WO2005030747A1 - A process for the synthesis of 3-hydroxy-gamma-butyrolactone - Google Patents
A process for the synthesis of 3-hydroxy-gamma-butyrolactone Download PDFInfo
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- 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
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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
-
- 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.
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- 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
The present invention relates to a process for preparing pure 3-hydroxy-Ϝ-butyrolactone by hydrolyzing 4-chloro-3-hydroxy-butyronitrile in the presence of acids and conducting cyclization reaction under slightly basic condition.
Description
Description A PROCESS FOR THE SYNTHESIS OF 3-HYDROXY-GAMMA-BUTYROLACTONE
[1] TECHNICAL FIELD
[2]
[3] The present invention relates to a process for the synthesis of 3-hydroxy-γ-butyrdactone of the Mowing formula (1): [4]
[5]
[6] which is racemic or optically active form. Specifically, the present invention relates to a process for preparing 3-hydroxy-γ-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).
[7] BACKGROUND ART
[8]
[9] In the literature , the following methods for the preparation of 3-hydroxy- γ - butyrclactone have been known: (1) a synthetic method comprising 7 steps starting from isoascorbic acid or ascorbic acid as starting material (Synthesis, 1987, 570-573), (2) a method reducing diethyl malic acid esters with boran-dimethyl suFide and cydizing the resulted hydroxy esters in the presence of an acid (Chemistry Letters, 1984, 1389-1392), (3) a method cydiang 4- t-butyloxy-3-hydroxy butanoic acid esters in the presence of an acid (Synthesis, 1986, (1), 37-40), (4) a method preparing 3,4-dLhydroxy butanoic acid derivatives from carbohydrate and cydizing the same (US 6,329,311), and (5) a method oxidizing 3,4-unsaturated butanoic acid derivatives in the presence of metal catalyst and subsequent cydization of the intermedate (EP 1 302 469).
[10] However, in the above methods, 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 suϊide is expensive and a high level of precaution is required whϊe 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. Qi the other hand, 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.
[11]
[12] Furthermore, as for methods known in the prior art using natural starting materials such as carbohydrates or an organic acid, only one enantiomer is accessible and so it is dfficult to obtain unnatural enantiomer. Also, evenin the case thatunnatural enantiomer may be available, the cost is usually more expensive than that of the natural one.
[13] DISCLOSURE OF THE INVENTION
[14]
[15] Having the above background of the reported arts, the present inventors investigated an efficient synthesis of 3-hydroxy-γ-butyrolactone which is simple, economical, and suitable for commercial mass production. Thus, the purpose of the present invention is to provide a process enabling commercial mass supply and producing both enantiomers selectively in low costs. Specifically, 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. 1307], (2) treating 4-chloro-3-hydroxy-butyronitrile with an acidc aqueous solution to provide crude 3-hydroxy-γ-butyrdactone in a straightforward manner, and (3) conducting drect purification of the reaction mixture to give 3-hydroxy-γ-butyrolactone in high purity and yield.
[16] BEST MODE FOR CARRYING OUT THE INVENTION
[17]
[18] The present invention relates to a process for preparing the (R)-, (S)- or racemic compound represented by the following formula (1),
[19]
[20] [21] characterized in comprising the steps of, [22] [23] (a) hydrolyzing nitrile group of the (R)-, (S)- or racemic compound of the following formula (2)
[24]
[25] [26] by heating the above compound in acidcaqueous sdution to give the compound of the following formula (3)
[27] OH CL 1 COOH ^ >/ (3)
[28] [29] which maintains stereochemical integrity of the asymmetric carbon atom, and [30] [31] (b) neutralizing the above reaction sdution with base. [32] [33] The above reaction can be described by the foDowing reaction scheme (1), [34]
[35] [36] in which,
[37] CNECH means 4-chloro-3-hydroxy-butyronitrile, CL ACID means 4-chloro-3-hydroxy-butanoic acid, and HGB means 3-hydroxy-γ-butyrolactone.
[38]
[39] Hereinafter, the present invention will be described in detail.
[40]
[41] Compared with the precedents, 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-γ-butyrdactone.
[42]
[43] In the above process, for the step (a), any common acids that could hydrdyze the nitrile group are desirable. Among them,a typical inorganic acid such as hydrochloric acid, hydroiodc acid, sufuric acid, etc. is preferable. Among the above acids, hydrochloric acid or sulfuric acid are more preferable since they are easy to obtain at bw prices. When hydrochbric acid is used, 35% or more of hydrochbric acid is preferable to increase productivity. Cn the other hand, as for 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 . As the amount of acid used in the reaction is increased, 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 .
[44]
[45] In the step (b), 3-hydroxy-γ-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. When the neutralization temperature is high, furan-2-(5H)-one is produced, and thus it is preferable to maintain the reaction temperature as bw as possible. A preferable temperature is about 30 °C or less, more preferably 10 °C to 20 °C , and most preferably 5 °C to 10 °C .
[46]
[47] In the present invention, 3-hydroxy- γ -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. Or, 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. In the above process, 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.
[48]
[49] Hereinafter, the present invention wl be more specifically illustrated by the following examples. However, the folbwing examples should not be construed as limiting the scope of the present invention in any way.
[50]
[51] Example 1: Preparation of (S)-3-hydroxy-γ-butyrdactone
[52]
[53] (S)-4-chbro-3-hydroxy butyronitrie (10 g, 83.6 mmd) was mixed with 16.7 mL of concentrated hydrochbric acid, and the resulting reaction sdution was heated to 60 °C . Upon completing the hydrolysis reaction, the reaction sdution was coded in iced bath, and 50% of sodum hydroxide was added dropwise to the reaction sdution to adjust pH 7.5. The reaction mixture was extracted with 25mL of acetonitrile 5 times, and the organic layer was concentrated under reduced pressure to obtain 6.4 g of (S)-3-hydroxy-γ-butyrolactone.
[54] YieM: 88.8%
[55] Optical purity (GC): 100%ee
[57] Example 2: Preparation of (S)-3-hydroxy-γ-butyrdactone
[58]
[59] (S)-4-chbro-3-hydroxy butyronitrie (800 g, 6.69mol) was mixed with 0.9 kg of concentrated hydrochloric acid, and the reaction sdution was heated to 70 °C . Upon completing the hydrolysis reaction, the reaction sdution was coded to 10 °C , and 50% of sodum hydroxide was added dropwise to the reaction sdution to adjust the pH to 7.7. The reaction mixture was extracted with 2.5 L of n-butand twice. The organic layer was concentrated under reduced pressure, diluted with 0.5 L of ethyl acetate, and the formed solid was filtered. The filtrate was concentrated to provide 545 g of (S)-3-hydroxy-γ-butyrolactone.
[60] YieM: 80.0%
[61] Optical purity (GC): 100%ee
[62]
[63] Example 3: Rcemic-3-hydroxy-γ-butyrdactone
[64]
[65] 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-γ-butyrdactone. The above 3-hydroxy-γ-butyrdactone was dstled under the reduced pressure to give 600 g of the product as cdorless or light yelbw oi.
[66] YieM: 83.0%
[67] INDUSTRIAL APPLICABILITY
[68]
[69] Accordng to the present invention, a high purity of 3-hydroxy- γ -butyrolactone is prepared economically and simply.Hydrolysis of 4-chloro-3-hydroxy butyronitrie in the acid condtions and subsequent neutralization provided 3-hydroxy- γ - butyrdactone in high purity and yield. When an optically active form of
4-chloro-3-hydroxy butyronitrie is used, the complete retention of the optical integrity was observed.
Claims
Claims
[1] A process for preparing (R)-, (S)- or racemic compound represented by the folowing formula (1),
[6] (b) neutralizing the above reaction sdution with base.
[7] 2. The process accordng to daim 1, wherein acidc aqueous sdution is hydrochloric acid, hydroiodc acid, or suϊuric acid.
[8] 3. The process accordng to daim 2, wherein the concentration of hydrochbric acid is more than 35%, and the mde ratio of hydrochloric acid is 1.3 to 3 mole equivalent to the compound of formula (2)
[9] 4. The process accordng to daim 1, wherein the base is NaOH, KOH, Na CO , 2 3 or K CO . 2 3
[10] 5. The process accordng to daim 4, wherein the concentration of NaOH is more than 50%, and the amount of base is used to adjust the pH range of the reaction system into 6 to 8. [11] 6. The process accordng to daim 1, wherein the hydrdysis reaction temperature of step (a) is 50°C to 100°C, and the neutralization reaction temperature of step (b) is 5°C to 10°C. [12] 7. The process accordng to daim 1, further indudng a step of fitering and removing ammonium chbride precipitated by cooling the reaction sdution after
the step (a).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2003-0067282 | 2003-09-29 | ||
| KR1020030067282A KR20050031140A (en) | 2003-09-29 | 2003-09-29 | A process for the synthesis of 3-hydroxy-γ-butyrolactone |
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| Publication Number | Publication Date |
|---|---|
| WO2005030747A1 true WO2005030747A1 (en) | 2005-04-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2004/002488 Ceased WO2005030747A1 (en) | 2003-09-29 | 2004-09-24 | A process for the synthesis of 3-hydroxy-gamma-butyrolactone |
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| Country | Link |
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| KR (1) | KR20050031140A (en) |
| WO (1) | WO2005030747A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999033817A1 (en) * | 1997-12-25 | 1999-07-08 | Mitsubishi Rayon Co., Ltd. | PROCESS FOR PRODUCING β-HYDROXY-η-BUTYROLACTONE DERIVATIVES AND β-(METH)ACRYLOYLOXY-η-BUTYROLACTONE DERIVATIVES |
| JPH11228560A (en) * | 1998-02-09 | 1999-08-24 | Mitsubishi Rayon Co Ltd | Process for producing β-hydroxy-γ-butyrolactone and β- (meth) acryloyloxy-γ-butyrolactone |
| JP2002241374A (en) * | 2001-02-16 | 2002-08-28 | Sumitomo Chem Co Ltd | Method for producing 3-hydroxy-γ-butyrolactone |
| JP2003038194A (en) * | 2001-07-26 | 2003-02-12 | Mitsubishi Rayon Co Ltd | Method for producing β-hydroxy-γ-butyrolactone |
| JP2003096068A (en) * | 2001-09-25 | 2003-04-03 | Sumitomo Chem Co Ltd | Method for producing 3-hydroxy-γ-butyrolactone |
-
2003
- 2003-09-29 KR KR1020030067282A patent/KR20050031140A/en not_active Withdrawn
-
2004
- 2004-09-24 WO PCT/KR2004/002488 patent/WO2005030747A1/en not_active Ceased
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999033817A1 (en) * | 1997-12-25 | 1999-07-08 | Mitsubishi Rayon Co., Ltd. | PROCESS FOR PRODUCING β-HYDROXY-η-BUTYROLACTONE DERIVATIVES AND β-(METH)ACRYLOYLOXY-η-BUTYROLACTONE DERIVATIVES |
| JPH11228560A (en) * | 1998-02-09 | 1999-08-24 | Mitsubishi Rayon Co Ltd | Process for producing β-hydroxy-γ-butyrolactone and β- (meth) acryloyloxy-γ-butyrolactone |
| JP2002241374A (en) * | 2001-02-16 | 2002-08-28 | Sumitomo Chem Co Ltd | Method for producing 3-hydroxy-γ-butyrolactone |
| JP2003038194A (en) * | 2001-07-26 | 2003-02-12 | Mitsubishi Rayon Co Ltd | Method for producing β-hydroxy-γ-butyrolactone |
| JP2003096068A (en) * | 2001-09-25 | 2003-04-03 | Sumitomo Chem Co Ltd | Method for producing 3-hydroxy-γ-butyrolactone |
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| Publication number | Publication date |
|---|---|
| KR20050031140A (en) | 2005-04-06 |
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