[go: up one dir, main page]

WO2002065853A2 - Modification d'un catalyseur pour ameliorer la production de neotame - Google Patents

Modification d'un catalyseur pour ameliorer la production de neotame Download PDF

Info

Publication number
WO2002065853A2
WO2002065853A2 PCT/US2001/046956 US0146956W WO02065853A2 WO 2002065853 A2 WO2002065853 A2 WO 2002065853A2 US 0146956 W US0146956 W US 0146956W WO 02065853 A2 WO02065853 A2 WO 02065853A2
Authority
WO
WIPO (PCT)
Prior art keywords
catalyst
modified
neotame
group
hydrogenation
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/US2001/046956
Other languages
English (en)
Other versions
WO2002065853A3 (fr
Inventor
Mike G. Scaros
Indra Prakash
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.)
Nutrasweet Co
Original Assignee
Nutrasweet Co
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 Nutrasweet Co filed Critical Nutrasweet Co
Priority to AU2001297682A priority Critical patent/AU2001297682A1/en
Priority to EP01273796A priority patent/EP1349829A4/fr
Publication of WO2002065853A2 publication Critical patent/WO2002065853A2/fr
Anticipated expiration legal-status Critical
Publication of WO2002065853A3 publication Critical patent/WO2002065853A3/fr
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • C07K5/06121—Asp- or Asn-amino acid the second amino acid being aromatic or cycloaliphatic
    • C07K5/0613—Aspartame

Definitions

  • This invention relates to the field of the production of neotame. More particularly, it relates to the field of processes for producing neotame using a catalyst in the reductive alkylation of aspartame with 3,3- dimethylbutyraldehyde to produce neotame.
  • the sweetener N-[N-(3,3-dimethylbutyl)-L- ⁇ -aspartyl]-L-phenylalanine 1- methyl ester ("neotame") is a highly intense non-nutritive sweetening agent useful to impart sweetness to a wide variety of food, beverage, and other products.
  • This sweetener was disclosed in U.S. Patent No. 5,480,668.
  • the sweetener is approximately 8,000 times as sweet as sucrose, with variance depending on level of use and specific product to which it is added.
  • Catalysts are relatively expensive per pound, so low levels of use and successful recycling processes are two important means to reduce costs. Further, proper selection of catalyst can affect the overall purity and yield of the desired product.
  • the present invention details means for providing such an effective catalyst.
  • the present invention is directed to the selection of catalysts in a process for manufacturing neotame.
  • a catalyst is initially selected from the group of catalysts conventionally used in hydrogenation processes.
  • the catalyst is then altered by one of the following methods: 1) multiple re-use in the reductive alkylation produces a catalyst which is more selective and results in a decrease of certain impurities.
  • the catalyst on recycle agglomerated at the surface resulting in lower dispersion of palladium; 2) preparing the initial catalyst with same characteristics as found in the re-cycle catalyst (as described in case 1); 3) addition of catalyst modifiers in the preparation of catalyst or addition of the catalyst modifier in the reductive alkylation process; or 4) co-precipitated bi-metallic catalyst in the reductive alkylation process.
  • Advantages of these catalyst will be in higher purity and yield of neotame which will provide significant opportunities for cost reduction.
  • a modified catalyst is used in the reductive alkylation process to make neotame using aspartame and 3,3- dimethylbutyraldehyde.
  • This catalyst is preferably a modified palladium on activated carbon catalyst.
  • the use of the modified catalyst has been shown to reduce the level of dialkylated aspartame, one of the impurities resulting from conventional processes for manufacturing neotame.
  • the modified catalyst can be produced by recycling catalyst resulting in the agglomeration of the catalyst. It can also be produced directly in the catalyst manufacturing process. Any catalyst conventionally used in hydrogenation reactions is suitable for use and modification hereunder.
  • a catalyst is used in the reductive alkylation step of aspartame with 3,3-dimethylbutyraldehyde.
  • This reductive alkylation step is conventionally carried out in the presence of methanol or aqueous methanol, and under pressure conditions between 5 psig and 100 psig hydrogen and temperature conditions between 25-60°C.
  • the catalysts used include, but are not limited to palladium (in a preferred form of a 5% palladium on a carbon support), platinum, rhodium, ruthenium, and nickel.
  • the resulting product, neotame, is isolated, and conventionally, the catalyst is recovered and recycled.
  • impurities there are small amounts of impurities which are produced during the above process.
  • One of these impurities is dialkylated aspartame [ N,N-di (3,3- dimethylbutyl)-L- ⁇ -aspartyl-L-phenylalanine 1 -methyl ester]. This impurity has been found to be produced in amounts between 1.25-2.50% in conventional neotame coupling processes using fresh palladium catalyst.
  • Initially modified catalysts as found in the recycle catalyst, also have been found to improve the overall yield of the process and reduce the level of impurities.
  • Another form of modification is the addition of catalyst modifiers to a catalyst such as 5% palladium on a carbon or other conventional support.
  • the modifiers are preferably selected from the group including, but not limited to, carbon dioxide, quinoline, morpholines, piperizine, pyridine, triphenylphosphine, phosphorous acid, thiocyanates, cyanamid, ethylenediamine, amidines, thiourea, ethyl di-isopropylamine, zinc, lead, silver, copper, mercury, tin, vanadium and other metallic salts, sodium hydroxide, ferrous sulfate or other salts, cadmium sulfate or other salts, and lithium trioxide.
  • the supports are selected from the group comprising carbon, aluminum, silicate, clay, calcium, strontium carbonate, barium sulfate or molecular sieve support.
  • the palladium catalyst is modified as follows: The catalyst is mixed with the desired modifier either in the preparation of catalyst or addition of the catalyst modifier in the reductive alkylation process.
  • the amount of modifier to be added is selected from ppm-5% level.
  • the resulting modified catalyst is used in the neotame manufacturing process in the same manner as conventional catalyst, and under the same operating conditions.
  • the catalyst is more selective in forming neotame as opposed to other impurities, therefore, product can be crystallized at higher concentrations, thereby resulting in increased neotame yield.
  • the preferred bimetallic metal catalyst is a hydrogenation catalyst combined via co-precipitation with a metal from the Group VIII-IIB periodic chart of the elements.
  • Preferred hydrogenation catalysts include, but are not limited to palladium, platinum, rhodium, nickel, and ruthenium. Especially preferred mixtures include 3% palladium/2% rhodium on carbon support and 3% palladium/2%copper on carbon support.
  • this catalyst in a neotame manufacturing process results in less dialkylated aspartame being produced and an overall greater selectivity.
  • This selectivity is synergistic, as it is considerably greater than what is observed when either of the component metals is used individually with the same total level of use. Further, this allows the subsequent crystallization step to be carried out under conditions in which reduced amounts of methanol and at a higher concentration, which lead to higher yields of neotame.
  • the co-precipitated catalyst is formed by conventional methods as described in the literature, see Augustine, "Heterogeneous Catalysts for Synthetic Chemist,” Marcel Dekker, Inc. 1996 pp268, 301-305.
  • the modified catalysts above have been proven to reduce impurities and improve yields of neotame in the coupling of 3,3-dimethylbutyraldehyde. It is expected that such catalysts would have similar benefits in the production of neotame by alternative couplings, for example, N-(3,3-dimethylbutyl)-L- aspartic acid. These catalysts will be useful in any such reductive alkylation as long as such reductive alkylations are done in the similar fashion.
  • Aspartame (50.0 g) was charged to a stirred hydrogenation vessel. Then a recycled palladium on carbon catalyst (containing approximately 60% water) was added to the vessel. The loading of the catalyst was 5% on a dry basis at the first use with an additional 0.5% charge of fresh catalyst upon each recycle. This was the fourth recycle of the catalyst.
  • the reactor was pressure purged with nitrogen (4X) and methanol (500 g) was added. The reactor was purged again with nitrogen (4X), then with hydrogen (4X). The vessel was brought up to 40 psi hydrogen and the contents heated to 40°C. Over 4 hours, 16.3 g of 3,3-dimethylbutyraldehyde were pumped into the vessel. The temperature throughout the addition was controlled at 38-40°C.
  • the line was flushed with methanol (10 ml) to ensure complete charging.
  • methanol 10 ml
  • the reaction solution was stirred under hydrogen pressure for 2 hours.
  • the catalyst was filtered from the methanol solution using powdered cellulose as a filter aid.
  • the catalyst cake was washed with 60ml of methanol.
  • Analysis of the combined filtrate and wash showed the dialkylated aspartame to neotame ratio to be 0.66%.
  • Methanol was distilled under reduced pressure. The bulk temperature of the solution was kept below 38°C. The solution was concentrated to approximately one-third the original volume. Water and methanol were added to bring the neotame and methanol concentrations to 13% and 27% respectively.
  • the solution was held at 40°C for 5 hours to hydrolyze the dialkylated imidazolidinone. After testing to ensure the dialkylated imidazolidinone is less than 0.025% (wt), the solution was cooled to 28°C and seeded with 0.14 g of neotame. The seeded solution was further cooled to 5°C over 2.5 hours. The filtered solid was washed with 45 ml of cold Dl water then dried under house vacuum at 25°C. The yield was 46.03 g (71.6%). The purity of the isolated neotame was >98% and it contained
  • the vessel was vented and purged with nitrogen (4x).
  • the catalyst was removed by filtration through powdered cellulose on a Buchner funnel.
  • the vessel was rinsed with 300 grams of Dl water. This rinse was also used to wash the catalyst and combined with the filtrate.
  • An HPLC analysis of the crude reaction mixture indicates 0.56% of dialkylated aspartame.
  • the methanol was removed under reduced pressure at or below 40°C to a methanol content of 25% by weight.
  • the solution was then cooled to 28°C and seeded with 0.17 g of neotame.
  • the neotame slurry was held at 5°C for 1 hour.
  • the neotame was filtered, and the wet cake was washed with 70 mL cold water.
  • the isolated neotame was dried at 40°C under vacuum for 48 hours, with 70% yield and neotame , purity >98% (by HPLC), dialkylated aspartame ( ⁇ 0.05%) and methylated neotame ( ⁇ 0.05%).
  • Aspartame (100 g) was charged into a 1.0 L Parr vessel followed by 3% Palladium/2% Rhodium catalyst on carbon (57.4% wet, 11.7 g) and methanol (319 g). The mixture was stirred for approximately 5 minutes. Water (172 g) was added and the mixture was stirred for approximately 1 minute. The Parr vessel was sealed and purged with nitrogen (3x) followed by hydrogen (3x).
  • This crude hydrogenation mixture was placed into a 2-L Erlenmeyer flask. The mixture was hydrolyzed for 3 hours at 40°C and then cooled to room temperature and seeded at 25°C. The mixture was refrigerated and allowed to statically crystallize overnight. The end temperature of the mixture was 7- 8°C. The crystals were filtered, washed with 150 mL cold water and dried under vacuum at 40°C for 24 hours. The resulting product contained 100% neotame (73% yield based on starting materials). None of the impurities referenced above were detected.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)

Abstract

L'invention concerne des procédés d'utilisation de catalyseurs modifiés à fonctionnalité améliorée dans la production de neotame. Ces catalyseurs modifiés permettent d'améliorer de façon étonnante la sélectivité par rapport à d'autres catalyseurs conventionnels et de réduire la concentration de certaines impuretés dans les procédés de production de neotame.
PCT/US2001/046956 2000-11-06 2001-11-05 Modification d'un catalyseur pour ameliorer la production de neotame Ceased WO2002065853A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2001297682A AU2001297682A1 (en) 2000-11-06 2001-11-05 Catalyst modification to enhance neotame production
EP01273796A EP1349829A4 (fr) 2000-11-06 2001-11-05 Modification d'un catalyseur pour ameliorer la production de neotame

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US24615400P 2000-11-06 2000-11-06
US60/246,154 2000-11-06

Publications (2)

Publication Number Publication Date
WO2002065853A2 true WO2002065853A2 (fr) 2002-08-29
WO2002065853A3 WO2002065853A3 (fr) 2003-07-24

Family

ID=22929515

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/046956 Ceased WO2002065853A2 (fr) 2000-11-06 2001-11-05 Modification d'un catalyseur pour ameliorer la production de neotame

Country Status (3)

Country Link
EP (1) EP1349829A4 (fr)
AU (1) AU2001297682A1 (fr)
WO (1) WO2002065853A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104177473A (zh) * 2014-08-20 2014-12-03 山东奔月生物科技有限公司 纽甜的合成方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4043942A (en) * 1969-12-03 1977-08-23 The Goodyear Tire & Rubber Company Modified nickel catalyst systems and their use in reductive alkylation reactions
FR2719590B1 (fr) * 1994-05-09 1996-07-26 Claude Nofre Procédé perfectionné de préparation d'un composé dérivé de l'aspartame utile comme agent édulcorant.
US5728862A (en) * 1997-01-29 1998-03-17 The Nutrasweet Company Method for preparing and purifying an N-alkylated aspartame derivative
US6465677B1 (en) * 1998-11-19 2002-10-15 The Nutrasweet Company Method for the preparation of N-neohexyl-α-aspartyl-L-phenylalanine methyl ester from imidazolidin-4-one intermediates

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104177473A (zh) * 2014-08-20 2014-12-03 山东奔月生物科技有限公司 纽甜的合成方法

Also Published As

Publication number Publication date
WO2002065853A3 (fr) 2003-07-24
EP1349829A4 (fr) 2005-11-09
AU2001297682A1 (en) 2002-09-04
EP1349829A2 (fr) 2003-10-08

Similar Documents

Publication Publication Date Title
JPH0363556B2 (fr)
US6720446B2 (en) Catalyst modification to enhance neotame production
JPH0564159B2 (fr)
WO2002065853A2 (fr) Modification d'un catalyseur pour ameliorer la production de neotame
US6335461B1 (en) Process for purification of aspartame derivative
JP3163661B2 (ja) α−Ｌ−アスパルチル−Ｌ−フェニルアラニンメチルエステル、及びＬ−フェニルアラニン、Ｌ−アスパラギン酸の回収方法
JPH0259159B2 (fr)
KR900003726B1 (ko) α-L-아스파르틸-L-페닐알라닌메틸에스테르 또는 그 할로겐화 수소산의 제법
KR950006893B1 (ko) 신규의 아스파트산 결정 및 이의 제조방법
US6939987B2 (en) Method for producing Aspartame derivative, method for purifying the same, crystals thereof and uses of the same
JP2662287B2 (ja) α―Ｌ―アスパルチル―Ｌ―フェニルアラニンメチルエステルの分離方法
US6245934B1 (en) Method for preparing salts of aspartame from N-protected aspartame
JP3162366B2 (ja) フェニルアラニンの単離方法
JP2976609B2 (ja) α−Ｌ−アスパルチル−Ｌ−フェニルアラニンメチルエステル又はその塩酸塩の製造法
CA2385968A1 (fr) Derives esters aspartyl-dipeptidiques et edulcorants
JP2896259B2 (ja) フェニルアラニンの単離方法
JPS6011457A (ja) ５−（フエニルメチル）−２，４−イミダゾリジンジオンおよびｎ−（アミノカルボニル）−ｄｌ−フエニルアラニンの併産方法
JP3314515B2 (ja) Ｌ−フェニルアラニンの回収方法
JP2508803B2 (ja) α−Ｌ−アスパルチル−Ｌ−フェニルアラニン誘導体の製造法
JP2598470B2 (ja) Ｎ−ベンジルオキシカルボニル―αーＬ―アスパルチル―Ｌ―フェニルアラニンメチルエステルの製造方法
JP3220484B2 (ja) Ｎ−ベンジルオキシカルボニル−α−Ｌ−アスパルチル−Ｌ−フェニルアラニンメチルエステルの製造法
JP3238175B2 (ja) Ｎ−ベンジルオキシカルボニル−α−Ｌ−アスパルチル−Ｌ−フェニルアラニンメチルエステルの製造法
JPH07116226B2 (ja) α−Ｌ−アスパルチル−Ｌ−フエニルアラニンメチルエステルまたはそのハロゲン化水素酸塩の製法
JPS61227593A (ja) α−Ｌ−アスパルチル−Ｌ−フエニルアラニンメチルエステルまたはその塩酸塩の製造方法
JPH07116225B2 (ja) α−Ｌ−アスパルチル−Ｌ−フエニルアラニンメチルエステルのハロゲン化水素酸塩の製造方法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2001273796

Country of ref document: EP

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 2001273796

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP