WO2009087676A1 - Procédé améliore d'obtention de 2, 3, 6, 3 ', 4 ' - penta- o -acétylsucrose - Google Patents

Procédé améliore d'obtention de 2, 3, 6, 3 ', 4 ' - penta- o -acétylsucrose Download PDF

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Publication number
WO2009087676A1
WO2009087676A1 PCT/IN2008/000852 IN2008000852W WO2009087676A1 WO 2009087676 A1 WO2009087676 A1 WO 2009087676A1 IN 2008000852 W IN2008000852 W IN 2008000852W WO 2009087676 A1 WO2009087676 A1 WO 2009087676A1
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WIPO (PCT)
Prior art keywords
penta
pas
acetylsucrose
reaction mixture
hours
Prior art date
Application number
PCT/IN2008/000852
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English (en)
Inventor
Keshav Deo
Ashok Prasad
Sanjiv Tomer
Kedar Kulkarni
Prashant Bodkhe
Original Assignee
Alembic Limited
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 Alembic Limited filed Critical Alembic Limited
Publication of WO2009087676A1 publication Critical patent/WO2009087676A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/02—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C07H13/06—Fatty acids

Definitions

  • the present invention relates to an improved process for the preparation of 2, 3, 6, 3', 4'- Penta-O-acetylsucrose (6-PAS) (V) from sucrose.
  • 6-PAS 2, 3, 6, 3', 4'-Penta-O-acetylsucrose
  • the structural formula of 6-PAS and Sucralose is represented by formula (V) and (I) respectively as given below.
  • Sucralose is a potent sweetener having sweetness several hundred times that of sucrose. It is chemically known as l j ⁇ -dichloro-l ⁇ -dideoxy- ⁇ -D-fructofuranosyl ⁇ -chloro ⁇ -deoxy- ⁇ - galactopyranoside and having formula is Ci 2 Hi 9 Cl 3 Og and molecular weight 397.64. Sucralose is used as sweetner in beverage, as coating tablet, chewing gum and other food products. It is marketed by McNeil under tradename Splenda ® .
  • sucrose 4,r,6'-trichloro-4,r,6'-trideoxygalactosucrose, (hereinafter referred to as "Sucralose”) involves the substitution of chlorine atoms in the sucrose molecule in one of the five secondary hydroxyl positions and in two of the three primary hydroxyl positions. This particular selection of positions usually means that any synthetic route must involve the preparation of an intermediate sucrose derivative having the required positions available for chlorination while the other positions are blocked. In particular, the reactive 6- position must not be chlorinated, while the 4-position must ' be rendered available for chlorination.
  • a process for preparing Sucralose is set forth in U.S. Pat. No.4,362, 869. This process converts sucrose through a number of steps into Sucralose. This process describes the sequential steps of (1) tritylation of sucrose to block the three primary alcohol groups; (2) acetylation of the five secondary alcohol groups as acetates; (3) detritylation of the three primary alcohol groups to deblock them; (4) acetyl migration from the 4-position to the 6- position; (5) chlorinating the desired alcohol groups at positions 4, 1', 6'; and (6) deblocking the remaining five alcohol groups by deacetylation using sodium methoxide in methanol thereby yielding Sucralose.
  • U.S. Patent No.4801700 discloses a process for preparation of Sucralose which comprise tritylation and acetylation, detritylation, acetyl migration and chlorination followed by deacetylation.
  • tritylation is done by addition of trityl chloride in 3 portion in the presence of DMF and activated poly-2-vinylpyridine.
  • Detritylation is carried out by passing HCl(g) in toluene wherein 2, 3, 4, 3', 4'-Penta-O-acetylsucrose (4-PAS) (IV) is precipitate out which is recovered by filtration.
  • Acetyl migration is done using t-butylamine in ethylacetate and heptane.
  • WO2007072496 discloses a process for preparation of Sucralose which comprise tritylation and acetylation, detritylation, acetyl migration and chlorination followed by deacetylation.
  • tritylation is done by addition of trityl chloride in 3 portion in the presence of DMF and triethyl amine.
  • Detritylation is carried out by passing HCl(g) in chloroform.
  • 4-PAS and trytinol is extracted in chloroform.
  • the chloroform is removed to give thick pasty mass which is extracted in hot water, saturated with sodium chloride and extracted with methylene chloride "3-4 times.
  • isolation of 4-PAS (IV) at pH 7 and above gives rise to deacylation of 1 position of sucrose ring. This will result in formation of impurity which is carried forward to the next step and finally to Sucralose.
  • the present inventors have directed their research work towards developing a new process which minimizes the formation unwanted impurities. They found that the addition of trityl chloride in portions minimizes the formation of unwanted impurity of tetra isomer and improves the yield and quality of 6, 1 ', 6'-Tri-O-tritylsucrose pentaacetate (TRISPA) (III). They observed that when 4-PAS is isolated at acidic pH (below 4), 4-PAS is not stable and degradation is observed and when 4-PAS is isolated at basic pH (more than 7.2), an impurity formation was observed resulting in low yield and inferior quality of 6-PAS. They found that when 4-PAS is isolated under controlled pH condition being 6 to 6.5, the generation of degradation impurity is minimized.
  • TRISPA 6, 1 ', 6'-Tri-O-tritylsucrose pentaacetate
  • a primary object of the present invention is to provide an improved process for the preparation of 6-PAS (V)
  • Another object of the present invention is to provide an improved process for the preparation of Sucralose (I). •
  • Another object of the present invention is to provide an improved process for the preparation of 6-PAS (V) with improved yield and high purity.
  • Another object of the present invention is to provide an improved process for the preparation of 6-PAS (V) in which TRISPA (III) is prepared by portion wise addition of trityl chloride which in turn resulting in improved purity and increased yield of 4-PAS (IV).
  • Another object of the present invention is to provide an improved process for the preparation of 6-PAS (V) in which isolation of 4-PAS (IV) is carried out at pH of 6.0 to 6.5 resulting in improved purity and increased yield of 4-PAS (IV).
  • Yet another object of the present invention is to provide an improved process for the preparation of 6-PAS, which is simple, easy to handle and feasible at commercial scale.
  • present invention provides a process for the preparation of 2, 3, 6, 3', 4'-Penta- O-acetylsucrose (6-PAS) (V) comprising steps of (i) Titylation and acetylation of sucrose to give 6, V, 6'-Tri-O-tritylsucrose pentaacetate
  • present invention provides a process for the preparation of Sucralose (I) comprising steps of (a) Titylation and acetylation of sucrose to give 6, 1 ', 6'-Tri-O-tritylsucrose pentaacetate (TRISPA) (III);
  • trityl chloride is added in six equal portions in approximately 3.5 hours in to a solution of sucrose wherein first four portions are added at an interval of 30 min and last two portions are added at an interval of 45 min.
  • the organic solvent used to isolate 4-PAS is selected from methylene chloride, dichloroethane, chloroform, ethylacetate or any other water immiscible solvent in which 4-PAS is extracted.
  • Table-3 Comparison of results obtained in recovery of 4-PAS at various pH levels.
  • n-Hexane 150 ml was added slowly within 30 min and stirred the mixture for 2 hr at 25°C to 3O 0 C. The reaction mixture was cooled to 8 0 C tolO°C and stirred for 30 min. The solid was filtered, washed with n-Hexane (75 ml x 2) and dried under vacuum at 40°C to 45°C for 12 hr to get solid product (53 g). Purity by HPLC: 99 % Yield: 0.35% w/w

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré d'obtention de 2, 3, 6, 3', 4'- Penta-O-acétylsucrose (6-PAS) (V) à partir de sucrose. Formule (V)
PCT/IN2008/000852 2007-12-24 2008-12-22 Procédé améliore d'obtention de 2, 3, 6, 3 ', 4 ' - penta- o -acétylsucrose WO2009087676A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2553MU2007 2007-12-24
IN2553/MUM/2007 2007-12-24

Publications (1)

Publication Number Publication Date
WO2009087676A1 true WO2009087676A1 (fr) 2009-07-16

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2008/000852 WO2009087676A1 (fr) 2007-12-24 2008-12-22 Procédé améliore d'obtention de 2, 3, 6, 3 ', 4 ' - penta- o -acétylsucrose

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5166334A (en) * 1990-12-07 1992-11-24 Hawaiian Sugar Planter's Ass. 1',2,3,3',4,4'-hexa-O-methylsucrose
WO2007096726A2 (fr) * 2006-02-20 2007-08-30 Emcure Pharmaceuticals Limited Procédé de synthèse d'un dérivé de glucose

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5166334A (en) * 1990-12-07 1992-11-24 Hawaiian Sugar Planter's Ass. 1',2,3,3',4,4'-hexa-O-methylsucrose
WO2007096726A2 (fr) * 2006-02-20 2007-08-30 Emcure Pharmaceuticals Limited Procédé de synthèse d'un dérivé de glucose

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