• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    A process for preparing N-formyl- alpha -aspartyl phenylalanine by condensing N-formyl aspartic acid anhydride and phenylalanine which comprises effecting the condensation reaction in a water medium while maintaining the pH during the reaction in the range of 7-12 and preferably at a reaction temperature of 50 DEG C or below.
    公开号:SU1433414A3
    申请号:SU3995761
    申请日:1985-12-16
    公开日:1988-10-23
    发明作者:Мита Рюити；Катох Тосио；Хигути Тодзиро；Оура Такеси；Ямагути Акихиро
    申请人:Мицуи Тоацу Кемикалз,Инкорпорейтед (Фирма)；
    IPC主号:
    专利说明:

    four
    I
     CM
    This invention relates to a process for the preparation of N-formyl-about-aspartylphenyl-, which is an intermediate in the preparation of compressed ot-L-acnaptil-b-phenylalanine methyl ester (aspartame), an artificial sweetening agent. I The purpose of the invention is to simplify the process and increase the content of oi-iso- in the target product.
    I A p p and m in p 1. To an aqueous solution containing 13.2 g of hydroxide to tires, dissolved in 330 ml of water, give 33.0 g (0.20 mol) of L-phenylshanine with re-formation of the solution, After cooling to -5 ° C, 30.0 g (0.21 M5) of anhydride of L-formyl-L asparaginic acid is added to the solution of Penneum within one hour, and the temperature in the range ale-5 is 5 C at the same time. An aqueous solution of sodium hydroxide is added to this solution to maintain the pH of the reaction liquid 8-11. Thereafter, the reaction is carried out at the same temperature for one hour. The reaction mixture was analyzed by liquid chromatography. It was established that the ratio of the formation of isomers of the N-th Imyl-on-L-acPartil-B-phenylalanine and -formed 2 -Y-aspart-1-b-pheny, palanine, while the total yield with c; pressure is 98% , coming from L-phenylalany On,
    To the reaction liquid is added dropwise concentrated hydrochloric acid 1 at 10 ° C or lower to achieve a pH of: then the resulting liquid mixture is stirred at 0-5 ° C for one hour. The precipitate thus obtained is filtered off, washed with cold water and dried to obtain 44.9 g of a white crystal N-forms 1-e6-b-aspartyl-b-phenylalanine in a yield of 72.9%.
    This crystal is analyzed by flash chromatography. The 2.0% isomer was found to be in a mixture with the oi-isomer and the N-formyl-i-b-aspartyl-b-phenylalanine has a purity of 97.8%.
    Example 2. (comparative). 330 ml of water was added 33.0 g (0.20 mol) of L-phenylalanine and the resulting suspension was cooled to OC. 30.0 g are gradually added to this suspension.
    five
    O
    5 0 0
    0 5

    five
    (0.21 mol) of N-formyl-L-ac-paraginic acid anhydride at, performed this operation for approximately one hour. Thereafter, the reaction is carried out at the same temperature for two hours. Then a portion of the peaij mixture is analyzed by means of express chromatography. N-formyl-oi-L-acnaptil-b-phenylalanine was found to be almost not formed.
    Example 3. (comparative). To an aqueous solution containing 14.5 g of potassium hydroxide dissolved in 330 ml of water, add 33.0 g (0.20 mol) of L-phenylalanine to form a solution. After cooling to 0- (-5) C, anhydride N-formyl-L-ac-paraagic acid is gradually added to this solution over one hour while maintaining the temperature in the range of 0-5 C. At the same time, 10% is added dropwise to this solution. an aqueous solution of sodium hydroxide to maintain the pH of the reaction medium 12-14. After that, the reaction is continued at the same temperature for one hour. A portion of the reaction mixture is analyzed by means of express chromatography. It was established that the ratio of the formation of isomers of N-formyl-ot-b-aspartyl-b-phenylalanine and H-formyl-y-b-aspartyl-L-phenylalanine was 78:22, which corresponds to the index obtained in Example 1, this gives a total yield of 80.4%, based on b-phenylalanine, and 10.5% of the starting L-phenylalanine remains in solution. In addition, about 10% of the impurities are conducted to form by-products, and the reaction liquid is extremely yellowish.
    P p i. M ery s 4-7. The reaction is carried out using 33.0 g (0.20 mol) of L-phenylalanine and 31.5 g (0.22 mol) of N-formyl-L-ac-paraginic acid anhydride as in example 1e, the type of alkali is changed, the reaction temperature , pH and other conditions, as shown in table. one.
    Example 8. The reaction was carried out using 33.0 (0.20 mol) of L-phenylalanine and 30.0 g (0.21 mol) of L anacid anhydride as in Example 1. After the end of the reaction, the reaction mixture was added dropwise to the reaction mixture.
    hydrochloric acid is added until the pH reaches 1 while maintaining the temperature, 10 ° C or lower. The resulting mixture was stirred at 0-5 ° C for one hour to precipitate a precipitate. The precipitate obtained is filtered, washed with cold water and then dried under vacuum, resulting in a yield of 58.6 g of crystal with a yield of 95.1%.
    This crystal is analyzed by flash liquid chromatography. The ratio of N-formyl-o-b-aspartyl-b-phenylalanine and L-formyl- (5-b-aspartyl-b-phenylalanine) was found to be 78:22.
    Example9. To an aqueous solution containing 8 g of sodium hydroxide in 330 ml of water was added 33.0 g (0.2 mol) L of phenylalanine. The solution is little by little combined with 31.5 g (0.22 mol) of N-formyl-L-acparginic acid anhydride for one hour, maintaining the temperature at 20-30 ° C. A 10% aqueous solution of sodium hydroxide is added simultaneously. The pH of the reaction mixture is up to 8-12. Then the reaction is carried out at the same temperature for one hour.
    The reaction mixture is analyzed by high-speed liquid chromatography. The ratio of isomers of L-formyl-C-L-aspartic-1-b-phenylalanine and L-formyl-L-aspartyl-b-phenylalanine was found to be 76.2: 23.8, the total yield is 96.8% weight based on the original L-phenylalanine.
    Example 10 To the reaction mixture obtained in Example 9, 50% sulfuric acid was added dropwise until the pH was adjusted to 3.4. After that, the reaction mixture is cooled to and stirred at this temperature for one hour. The precipitate formed is filtered off, washed with cold water and dried to obtain 41.8 g of white L-formyl-L-L-aspartyl-b-phenylalanine crystals with a yield of 67.6% based on the starting L-phenylalanine. Crystals analyze high;
    high-speed liquid chromatography Crystals were found to contain 0.5% fs-isomer impurity, N-formyl-L-b-aspart-b-phenylalanine purity was 99.1%.
    Example 11 To the reaction mixture obtained in Example 9, 50% sulfuric acid was added dropwise to bring the RP to 2.6. Analogously to Example 10, g of white K-formyl- (1 {.71 -partyl-b-phenylalanine) crystals are obtained with a yield of 73.5% based on L-phenylalanine. A chromatographic study shows that the crystals contain 3.2% of impurities b-isomer, N-formyl-o purity (-L-ac-partil-L-phenylalanine 96.5%.
    Example 12. To the reaction mixture of 0.2 mol of flaked L-phenylalanine, prepared according to the procedure of Example 1, 35% hydrochloric acid was added dropwise at 10 ° C or more to bring the pH to the values shown in the table below. . 2, get crystals N-formyl bt-L-acpaptil-L-phenylalanine in quantity, with the release (based on the initial L-phenylalanine) and purity (ratio of isomers), respectively, are shown in Table. 2
    Thus, by the proposed method, the desired product is obtained, containing the oi-isomer in the overwhelming amount (the ratio of ui -i -isomers is 8: 2, respectively), the total yield is 95%.
    权利要求:
    Claims (1)
    [1]
    Formula invented and
    The method of producing H-formyl-aspartyphenylalanine by condensation of anhydride of N-formylparaginic acid and phenylalanine, characterized in that, in order to simplify the process and increase the content of the oi.-isomer in the target product, the condensation is carried out in an aqueous medium at pH 7.5-12 followed by isolation of the target product by acidifying the reaction mass to a pH of 3.5-2.5.
    Editor I.Gorn
    Compiled by L.Ioffe Tehred l. Oliynyk
    Order 5471/59
    Circulation 348
    BNShShI State Committee of the USSR
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Table 1
    Proofreader M.Vasilyeva
    Subscription
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1433414A3|1988-10-23|Method of producing n-formyl-alpha-aspartylphenylalanine
    KR0123935B1|1997-11-25|Process for preparing erythromycin a oxime or a salt thereof
    DK163303B|1992-02-17|METHOD FOR PREPARING CIMETIDINE POLYMORF B.
    Yamada et al.1978|Preparation of d-p-Hydroxyphenylglycine: Optical Resolution of dl-p-Hydroxyphenylglycine by Preferential Crystallization Procedure
    EP0200311B1|1990-10-10|Preparation process of alpha-l-aspartyl-l-phenylalanine methyl ester or hydrochloride thereof
    US4062854A|1977-12-13|Process for preparing N-substituted-8,13-dioxodinaphtho-(2,1-b; 2',3'-di-fluran-6-carboxamides
    JP2007526890A|2007-09-20|Method for producing chiral pure N- | -D-phenylalanine and their crystal structure modified products
    SU645549A3|1979-01-30|Method of obtaining 1,2-dioxycyclobutendion-3,4
    US4222970A|1980-09-16|Process for producing phosphonomycin
    US6673944B2|2004-01-06|Preparation of warfarin sodium from warfarin acid
    JPH0616617A|1994-01-25|Production of guanidine derivative
    CA1303293C|1992-06-09|PREPARATION METHOD OF .alpha.-L-ASPARTYL-L-PHENYLALANINE METHYL ESTER HAVING IMPROVED SOLUBILIZATION
    FR2516077A1|1983-05-13|PROCESS FOR THE PREPARATION OF ESTER-METHYLIC OF A-ASPARTYL PHENYLALANINE
    EP0115539B1|1986-10-29|Single crystalline dl-cysteine and process for their preparation
    US5616766A|1997-04-01|Method for recovering L-phenylalanine
    US5591889A|1997-01-07|Method for the synthesis of trisodium phosphonoformate hexahydrate
    JP2987058B2|1999-12-06|Method for producing sodium 3-alizarin sulfonate
    US5332829A|1994-07-26|Process for reducing 5-| hydantoin to 5-| hydantoin
    SU1293171A1|1987-02-28|Method of producing n-acetyl-d,l-alanine
    EP0009290B1|1982-07-07|3-azabicyclo|hexane derivatives and process for their preparation
    JP2533864B2|1996-09-11|Optical resolution method of DL-alanine
    JP2605127B2|1997-04-30|Process for producing α-L-aspartyl-L-phenylalanine methyl ester having improved solubility
    EP0479960B1|1995-10-18|Method for the synthesis of trisodium phosphonoformate hexahydrate
    SU1082318A3|1984-03-23|Process for isolating z-1,2-diphenyl-1/n-|butene-1 or its salts
    SU1182026A1|1985-09-30|Method of producing n-|-aminoacetic acid
    同族专利:
    公开号 | 公开日
    KR860004922A|1986-07-16|
    JPH07636B2|1995-01-11|
    US4745210A|1988-05-17|
    EP0186378B1|1992-01-15|
    NO855067L|1986-06-18|
    KR870000811B1|1987-04-20|
    ES549975A0|1987-01-01|
    DE3585219D1|1992-02-27|
    NO169126B|1992-02-03|
    NO169126C|1992-05-13|
    EP0186378A2|1986-07-02|
    BR8506312A|1986-08-26|
    MX162986B|1991-07-30|
    ES8702435A1|1987-01-01|
    JPS61143397A|1986-07-01|
    AU5100385A|1986-06-26|
    AU555831B2|1986-10-09|
    EP0186378A3|1988-07-27|
    CA1273749A|1990-09-04|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    BE791544A|1971-11-19|1973-05-17|Stamicarbon|PREPARATION OF ALKYL ESTERS OF DIPEPTIDE|
    JPS4896557A|1972-03-22|1973-12-10|
    CA1028197A|1973-04-02|1978-03-21|Jeffrey H. Berg|Concentrated liquid low calorie sweetener|
    US3933781A|1973-11-05|1976-01-20|Monsanto Company|Process for the preparation of α-L-aspartyl-L-phenylalanine alkyl esters|
    JPS5140069A|1974-10-02|1976-04-03|Hitachi Ltd|
    JPS5823380B2|1974-12-05|1983-05-14|Ajinomoto Kk|
    JPS51113841A|1975-03-28|1976-10-07|Ajinomoto Co Inc|Process for preparing lower alkyl esters of n-formyl-alpha -l-aspartyl-l-phenylalanine|
    JPS5726588B2|1975-08-14|1982-06-05|
    MX4704E|1976-12-27|1982-08-04|Monsanto Co|IMPROVED PROCEDURE FOR THE PREPARATION OF ALPHA-L-ASPARTIL-L-PHENYLALANINE METHYL ESTER|
    JPH0372640B2|1982-04-22|1991-11-19|Ajinomoto Kk|
    GB2133409B|1983-01-13|1986-03-05|Erba Farmitalia|Aspartame synthesis|
    GB8300810D0|1983-01-13|1983-02-16|Erba Farmitalia|Aspartame synthesis|
    JPH0363556B2|1983-05-28|1991-10-01|Ajinomoto Kk|
    JPH0441155B2|1983-06-02|1992-07-07|Ajinomoto Kk|
    JPH0613550B2|1983-06-03|1994-02-23|味の素株式会社|Process for producing α-L-aspartyl-L-phenylalanine-lower alkyl ester|JPH0680074B2|1985-07-01|1994-10-12|味の素株式会社|Method for producing N-formyl-L-α-aspartyl-L-phenylalanine|
    DE3600731A1|1986-01-13|1987-07-16|Green Cross Korea|METHOD FOR PRODUCING-L-ASPARTYL-L-PHENYLALANINE METHYLESTER|
    JPH0696595B2|1986-05-07|1994-11-30|味の素株式会社|Process for producing N-protected-L-α-aspartyl-L-phenylalanine|
    JPS6344594A|1986-08-11|1988-02-25|Ajinomoto Co Inc|Separation of n-protected-alpha-l-aspartyl-l-phenylalanine|
    DE3635582A1|1986-10-20|1988-04-21|Hoechst Ag|METHOD FOR PURIFYING N-ACYL ASPARTAM|
    JPH05500371A|1988-02-12|1993-01-28|
    US5053532A|1988-02-12|1991-10-01|The Nutra Sweet Company|One-pot process for the preparation of α-L-aspartyl-L-phenylalanine methyl ester hydrochloride|
    US4946988A|1988-07-14|1990-08-07|The Nutrasweet Company|Process for the preparation of α-L-aspartyl-L-phenylalanine methyl ester hydrochloride by use of isolated N-formyl L-aspartic anhydride|
    WO1991013860A1|1990-03-12|1991-09-19|The Nutrasweet Company|Method for increasing the alpha to beta ratio in an aspartame coupling reaction|
    JPH05117246A|1991-10-23|1993-05-14|Ajinomoto Co Inc|New 2,5-dioxopiperazine compound, its production and production of alpha-l-aspartyl-l-phenylalanine methyl ester derivative|
    EP1371633A1|2002-06-14|2003-12-17|Bayer Ag|Process for the purification of mixtures of toluenediisocyanate incorporating a dividing-wall distillation column|
    ES2271171T3|2002-10-22|2007-04-16|Bayer Materialscience Ag|PROCEDURE FOR THE PURIFICATION OF TOLUENDIISOCIANATE THAT INCORPORATES A DIVISORY WALL DISTILLATION COLUMN FOR FINAL PURIFICATION.|
    法律状态:
    2005-01-10| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20021217 |
    优先权:
    申请号 | 申请日 | 专利标题
    JP59264618A|JPH07636B2|1984-12-17|1984-12-17|Process for producing N-formyl-α-aspartyl phenylalanine|
    [返回顶部]