JP2921051B2 - Method for producing 3-hydroxybutyl sulfide derivative - Google Patents
Method for producing 3-hydroxybutyl sulfide derivativeInfo
- Publication number
- JP2921051B2 JP2921051B2 JP2186110A JP18611090A JP2921051B2 JP 2921051 B2 JP2921051 B2 JP 2921051B2 JP 2186110 A JP2186110 A JP 2186110A JP 18611090 A JP18611090 A JP 18611090A JP 2921051 B2 JP2921051 B2 JP 2921051B2
- Authority
- JP
- Japan
- Prior art keywords
- butanediol
- derivative
- mol
- formula
- mixture
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は一般式（Ｉ） （式中Ｒはフェニル基、又は置換フェニル基を示す。）
で表される３−ヒドロキシブチルスルフィド誘導体を製
造する方法に関する。特に３位に光学活性な水酸基を持
つ３−ヒドロキシブチルスルフィド誘導体は、カルバペ
ネムまたはペネム系β−ラクタム抗生物質の鍵中間体で
ある４−アセトキシアゼチジン−２−オン誘導体の合成
原料として用いられる。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a compound represented by the general formula (I): (In the formula, R represents a phenyl group or a substituted phenyl group.)
And a method for producing a 3-hydroxybutyl sulfide derivative represented by the formula: Particularly, a 3-hydroxybutyl sulfide derivative having an optically active hydroxyl group at the 3-position is used as a raw material for synthesizing a 4-acetoxyazetidin-2-one derivative which is a key intermediate of carbapenems or penem β-lactam antibiotics.
〔従来の技術〕 1,3−ジタンジオールを出発原料とする前記一般式
（Ｉ）の合成方法としては、以下の反応式で示される方
法が知られている（特開昭61−207373）。[Prior Art] As a method for synthesizing the general formula (I) using 1,3-ditandiol as a starting material, a method represented by the following reaction formula is known (JP-A-61-207373).
（上記式中Ａはトシル基またはメシル基を示し、Ｒは前
記と同じ意義を示す。） しかしながらこの方法では、中間体としてトシレート
またはメシレートを合成するため２段階の反応となるこ
と、また、一般式（II） （式中Ｒは前記と同じ意義を示す。）で表される異性体
や一般式（III） （式中Ｒは前記と同じ意義を示す。）で表されるジ置換
体が副生する等の問題点を有していた。 (In the above formula, A represents a tosyl group or a mesyl group, and R has the same meaning as described above.) However, in this method, a two-step reaction is required to synthesize tosylate or mesylate as an intermediate. Formula (II) (Wherein R has the same meaning as described above), or an isomer represented by the general formula (III): (Wherein, R has the same meaning as described above).
本発明者等は上記従来技術の欠点を改良すべく鋭意研
究した結果、本発明を完成した。即ち、本発明は一般式
（IV）RSSR（式中、Ｒは前記と同じ意味を示す。）で表
されるジスルフィド誘導体と一般式（Ｖ）R1 3P（式中、
R1はアルキル基又はアルコキシ基を示す。）で表される
リン化合物を1,3−ブタンジオールに作用させることを
特徴とする一般式（Ｉ） （式中、Ｒは前記と同じ意味を示す。）で表される３−
ヒドロキシブチルスルフィド誘導体の製造方法である。The present inventors have intensively studied to improve the above-mentioned disadvantages of the prior art, and as a result, completed the present invention. That is, the present invention is (wherein, R. As defined above) Formula (IV) RSSR 1 3 P (where disulfide derivative of the general formula (V) R represented by,
R 1 represents an alkyl group or an alkoxy group. Wherein the phosphorus compound of formula (I) is allowed to act on 1,3-butanediol (Wherein, R has the same meaning as described above)
This is a method for producing a hydroxybutyl sulfide derivative.
反応は０℃から50℃、好ましくは室温付近で上記ジス
ルフィド誘導体と1,3−ブタンジオールの混合物あるい
は混合物に有機溶媒を加えたものに上記リン化合物を滴
下し、反応が完結するまで反応させることにより行われ
る。反応のモル比は1,3−ブタンジオール１モルに対
し、上記ジスルフィド誘導体及びリン化合物１モル以
上、好ましくは、1.1モルである。有機溶媒は混合物の
撹拌を良好にするために加える。The reaction is carried out at 0 ° C. to 50 ° C., preferably around room temperature, by dropping the phosphorus compound into a mixture of the above disulfide derivative and 1,3-butanediol or a mixture obtained by adding an organic solvent to the mixture, and reacting until the reaction is completed. It is performed by The molar ratio of the reaction is 1 mol or more, preferably 1.1 mol, of the disulfide derivative and the phosphorus compound per 1 mol of 1,3-butanediol. Organic solvents are added to improve the stirring of the mixture.
完結後、水を加え反応を停止させ、有機溶媒で抽出洗
浄後カラムクロマトグラフィーにて精製し目的の３−ヒ
ドロキシブチルスルフィド誘導体を取得することができ
る。また、３−ヒドロキシブチルスルフィド誘導体を単
離せず、その３位水酸基に保護基を導入した一般式（V
I） （式中Ｒは前記と同じ意味を示し、R2はｔ−ブチルジメ
チルシリル基を示す。）で表される３−ｔ−ブチルジメ
チルシリルオキシブチルスルフィド誘導体を製造するこ
ともできる。さらにこの一般式（VI）で表される化合物
は閉環することにより、アゼチジノン誘導体に導くこと
ができる。After completion, the reaction is stopped by adding water, and the mixture is extracted and washed with an organic solvent, and then purified by column chromatography to obtain a target 3-hydroxybutyl sulfide derivative. In addition, a 3-hydroxybutyl sulfide derivative was not isolated, but a general formula (V
I) (Wherein R has the same meaning as described above, and R 2 represents a t-butyldimethylsilyl group.) A 3-t-butyldimethylsilyloxybutylsulfide derivative represented by the following formula can also be produced. Further, the compound represented by the general formula (VI) can be converted to an azetidinone derivative by ring closure.
以下に実施例を挙げて本発明をさらに具体的に説明す
る。ただし本発明は、この実施例に限定されるものでは
ない。Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to this embodiment.
実施例−１ Ｒ−（−）−３−ヒドロキシブチルフェニルスルフィ
ド； Ｒ−（−）−1,3−ブタンジオール3.60g（0.0400mo
l）、ジフェニルジスルフィド10.52g（0.0460mol）を塩
化メチレン4mlに溶解させた後、室温に保ちながらｎ−
トリブチルフォスフィン9.32g（0.0460mol）を滴下し
た。Example-1 R-(-)-3-hydroxybutylphenyl sulfide; 3.60 g of R-(-)-1,3-butanediol (0.0400mo
l), 10.52 g (0.0460 mol) of diphenyl disulfide was dissolved in 4 ml of methylene chloride, and n-
9.32 g (0.0460 mol) of tributylphosphine was added dropwise.
室温で５時間撹拌した後、水を水20ml加え10分撹拌
し、さらに水50mlを加えてから塩化メチレン15mlで３回
抽出した。塩化メチレン溶液を飽和炭酸ナトリウム水溶
液で洗浄後、塩化メチレンを留去しシリカゲルカラムク
ロマトグラフィーにて分取し、標題化合物を90％の収率
で得た。After stirring at room temperature for 5 hours, water (20 ml) was added, and the mixture was stirred for 10 minutes. After adding water (50 ml), the mixture was extracted three times with methylene chloride (15 ml). After washing the methylene chloride solution with a saturated aqueous solution of sodium carbonate, the methylene chloride was distilled off and the residue was separated by silica gel column chromatography to obtain the title compound in a yield of 90%.
性状 無色油状物質 沸点 115℃/0.05mmHg Ｈ−NMRスペウトル＜CDCl3δ＞1.18（3H d J＝6Hz）1.5
3−1.95（2H m）2.06（1H s）3.00（2H t J＝7Hz）3.85
（1H m）7.12（5H brs） 比較例−１ Ｒ−（−）−３−ヒドロキシブチルフェニルスルフィ
ド； Ｒ−（−）−1,3−ブタンジオール3.60g（0.0400mo
l）、ｐ−トルエンスルホニルクロリド8.39g（0.0440mo
l）、ピリジン3.48g（0.0440mol）を塩化メチレン40ml
に溶解し、室温で15時間撹拌した。反応液を水で希釈し
塩化メチレンで抽出し、抽出液を水洗後、溶媒を留去し
シリカゲルカラムクロマトグラフィーで分取した。目的
のＲ−（−）−３−ヒドロキシブチル−ｐ−トルエンス
ルホネートを65％の収率、その異性体であるＲ−（−）
−２−ｐ−トルエンスルホニルオキシ−１−ブタノール
を６％の収率、di−トシル体であるＲ−（−）−1,3−d
i−（ｐ−トルエンスルホニルオキシ）ブタンを12％の
収率で得た。Properties Colorless oil Boiling point 115 ° C / 0.05mmHg H-NMR spectrum <CDCl 3 δ> 1.18 (3H d J = 6Hz) 1.5
3-1.95 (2H m) 2.06 (1H s) 3.00 (2H t J = 7Hz) 3.85
(1Hm) 7.12 (5Hbrs) Comparative Example-1 R-(-)-3-hydroxybutylphenyl sulfide; 3.60 g of R-(-)-1,3-butanediol (0.0400mo
l), 8.39 g of p-toluenesulfonyl chloride (0.0440mo
l), 3.48 g (0.0440 mol) of pyridine in 40 ml of methylene chloride
And stirred at room temperature for 15 hours. The reaction mixture was diluted with water and extracted with methylene chloride. The extract was washed with water, the solvent was distilled off, and the residue was separated by silica gel column chromatography. The desired R-(-)-3-hydroxybutyl-p-toluenesulfonate was obtained in a yield of 65%, and its isomer, R-(-).
-2-p-Toluenesulfonyloxy-1-butanol was converted to a di-tosyl form of R-(-)-1,3-d in 6% yield.
i- (p-Toluenesulfonyloxy) butane was obtained in a yield of 12%.
テトラヒドロフラン40mlに上記Ｒ−（−）−３−ヒド
ロキシブチル−ｐ−トルエンスルホネート2.00g（0.008
19mol）、ソジウムチオフェノキシド1.30g（0.00982mo
l）を加え１時間加熱還流した。冷却後、反応液に水を
加え塩化メチレンで抽出し、抽出液を水洗後、溶媒に留
去しシリカゲルカラムクロマトグラフィーで分取した。
1,3−ブタンジオールに対し標題化合物を64％の収率で
得た。R-(-)-3-hydroxybutyl-p-toluenesulfonate (2.00 g, 0.008) was added to tetrahydrofuran (40 ml).
19 mol), 1.30 g of sodium thiophenoxide (0.00982mo)
l) was added and the mixture was heated under reflux for 1 hour. After cooling, water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was washed with water, distilled off in a solvent, and separated by silica gel column chromatography.
The title compound was obtained in a yield of 64% based on 1,3-butanediol.
物性値は実施例−１に示した値に一致した。 The physical properties matched the values shown in Example-1.
実施例−２ Ｒ−（−）−３−ｔ−ブチルジメチルシリルオキシブチ
ルフェニルスルフィド； Ｒ−（−）−1,3−ブタンジオール3.60g（0.0400mo
l）、ジフェニルジスルフィド10.52g（0.0460mol）をテ
トラヒドロフラン4mlに溶解させた後、室温に保ちなが
らｎ−トリブチルフォスフィン9.32g（0.0460mol）を滴
下した。室温で５時間撹拌した後、水を10ml加え10分撹
拌し、飽和炭酸ナトリウム水溶液で洗浄後、水層を分離
し、N,N−ジメチルホルムアミド6mlを加え硫酸マグネシ
ウムで乾燥した。Example-2 R-(-)-3-t-butyldimethylsilyloxybutylphenylphenyl sulfide; 3.60 g of R-(-)-1,3-butanediol (0.0400mo
l), 10.52 g (0.0460 mol) of diphenyl disulfide was dissolved in 4 ml of tetrahydrofuran, and 9.32 g (0.0460 mol) of n-tributylphosphine was added dropwise at room temperature. After stirring at room temperature for 5 hours, 10 ml of water was added and the mixture was stirred for 10 minutes. After washing with a saturated sodium carbonate aqueous solution, the aqueous layer was separated, 6 ml of N, N-dimethylformamide was added, and the mixture was dried over magnesium sulfate.
上記N,N−ジメチルホルムアミド溶液にｔ−ブチルジ
メチルシリルクロライド6.54g（0.0434mol）、イミダゾ
ール2.96g0.043mol）を加え50℃で４時間撹拌した。反
応液にｎ−ヘキサン30ml、水30mlを加え水洗後、水層を
分離し、溶媒を留去後シリカゲルカラムクロマトグラフ
ィーにて分取し標題化合物をブタンジオールより90％の
収率で得た。6.54 g (0.0434 mol) of t-butyldimethylsilyl chloride and 2.96 g of imidazole (0.043 mol) were added to the above N, N-dimethylformamide solution, followed by stirring at 50 ° C. for 4 hours. After adding 30 ml of n-hexane and 30 ml of water to the reaction solution and washing with water, the aqueous layer was separated, the solvent was distilled off, and the residue was separated by silica gel column chromatography to obtain the title compound in a 90% yield from butanediol.
性状 無色油状物質 沸点 135℃/0.2mmHg Ｈ−NMRスペクトル＜CDCL3δ＞0.06（6H s）0.89（9H
s）1.14（3H d J＝6Hz）1.53−1.95（2H m）2.81−3.14
（2H m）3.90（1H m）7.22（5H brs） 実施例−３ （１′R,3S,4R）−３−（１′−ｔ−ブチルジメチルシ
リルオキシ）エチル−４−フェニルチオ−２−アゼチジ
ノン； Ｒ−（−）−1,3−ブタンジオール7.21g（0.0800mo
l）、ジフェニルジスルフィド21.04g（0.092mol）をテ
トラヒドロフラン8mlに溶解させた後、室温に保ちなが
らｎ−トリブチルフォスフィン18.64g（0.092mol）を滴
下した。室温で５時間撹拌した後、水を20ml加え10分撹
拌し、メタノール40mlを加え均一溶液とした。次にこの
溶液をｎ−ヘキサンで洗浄した後、溶液が２層になるま
で溶媒を留去し、水層を除去した。有機層を飽和炭酸ナ
トリウム水溶液で洗浄後、N,N−ジメチルホルムアミド1
2mlを加え硫酸マグネシウムで乾燥した。Properties colorless oil boiling point 135 ℃ / 0.2mmHg H-NMR spectrum <CDCL 3 δ> 0.06 (6H s) 0.89 (9H
s) 1.14 (3H d J = 6 Hz) 1.53-1.95 (2H m) 2.81-3.14
(2Hm) 3.90 (1Hm) 7.22 (5Hbrs) Example-3 (1'R, 3S, 4R) -3- (1'-t-butyldimethylsilyloxy) ethyl-4-phenylthio-2-azetidinone ; 7.21 g of R-(-)-1,3-butanediol (0.0800mo
l), 21.04 g (0.092 mol) of diphenyl disulfide was dissolved in 8 ml of tetrahydrofuran, and 18.64 g (0.092 mol) of n-tributylphosphine was added dropwise at room temperature. After stirring at room temperature for 5 hours, 20 ml of water was added and the mixture was stirred for 10 minutes, and 40 ml of methanol was added to make a homogeneous solution. Next, after this solution was washed with n-hexane, the solvent was distilled off until the solution became two layers, and the aqueous layer was removed. After washing the organic layer with a saturated aqueous solution of sodium carbonate, N, N-dimethylformamide 1
2 ml was added and dried over magnesium sulfate.
上記N,N−ジメチルホルムアミド溶液にｔ−ブチルジ
メチルシリルクロライド13.08g（0.0868mol）、ジメチ
ルアミノピリジン10.6g（0.0868mol）を加え50℃で４時
間撹拌した。反応液にｎ−ヘキサン60ml、水60mlを加え
水洗後、溶媒を留去し、Ｒ−（−）−３−ｔ−ブチルジ
メチルシリルオキシブチルフェニルスルフィドを純度74
％（HPLCで定量）で28.85g、ブタンジオールより90％の
収率で得た。13.08 g (0.0868 mol) of t-butyldimethylsilyl chloride and 10.6 g (0.0868 mol) of dimethylaminopyridine were added to the N, N-dimethylformamide solution, and the mixture was stirred at 50 ° C. for 4 hours. 60 ml of n-hexane and 60 ml of water were added to the reaction solution, washed with water, and the solvent was distilled off.
% (Quantitated by HPLC) in a yield of 28.85 g, 90% from butanediol.
上記Ｒ−（−）−３−ｔ−ブチルジメチルシリルオキ
シブチルフェニルスルフィドを特開昭61−207373記載の
方法に従って反応し、標題化合物をＲ−（−）−３−ｔ
−ブチルジメチルシリルオキシブチルフェニルスルフィ
ドより55％の収率で得た。The above-mentioned R-(-)-3-t-butyldimethylsilyloxybutylphenyl sulfide is reacted according to the method described in JP-A-61-207373, and the title compound is converted to R-(-)-3-t
Obtained from -butyldimethylsilyloxybutylphenyl sulfide in a yield of 55%.
性状 白色針状晶 融点 124−125℃ （α）Ｄ＝＋64.3（Ｃ＝0.12 クロロホルム） IRスペクトル＜KBr,cm-＞1764 Ｈ−NMRスペクトル＜CDCL3δ＞0.05（3H s）0.07（3H
s）0.87（9H s）1.20（3H d J＝6.1Hz）4.24（1H m）5.
39（1H d J＝2.4Hz）5.98（1H brs）7.30−7.60（5H
m） 〔発明の効果〕 本発明により、医薬品中間体として有用なアゼチジノ
ン誘導体の原料となるＲ−（−）−３−ヒドロキシブチ
ルフェニルスルフィドをＲ−（−）−1,3−ブタンジオ
ールより、異性体の副生を抑え高収率で製造することが
できる。State: White needles, mp 124-125 ℃ (α) D = + 64.3 (C = 0.12 chloroform) IR spectrum <KBr, cm -> 1764 H -NMR spectrum <CDCL 3 δ> 0.05 (3H s) 0.07 (3H
s) 0.87 (9H s) 1.20 (3H d J = 6.1Hz) 4.24 (1H m) 5.
39 (1H d J = 2.4Hz) 5.98 (1H brs) 7.30-7.60 (5H
m) [Effect of the Invention] According to the present invention, R-(-)-3-hydroxybutylphenyl sulfide, which is a raw material of an azetidinone derivative useful as a pharmaceutical intermediate, is converted from R-(-)-1,3-butanediol by By-products of the isomer can be suppressed and can be produced in high yield.
───────────────────────────────────────────────────── フロントページの続き (58)調査した分野(Int.Cl.6，ＤＢ名) C07C 323/00 C07C 319/00 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. 6 , DB name) C07C 323/00 C07C 319/00 CA (STN) REGISTRY (STN)
Claims (2)
で表されるジスルフィド誘導体と一般式 R1 3P （式中R1はアルキル基、又はアルコキシ基を示す。）で
表されるリン化合物を1,3−ブタンジオールに作用させ
ることを特徴とする一般式 （式中Ｒはフェニル基、又は置換フェニル基を示す。）
で表される３−ヒドロキシブチルスルフィド誘導体の製
造方法。1. The general formula RSSR (wherein R represents a phenyl group or a substituted phenyl group)
In disulfide derivative with the general formula R 1 3 P represented, characterized in that the action (wherein R 1 is an alkyl group, or an alkoxy group.) The phosphorus compound represented by the 1,3-butanediol General formula (In the formula, R represents a phenyl group or a substituted phenyl group.)
A method for producing a 3-hydroxybutyl sulfide derivative represented by the formula:
ブチルスルフィド誘導体が光学活性体である請求項１記
載の製造方法。2. The method according to claim 1, wherein the 1,3-butanediol and the 3-hydroxybutyl sulfide derivative are optically active substances.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2186110A JP2921051B2 (en) | 1990-07-13 | 1990-07-13 | Method for producing 3-hydroxybutyl sulfide derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2186110A JP2921051B2 (en) | 1990-07-13 | 1990-07-13 | Method for producing 3-hydroxybutyl sulfide derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0474161A JPH0474161A (en) | 1992-03-09 |
| JP2921051B2 true JP2921051B2 (en) | 1999-07-19 |
Family
ID=16182537
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2186110A Expired - Fee Related JP2921051B2 (en) | 1990-07-13 | 1990-07-13 | Method for producing 3-hydroxybutyl sulfide derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2921051B2 (en) |
-
1990
- 1990-07-13 JP JP2186110A patent/JP2921051B2/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| Ｃｈｅｍ．Ｌｅｔｔ．（１１），２２２７−２２２８（１９８７） |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0474161A (en) | 1992-03-09 |
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