WO2007035066A1 - Procédé de fabrication de 3-acyloxy-gamma-butyrolactone optiquement actif et de 3-hydroxy-gamma-butyrolactone optiquement actif par procédé enzymatique - Google Patents
Procédé de fabrication de 3-acyloxy-gamma-butyrolactone optiquement actif et de 3-hydroxy-gamma-butyrolactone optiquement actif par procédé enzymatique Download PDFInfo
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- WO2007035066A1 WO2007035066A1 PCT/KR2006/003799 KR2006003799W WO2007035066A1 WO 2007035066 A1 WO2007035066 A1 WO 2007035066A1 KR 2006003799 W KR2006003799 W KR 2006003799W WO 2007035066 A1 WO2007035066 A1 WO 2007035066A1
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- WO
- WIPO (PCT)
- Prior art keywords
- gamma
- butyrolactone
- acyloxy
- optically active
- racemic
- 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.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
Definitions
- the present invention relates to process for the preparation of optically active
- 3-acyloxy-gamma-butyrolactone repesented by the general formula 5 and optically active 3-hydroxy-gamma-butyrolactone represented by the general formula 6 in scheme 1 from racemic 3-acyloxy-gamma-butyrolactone by enzymatic method.
- racemic 4-chloro-3-hydroxybutyronitrile(2), racemic 3-hydroxy-gamma-butyrolactone(3), racemic 3-acyloxy-gamma-butyrolactone (4) is prepared from racemic epichlorohydrin(l) in turn, racemic
- 3-acyloxy-gamma-butyrolactone is hydrolyzed stereospecifically by lipases or lipase- producing microorganisms in aqeous phase or organic Dphase containing water for the preparation of optically active 3-hydroxy-gamma-butyrolactone and optically active 3-acyloxy-gamma-butyrolactone.
- Optically active 3-acyloxy-gamma-butyrolactone can be converted to optically active 3-hydroxy-gamma-butyrolactone by deacylation, and is used for precursor of other useful substances. According to this invention, it is possible to transform 3-acyloxy-gamma-butyrolactone with low optical purity into 3-acyloxy-gamma-butyrolactone or 3-hydroxy-gamma-butyrolactone with high optical purity.
- 3-acyloxy-gamma-butyrolactone are important intermediates. Particularly they are used in preparing pharmaceuticals such as L-carnitine, hypertension drug and hyper- lipidemia drug.
- Daicel, Ltd. produced optically active 3-hydroxy-gamma-butyrolactone(93.9%e.e) from optically active ethyl 4-chloro-3-hydroxybutyrate using microorganism, but this method is not useful for industrial use because substrate concentration is low(JP 2002-204699). And in the same way, they produced optically active 3-hydroxy-gamma-butyrolactone from racemic ethyl 4-chloro-3-hydroxybutyrate, but they obtained the compound with low optical purity.
- the present invention relates to process for the preparation of optically active
- this invention includes the process for preparing 3-hydroxy-gamma-butyrolactone from epichlorohydrin one by one, and 3-acyloxy-gamma-butyrolactone is obtained by acylation. Racemic 3-acyloxy-gamma-butyrolactone is subjected to produce optically active 3-acyloxy-gamma-butyrolactone and optically active
- lipases such as CAL B(Novozym 435,
- Racemic 3-hydroxy-gamma-butyrolactone is determined using HP-FFAP column(Agilent, Inc., 3O m X 0.53 mm). The oven temperature was maintained initially at 100 0 C for 5 min and then raised at the rate of 20 °C/min to 220 0 C, and maintained for 10 min. Helium gas was used as carrier and compounds were detected using FID at 220 0 C. In this condition the typical retention time of the compounds was as follows:
- 3-acyloxy-gamma-butyrolactone were determined by HPLC(LAB Alliance, Model 201) equipped with chiral column AD-H(Daicel, 0.46 cm X 25 cm). Hexane and isopropyl alcohol mixture(90:10) used as mobile phase and flow rate was 0.7 ml/min, and the absorbance was 220nm.
- the typical retention time of the compounds in this invention was as follows:
- Example 1 Preparing of racemic 3-acetoxy-gamma-butyrolactone [37] [38] Pyridine(1.8 g) and acetyl chloride(1.57 g) was added to 20 ml of chloroform containing racemic 3-hydroxy-gamma-butyrolactone at 0 0 C and stirred at room temperature for 2 hours. The reaction mixture was extracted with organic solvent and concentrated to afford 1.83 g of racemic 3-acetoxy-gamma-butyrolactone. And this compound was confirmed by nuclear magnetic resonance.
- Example 2 Hydrolysis of racemic 3-acetoxy-gamma-butyrolactone
- Example 3 Racemic 3-acetoxy-gamma-butyrolactone(5%(v/v)) prepared from Example 1 was added to 4.75 ml 0.2 M potassium phosphate buffer(pH 7.0) and the reaction was carried out at 30 0 C after adding lipase CAL B. The reaction mixture was extracted with ethyl acetate and (R)-3-acetoxy-gamma-butyrolactone and (S)-3-hydroxy-gamma-butyrolactone was analyzed by above-mentioned method. The results are shown in Table 1.
- Example 3 Preparation of racemic 3-butoxy-gamma-butyrolactone [47] [48] Pyridine(3.5g) and butyryl chloride(4.7 g) was added to 100 ml of chloroform containing racemic 3-hydroxy-gamma-butyrolactone at 0 0 C and stirred at room temperature. The reaction mixture was extracted with organic solvent and concentrated to afford racemic 3-butoxy-gamma-butyrolactone. And this compound was confirmed by nuclear magnetic resonance.
- racemic 3-acyloxy-gamma-butyrolactone is hydrolyzed to optically active 3-acyloxy-gamma-butyrolactone and optically active 3-hydroxy-gamma-butyrolactone, also it is easy to seperate products from reaction mixture.
- Optically active 3-acyloxy-gamma-butyrolactone produced according to this invention can be converted to optically active 3-hydroxy-gamma-butyrolactone by deacylation. Therefore, this method is an useful process on the industrial scale for making optically active 3-acyloxy-gamma-butyrolactone or optically active 3-hydroxy-gamma-butyrolactone used as pharmaceutical intermediates.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
La présente invention concerne le procédé de préparation par procédé enzymatique de 3-acyloxy-gamma-butyrolactone optiquement actif représenté par la formule générale 5 et de 3-hydroxy-gamma-butyrolactone optiquement actif représenté par la formule générale 6 dans le schéma 1 à partir de 3-acyloxy-gamma-butyrolactone racémique optiquement actif représenté par la formule générale 4. Plus précisément, la présente invention concerne le procédé de préparation de 3-acyloxy-gamma-butyrolactone optiquement actif et de 3-hydroxy-gamma-butyrolactone optiquement actif où de l’épichlorohydrine représentée par la formule générale 1 est soumise à la production de 4-chloro-3-hydroxybutyronitrile racémique, de 3-hydroxy-gamma-butyrolactone racémique et de 3-acyloxy-gamma-butyrolactone racémique à tour de rôle et où l’on hydrolyse stérospécifiquement le 3-acyloxy-gamma-butyrolactone à l’aide de lipases ou de microorganismes producteurs de lipase en phase aqueuse ou en phase organique contenant de l’eau. Ce procédé est utile dans le procédé pratique car la production et la séparation de composés avec une grande pureté optique sont plus faciles qu’avec les autres procédés ayant fait l’objet d’un rapport.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2005-0089119 | 2005-09-26 | ||
| KR20050089119 | 2005-09-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2007035066A1 true WO2007035066A1 (fr) | 2007-03-29 |
Family
ID=37889072
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2006/003799 Ceased WO2007035066A1 (fr) | 2005-09-26 | 2006-09-25 | Procédé de fabrication de 3-acyloxy-gamma-butyrolactone optiquement actif et de 3-hydroxy-gamma-butyrolactone optiquement actif par procédé enzymatique |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2007035066A1 (fr) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5084392A (en) * | 1990-02-02 | 1992-01-28 | Chisso Corporation | Process for producing optically active hydroxy lactones |
| JP2002204699A (ja) * | 2001-01-11 | 2002-07-23 | Daicel Chem Ind Ltd | β−ヒドロキシ−γ−ブチロラクトンの製造方法 |
-
2006
- 2006-09-25 WO PCT/KR2006/003799 patent/WO2007035066A1/fr not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5084392A (en) * | 1990-02-02 | 1992-01-28 | Chisso Corporation | Process for producing optically active hydroxy lactones |
| JP2002204699A (ja) * | 2001-01-11 | 2002-07-23 | Daicel Chem Ind Ltd | β−ヒドロキシ−γ−ブチロラクトンの製造方法 |
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