated solid was filtered off to obtain an aqueous solution of aminooxyacetic acid (2.25wt%, 34.3g, yield 85%). The sulfate ion contained in the aqueous solution of aminooxyacetic acid was calculated by ion chromatography (0.19wt%). When the solution was diluted until the concentration of aminooxyacetic acid became 1wt%, the sulfate ion concentration was 0.084wt%.

比較例1
2-[(1,3-ジオキソイソインドリン-2-イル)オキシ]酢酸エチル(2.49g,10mmol)に、1.2M塩酸(10mL)を加え、75℃で4時間撹拌した。反応終了後、反応液を室温まで放冷し、析出した固体をろ別した。ろ液に水酸化ナトリウム(0.48g,12mmol)を加え、アミノオキシ酢酸水溶液(3.17wt%,25.0g,収率87%)を得た。アミノオキシ酢酸水溶液に含まれる塩化物イオンをイオンクロマトグラフィーで算出した(1.70wt%)。アミノオキシ酢酸が1wt%になるまで水で希釈したところ、塩化物イオン濃度は0.54wt%であった。
Comparative Example 1
1.2 M hydrochloric acid (10 mL) was added to ethyl 2-[(1,3-dioxoisoindolin-2-yl)oxy]acetate (2.49 g, 10 mmol), and the mixture was stirred at 75° C. for 4 hours. After the reaction was completed, the reaction solution was allowed to cool to room temperature, and the precipitated solid was filtered off. Sodium hydroxide (0.48 g, 12 mmol) was added to the filtrate to obtain an aqueous solution of aminooxyacetic acid (3.17 wt %, 25.0 g, yield 87%). The chloride ion content of the aqueous solution of aminooxyacetic acid was calculated by ion chromatography (1.70 wt %). When the aminooxyacetic acid was diluted with water until it reached 1 wt %, the chloride ion concentration was 0.54 wt %.

本発明の製造方法は、アルデヒド捕捉剤の有効成分として有用なO-置換ヒドロキシルアミン誘導体を純度良く製造する方法として有用である。 The manufacturing method of the present invention is useful as a method for producing O-substituted hydroxylamine derivatives with high purity, which are useful as active ingredients in aldehyde scavengers.

Claims (4)

一般式(2)
(式中、Rは水素原子、又は炭素数1~4のアルキル基を表す。Rは炭素数1~4のアルキル基を表す。)
で示される化合物を加水分解して、一般式(1)
(式中、Rは前記と同じ意味を表す。)
で示されるO-置換ヒドロキシルアミン誘導体を製造する方法において、
a)前記一般式(2)の化合物を酸と接触させる工程と、
b)工程a)で得られた前記一般式(1)の化合物と酸の反応物をCaの塩に接触させる工程と、
c)工程b)で生成した酸塩を除去する工程と、
を含むO-置換ヒドロキシルアミン誘導体の製造方法。
General formula (2)
(In the formula, R 1 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. R 2 represents an alkyl group having 1 to 4 carbon atoms.)
to hydrolyze a compound represented by the general formula (1)
(In the formula, R1 has the same meaning as above.)
A method for producing an O-substituted hydroxylamine derivative represented by
a) contacting the compound of formula (2) with sulfuric acid ;
b) contacting the reaction product of the compound of general formula (1) obtained in step a) with sulfuric acid with a Ca salt ;
c) removing the sulfate produced in step b);
A method for producing an O-substituted hydroxylamine derivative comprising the steps of:
工程a)の反応後、フタル酸を除去することを特徴とする、請求項1に記載のO-置換ヒドロキシルアミン誘導体の製造方法。 The method for producing the O-substituted hydroxylamine derivative according to claim 1, characterized in that phthalic acid is removed after the reaction in step a). 工程b)で使用するCaの塩が、Caの炭酸塩、炭酸水素塩又は水酸化物であることを特徴とする、請求項1又は2に記載のO-置換ヒドロキシルアミン誘導体の製造方法。 3. The method for producing an O-substituted hydroxylamine derivative according to claim 1 or 2 , wherein the Ca salt used in step b) is a Ca carbonate, hydrogen carbonate or hydroxide. 工程b)で使用するCaの塩が、水酸化カルシウムであることを特徴とする、請求項1又は2に記載のO-置換ヒドロキシルアミン誘導体の製造方法。 The method for producing an O-substituted hydroxylamine derivative according to claim 1 or 2 , wherein the Ca salt used in step b) is calcium hydroxide.
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Citations (1)

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Publication number Priority date Publication date Assignee Title
JP2002509885A (en) 1998-03-31 2002-04-02 ニューロサーチ、アクティーゼルスカブ Indole-2,3-dione-3-oxime derivatives for use in therapy

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Publication number Priority date Publication date Assignee Title
JP2002509885A (en) 1998-03-31 2002-04-02 ニューロサーチ、アクティーゼルスカブ Indole-2,3-dione-3-oxime derivatives for use in therapy

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Title
Journal of Lanzhou University of Technology,2012年,第38巻第6期,p.62-65
The Journal of Organic Chemistry,1959年,24,p.1794-1795

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