JP6239458B2 - Process for producing 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester - Google Patents
Process for producing 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester Download PDFInfo
- Publication number
- JP6239458B2 JP6239458B2 JP2014148580A JP2014148580A JP6239458B2 JP 6239458 B2 JP6239458 B2 JP 6239458B2 JP 2014148580 A JP2014148580 A JP 2014148580A JP 2014148580 A JP2014148580 A JP 2014148580A JP 6239458 B2 JP6239458 B2 JP 6239458B2
- Authority
- JP
- Japan
- Prior art keywords
- carboxylic acid
- acid ester
- cycloalkene
- benzylsulfinyl
- mol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- -1 benzylsulfinyl Chemical group 0.000 title claims description 24
- 238000000034 method Methods 0.000 title description 7
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 claims description 34
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- PZBBESSUKAHBHD-UHFFFAOYSA-N methyl 2-oxocyclopentane-1-carboxylate Chemical compound COC(=O)C1CCCC1=O PZBBESSUKAHBHD-UHFFFAOYSA-N 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- QOSATHPSBFQAML-UHFFFAOYSA-N hydrogen peroxide;hydrate Chemical compound O.OO QOSATHPSBFQAML-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、２−（ベンジルスルフィニル）−１−シクロアルケン−１−カルボン酸エステルの製造方法に関する。 The present invention relates to a method for producing 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester.
２−（ベンジルスルフィニル）−１−シクロアルケン−１−カルボン酸エステルは抗菌剤の原料として用いられている（特許文献１または２）。２−（ベンジルスルフィニル）−１−シクロアルケン−１−カルボン酸エステルの製造方法が特許文献１または２に記載されている。この方法では、ベンジルスルフィニル基を導入する反応の際にチオエステル体が副生しやすいため収率が低い。 2- (Benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester is used as a raw material for antibacterial agents (Patent Document 1 or 2). A method for producing 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester is described in Patent Document 1 or 2. In this method, the yield is low because a thioester is easily produced as a by-product in the reaction for introducing a benzylsulfinyl group.
本発明の課題は、副生成物を低減して、２−（ベンジルスルフィニル）−１−シクロアルケン−１−カルボン酸エステルを高収率で製造する方法を提供することである。 An object of the present invention is to provide a method for producing 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester in a high yield by reducing by-products.
上記課題を解決すべく鋭意研究した結果、以下の形態を包含する本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present invention including the following modes has been completed.
〔１〕 （２−オキソ−シクロアルカン）−１−カルボン酸エステル１モル部に、温度−５℃〜１５℃にてフェニルメタンチオール１〜１．５モル部を０．５〜１０時間かけて添加して、２−（ベンジルスルファニル）−１−シクロアルケン−１−カルボン酸エステルを得、
次いで、２−（ベンジルスルファニル）−１−シクロアルケン−１−カルボン酸エステル１モル部に、温度５０℃〜８０℃にて過酸化水素水１〜３モル部を５〜１０時間かけて添加することを含む、
２−（ベンジルスルフィニル）−１−シクロアルケン−１−カルボン酸エステルの製造方法。
[1] 1 mol part of (2-oxo-cycloalkane) -1-carboxylic acid ester is added with 1 to 1.5 mol parts of phenylmethanethiol at a temperature of -5 ° C to 15 ° C for 0.5 to 10 hours. To give 2- (benzylsulfanyl) -1-cycloalkene-1-carboxylic acid ester,
Subsequently, 1 to 3 mole parts of hydrogen peroxide is added to 1 mole part of 2- (benzylsulfanyl) -1-cycloalkene-1-carboxylic acid ester at a temperature of 50 ° C. to 80 ° C. over 5 to 10 hours. Including that,
A method for producing 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester.
〔２〕 フェニルメタンチオール添加時の温度が０℃〜１０℃である〔１〕に記載の製造方法。
〔３〕 過酸化水素水添加時の温度が６０℃〜６５℃である〔１〕または〔２〕に記載の製造方法。
[2] The production method according to [1], wherein the temperature when phenylmethanethiol is added is 0 ° C to 10 ° C.
[3] The production method according to [1] or [2], wherein the temperature when the hydrogen peroxide solution is added is 60 ° C to 65 ° C.
本発明の方法によれば、副生成物が少なく、２−（ベンジルスルフィニル）−１−シクロアルケン−１−カルボン酸エステルを高収率で製造することができる。 According to the method of the present invention, there are few byproducts, and 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester can be produced in a high yield.
本発明に係る２−（ベンジルスルフィニル）−１−シクロアルケン−１−カルボン酸エステルの製造方法は、（２−オキソ−シクロアルカン）−１−カルボン酸エステル１モル部に、温度−５℃〜＋１５℃にてフェニルメタンチオール１〜１．５モル部を０．５〜１０時間かけて添加して、２−（ベンジルスルファニル）−１−シクロアルケン−１−カルボン酸エステルを得、
次いで、２−（ベンジルスルファニル）−１−シクロアルケン−１−カルボン酸エステル１モル部に、温度＋５０℃〜＋８０℃にて過酸化水素水１〜３モル部を５〜１０時間かけて添加することを含むものである。
The method for producing 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester according to the present invention is carried out at a temperature of −5 ° C. to 1 mol part of (2-oxo-cycloalkane) -1-carboxylic acid ester. Phenylmethanethiol 1-1.5 mol part was added over 0.5-10 hours at + 15 ° C. to obtain 2- (benzylsulfanyl) -1-cycloalkene-1-carboxylic acid ester,
Subsequently, 1 to 3 mole parts of hydrogen peroxide is added to 1 mole part of 2- (benzylsulfanyl) -1-cycloalkene-1-carboxylic acid ester at a temperature of + 50 ° C. to + 80 ° C. over 5 to 10 hours. Including things.
本発明の反応原料である（２−オキソ−シクロアルカン）−１−カルボン酸エステルは、例えば、式（１）で表される化合物である。 The (2-oxo-cycloalkane) -1-carboxylic acid ester which is a reaction raw material of the present invention is a compound represented by the formula (1), for example.
本発明の製造方法では、先ず、（２−オキソ−シクロアルカン）−１−カルボン酸エステルとフェニルメタンチオールとを反応させる。この反応は、溶媒中にて行うことができる。溶媒は、（２−オキソ−シクロアルカン）−１−カルボン酸エステルとフェニルメタンチオールとを溶解でき、且つ以下に述べる酸と反応しないものであれば特に限定されない。溶媒としては、例えば、トルエン、ヘキサン、シクロヘキサン、メタノール、エタノール、酢酸エチル、ギ酸、酢酸、プロピオン酸などが挙げられる。溶媒の使用量は、（２−オキソ−シクロアルカン）−１−カルボン酸エステル１モルに対して、好ましくは５０〜１０００ｍＬ、より好ましくは１００〜３００ｍＬである。 In the production method of the present invention, first, (2-oxo-cycloalkane) -1-carboxylic acid ester is reacted with phenylmethanethiol. This reaction can be performed in a solvent. The solvent is not particularly limited as long as it can dissolve (2-oxo-cycloalkane) -1-carboxylic acid ester and phenylmethanethiol and does not react with the acid described below. Examples of the solvent include toluene, hexane, cyclohexane, methanol, ethanol, ethyl acetate, formic acid, acetic acid, propionic acid and the like. The amount of the solvent to be used is preferably 50 to 1000 mL, more preferably 100 to 300 mL, with respect to 1 mol of (2-oxo-cycloalkane) -1-carboxylic acid ester.
（２−オキソ−シクロアルカン）−１−カルボン酸エステルとフェニルメタンチオールとの反応を促進させるために酸を反応系に存在させることができる。酸としては、硫酸、有機スルホン酸、ハロゲン化水素、リン酸などが挙げられる。酸の使用量は、酸によって供給できるプロトンの量で設定する。係るプロトンの量は、（２−オキソ−シクロアルカン）−１−カルボン酸エステル１モル部に対して、好ましくは０．１〜１．０モル部、より好ましくは０．３〜０．７モル部である。 An acid can be present in the reaction system to promote the reaction between (2-oxo-cycloalkane) -1-carboxylic acid ester and phenylmethanethiol. Examples of the acid include sulfuric acid, organic sulfonic acid, hydrogen halide, and phosphoric acid. The amount of acid used is set by the amount of protons that can be supplied by the acid. The amount of such protons is preferably 0.1 to 1.0 mol, more preferably 0.3 to 0.7 mol, relative to 1 mol of (2-oxo-cycloalkane) -1-carboxylic acid ester. Part.
（２−オキソ−シクロアルカン）−１−カルボン酸エステルとフェニルメタンチオールとの反応は、通常、−５℃〜＋１５℃、好ましくは０℃〜＋１０℃で行う。
また、フェニルメタンチオールは反応系に長い時間をかけて徐々に添加する。具体的に、（２−オキソ−シクロアルカン）−１−カルボン酸エステル１モル部に対して、１〜１．５モル部のフェニルメタンチオールを、好ましくは１．０１〜１．０５モル部のフェニルメタンチオールを、通常、０．５〜１０時間、好ましくは２〜６時間かけて、添加する。このように低温度で長い時間をかけてフェニルメタンチオールを添加すると、２−（ベンジルスルファニル）−１−シクロアルケン−１−カルボン酸エステル（例えば、式（２）で表される化合物）の収率が高くなる。
The reaction between (2-oxo-cycloalkane) -1-carboxylic acid ester and phenylmethanethiol is usually performed at -5 ° C to + 15 ° C, preferably 0 ° C to + 10 ° C.
Phenylmethanethiol is gradually added to the reaction system over a long period of time. Specifically, with respect to 1 mol part of (2-oxo-cycloalkane) -1-carboxylic acid ester, 1 to 1.5 mol parts of phenylmethanethiol, preferably 1.01 to 1.05 mol parts Phenylmethanethiol is usually added over a period of 0.5 to 10 hours, preferably 2 to 6 hours. When phenylmethanethiol is added over a long period of time at such a low temperature, the yield of 2- (benzylsulfanyl) -1-cycloalkene-1-carboxylic acid ester (for example, the compound represented by the formula (2)) can be reduced. The rate is high.
フェニルメタンチオールの添加終了後、反応が完了するまで、すなわち転化率が変動しなくなるまで撹拌する。該撹拌時において、反応系の温度は、通常、−５℃〜＋１５℃、好ましくは０℃〜＋１０℃に維持する。撹拌時間は、反応規模、反応装置などによって異なるが、通常、２〜６時間である。 After completion of the addition of phenylmethanethiol, stirring is performed until the reaction is completed, that is, until the conversion does not change. During the stirring, the temperature of the reaction system is usually maintained at −5 ° C. to + 15 ° C., preferably 0 ° C. to + 10 ° C. The stirring time varies depending on the reaction scale, reaction apparatus, and the like, but is usually 2 to 6 hours.
上記反応で得られる２−（ベンジルスルファニル）−１−シクロアルケン−１−カルボン酸エステルは、次の工程で使用するために、反応液から公知の方法で単離してなる精製品にしてもよいし、反応液に含まれたままの粗製品であってもよい。 The 2- (benzylsulfanyl) -1-cycloalkene-1-carboxylic acid ester obtained by the above reaction may be a purified product isolated from the reaction solution by a known method for use in the next step. However, it may be a crude product as it is contained in the reaction solution.
次に、上記反応で得られる２−（ベンジルスルファニル）−１−シクロアルケン−１−カルボン酸エステルに過酸化水素水を作用させて酸化反応させる。
この酸化反応は、溶媒中にて行うことができる。溶媒として、例えば、トルエン、ヘキサン、シクロヘキサン、メタノール、エタノール、酢酸エチル、ギ酸、酢酸、プロピオン酸などが挙げられる。
Next, the 2- (benzylsulfanyl) -1-cycloalkene-1-carboxylic acid ester obtained by the above reaction is reacted with hydrogen peroxide to cause an oxidation reaction.
This oxidation reaction can be performed in a solvent. Examples of the solvent include toluene, hexane, cyclohexane, methanol, ethanol, ethyl acetate, formic acid, acetic acid, propionic acid and the like.
該酸化反応は、酸性の液中で行うことが好ましい。酸化反応時のｐＨは、好ましくは２〜７、より好ましくは２〜３である。ｐＨの調整は、塩酸などの酸、水酸化ナトリウムなどの塩基を用いて行う。酸化反応時の温度は、通常、５０〜８０℃、好ましくは６０〜６５℃である。 The oxidation reaction is preferably performed in an acidic liquid. The pH during the oxidation reaction is preferably 2-7, more preferably 2-3. The pH is adjusted using an acid such as hydrochloric acid or a base such as sodium hydroxide. The temperature during the oxidation reaction is usually 50 to 80 ° C, preferably 60 to 65 ° C.
過酸化水素水は反応系に長い時間をかけて徐々に添加する。具体的に、２−（ベンジルスルファニル）−１−シクロアルケン−１−カルボン酸エステル１モル部に対して、１〜３モル部の過酸化水素水を、好ましくは１．０〜１．７モル部の過酸化水素水を、通常、５〜１０時間、好ましくは５〜７時間かけて、添加する。このように長い時間をかけて過酸化水素水を添加すると、２−（ベンジルスルフィニル）−１−シクロアルケン−１−カルボン酸エステル（例えば、式（３）で表される化合物）の収率が高くなる。 Hydrogen peroxide solution is gradually added to the reaction system over a long period of time. Specifically, with respect to 1 mol part of 2- (benzylsulfanyl) -1-cycloalkene-1-carboxylic acid ester, 1 to 3 mol parts of hydrogen peroxide solution, preferably 1.0 to 1.7 mol. A part of hydrogen peroxide solution is usually added over 5 to 10 hours, preferably 5 to 7 hours. When hydrogen peroxide solution is added over such a long time, the yield of 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester (for example, a compound represented by the formula (3)) is increased. Get higher.
過酸化水素水の添加終了後、反応が完了するまで、すなわち転化率が変動しなくなるまで撹拌する。該撹拌時において、反応系の温度は、通常、５０〜８０℃、好ましくは６０〜６５℃に維持する。撹拌時間は、反応規模、反応装置などによって異なるが、通常、２〜６時間である。 After the addition of the hydrogen peroxide solution, stirring is performed until the reaction is completed, that is, until the conversion rate does not change. During the stirring, the temperature of the reaction system is usually maintained at 50 to 80 ° C, preferably 60 to 65 ° C. The stirring time varies depending on the reaction scale, reaction apparatus, and the like, but is usually 2 to 6 hours.
上記反応で得られる２−（ベンジルスルフィニル）−１−シクロアルケン−１−カルボン酸エステルは、次の工程、例えば、殺菌剤の製造工程で使用するために、反応液から公知の方法で単離してなる精製品にしてもよいし、反応液に含まれたままの粗製品であってもよい。単離方法は特に制限されない。２−（ベンジルスルフィニル）−１−シクロアルケン−１−カルボン酸エステルの単離方法として、例えば、水酸化ナトリウム水溶液を添加してｐＨを７前後に調整した後、ろ過などによって固液分離する方法が挙げられる。 The 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester obtained by the above reaction is isolated from the reaction solution by a known method for use in the next step, for example, the step of producing a bactericide. It may be a refined product or a crude product as it is contained in the reaction solution. The isolation method is not particularly limited. As a method for isolating 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester, for example, a method in which an aqueous sodium hydroxide solution is added to adjust the pH to around 7, and then solid-liquid separation is performed by filtration or the like. Is mentioned.
以下、実施例で本発明を更に詳細に説明するが、本発明はこれら実施例に限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.
実施例１ Example 1
１０００ｍＬ四口フラスコに酢酸１１５ｍＬ、濃硫酸１９．６ｇ（０．２００ｍｏｌ）、およびメチル ２−オキソ−シクロペンタンカルボキシレート１４２ｇ（１．００ｍｏｌ）を加えた。次に、７℃に冷却し、内容物を撹拌しながら、容器内にフェニルメタンチオール１２８ｇ（１．０３ｍｏｌ）を４時間かけて滴下した。滴下終了後、容器内の温度を７〜１０℃に維持しながらさらに４時間撹拌した。メチル ２−（ベンジルスルファニル）シクロペンタン−１−エン−１−カルボキシレートを含む懸濁液が得られた。
得られた懸濁液に４９％水酸化ナトリウム水溶液３３．４ｇ（０．４０９ｍｏｌ）を２０〜３０℃で加えてｐＨを２とした。その後、３５％過酸化水素水１４６ｇ（１．５０ｍｏｌ）を６０〜６５℃で５時間かけて滴下した。滴下終了後、６０〜６５℃に維持しながらさらに３時間撹拌した。
To a 1000 mL four-necked flask, 115 mL of acetic acid, 19.6 g of concentrated sulfuric acid (0.200 mol), and 142 g (1.00 mol) of methyl 2-oxo-cyclopentanecarboxylate were added. Next, the mixture was cooled to 7 ° C., and 128 g (1.03 mol) of phenylmethanethiol was dropped into the container over 4 hours while stirring the contents. After completion of dropping, the mixture was further stirred for 4 hours while maintaining the temperature in the container at 7 to 10 ° C. A suspension containing methyl 2- (benzylsulfanyl) cyclopentan-1-ene-1-carboxylate was obtained.
The obtained suspension was adjusted to pH 2 by adding 33.4 g (0.409 mol) of 49% aqueous sodium hydroxide solution at 20-30 ° C. Thereafter, 146 g (1.50 mol) of 35% aqueous hydrogen peroxide was added dropwise at 60 to 65 ° C. over 5 hours. After completion of dropping, the mixture was further stirred for 3 hours while maintaining the temperature at 60 to 65 ° C.
これに、水２５０ｍＬを加え、３０℃に冷却し、次いで４９％水酸化ナトリウム水溶液１６１ｇ（１．９７ｍｏｌ）を加えてｐＨを７にした。固形分を濾過で取り出し、水５０ｍＬで洗浄し、次いで乾燥させた。メチル ２−（ベンジルスルフィニル）シクロペンタン−１−エン−１−カルボキシレートを含む乾燥品２５９ｇ（有姿収率９８％）を得た。得られた乾燥品をＨＰＬＣ分析したところ、メチル ２−（ベンジルスルフィニル）シクロペンタン−１−エン−１−カルボキシレート、およびメチル ２−（ベンジルスルファニル）シクロペンタン−１−エン−１−カルボキシレートの面積比がそれぞれ９２．３％、および０．３％であった。 To this, 250 mL of water was added and cooled to 30 ° C., and then 161 g (1.97 mol) of 49% aqueous sodium hydroxide solution was added to adjust the pH to 7. The solid was removed by filtration, washed with 50 mL water and then dried. Obtained 259 g (solid yield 98%) of dried product containing methyl 2- (benzylsulfinyl) cyclopentan-1-ene-1-carboxylate. The obtained dried product was analyzed by HPLC. As a result, methyl 2- (benzylsulfinyl) cyclopentan-1-ene-1-carboxylate and methyl 2- (benzylsulfanyl) cyclopentane-1-ene-1-carboxylate were obtained. The area ratios were 92.3% and 0.3%, respectively.
比較例１
２００ｍＬ四口フラスコに酢酸１２ｍＬ、濃硫酸３．５０ｇ（０．０３６ｍｏｌ）、およびメチル ２−オキソ−シクロペンタンカルボキシレート１４．２ｇ（０．１０ｍｏｌ）を加えた。次に、２０〜２５℃で内容物を撹拌しながら、容器内にフェニルメタンチオール１２．４ｇ（０．１０ｍｏｌ）を５分間かけて滴下した。滴下終了後、容器内の温度を２０〜２５℃に維持しながらさらに２時間撹拌した。
得られた懸濁液に４７％水酸化ナトリウム水溶液５．９７ｇ（０．０７０ｍｏｌ）を２０〜２５℃で加えた。その後、３０％過酸化水素水１４．７ｇ（０．１３ｍｏｌ）を６０〜６５℃で５分間かけて滴下した。滴下終了後、６０〜６５℃に維持しながらさらに５時間撹拌した。
Comparative Example 1
To a 200 mL four-necked flask, 12 mL of acetic acid, 3.50 g (0.036 mol) of concentrated sulfuric acid, and 14.2 g (0.10 mol) of methyl 2-oxo-cyclopentanecarboxylate were added. Next, 12.4 g (0.10 mol) of phenylmethanethiol was dropped into the container over 5 minutes while stirring the contents at 20 to 25 ° C. After completion of the dropwise addition, the mixture was further stirred for 2 hours while maintaining the temperature in the container at 20 to 25 ° C.
To the obtained suspension, 5.97 g (0.070 mol) of a 47% aqueous sodium hydroxide solution was added at 20 to 25 ° C. Thereafter, 14.7 g (0.13 mol) of 30% hydrogen peroxide water was added dropwise at 60 to 65 ° C. over 5 minutes. After completion of dropping, the mixture was further stirred for 5 hours while maintaining the temperature at 60 to 65 ° C.
これに、水５５ｍＬを加え、２０〜２５℃に冷却し、次いで４７％水酸化ナトリウム水溶液１７．７ｇ（０．２１ｍｏｌ）を加えてｐＨを７にした。０〜５℃まで冷却し、析出した固体を濾過で取り出し、水７５ｍＬで洗浄し、乾燥させた。メチル ２−（ベンジルスルフィニル）シクロペンタン−１−エン−１−カルボキシレートを含む乾燥品２２．４ｇ（有姿収率８５％）を得た。
得られた乾燥品をＨＰＬＣ分析したところ、メチル ２−（ベンジルスルフィニル）シクロペンタン−１−エン−１−カルボキシレートの面積比が９８．５％であった。
To this, 55 mL of water was added and cooled to 20 to 25 ° C., and then 17.7 g (0.21 mol) of a 47% aqueous sodium hydroxide solution was added to adjust the pH to 7. It cooled to 0-5 degreeC, the depositing solid was taken out by filtration, washed with 75 mL of water, and dried. 22.4 g (solid yield 85%) of a dried product containing methyl 2- (benzylsulfinyl) cyclopentan-1-ene-1-carboxylate was obtained.
The obtained dried product was analyzed by HPLC. As a result, the area ratio of methyl 2- (benzylsulfinyl) cyclopentan-1-ene-1-carboxylate was 98.5%.
以上のとおり、本発明に従って、フェニルメタンチオールを低温度で長い時間をかけて添加しながら反応させ、且つ過酸化水素水を長い時間をかけて添加しながら反応させる（実施例）と、高収率で２−（ベンジルスルフィニル）−１−シクロアルケン−１−カルボン酸エステルを得ることができる。 As described above, according to the present invention, when phenylmethanethiol is reacted at a low temperature over a long period of time and reacted while hydrogen peroxide is added over a long period of time (Example), a high yield is obtained. 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester can be obtained at a high rate.
Claims (3)
次いで、２−（ベンジルスルファニル）−１−シクロアルケン−１−カルボン酸エステル１モル部に、温度５０℃〜８０℃にて過酸化水素水１〜３モル部を５〜１０時間かけて添加することを含む、
２−（ベンジルスルフィニル）−１−シクロアルケン−１−カルボン酸エステルの製造方法。 To 1 mol part of (2-oxo-cycloalkane) -1-carboxylic acid ester, 1 to 1.5 mol parts of phenylmethanethiol was added over 0.5 to 10 hours at a temperature of -5 ° C to 15 ° C. 2- (benzylsulfanyl) -1-cycloalkene-1-carboxylic acid ester,
Subsequently, 1 to 3 mole parts of hydrogen peroxide is added to 1 mole part of 2- (benzylsulfanyl) -1-cycloalkene-1-carboxylic acid ester at a temperature of 50 ° C. to 80 ° C. over 5 to 10 hours. Including that,
A method for producing 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2014148580A JP6239458B2 (en) | 2014-07-22 | 2014-07-22 | Process for producing 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2014148580A JP6239458B2 (en) | 2014-07-22 | 2014-07-22 | Process for producing 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2016023161A JP2016023161A (en) | 2016-02-08 |
| JP6239458B2 true JP6239458B2 (en) | 2017-11-29 |
Family
ID=55270252
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2014148580A Expired - Fee Related JP6239458B2 (en) | 2014-07-22 | 2014-07-22 | Process for producing 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP6239458B2 (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8921221D0 (en) * | 1989-09-20 | 1989-11-08 | Ici Plc | Compound,preparation and use |
| AU642537B2 (en) * | 1990-11-01 | 1993-10-21 | Sanofi | 2-saccharinylmethyl aryl carboxylates useful as proteolytic enzyme inhibitors and compositions and method of use thereof |
| JPH0539259A (en) * | 1991-08-02 | 1993-02-19 | Nippon Soda Co Ltd | Production of substituted benzoic acid |
| DE19924668A1 (en) * | 1999-05-28 | 2000-11-30 | Bayer Ag | Substituted alpha-phenyl-beta-ketosulfones |
-
2014
- 2014-07-22 JP JP2014148580A patent/JP6239458B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2016023161A (en) | 2016-02-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5260636B2 (en) | Process for producing pyrazole | |
| JP5559066B2 (en) | Process for producing alkyl 2-alkoxymethylene-4,4-difluoro-3-oxobutyrate | |
| EP3882236B1 (en) | Production method for 2,5-dicyano-3,6-dihalogenopyrazine | |
| EP2042497B1 (en) | Method for producing strontium ranelate and its hydrates | |
| KR101730393B1 (en) | New process for preparing pyrazole carboxylic acid derivatives | |
| JP5815507B2 (en) | Process for purification of 1-methylpyrazole-4-carboxylic acid ester | |
| JP6239458B2 (en) | Process for producing 2- (benzylsulfinyl) -1-cycloalkene-1-carboxylic acid ester | |
| RU2458050C2 (en) | Method for preparing methylulphate neostigmine and iodide neostigmine | |
| KR102221534B1 (en) | Process for the synthesis of substituted gamma lactams | |
| CN104140430B (en) | A kind of racemization method of isomer | |
| US20110098482A1 (en) | Methods of preparing 1-(4-((1r,2s,3r)-1,2,3,4-tetrahydroxybutyl)-1h-imidazol-2-yl)ethanone | |
| JP2018024643A (en) | Method for producing intermediate of biotin, and method for producing biotin | |
| JP2002155058A (en) | Method for producing 1-substituted hydratoin compound | |
| EP3609877B1 (en) | Process for the synthesis of firocoxib | |
| KR101723832B1 (en) | Process for Preparing Ethyl-4-methyl-5-thiazolecarboxyate | |
| JP2018108979A (en) | Method for producing lactone compound and method for producing biotin using the lactone compound | |
| EP3245190B1 (en) | Method for preparing 4-cyanopiperidine hydrochloride | |
| TW202302551A (en) | Method for preparing alkyl 4-oxotetrahydrofuran-2-carboxylate | |
| EP3406595B1 (en) | Method for producing 2-aminonicotinic acid benzyl ester derivative | |
| JP6425980B2 (en) | Process for producing corresponding ketone compounds from ketoxime alkali metal salts or ketoxime alkaline earth metal salts | |
| EP2857387A1 (en) | Process for manufacturing 1,6-dihydro-6-oxo-4-pyridazine carboxylic acid | |
| JP5843106B2 (en) | Process for producing 4-substituted piperidine-2-carbonitriles and process for producing 4-substituted piperidine-2-carboxylic acid mineral salts | |
| JP2015107948A (en) | Process for producing aromatic thiazole compound | |
| JP2009292726A (en) | Method for producing hydrazone compounds | |
| JP2019218333A (en) | Method for producing amidocarboxylic acid compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20170616 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20171011 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20171031 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20171101 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6239458 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |