• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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  • 优先权
    • 专利摘要:
    The invention relates to organic carbamic acids, in particular to the preparation of N-protected L-amino acids of the general formula IR, -0-C (0) -N (Rj) -R-COOH, where R is tert-butyl, 9- fluorenylmethyl, 2,2,2-trichloroethyl or trimethylsilylethane. , R is an aliphatic C, -C-radical; unsubstituted or substituted by the group CH, S-, SH-, -COOH, -OH, -NH,., -NHSOjCbH CH ,, sn, -. H - CHn-CH C 1-Mu 1 (CH,) 3-BN-C PU-XltT or NH or C -a-aliphatic radical, J is substituted or substituted by -OH or R, is an atom of hydrogen, or R and R, j together with the nitrogen atom form the pyrrolidine cycle, which are used in the synthesis of peptides. The goal is to simplify the process technology and expand the range of target products. Compounds I are prepared by the interaction of the L-amino acid of the formula NH (R) -R-COOH and ei-chlorinated carbonate of the formula R, -0-C (0) -0-CH (C1) -CC1, where R ,, R and R have the indicated values in an acetic acid, alcohol, aqueous dioxin environment (preferably in a mixture of dioxane and at a ratio of 1: 1), dimethylformamide or pyridine in the presence of a basic reagent, triethylamine or NaOH, and the reaction is carried out at a constant value rI. The method allows to simplify the process by using available source reagent and carrying out the process under stringent conditions in obtaining easily removable by-products. 2 hp f-ly, 2 tab. i СО С со с ю с со см
    公开号:SU1375123A3
    申请号:SU853860251
    申请日:1985-02-15
    公开日:1988-02-15
    发明作者:Барсело Жерар；Сене Жан-Пьер；Сенние Жерар
    申请人:Сосьете Насьональ Де Пудр Э Эксплозиф (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing N-protected L-amino acids that are used in the synthesis of peptides.
    The aim of the invention is to simplify the process technology and expand the range of target products by reacting L-amino acid with o-chlorinated carbonate of the formula
    Ri-0-C-0-CH-CCl3 O
    C1
    in acetic acid, alcohol, aqueous dioxane, dimethylformamide or pyridine in the presence of an acid acceptor, such as triethylamine or sodium hydroxide, at 0-20 ° C. Preferably, the reaction is carried out in a mixture of dioxane and water at a ratio of 1: 1 and at a constant pH value,
    Example 1. Preparation of tert-butyl-1,2,2,2-tetrachloroethyl carbonate.
    9.9 g (0.04 mol of chloroformic acid, 2,2,2-tetrachloroethyl) are added per time to a solution of tert-butanol (3 g, 0.04 mol) in dichloromethane (50 ml). Cool to 0 ° C and 3.2 g (0.04 mol) of pyridine was added dropwise. The mixture was stirred at room temperature for 4 hours. Then 20 ml of ice water was added, the organic phase was separated and washed with 20 ml of ice water. water, dried over magnesium sulfate and the solvent evaporated to give 11.3 g of a white solid (99%), which is recrystallized from petroleum ether (yield 87%, mp. 70 ° C.), and you get g of purified arbonata. B.p.. 9b sec / 866 Pa (6.5 mm Hg).
    IR - WITH 1770 cm
    NMR spectrum H (CDC1 ,, TMS): 1.5 (S; CH,) 6.7 (S, CH).
    Example 2
    a) Preparation of tert-butyloxycarbonyl-b-phenylalanine.
    To a solution of L-phenylalanine (1.65 g 10 mmol) in aqueous dioxane (1: 1, 30 ml) was added 4.2 ml (30 mmol) of triethylamine and stirred until dissolved (10 min). Then, 2.85 g (10 mmol) of tert-butyl-1,2,2,2-tetrachloroethyl carbonate is added and stirred for 6 hours at. 50 ml of water are then added and the mixture is extracted with 2 20 ml.
    five
    five
    0
    0 5 0
    five
    Q

    ethyl acetate. The aqueous phase is acidified (pH 2-3) with normal HCl, then extracted with 3 to 30 ml of ethyl acetate. The extract is washed with a saturated solution of NaCl, dried over MgSO4 and evaporated. The resulting product is crystallized from ethyl acetate and petroleum ether. Obtain 2.1 g of the target carbamate (79%). M.p. 85-87 C (according to literature data 86-88 C), rotational ability 01 1 +28 (c 1.5 EtOH), (/. 3 (according to literature data) +24.7 (c 1.5 EtOH).
    b) Preparation of N-tert-butyloxycarbonyl-b-alanine (BOC-b-alanine).
    Analogously to Example 2a, but starting from 1.78 g (20) of alanine, 3.4 g (90%) of BOC-b-alanine is obtained. M.p. 80-81 C (according to literary data- HbiM 83-84 c) reil p 24.9 (with 2.1 AcOH), W (no literary data) -22.5 (with 2.1 AcOH).
    Example 3. Preparation of t-butyloxycarbonyl-b-proline.
    As in Example 2a, but starting from 1.15 g (U mmol) of L-proline, 1.95 g (yield 91%) of carbamate is obtained. M.p. 130-131 C (according to literary data 132-133 s). vg- -60 (with 2.0 AcOH). lZ (according to literary data) -60.2 (with 2.0 AcOH).
    Example 4. Preparation of tert-butyloxycarbonyl-glycine (BOC-Gly).
    As in Example 2a, but starting from 0.75 g (10 mmol) of glycine, 1.5 g (86%) of the desired carbamate are obtained. So pl. 80-85 ° С (according to literary data) 86-88 s.
    Example 5. a) Getting the BOK-Gly at a controlled value
    pH
    I.
    5.6 g (0.075 mol) of glycine is dissolved in 150 ml of aqueous dioxane (50%) and the pH is adjusted with 4N sodium hydroxide. 23.6 g (0.083 mol) of tert-butyl -1,2,2,2-tetrachloroethyl carbonate are added over time and the pH is kept constant by adding 4N sodium hydroxide. When the reaction is complete, 200 ml of water is added, then the aqueous phase is washed with 2 times 100 mp of ethyl ether, acidified to pH 3 at 6 N.HC1 and extracted 3 times with 200 ml of ethyl acetate (ACOEt). After drying and evaporation of the solvent, the product is crystallized from ethyl acetate / petroleum ether (4070 ° C). Get the BOC-glycine with so pl. 85-87 s. The dependence of the yield of BOC-Gly on pH and time is given in Table. one.
    b) Carry out similarly to the previous step a), but use different amino acids.
    The results are shown in Table. 2
    Example 6. Preparation of tert-β-butyloxycarbonyl-L-tyrosine.
    1.81 g (10 mmol) of tyrosine is dissolved in 20 ml of aqueous dioxane (1: 1, 1.4 ml (10 mmol) of triethylamine and 15 mmol of sodium hydroxide are added. Then 2.85 g (10 mmol) are added) tert-butyl-1,2,2,2-tetrachloroethyl carbonate carbonate and stirred for 6 hours at. Further, proceed as in example 2a.
    The resulting product is crystallized in the form of a dicyclohexylammonium salt. 3.8 g (82%) are obtained. M.p. 20b ° С (according to the literary data 212 С).
    Example 7. Getting tert-butyloxycarbonyl-b-serine.
    Similar to Example 2a, only the reaction time is 24 hours instead of 6 hours and starts from 1.05 g (10 mmol) of L-serine, 3.1 g (78%) of the desired carbamate in the form of a dicyclohexylammonium salt are obtained. T. pl. 139-140 С (according to lit. 140-142 С). d. +8 (with 2.8 MeOH), o (. (lit.) +13 (with 3, Q MeOH).
    Example 8. The preparation of tert- -buttoxycarbonyl-b-aspartic acid.
    As in the previous example, but “a drop from 1.33 g (10 mmol) of L-aspartic acid, 1.4 g (60%) of the expected acid is obtained. M.p. 116-118 ° C (ik) lit. data 114-1 IS c). -5 (with 1.0 MeOH), (liter) -6.2 (with 1.0 MeOH).
    Example 9. Preparation of 9-fluoride, nylmethyl-1,2,2,2-tetrachloroethyl carbonate.
    6.7 g (0.027 mol of chloroformic acid ester of 1,2,2,2-tetrachloroethyl is added to a solution of 9-fluoro nylmethanol (4.9 g, 0.025 mol) in 50 ml of dichloromethane. Cool to 0 ° C and 2.2 ml of pyridine is added dropwise. The mixture is stirred for 4 hours at 0 ° C. Then 50 ml of dichloromethane is added and the organic phase is washed 2 times with 50 ml of ice water. The mixture is dried over magnesium sulfate and the solvent is evaporated. The residue is crystallized from hexane 9.3 g of the desired product are obtained (98%) with a melting point of 98-110 ° C. IR С О 175П cm NM N: (CD 01 ,, TMS) 4.5 nnm СН, -0.6.75 nntn CH-Cl.
    ABOUT
    Example 10. Preparation of 9-fluoro-rhenylmethyloxycarbonyl-b-phenylapanin.
    Dissolve 0.83 g of L-phenylalanine (5 mmol) in aqueous dioxane (1: 2, 12 ppm) containing 1.4 ml of triethyl per 10 mmol. Cool down to and add 2.05 g (5 mmol) of carbonate obtained in Example 9 dissolved in 4 ml of dioxane. After 2 hours, 20 ml of water are added at O & C and extracted with 2 times 20 ml of ether. The aqueous phase is then acidified (pH 2-3 with 6 NPS1 and extracted 3 times with 50 ml of ethyl acetate. Dried over MgSOj and evaporated. The resulting product is crystallized from ethyl acetate and petroleum ether. 1.44 g of the desired carbamate is obtained (75%) Mp. 178–179 ° С according to literature data 178-179 ° С.
    Example 11. Preparation of 9-fluorobenzylmethyloxycarbonyl-b-proline (FMOC-Pro).
    As in Example 10, but starting from 0.58 g (5 mmol) of L-proline, 1.4 g (83%) of the desired product are obtained. M.p. 112-113 ° С (according to the data of data 116-117 ° С).
    Example 12. Preparation of 9-fluorobenzylmethyloxycarbonyl-b-serine.
    It is carried out as in Example 10, but the reaction is continued for 24 hours at 20 ° C. Starting from 0.53 g (5 mmol) of L-serine, 1.32 g (81%) of the expected product is obtained. M.p. 73-75 ° C. After recrystallization so pl. 83-86 ° С (according to the lit. data 86-88 ° С).
    Example 13. Preparation of l, 2,2, 2-tetrachloroethyl-2,2,2-tri-chloro tetylcarbonate.
    As in Example 1, but starting from 14.9 g of trichloroethanol (0.1 mol), 24.1 g (67%) of the desired carbamate are obtained. M.p. 108 ° C / 6.6 Pa, mp.
    IR, CO 1770 cm-.
    NMR H (CDClI, TMS): 4.85 (S, CH. 6.7 (S, CH).
    Example 14. Preparation of tri-chloroethoxycarbonyl-b-phenylalanine (TPOK-L-Phe).
    As in example 10, but starting from 0.83 g (5 mmol) of L-phenylalanine and 1.98 g (5.5 mmol) of 1, 2.2.2-tetrachloroethyl-2,2,2-trichloroethyl carbonate, get 1.43 g (84%) of the target product. M.p. 128-129 seconds (according to literature data 129-130 seconds).
    Example 15, Preparation of tri-chloroethoxycarbonyl- (L) -serim.
    As in example 12, but the outcome, from 0.53 g (5 mmol) of L-serine and 1.98 g (5.5 mmol) of carbonate of example 13, is obtained 1.15 g (82%) of the desired product. M.p. 111-113 s (according to the lit. data 114-115 ° С).
    Example 16. Preparation of 2-trimethylsilyl-1,2,2,2-tetrachlorfate 1 -carbonate.
    In Example 1, but starting from 5.91 g of trimethylsilylethanol and 12.35 g of chloroformate ethyl chloroformate, 13.6 g (83%) of the desired product are obtained, b.p. 92-94 C, 6.6 Pa.
    IR: CO 1750.
    NMR: H (CD C1e, TMS. External): 0.1 (S, Si-CH3) 1.1 (t, Si-CHj) 4.35 (t, CHj-0) 6.7 (S, CH- Cl)
    EXAMPLE 17 Preparation of trimethyl silane, ethylethyloxycarbonyl- (b) phenylalanine.
    In Example 12, but starting from 0.83 (5 mmol) of phenylalanine and 1.8 g (5.5 mmol) of carbonate obtained in Example 16, 1.4 g (100%) of trimethylsilyl-to-carboxycarbonyl-b-phenyl-alanine are obtained. form of oil.
    NMR: n (CD C 1 h, TMS): O (S, Si — CH,) 0.9 (t, Si — CH) 3.0 (
    4.0 (t, ocH -c-si) 4.5 (tsn-k1
    C02
    5.2 (S, W) 7.2 (S, Ph-H) 8.7 (C-OH
    0
    Add 2 ml of dicyclohexylamine to this oil, dissolved in 5 ml of ether, to obtain, after crystallization, 1.93 g (78%) of the dicyclohexyl ammonium salt of the desired product with mp. 111-112 ° C.
    Example 18. Preparation of 1,2,2,2-tetrachloroethyl-1-p-nitrobenzsh-1-carbonate.
    3.83 g (25 mol) of p-nitrobenzyl alcohol and 6.17 g (25 mmol) of 1,2,2,2-tetrachloro ethidone are dissolved.
    th chloroformate ester, 50 MP dichloromethane. The mixture is cooled to 0 ° C and 2.02 ml of pyridine is added dropwise. Stir for 4 hours at 10 ° C, then add 50 ml of ice water, separate the organic phase and wash another two times with 50 ml of water. Dry the organic phase on magnesium sulphate,
    the solvent is evaporated off and 8.7 g of the desired product are obtained (96%), b.p. 190-195 C / O, 05 mmHg and so on 53-55 ° C (crystallization solvent is aqueous ethanol, yield after
    crystallization 54%).
    The proposed method allows to simplify the process due to the use of a more affordable starting ot-chlorinated carbonate, less
    权利要求:
    Claims (3)
    [1]
    1. A method for producing H-protected L-amino acids of general formula I
     ABOUT
    RI-O-C-N-R -COOH k
    where R is t-butyl, 9-fluorenylmethyl, 2,2,2-trichloroethyl or trimethylsilylethyl, Kd is an aliphatic C, -C-radical, unsubstituted or substituted by the group CHjS-, SH-, -COOH, -OH, - NH ,,
    SNG-,
    I n
    N.
    TH-NH
    0
    five
    - (
    five
    --- ct,
    NH-i
    CgH.-CH, OCO-, -NHSO C H CHj CfcHjCH - or
    or C.-araliphatic radical, unsubstituted or substituted by a group - OH or
     a hydrogen atom, or R and R, together with a nitrogen atom form a pyrrolidine cycle, the interaction of L-amino acid and carbonic ester in a solvent medium in the presence of a basic reagent characterized in that
    7
    To simplify the process technology and expand the range of target products, oi-chlorinated carbonate of formula II is used as a carbonic ester
    .RL-O-C-O-CH-CCI
    about C1
    where R has the indicated meanings, which is reacted with an L-amino acid of formula III
    IjlH-R -COOH
    Yach


    eight
    where RJ and R have the indicated meanings in an environment of acetic acid, alcohol, aqueous dioxane, dimethylformamide or pyridine in the presence of an acid acceptor such as triethylamine
    or sodium hydroxide, at 0-20 C. 1
    [2]
    2. A method according to claim 1, wherein the reaction is carried out in a mixture of dioxane and water at a ratio of 1: 1.
    [3]
    3. The method according to claim 1, characterized in that the reaction is carried out at a constant pH value.
    (OBzl)
    (Tos)
    )
    8.6 8.3
    four
    ten
    10.1 9.5 9.5 9.75 9.7 9
    80
    74
    42
    50
    70
    80
    71
    95
    75
    42
    Table 1
    table 2
    136,140,100 o
    DSN)
    -602 / Ac OH
    -21.21 / Ac OH
    -192 / DMF
    , 4I / Me OH
    -25.52 / Ac OH
    -6.01 / Ac OH
    + 3.31 / Ac OH
    -271 / Ac OH
    + 13,61,1 / Me OH
    1375123
    Base used: triethylamine.
    10 Continuation of table 2
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    同族专利:
    公开号 | 公开日
    IL74302D0|1985-05-31|
    FI850589A0|1985-02-13|
    FI87194C|1992-12-10|
    DK70285A|1985-08-17|
    US4960881A|1990-10-02|
    CN85101227A|1987-01-24|
    IL74302A|1989-01-31|
    FR2559764A1|1985-08-23|
    US4652665A|1987-03-24|
    JPH06184059A|1994-07-05|
    DE3563205D1|1988-07-14|
    EP0154581B1|1988-06-08|
    ES540448A0|1985-12-01|
    ES8602593A1|1985-12-01|
    HUT37383A|1985-12-28|
    DK168332B1|1994-03-14|
    JPH0713029B2|1995-02-15|
    CS249538B2|1987-03-12|
    IE58113B1|1993-07-14|
    HU196738B|1989-01-30|
    FI850589L|1985-08-17|
    JPH0699369B2|1994-12-07|
    CA1244452A|1988-11-08|
    HU194813B|1988-03-28|
    DK70285D0|1985-02-15|
    EP0154581A1|1985-09-11|
    SG86188G|1989-09-01|
    IE850316L|1985-08-16|
    JPS60237050A|1985-11-25|
    FR2559764B1|1988-01-29|
    AT34973T|1988-06-15|
    FI87194B|1992-08-31|
    引用文献:
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    DE121223C|
    GB828871A|1957-07-12|1960-02-24|Shell Res Ltd|Herbicidal compositions|
    US3467690A|1965-05-12|1969-09-16|Lilly Co Eli|3,5-dimethoxybenzyl carbonate esters|
    DE1543630A1|1966-12-23|1969-07-31|Bayer Ag|Process for the production of tert. Butyloxycarbonyl derivatives of amino acids|
    US3944590A|1967-01-25|1976-03-16|Ciba-Geigy Corporation|Process for the temporary protection of amino groups in peptide syntheses|
    US3875207A|1967-01-25|1975-04-01|Ciba Geigy Corp|Process for the temporary protection of amino groups in peptide syntheses|
    GB1426717A|1972-03-13|1976-03-03|Astra Laekemedel Ab|Penicillins|
    LU80207A1|1978-09-07|1980-04-21|H Kalbacher|NEW SUBSTITUTED CARBONIC ESTERS AND URETHANE, METHOD FOR THE PRODUCTION AND USE THEREOF|
    FR2482587B1|1980-05-14|1983-09-30|Poudres & Explosifs Ste Nale|FR2574075B1|1984-12-04|1987-09-18|Poudres & Explosifs Ste Nale|PROCESS FOR THE SYNTHESIS OF ACTIVE ESTERS OF CARBOXYLIC ACIDS, NOVEL ALPHA-HALOGEN CARBONATES USEFUL FOR THIS SYNTHESIS AND THEIR METHOD OF OBTAINING|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8402328A|FR2559764B1|1984-02-16|1984-02-16|NOVEL A-CHLORINE CARBONATES, THEIR MANUFACTURING PROCESS AND THEIR APPLICATION TO PROTECT THE AMINE FUNCTIONS OF AMINO ACIDS|
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