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WO2005030747A1 - Procede de synthese de 3-hydroxy-gamma-butyrolactone - Google Patents

Procede de synthese de 3-hydroxy-gamma-butyrolactone Download PDF

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Publication number
WO2005030747A1
WO2005030747A1 PCT/KR2004/002488 KR2004002488W WO2005030747A1 WO 2005030747 A1 WO2005030747 A1 WO 2005030747A1 KR 2004002488 W KR2004002488 W KR 2004002488W WO 2005030747 A1 WO2005030747 A1 WO 2005030747A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydroxy
reaction
acid
daim
sdution
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.)
Ceased
Application number
PCT/KR2004/002488
Other languages
English (en)
Inventor
Hyun-Ik Shin
Jay-Hyok Chang
Young-Min Woo
Young-Sook Kim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
LG Chem Ltd
Original Assignee
LG Life Sciences Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by LG Life Sciences Ltd filed Critical LG Life Sciences Ltd
Publication of WO2005030747A1 publication Critical patent/WO2005030747A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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

Definitions

  • the present invention relates to a process for the synthesis of 3-hydroxy- ⁇ -butyrdactone of the Mowing formula (1): [4]
  • the present invention relates to a process for preparing 3-hydroxy- ⁇ -butyrdactone in high yield by using 4-chloro-3-hydroxy-butyronitrile as starting material, which is useful as an intermediate for medicines such as L-carnitine, atorvastatin, etc. and is used for various purposes (refer to US 5,473,104).
  • method (1) is too complicated since the operation process is composed of 7 steps and the yield is also too low.
  • Method (2) has disadvantages that boran-fJmethyl su ⁇ ide is expensive and a high level of precaution is required wh ⁇ e handling it.
  • Method (3) is simple, but a large amount of trifluoroacetic acid should be used.
  • Method (4) is advantageous in that the final product is simply prepared from carbohydrate, but the separation process of the titled product and yield thereof are not dsdosed.
  • method (5) provides a convenient process using metal catalyst and hydrogen peroxide, but has a drawback that particular caution is needed in dealing with hydrogen peroxide due to excessive exotherm.
  • the purpose of the present invention is to provide a process enabling commercial mass supply and producing both enantiomers selectively in low costs.
  • the purpose of the present invention is to provide a process comprising:(l) preparing 4-chloro-3-hydroxy-butyronitrile from epichlorohydrinunder the slightly modfied condtions of a known method [J. Amer. Chem. Soc. 2002. 124.
  • the present invention relates to a process for preparing the (R)-, (S)- or racemic compound represented by the following formula (1),
  • CNECH means 4-chloro-3-hydroxy-butyronitrile
  • CL ACID means 4-chloro-3-hydroxy-butanoic acid
  • HGB means 3-hydroxy- ⁇ -butyrolactone
  • the present invention is a simple and economical process.
  • the present invention comprises: (1) the reaction of (R)-, (S)- or racemic epichbrohydrine with metal cyanide to provide (R)-, (S)- or racemic 4-chloro-3-hydroxy-butyronitrile, (2) subsequent hydrolysis by the treatment of acidc aqueous solution to give 4-chbro-3-hydroxy butanoic acid [step (a)], (3) neutralization of the resulting product by base without a particular separation process to cause lac- tonization[step (b)], and (4)the final dstiation of the residue obtained by a conventional separation process, to give high purity of 3-hydroxy- ⁇ -butyrdactone.
  • any common acids that could hydrdyze the nitrile group are desirable.
  • a typical inorganic acid such as hydrochloric acid, hydroiodc acid, sufuric acid, etc. is preferable.
  • hydrochloric acid or sulfuric acid are more preferable since they are easy to obtain at bw prices.
  • hydrochbric acid 35% or more of hydrochbric acid is preferable to increase productivity.
  • the mde ratio of acid used in the reaction 1 equivalent is sufficient theoretically, but more than 1 equivalent is proper to reduce the reaction time, and 1.3 to 3 mde equivalent to the compound of the above formula (2) is preferable.
  • the reaction temperature is within the range of room temperature to 100 °C .
  • the reaction temperature does not have to be increased, but to reduce the reaction time, the preferable reaction temperature is in the range of 50 °C to 100 °C . Therefore, the preferable reaction system is to react 1.3 to 3 mde equivalent of concentrated hydrochloric acid to 4-chbro-3-hydroxy butyronitrie at the range of 50 °C to 100 °C .
  • step (b) 3-hydroxy- ⁇ -butyrolactone is prepared by coding and neutralizing the mixture resulted from the reaction of step (a).
  • the base that can be used in the step (b) indudes NaOH, KOH, Na CO , or K CO , but preferably NaOH or KOH.
  • the base 2 3 2 3 used in the neutralization can be added in the form of solid or aqueous solution of a suitable concentration. However, a conventional 50% NaOH is preferable because a higher concentration of NaOH is advantageous to increase productivity.
  • the amount of base used in the reaction is suitable to adjust the pH range of the reaction system into 4 to 11, preferably 5 to 9, more preferably 6 to 8. In neutralizing the reaction sdution, the reaction temperature affects the qualityof the product.
  • a preferable temperature is about 30 °C or less, more preferably 10 °C to 20 °C , and most preferably 5 °C to 10 °C .
  • 3-hydroxy- ⁇ -butyrdactone can be separated from the reaction mixture by extracting with ethyl acetate, acetonitrile, isopropanol, acetone, and n-butand, respectively or with a mixture of solvent thereof.
  • the titled compound could be easily obtained by concentrating the reaction sdution under the reduced pressure, precipitating inorganic substance by suspendng the concentrated sdution in ethyl acetate, isopropand, acetone, methylethylketone, respectively, and removing the above inorganic substance by filtration.
  • step (a) if ammonium chbride precipitated by cooling the reaction solution at bw temperature is removed by filtration after completing the reaction of step (a), the amount of base required for the neutralization may be reduced more. Also, in this process, it is advantageous to filter NaCl produced by cydization reaction before concentrating under the reduced pressure.
  • Racemic-4-chbro-3-hydroxy butyronitrie (920 g, 7.7 md) was mixed with 1.28 kg of concentrated hydrochloric acid, and the reaction mixture was heated to 70 °C . Upon completing the hydrdysis reaction, the reaction solution was cooled to 0 °C , and 1.3kg of acetone was added. The precipitated ammonium chloride was fitered, and the filter cake was rewashed with 0.9 kg of acetone. To the collected filtrate was added dropwise 50% of sodum hydroxide to adjust the pH to 7.7. The precipitated NaCl was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with 2.5L of acetone, and the formed solid was fitered.
  • the fitrate was concentrated under reduced pressure to give 775 g of 3-hydroxy- ⁇ -butyrdactone.
  • the above 3-hydroxy- ⁇ -butyrdactone was dstled under the reduced pressure to give 600 g of the product as cdorless or light yelbw oi.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé de préparation de 3-hydroxy-η-butyrolactone pur, consistant à hydrolyser du 4-chloro-3-hydroxy-butyronitrile en présence d'acides et à effectuer une réaction de cyclisation dans des conditions légèrement basiques.
PCT/KR2004/002488 2003-09-29 2004-09-24 Procede de synthese de 3-hydroxy-gamma-butyrolactone Ceased WO2005030747A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020030067282A KR20050031140A (ko) 2003-09-29 2003-09-29 3-하이드록시-감마-부티로락톤의 제조방법
KR10-2003-0067282 2003-09-29

Publications (1)

Publication Number Publication Date
WO2005030747A1 true WO2005030747A1 (fr) 2005-04-07

Family

ID=34386630

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2004/002488 Ceased WO2005030747A1 (fr) 2003-09-29 2004-09-24 Procede de synthese de 3-hydroxy-gamma-butyrolactone

Country Status (2)

Country Link
KR (1) KR20050031140A (fr)
WO (1) WO2005030747A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999033817A1 (fr) * 1997-12-25 1999-07-08 Mitsubishi Rayon Co., Ltd. PROCEDE DE PRODUCTION DE DERIVES DE β-HYDROXY-η-BUTYROLACTONE ET DE DERIVES DE β-(METH)ACRYLOYLOXY-η-BUTYROLACTONE
JPH11228560A (ja) * 1998-02-09 1999-08-24 Mitsubishi Rayon Co Ltd β−ヒドロキシ−γ−ブチロラクトン類およびβ−（メタ）アクリロイルオキシ−γ−ブチロラクトン類の製造方法
JP2002241374A (ja) * 2001-02-16 2002-08-28 Sumitomo Chem Co Ltd ３−ヒドロキシ−γ−ブチロラクトンの製造法
JP2003038194A (ja) * 2001-07-26 2003-02-12 Mitsubishi Rayon Co Ltd β−ヒドロキシ−γ−ブチロラクトン類の製造方法
JP2003096068A (ja) * 2001-09-25 2003-04-03 Sumitomo Chem Co Ltd ３−ヒドロキシ−γ−ブチロラクトンの製造法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999033817A1 (fr) * 1997-12-25 1999-07-08 Mitsubishi Rayon Co., Ltd. PROCEDE DE PRODUCTION DE DERIVES DE β-HYDROXY-η-BUTYROLACTONE ET DE DERIVES DE β-(METH)ACRYLOYLOXY-η-BUTYROLACTONE
JPH11228560A (ja) * 1998-02-09 1999-08-24 Mitsubishi Rayon Co Ltd β−ヒドロキシ−γ−ブチロラクトン類およびβ−（メタ）アクリロイルオキシ−γ−ブチロラクトン類の製造方法
JP2002241374A (ja) * 2001-02-16 2002-08-28 Sumitomo Chem Co Ltd ３−ヒドロキシ−γ−ブチロラクトンの製造法
JP2003038194A (ja) * 2001-07-26 2003-02-12 Mitsubishi Rayon Co Ltd β−ヒドロキシ−γ−ブチロラクトン類の製造方法
JP2003096068A (ja) * 2001-09-25 2003-04-03 Sumitomo Chem Co Ltd ３−ヒドロキシ−γ−ブチロラクトンの製造法

Also Published As

Publication number Publication date
KR20050031140A (ko) 2005-04-06

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