• 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:
    There is disclosed a process for preparing 9-(2-hydroxyethoxymethyl)-guanine (acyclovir) of the formula IV <IMAGE> IV wherein a novel compound of the formula I <IMAGE> I wherein R and R' may be the same or different and represent hydrogen, (C1-C8)acyl or benzyl and R1 represents (C1-C8)acyl, is hydrolyzed under mild basic conditions. Also disclosed is the novel compound of the formula I, a process for the preparation thereof by condensing a novel compound of the formula II <IMAGE> II with a compound A-CH2-O-CH2CH2-OR' (A is a leaving group, Q is hydrogen or a leaving group), the novel compound of the formula II and a process for the preparation thereof by means of condensing glyoxal hydrate and a compound of the formula V <IMAGE> V
    公开号:SU1454253A3
    申请号:SU853990801
    申请日:1985-12-19
    公开日:1989-01-23
    发明作者:Кобе Йоже；Гнидовец Йоже；Зупет Павле
    申请人:Крка,Товарна Здравил,Н.Сол.О (Инопредприятие)；
    IPC主号:
    专利说明:


    s
    The invention relates to a method for producing 9- (2-hydroxyethoxymethyl) guanine, which has antiviral activity, which can be used in the medical industry.
    The purpose of the invention is to increase the yield of the target product.
    I Example 1. N2, 9 (7) -Diacetyl- I guanine. I Guanine (152 g) is suspended in N-methyl-2-pyrrolidone (800 ml) and with x-anhydride (250 liters). The reaction j mixture is heated before and pereimeni: wave within 2-3 hours to complete: about the dissolution of guanine. After that, the solution is cooled to room temperature and left to stand overnight in a refrigerator. The precipitation of crystals I is aspirated and washed with 50 ml of fresh; ethyl acetate. The resulting product is dried in an oven at 50 ° C to a constant weight. “200 g, 9 (7) -diacetylguanine (yield –85%) are obtained in a recipe. The mother liquor from filtration is F (the reaction mixture is returned to the reactor, guanine (100 g) and acetic anhydride (150 ml) are added to it, and the whole process is repeated. As a result, 150 g of N2, 9 are obtained (7) -diacetylguanine. Total yield, product 96%,
    PRI mme R 2. The product is attached or glyoxal to N-acetylguanine.
    Glyoxal monohydrate (280 g) Suspended naryug in dry pyridine (950 ml) and the reaction mixture is stirred for 1 h at which time all the glyoxal dissolves in pyrmideneo. (236 g) and the reaction mixture is vigorously stirred for 1.5 hours. After that, pyridine is distilled off at 50 ° C under vacuum (67 mbar.), Water (1000 ml) is added to the residue, and stirring is continued for half an hour. whereby the solid residue is dissolved. The azeotropic mixture of pyridine and water (400 ml) is distilled off at 50 ° C under reduced pressure. Already in the process of distillation begins to fall white precipitate. The residue is drunk in cold water (2500 kt), the mixture is overlaid for 1 hour and left to stand overnight in a refrigerator. The precipitate is filtered off with suction, washed with water (150 ml) and dried in a drying cabinet. An inductance of 227 g of adduct (R is a hydrogen atom,, R is CHgCO (90%), mp 223 C of the formula
    The results of the analysis correspond to the formula CgHgNjO. m / 1 251. 1I-NMR (DMSO - d,) .- 2.68 (s, 3,); 5.55 (yes, 2, CH); 8.10 (s, 1 Hg):
    Example 3: Adduct of tetraacetylglyoxalguanine.
    The adduct of this formula 252 g (R-H) is dissolved in pyridine (2500 ml). Acetic anhydride (280 mp) is poured into the solution and stirring is continued for 1.5 h at room temperature. After that, pyridine is distilled off at 50 ° C under reduced pressure, ethyl acetate (1000 ml) is added to the residue, and the mixture is stirred for 1 hour at room temperature; then left in the refrigerator overnight. The precipitated white crystals are sucked off, washed with ethyl acetate (150 ml) and dried in a drying oven to constant weight. The result is 272 g (72%) of the product (where R Q -).
    The ethyl acetate is washed three times with 5% sodium bicarbonate solution and then with water, dried with sodium sulfate and evaporated to dryness, resulting in an additional 72 g of the expected product. Total yield 93%, so pl. 197-199 C (after recrystallization from ethyl acetate).
    The results of the analysis correspond to the formula fjNjO, m / e 377.
    1H-NMR (SDTS, sG): 2.1 (ds, 6As); 2.7 (s, 3, N Ac); 2.83 (s, 3, NAc); 6.8 (broad, 2, CH); 8.35 (s,, 1Hg).
    Example 4: Adduct of diacetoxyglyoxal and N acetyl-guanine.
    Method A. An adduct of the indicated formula 252 g (R-H, Q-H) is dissolved in a mixture of pyridine (2500 ml) and acetic anhydride (280 ml).
    The mixture is stirred for 1.5 hours at room temperature, pyridine
    ten
    15
    20
    25
    was distilled off at 50 ° C under reduced pressure, 50% ethyl alcohol (800 ml) was added to the residue and the mixture was heated to boiling. The reflux was continued for 15 minutes until a clear solution was obtained, after which the contents were slowly cooled to room temperature and left in the refrigerator overnight. The precipitated crystals 1 are sucked off, washed with 50% ethanol and dried in a drying cabinet. Yield 234 g (70%). T. pl. 242-.
    The results of the analysis correspond to the formula / e 335.
    1H-NMR (SDS1e, e „5): 2.15 (s, 6, Ac); 2.83 (s, 3, NAc); 6.82, 6.93 (dd, 2, CH); 8.15 (s, 1, Hg).
    Method B. A compound of the indicated formula 272 g (R - Ac, Q - Ac) is suspended in 50% ethyl alcohol (1200 mp), the suspension is boiled for 15 minutes under reflux until everything the solid is not dissolved. After that, the contents of the flask are slowly cooled to room temperature and placed in a refrigerator overnight. The falling out crystals are sucked off, washed with 50% ethyl alcohol and dried. The result is 173 g (72%) of the product (R - Ac, Q - H).
    PRI me R 5. Method A. The product g is the addition of 9- (2-acetoxyethoxymethyl) -diacetoxyglyoxal and N-acetyl-guanine (R - CHjCO, R, - CHjCO).
    A mixture of the above compound 3.85 g (R - CHjCO, R, - CHjCO, Q - H) and 2-JO oxo-1,4-butane-diol diacetate (R -) (2 g) and p-toluenesulfonic acid (0.03 d) stirred in dry toluene (40 ml) for 7 hours at reflux. Thereafter, toluene is distilled off to dryness, benzene (150 ml) is added to the residue, the suspension is heated with stirring to a boil and filtered while hot through a glass filter. 2 g (44%) of the compound R - CHjCO remain on the filter; R — CHjCO), R — CHjCO, which recrystallizes from toluene, mp. 197-199 C.
    2,); 3.74 (m, 2CH20); 5.5 (s, 2, men ,, ,,); 6.87 (dd, s, CH); 7.84 (s, 1, H,).
    PRI me R 6. Method B. Adduct diisobutyroxyglyoxal and N-acetyl-guanine (ROCCH- (CHD) 2, CHjCG
    Q - H).
    A compound of the indicated 1.26 g (R-H, R, -CHjCO; Q-H) is suspended in pyridine (25 ml), isobutyric acid anhydride (2.5 ml) is added to the suspension and the mixture is left overnight at stirring. After that, pyridine was distilled off, the residue was dissolved in ethyl acetate and the resulting solution was washed first with water (40 ml), then with 5% sodium bicarbonate solution (three times with 20 ml portions) and finally with water (20 ml). The washed solution is dried with sodium sulfate and as a result, 1.55 g of crude product is obtained, to which 50% ethyl alcohol is added and the mixture is boiled for 15 minutes under reflux. The resulting solution was evaporated and a small amount of ethyl acetate was added to the residue. The result .. 1,2 g of the target product with so pl. 171-172 seconds
    The results of the analysis correspond to the formula C 1 391.
    1 H-NMR (CDS1, AMS): t, t6 (s, 3, CH (CHz) 2, 1.25 (s, 3, CH (SI.)); 2.53 (m, 2, CH () 2); 2.8 (s, 3, NAc); 6.7 (dd, 2, CH); 8.15 (s. 1, Hg).
    Example 7. Addition product of 9- (2-acetoxyethoxymethyl) diisobutyroxyglyoxal and N-acetylguanine.
    The compound of the indicated 200 mg (R - COCH (CHj), CHjCO, Q - H) is boiled for 5 min with a reverse refrigeration in hexamethyldisilazane in the presence of a catalytic amount of ammonium sulfate. During this time, all of the starting material is dissolved and a silylated compound is formed (R - COCH (CHj)., CHjCO, Q - -51- (CH3) h), which is dissolved immediately after the distillation of the excess solvent in dry benzene (15 ml ) and add to the solution mercury dibromide
    50
    f-- - t, f, l tJI J Ji fifJt Y Y
    The results of the analysis based on gg (180 mg) and BrCH OCHjCH OAc (100 mg).
    ..L ......... / -. /. C4
    formula C, gH fN503; m / e 4-51.
    1 H-NMR (SDS1, cf-rMs): 2.05 (s, 3, Ac); 2.12 (s, 3, Ac); 2.25 (s, 3, Ac); 2.75 (s, 3 N Ac); 3.69 (m
    The mixture was left overnight, refluxed, after which the solvent was distilled off, and the residue was dissolved in chloroform. Received by
    ten
    15
    20
    25

    ZO
    g
    JO
    2,); 3.74 (m, 2CH20); 5.5 (s, 2, men ,, ,,); 6.87 (dd, s, CH); 7.84 (s, 1, H,).
    PRI me R 6. Method B. Adduct diisobutyroxyglyoxal and N-acetyl-guanine (ROCCH- (CHD) 2, CHjCG.
    Q - H).
    The compound of the indicated 1.26 g (R - H, R, - CHjCO; Q - H) is suspended in pyridine (25 ml), isobutyric acid anhydride (2.5 ml) is added to the suspension and the mixture is left overnight with stirring . After that, pyridine was distilled off, the residue was dissolved in ethyl acetate and the resulting solution was washed first with water (40 ml), then with 5% sodium bicarbonate solution (three times with 20 ml portions) and finally with water (20 ml). The washed solution is dried with sodium sulfate and as a result, 1.55 g of crude product is obtained, to which 50% ethyl alcohol is added and the mixture is boiled for 15 minutes under reflux. The resulting solution was evaporated and a small amount of ethyl acetate was added to the residue. The result .. 1,2 g of the target product with so pl. 171-172 seconds
    The results of the analysis correspond to the formula C 1 391.
    1 H-NMR (CDS1, AMS): t, t6 (s, 3, CH (CHz) 2, 1.25 (s, 3, CH (SI.)); 2.53 (m, 2, CH () 2); 2.8 (s, 3, NAc); 6.7 (dd, 2, CH); 8.15 (s. 1, Hg).
    Example 7. Addition product of 9- (2-acetoxyethoxymethyl) diisobutyroxyglyoxal and N-acetylguanine.
    The compound of the indicated 200 mg (R - COCH (CHj), CHjCO, Q - H) is boiled for 5 min with a reverse refrigeration in hexamethyldisilazane in the presence of a catalytic amount of ammonium sulfate. During this time, all of the starting material is dissolved and a silylated compound is formed (R - COCH (CHj)., CHjCO, Q - -51- (CH3) h), which is dissolved immediately after the distillation of the excess solvent in dry benzene (15 ml ) and add to the solution mercury dibromide
    0
    - - t, f, l tJI J Ji fifJt G Y
    g (180 mg) and BrCH OCHjCH OAc (100 mg).
    (180 mg) and BrCH OCHjCH OAc (100 mg).

    The mixture was left overnight, refluxed, after which the solvent was distilled off, and the residue was dissolved in chloroform. Received by
    14
    the solution is washed with a 20% potassium iodide solution (twice in portions of 1 ~ 0 mp) and water (twice in portions of liO ml), dried with sodium sulfate vi and evaporated to form Iassa frothy. A yield of 210 mg of dry product. After chromatography on 10 g of silica gel, 120 g of compound are obtained (R - -yrene (CHj), R, - CHjCO, R-)
    I 1H-NMR (SDS1z, JVMS L11 (s, 6, f (CH3), j); 1.25 (s, 6, SI (CHj));
    2.06 (s, 3, Ac); 2.8 (s, 3, N Ac);
    3.7 (m, 2, OSI); 3.76 (m, 2, OCHa); a, 5 (s, 2, NCHiO; 6.85 (dd, 2, CH); 80 (p. 1, H).
    I Example. 9- (2-hydroxyethoxyme-1 | yl) guanine (acyclovir). Compound of this formula: 1 g (R R, R - CHjCO). Is placed in 50% methylamine solution (10 ml). With this, an exothermic reaction immediately proceeds, as a result of which 1 | the reaction mixture becomes transparent. The mixture is heated for another 5 minutes on a steam bath or left ijia overnight at room temperature, this solvent and an excess of 4 min are distilled off under reduced pressure, ethyl acetate (10 ml) is added to the residue and the solvent is again distilled off. Methyl alcohol (15 ml) is added to the residue, then methyl



    the alcohol is separated by decantation, and the residue is recrystallized from a mixture of methyl alcohol and water. The result is DOO g of the target product (yield 81%), so pl. 264-266 C, t / e 225,
    1H-NMR (DMSO-df, fi75s): 3.49 (m, | AXI.); 4.69 (s, 1, OH); 5.4 (s, 2, NCHjO); 6.54 (s, 2, NHj); 7.84 (s, 1, H “). .
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    A method for preparing 9- (2-hydroxyethoxymethyl) guanine, which involves treating the 9- (2-hydroxy-toxymethyl) guanine derivative with a base, characterized in that, in order to increase the yield of the target product,
    RO
    OR
    one
    RI
    where R, R,
    CHjOCHjCHjOR
    and R
    - identical or different, lower acyl, exposed to methylamine in water,
    Editor M. Blanan
    Compiled by V. Volkov
    Tehred A. Kravchuk Proofreader c. But ha
    . Order 7306/58
    Circulation 352
     VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, .Raushsk nab. 4/5
    Subscription
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    同族专利:
    公开号 | 公开日
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    CS966685A2|1990-03-14|
    HUT41028A|1987-03-30|
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    PL256987A1|1988-03-03|
    JPH05255328A|1993-10-05|
    JPH0529228B2|1993-04-28|
    DD246301A5|1987-06-03|
    JPH05255329A|1993-10-05|
    AT386826B|1988-10-25|
    YU219084A|1987-08-31|
    引用文献:
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    US4199574A|1974-09-02|1980-04-22|Burroughs Wellcome Co.|Methods and compositions for treating viral infections and guanine acyclic nucleosides|
    YU41079B|1976-08-27|1986-12-31|Wellcome Found|Process for the synthesis of substituted purine compounds|
    US4146715A|1975-08-27|1979-03-27|Burroughs Wellcome Co.|2-amido-9-hypoxanthines|
    BE863525A|1977-02-14|1978-07-31|Bristol Myers Co|HETEROCYCLOPYRIMIDINES|
    IL64501A|1980-12-22|1985-07-31|Astra Laekemedel Ab|9-substituted 4-hydroxybutyl guanine derivatives,their preparation and antiviral use|US4916225A|1986-11-25|1990-04-10|Institut Organicheskogo Sinteza Akademii Nauk Latviiskoi Ssr|9-substituted guanines|
    EP0289992B1|1987-05-04|1994-04-27|Kemijski Institut|Process for preparing purine derivates|
    GB8724765D0|1987-10-22|1987-11-25|Beecham Group Plc|Process|
    JPH0418053B2|1988-07-01|1992-03-26|Nippon Tangusuten Kk|
    ES2047457B1|1992-08-03|1994-10-01|Union Quimico Farma|PROCEDURE TO OBTAIN ACICLOVIR.|
    DE19839013B4|1998-08-27|2004-08-26|Degussa Ag|Process for the production of guanine|
    DE19857949A1|1998-12-16|2000-06-21|Degussa|Process for the production of guanine under pressure|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    YU219084A|YU45690B|1984-12-22|1984-12-22|PROCEDURE FOR PREPARING 9--GUANINE|
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