• 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:
    The invention relates to substituted esters, in particular, compounds of the general formula 1: R 1 -OC (O) -Y, where Y is the residue of an acid — 2,2-dimethacrylic, 2-thiophenecarboxylic or N-protected amino acid of the formulas BOC-A with A = ALA, PHE, GLY, VAL, PRO, TYR, MET, SER, TRP, Z = LYS, (OBZL) SER, (OBZL) THR, (OBZL) TYR, (OBZL) GLY, CYS, (SBZL) CYS, DNP = HIS, (OBZL) LYS Z-A with A-ALA, PRO, MET F-MOC-A with A-ALA, PRO, PHE R 1 --NC (O) -CH 2 -CH 2 -C = O, 2,4,6-trichlorophenyl, 2,4,5-trichlorophenyl, pentachlorophenyl, pentafluorophenyl, N-NO 2 -C 6 H 4 , 2 , 4-dinitrophenyl, -NN = NC = CH-CH = CH = CH-intermediates for peptide synthesis. The goal is to simplify the process. The latter lead from the corresponding α-chlorocarbonate and acids of the formulas P and W: R 1 -OC (O) -OCHCL-R 2 (P) and YC (O) -OH (W), where R 1 and Y - see above, R 2 -CCL 3 , C 2 -C 5 -alkyl or 2-chlorophenyl, in an inert organic solvent in the presence of an HCL acceptor. Tetrahydrofuran, dioxane, ethyl acetate, dimethylformamide or methanol are used as a solvent, and triethylamine or N-methylmorpholine is used as an acceptor. The method provides a high yield of the target product (90-99%). 2 hp f-ly, 4 tab.
    公开号:SU1493102A3
    申请号:SU853986026
    申请日:1985-12-03
    公开日:1989-07-07
    发明作者:Барсело Жерар；Кастро Бертран；Жауади Махмуд；Мартинез Жан；Сене Жан-Пьер；Сенниеи Жерар
    申请人:Сосьете Насьональ Де Пудр Э Эксплозиф (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to an improved process for the preparation of carboxylic acid esters, which is used in a peptide chemist; .
    The purpose of the invention is to simplify the process for the preparation of carboxylic acid esters.
    Examples 1-10. Synthesis of alpha-halogenated carbonates.
    Get carbonates in accordance with one or more of the following methods. The results are summarized in table 1.
    Method A. At one time, 12.35 g (0.05 mol) of 1,2,2,2-tetrachloroethyl chloroformate was added to a solution of 5.75 g (0.05 mol) of N-hydroxy succinimide in dichloromethane ( 50 ml). The mixture is cooled to 0 ° C, after which 4 g (0.05 mol) of pyridine is added dropwise to it. At the end of the coupling, leave the mixture until it acquires the ambient temperature, and
    then stirred for 3 hours. Then, 20 ml of ice water is added, the organic phase is separated, which is washed as many times with 20 ml of ice water as is necessary so that the pH is not more acidic (mostly 3 or 4 times ). The organic phase is dried over magnesium sulfate, evaporated and a white solid is obtained which is crystallized in petroleum ether. 13.5 g (yield 83%) of the desired carbonate are obtained. It is possible to eliminate this recrystallization. In this case, the yield is 94%, and the resulting product has a satisfactory purity.
    Method B. They act similarly to Method A, but they replace pyridine with three ples. The reaction is carried out for 1 hour at, and then for another 1 hour at ambient temperature. The organic phase is washed quickly with a saturated solution of NaHS04. After evaporation, the carbonate of N-oxysuccinimide is crystallized in ethyl ether (83%).
    Method C. Add 27 g (0.11 mol) of chloroformate 1,2,2,2-
    - tetrachloroethyl to a suspension of 18.4 g (0.1 mol) of 2,4-dinitrophenol in 150 ml of benzene and 150 ml of petroleum ether. Cooling is carried out.
    0 ° C and 11 g (0.11 mol) of triethylamine was added dropwise, maintaining vigorous stirring. Stirring is carried out for 4 hours.
    at 20 ° C, after which the filtration is carried out through a layer of celite. Extract solvents and obtain 26 g (66%) of white crystals after washing in a small amount of petroleum ether.
    Example 11. Preparation of H- (tre: -butyloxycarbonyl) -L-alaninate L-succinimidyl a.
    Dissolve in 0.95 g (5 mmol) of H- (tert-butyloxycarbonyl) -b-alanine and 0.66 ml (5.5 mmol) of N-methylmorpho: linine in 6 ml of THF, then add mixture 1, 8 g (5.5 mol) of succinimidyl carbonate and 1,2,2,2-tetrachloroethyl. Stir for 2 hours at 20 ° C. Approximately 25 ml of ethyl acetate is added, the organic phase is washed quickly.
    1n. HC1 solution, then potassium bicarbonate solution and washing twice
    Q 5
    0 5
    0
    with
    0
    d
    0
    five
    Yut water. The precipitation was carried out on magnesium sulphate, then evaporated. The residue is crystallized in a mixture of ethyl acetate-ethyl ether and obtain 1.25 g (87%) of white crystals. Evaporation of the uterine waters and crystallization allow one more glue to be recovered, 1 g, which raises the yield to 94%. F (melting point) 158 ° C; Co (0 -50.7 (, dioxane).
    Example 12. Preparation of - (t-butyloxycarbonyl) -KE-benzyl-oxycarbonyl) -L-lysinate N-succinimidyl.
    1.64 g (5 mmol) of N-succinimidyl carbonate and 1, 2/2, 2-tetrachloroethyl are added to a solution of 1.9 g (5 mmol) of Nd-BOC-NE-z-lysine and 0, 7 ml (5 mmol) of triethylag 1 in 15 ml of THF. Stirring is carried out at ambient temperature for 2 hours. Then 20 ml of ethyl acetate are added and the organic phase is washed with 0.5N. citric acid solution, then three times in 5% sodium bicarbonate solution and, finally, in a solution saturated with sodium chloride. Dry on sodium sulfate and evaporate to dryness. Obtain 2.03 i (85%) of white crystals. F 110 ° C, -21.51 (, dioxane).
    Calculated: C 56.79; H 6.79; N 8.64.
    C, DzNe080-5N.20
    Found: C, 56.32; H 6.44; N 8.77.
    PRI me R s 13-29. As described in Example 1 or 2, other N-succinimidyl esters are prepared. All the results obtained are collected in table 2,
     Example 30. Obtaining N- - (tert-butyloxycarbonyl) -b-fensh1-alaninate N-succinimidyl.
    To a solution of 1.33 g (5 mmol) of BOC-L-phenylalanine in 6 ml of THF, 0.8 g of anhydrous potassium carbonate and 1.8 g of 1,2,2,2-tetrachloroethyl carbonate and N-succinimide were added. . The mixture is stirred for 2 hours and then it is worked up as in Example 11. 1.15 g (63%) of BOC-L-Phe-OSu, F 135 C, are obtained.
    If 1 ml of an aqueous solution of potassium carbonate is used instead of anhydrous potassium carbonate, then 1.3 g (72%) of the indicated ester is obtained.
    Example 31. Preparation of N-tert-Buty icarbo NIH glycine and N-succinimidyl
    Act similar to that specified in example 11, while replacing THF with acetonitrile. From 1.76 g of BOC-glycine, 2.1 g (77%) of BOC-Gly-OSu F 158 ° C is obtained (known).
    Example 32. Preparation of N-succinimidyl N- - (tert-butyloxycarbonyl) -b-phenyl-alaninate.
    To a solution of 1.33 g (5 mmol) of BOC-L-phenylalanine in 6 ml of THF, 0.66 ml of N-methylmorpholine and 1.11 g (5 mmol) of 1-chloro-ethyl and N-succinimidyl carbonate were added. Stirring is carried out for 16 hours at which time it is treated as in Example 11. 1.40 g (77%) of BOC-L-Phe-OSu, F, about 3 D -16.6 (2, 2, dioxane) are obtained .
    Example 33. Preparation of N- - (tert-butyloxycarbonyl) -b-alaninate 2-x. Porphenylchloromethyl.
    To a solution of 0.95 g (5 mmol) of BOC-L-alanine and 0.66 kn of N-methyl morpholine in 6 ml of THF was added 2.0 g of carbonate-2-chlorophenyl chloromethyl and N-succinimidyl. Stirring is carried out for 1 hour 30 minutes at 20 ° C, then it is operated as in Example 11. 1.25 g (90%) of BOC-L-Ala-OSu, F 158-159 s, lcl are obtained. -49.5 (, dioxane).
    Examples 34-42. Preparation of 2,4,5-trichlorophenyl esters.
    These esters are prepared analogously to example 11 or 12 using 1,2,2,2-tetrachloroethyl and 2,4,5-trichlorophenyl carbonate. The results obtained are summarized in table 3.
    , Example 43. Preparation of N-tert-butyloxycarbonyl-b-alaninate pentachlorophenyl.
    Operate as in Example 12, From 2.04 g (5 mmol) of BOC-L-alanine and 2.27 g (5 mmol) of pentachlorophenyl carbonate and 1,2,2,2-tetrachloroethyl, 2.06 g (94%) of white are obtained. Cristaps (recrystallization solvent is ethyl acetate-hexane), F 170 C, lcill -24.47 (. CHClj), Pu9b Tbb C, L1 -22.2 (, 1, СНС1з).
    Example 44. Preparation of N-tert-butyloxycarbonyl-IE-benzyloxycarbonyl-1-lysinate pentachlorophenyl.
    0
    Anlpoguchir operate as in Example 12. Of 1.9 g of No (-BOC-NE-zL-lysine, l, 2.4 g (77%) of NC are obtained BOC-NE-ZL-Lizin-ORSR, F, -16.7 (s 1, CHCl j), F, B 141V.,: 1, -13.0 (c 4.99, CHCl j).
    Example 45: Preparation of N-tert-butyloxycarbonyl-b-phenylalaninate of 4-nitrophenyl.
    0.73 g (2.75 mmol) of BOC-L-phenylalanine and 0.3 ml of N-methylmorpholine are dissolved in 6 ui of THF and added in 87 g (2.5 mmol) of carbonate 1,2,2,2- tetrachloroethyl and 4-nitrophenyl. Stirring is carried out for 1 hour at ambient temperature. Then, 15 ml of ethyl acetate is added and washed in a solution of normal hydrochloric acid, and then in a sodium chloride solution. Drying is carried out on magnesium sulphate. It is evaporated to dryness and crystallized in 95% ethanol. 0.6 g of 5 (62%) white crystals are obtained, F, -20.9 (, DMF). F 38 38 C, -21 (, DMF).
    Example 46. Preparation of N-tert-butyloxycarbonyl) -L-alanine-0-2,4-dinitrophenyl,
    The procedure is the same as in example 45. From 0.945 g (5 mmol) of N-BOC-L-alanine, 1.45 g (82%) of N-BOC-L-Ala-0-2,4-DNP crystalline in 95% is obtained ethanol, F 95-96 ° C, Qo (5-51.5 (, 2, DMF).
    Examples 47-54. Preparation of pentafluorophenyl esters.
    . Operate analogously to example 1. The results are collected in table 4,
    EXAMPLE 55. Preparation of N- - (tert-butyloxycarbonyl) -b-phenyl alaninate pentafluorophenyl.
    Act analogously to example 48, while changing the reaction solvent. The results are shown in table 5.
    PRI me R s 56. Examples 56 and 57 illustrate the use of active esters of amine-containing acids in the synthesis of di- and tripeptides). Preparation of H- (BOC-b-phenylalanine glycinate ethyl) BOC-Phe-Gly-OEt).
    To a solution of 0.86 g (2 mmol) of N- (t- -butoxycarbonyl) -L-phenylalaninate pentafluorophenyl, prepared according to example 48 in 10 MP dioxane, was simultaneously added 0.28 g (2.2 mmol) of ethyl glycinate (hydrochloride) and
    0
    five
    0
    five
    0.31 g (3 mmol) of triethylamine. Stir for 1 hour at ambient temperature. The mixture is then diluted with 10 ml of ethyl acetate and washed with aqueous solutions of 0.1 and. hydrochloric acid, potassium bicarbonate and sodium chloride. Dried on magnesium sulfate, then evaporated. The residue is dissolved in a 4/6 ethyl acetate-hexane mixture, then filtered on silica. After evaporation, 0.53 i (76%) is obtained.
    in love
    mixtures of ethyl petat-hexane, F in-nS C, -24.6 (s 1,
     120 С, -26 (с 1,
    ten
    BOC-Phe-Gly-OEt, F
    8.9 C,

    and
    EtOH), Г „ev EtOH).
    Example 58. Preparation of N-succinimidyl 2,2-di-methyl acrylate.
    1.63 g of 1,2,2,2-tetrachloroethyl carbonate and N-succinimidyl and 0.7 ml of triethylamine are added to 0.5 g of 2,2-dimethylacrylic acid taken in 1.5 M THF THF. . Stir for 2 hours at 20 ° C, then wash with a strainer
    -4.8 (c 5.0, EtOH), F iBe 89.5 C, with sodium. Dried on magnesium sulphate, per (JO. - -
    Co / J -4.2 (c 5, EtOH).
    Example 57. Preparation of N-β-benzyloxycarbonyl-prolinyl-glycyl-glycinate ethyl
    the solvent is evaporated. Get 0.6 ester. Win ml
    g (56%) of the desired complex
    (CDC1
    TMS): 2.05 (S, CHj); 8 (S, CH, CH); 5.9
    z-Pro-GlyOH-z-PrO-Gly-OPFP
    -PrO-Gly-Gly-OEt
    zAdd 1.4 g (3.6 mmol) of 1,2,2,2-tetrachloroethyl carbonate and pentafluorophenyl to a solution of 1.07 g (3.6 mmol) of N-benzyloxycarbonyl-propyl-glycine and 0.4 ml N-methylmorpholine in 5 ml of dioxane. Stirring is carried out for 1 hour at 20 ° C, after which it is operated as in Example 55. 0.82 g (45%) of z-Pro-Gly-OPFP, Co-36.8 (c 1, dioxane) are obtained.
    Dissolve these 0.8 g in 10 nl dioxane, then 0.23 g (1.8 mmol) ethyl glycinate hydrochloride and 0.24 g triethylamine are added at the same time. Then, they act in a similar manner to Example 55. 0.55 g (94%) of z-Pro-Gly-Gly-OEt, F 95-96 ° C, o (-21.4 (c 1, EtOH)) is obtained, which is recrystallized in
    mixtures of ethyl petat-hexane, F in-nS C, -24.6 (s 1,
     120 С, -26 (с 1,
    EtOH), Г „ev EtOH).
    Example 58. Preparation of N-succinimidyl 2,2-di-methyl acrylate.
    1.63 g of 1,2,2,2-tetrachloroethyl carbonate and N-succinimidyl and 0.7 ml of triethylamine are added to 0.5 g of 2,2-dimethylacrylic acid taken in 1.5 M THF THF. . Stir for 2 hours at 20 ° C, then wash with a strainer

    the solvent is evaporated. Get 0.6 ester. Win ml
    g (56%) of the desired complex
    (CDC1
    0
    2.2 (S, CHj),
    five
    0
    five
    0
    TMS): 2.05 (S, CHj); 8 (S, CH, CH); 5.9
    (m, ns).
    Example 59. Preparation of N-succinimidyl 2-thiophencarboxylate.
    Act similarly to the previous example. From 0.64 g of 2-thiophenecarboxylic acid, 0.62 g (51%) is obtained, F 140-1424.
    RMN (CDClI, TMS): 2.8 (CH, CH,) i 7.0-7.2 (M, H-C), -7.6 (M, H-C); 7.8 (M, H-C).
    The proposed method makes it possible to produce carboxylic acid esters by a simpler, more economical method and with a yield of 98% versus 30% in the known method. Simplification of the process is achieved by using alpha-chlorocarbonate and carrying out the process in an inert organic solvent in the presence of a hydrohalic acid acceptor. In this case, the process proceeds with the failure of communication according to the scheme
    RiOCOOCH-R2 + Y-COOH- RiOC-Y4-R2CHO + HX + C02
    In addition, the dissociation of by-products to aldehyde and hydrochloric acid makes the inversion of the reaction impossible, which gives the method an additional advantage leading to a good yield and a high degree of purity of the obtained carboxylic esters. Formula and 3 gain e no
    1. A process for the preparation of carboxylic acid esters of the general formula
    Ri-0-C-Y
    inc
    ABOUT
    0
    five
    about
    where Y is the residue of -2,2-dimethylacrylic acid, -2-thiophenecarboxylic acid or -M-substituted amino acid, of the formula
    BOC-A, where A is Ala, Phe, Gly, Val, PrO,
    Tyr, Trp, Met, Ser, z-Lys, (OBzl) Ser, (OBzl) Thr, (OBzl) Tyr, (OBzl) Glu, Cys, (SBzl) Cys, DNP-His, (OBzl) Lys, Z-A,
    where A is Ala, Pro, Met. F-MOC-A,
    where A is Ala, Phe, Pro R. - 0
    r Cl ,, Cl
    is-, ci- {a -, C1- / YH, 0c ci ci
    Cl v- (f
    ci- /. (o) CIF F
    , N02 N O N / OX- 1 N () T
    including the interaction of a carboxylic acid derivative with a carboxylic acid, is also distinguished by i- with the fact that., in order to simplify the process, alpha chlorine carbonate of the general formula is used as a carboxylic acid derivative.
    Ri-0-C-p-CH-Ro
    权利要求:
    Claims (3)
    [1]
    1 II, I i
    About C1
    where R has the indicated meanings, RJ - CClj, C-C5 alkyl or
    C1 Cl-M-O O-x CClj
    ..
    C O C1
    C1
    / g about
    64-716.73 ()
    7.4 (“)
    701
    E0.02- 16.7 () 150-155 7.4 () 7.56 ()
    .a C1
     C1-O- (
    98
    AcOES1206.7 (t)
    91
    6 с75П "tro-80.05- 6.7 ()
    ABOUT 1657.3 (d)
    G-698.36 (d)
    CI
    a as a carbon kig.loty use compound f (
    .Y-COOH,
    where Y has the indicated value, and the process is carried out in an environment of an inorganic organic solvent P with the presence of an acceptor gal1L1dns1- hydrogen
    acid.
    [2]
    2. The method according to p. 1, about tl and hp ush and so that the solvent is used as an inert organic solvent, lypran
    groups containing tetrahydrofuram, dioxane, ethyl acetate, dimethylph. pmid, methanol.
    [3]
    3. The method according to A.1, about tl and h and Yu and shchu that kachestpe
    a hydrochloric acid acceptor use tertiary ammonia, preferably triethyl # 1n or N-methylmorpholine.
    Table 1
    Element Analysis
    6.73 ()
    7.4 (“)
    16.7 () 7.4 () 7.56 ()
    6.7 (t)
    0 6.7 ()
    6.7 ()
    7.3 (d)
    8.36 (d)
    1800
    1795
    tsoo
    1800
    1790
    Found: C, 26.00;
    H 1.74; N 4.10; From 23.54v
    Cl 43.55.
    Calculated: C 25,871
    H 1.55; N 4.311
    About 24.6; C1 43.55
    Found: C 26.61
    H 1.02; O AND, 56;
    C1 60.80.
    Calculate about: -C 26,
    H 0.74; O 11.78;
    C1 60.93.
    Found: C, 26.67;
    H 0.90} About t1.95i
    Cl 60.64.
    Calculated: C, 26.54;
    B 0.74; O 11.78;
    C1 60.93
    Found: C, 22.40
    H traces {C1 67,15.
    Calculated: From 22.66 |
    U 0.27; C1 67.05.
    Found; C, 27.60;
    H 0.47; C1 35.80i
    F 24.56.
    Calculation; From 27.44k
    B 0.26; with; 36.00;
    F 24.12.
    Weideno: C 30.87;
    B 1.53; I am 3.81
    C 22.23i Cl 41.15.
    Calculated from 30.97
    a 1.44; I am 4.01;
    O, 22.92; C1 40.6.
    i:; :: i
    NO,
     c 66
    D
    S (ci0
    N4 9 Cl Nf yN-O- O CCl to 8
    To xe
    L / N-Osji Ox- CClj A 66 0 Cl
    Petro-Leica
    J 6 t
    Extension; Table 1
    irnznzrzz
    0-122
    6.73 (")
    8.60 (a)
    9.06 (d)
    7.66 (d)
    1795
    1750
    1770 1790
    1750
    Found: C, 27.49;
    H 1.04; N 6.98 (
    About 27.99, C1 35.95.
    C, 27.44; H, 1.02; N 7; About 28.43i
    Cl 36.00
    M 18 336
    .thirty;
    Found: C, 31.98; H, 1.37; H 12.16; C1 41.03
    Calculated; C 31, I l, 45i I 12,17; C1 41.16) Found: C 37.80; H 3.64-, N 6.24; About 36.68; C1 15.88 Calculated: C 37.94 | H 3.64; N 6.32; About 36.10, C1 16.00.
    taOnHna 2
    Table 3
    13
    THF
    Dioxane Ethyl acetate DMF
    1A93102
    14 Table 4
    Table 5
    112 113 112 107
    16.9 -16.4 15.4 14.2
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    申请号 | 申请日 | 专利标题
    FR8418433A|FR2574075B1|1984-12-04|1984-12-04|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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