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EP1551796A1 - Verbesserte synthetonsynthese - Google Patents

Verbesserte synthetonsynthese

Info

Publication number
EP1551796A1
EP1551796A1 EP03754994A EP03754994A EP1551796A1 EP 1551796 A1 EP1551796 A1 EP 1551796A1 EP 03754994 A EP03754994 A EP 03754994A EP 03754994 A EP03754994 A EP 03754994A EP 1551796 A1 EP1551796 A1 EP 1551796A1
Authority
EP
European Patent Office
Prior art keywords
acylating agent
product
ethyl
reaction
reagent
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.)
Withdrawn
Application number
EP03754994A
Other languages
English (en)
French (fr)
Other versions
EP1551796A4 (de
Inventor
Taesoo Kwon
Chen Gu
Soon-Ha Yang
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.)
SK Energy and Chemical Inc
Original Assignee
SK Energy and Chemical Inc
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 SK Energy and Chemical Inc filed Critical SK Energy and Chemical Inc
Publication of EP1551796A1 publication Critical patent/EP1551796A1/de
Publication of EP1551796A4 publication Critical patent/EP1551796A4/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/16—Preparation of carboxylic acid nitriles by reaction of cyanides with lactones or compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms

Definitions

  • the present invention relates to a novel one-pot synthesis of the commercially important syntheton lower alkyl 4-cyano-3-hydroxybutyrate (ACHB) via the unisolated intermediate alkyl 4-halo-3-hydroxybutyrate which preferably can be either the 4-iodo (AIHB) or 4-bromo (ABHB) compound.
  • the ethyl esters EIHB or EBHB are utilized.
  • the synthesis is applicable to optically active or racemic product. It provides the desired end product in high yield, at high purity and is readily scaleable to commercial size runs employing reagents that do not pose environmental issues and mim ' mize undesirable side reactions.
  • the present invention relates to an improved synthesis of the commercially important syntheton ACHB starting from the readily available 3-hydroxy- ⁇ - butyrolactone.
  • the reaction employs a single pot procedure without isolation or purification of the intermediates. It has the advantage over procedures previously employed in the art of using reagents and conditions which minimize undesired side reactions and which can be readily employed at commercial scale.
  • the product is produced in high yield and is readily purified to provide an excellent intermediate for further synthesis of commercially important products such as L-carnitine and the pharmaceutically important active substances used in HMG-coA reductase inhibitor products such as Lipitor® (Atorvastatin, Pfizer).
  • the starting 3-hydroxy- ⁇ -butyrolactone is subjected to ring opening using a haliding agent.
  • This reaction proceeds faster, cleaner and in quantitative yield when conducted in the presence of an acylating agent and a lower alkanol.
  • Suitable haliding agents include reagents which provide either bromide or iodide which reagents include, for example, hydrogen bromide in solution or gaseous form, hydrogen iodide, trimethylsilyl bromide or iodide, or an alkali metal bromide or iodide such as, preferably, sodium bromide in the presence of a mineral acid such as hydrochloric acid, sulfuric acid and the like.
  • Suitable acylating agents include lower alkanoyl halides such as acetyl chloride or acetyl bromide, alkanoic anhydrides, such as acetic anhydride, lower alkyl alkanoates such as ethyl esters of lower aliphatic carboxylic acids, most preferably ethyl acetate or ethyl formate, and mixtures thereof.
  • lower alkanoyl bromide which serves both functionalities.
  • a preferred lower alkanoyl bromide is acetyl bromide. It is highly desirable to avoid the use of hydrogen bromide in the presence of acetic acid in this reaction to avoid undesirable side reactions.
  • the first step can be carried out at any convenient reaction conditions as such conditions are not narrowly critical.
  • a suitable reaction temperature can be within the range of 0° to 100°C.
  • a preferred temperature is within the range of 50-60°C.
  • the carboxylic acid produced is esterified in the presence of an alkylating agent such as a lower alkanol, most preferably ethanol, to provide the desired intermediate product AIHB or ABHB.
  • an alkylating agent such as a lower alkanol, most preferably ethanol
  • Both the acylating agent and the lower alkyl may be present in greater than equimolar amounts to the other reactants to thereby serve as solvent for the reaction.
  • the desired ring opening reaction is achieved in accordance with the procedures of the present invention so as to produce either AIHB or ABHB in quantitative crude yield and in a purity which allows this intermediate to be used directly in the next step without need for isolation and purification.
  • the crude, unisolated AIHB or ABHB product obtained in the first step is reacted with a source of cyanide ion to yield the desired product ACHB, most preferably as the ethyl ester (ECHB).
  • a suitable source of cyanide ion for this reaction step is an alkali metal cyanide, most preferably sodium or potassium cyanide.
  • the cyanation reaction is conveniently carried out using the same solvent used in the first step, that is a lower alkanol such as ethanol, which may be present in aqueous mixture (ratio 1:10 to 10:1 ethanol to water).
  • a lower alkanol such as ethanol
  • the temperature conditions employed are not narrowly critical. However, due to the exothermic reaction produced by the addition of the cyanide reagent to the AIHB or ABHB intermediate, it is desirable to initiate the reaction at a temperature of about 25 °C and to maintain a temperature at about that level or lower by cooling. After completion of the addition of the cyanide ion reagent, the reaction mixture can be heated to a temperature of about 35°C for a period of from 1 to 24 hours, most preferably for about 6 hours.
  • the pH of the reaction mixture is within a range of from 7 to 11, preferably 7.5-10.5, most preferably from 8-9.5.
  • a hydrogen halide such as hydrogen iodide or hydrogen bromide, may be added to effectuate the pH adjustment. It has been unexpectedly discovered that by conducting the reaction in this manner, side reactions known to occur when the reaction with cyanide ion is carried out under strongly basic conditions with EBHB in water or water/alcohol mixtures (ethyl 4- hydroxycrotonate formation and hydrolysis of an ester) are substantially reduced or even eliminated altogether.
  • the reaction mixture can then be worked up in a conventional manner by extraction with a suitable organic solvent or solvent mixture and concentration of the reaction solvent.
  • the final product can be purified in a batch or continuous mode by vacuum fraction distillation to provide the desired CHB in high yield and purity suitable for use in commercial scale, pharmaceutical preparations of medicinally important final products.
  • the practice of the present invention is further illustrated by the following non- limiting examples.
  • Example 2 To the solution obtained from Example 1 (starting from 20g of (S)-3- hydroxyGBL) , was added a solution of NaCN (additional mineral acid such as HBr or HC1 may be added to adjust pH to 8 ⁇ 9.5 if necessary). The solution from above was cooled to 25°C. A solution of 22.6g of NaCN in 40 ml of water was added over a period of 20 minutes. The reaction temperature was kept under 25°C during the addition. After addition, the reaction mixture was stirred at 25°C for 1 hour. The reaction was warmed to 35°C for 6 hours. The solution was cooled to 25°C and extracted with 100 ml of methylene chloride twice. After concentration, 33g of crude ethyl 4-cyano-3-hydroxybutyrate was obtained. Analyzed yield by quantitative GC averaged >80% yield of product.
  • NaCN additional mineral acid such as HBr or HC1 may be added to adjust pH to 8 ⁇ 9.5 if necessary
  • the ECHB product in R configuration, was further purified in a batch or continuous mode by vacuum fraction distillation. Recovery for distillation is > 95%. b.p. 270 °C (116°C/0.8mmHg)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Toxicology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP03754994A 2002-10-03 2003-09-30 Verbesserte synthetonsynthese Withdrawn EP1551796A4 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US41567202P 2002-10-03 2002-10-03
US415672P 2002-10-03
PCT/US2003/030869 WO2004031131A1 (en) 2002-10-03 2003-09-30 Improved syntheton synthesis

Publications (2)

Publication Number Publication Date
EP1551796A1 true EP1551796A1 (de) 2005-07-13
EP1551796A4 EP1551796A4 (de) 2007-03-14

Family

ID=32069896

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03754994A Withdrawn EP1551796A4 (de) 2002-10-03 2003-09-30 Verbesserte synthetonsynthese

Country Status (7)

Country Link
EP (1) EP1551796A4 (de)
JP (1) JP2006502201A (de)
KR (1) KR20050105164A (de)
CN (1) CN1688539A (de)
AU (1) AU2003272793A1 (de)
CA (1) CA2500668A1 (de)
WO (1) WO2004031131A1 (de)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6114566A (en) * 1999-05-24 2000-09-05 Board Of Trustees Operating Michigan State University 4-cyano-3-hydroxybutanoyl hydrazines, derivatives and process for the preparation thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of WO2004031131A1 *
WANG, GUIJUN ET AL: "Synthetic routes to L-carnitine and L-gamma-amino-beta- hydroxybutyric acid from (S)-3-hydroxybutyrolactone by functional group priority switching" TETRAHEDRON: ASYMMETRY , 10(10), 1895-1901 CODEN: TASYE3; ISSN: 0957-4166, 1999, XP002417432 *

Also Published As

Publication number Publication date
AU2003272793A1 (en) 2004-04-23
CA2500668A1 (en) 2004-04-15
CN1688539A (zh) 2005-10-26
WO2004031131A1 (en) 2004-04-15
JP2006502201A (ja) 2006-01-19
EP1551796A4 (de) 2007-03-14
KR20050105164A (ko) 2005-11-03

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