• 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 heterocyclic substances, in particular the hydrophilic derivatives of oxyisoindoline with the general formula I CH CH-CH-C C-CH-NX-C 0, where XC H H4 is napa CHR-C (0) -0-R ,; C4 alkyl; or C - C4-alkyl, or their pharmaceutically acceptable salts, which have analgesic and anti-inflammatory activity, which can be used in medicine. The goal of avoiding increasing the yield of the target product. Synthesis is carried out by reacting phthalic anhydride with a right-rotating amine of the total IIH -N-CgH-napa-CHR-C (0) -OR, followed by reduction of the resulting product and isolation of the target product in free form or in the form of the desired salt. If it is combined, then it is eterified. When compound II is used as a racemate, they are preliminarily optically separated into optical isomers with separation of almost 100% of the jj – J amine isomer, which racemized if necessary,. These conditions allow to obtain the desired right-handed isomer of a desired product with a high yield. YO XJ
    公开号:SU1731046A3
    申请号:SU884355276
    申请日:1988-03-09
    公开日:1992-04-30
    发明作者:Карниель Джованни；Орци Фабрицио；Черони Джорджио；Миорини Бруно；Гриджи Пьерлуиджи
    申请人:Фармиталиа Карло Эрба С.Р.Л. (Фирма)；
    IPC主号:
    专利说明:

    51
    under vacuum at 70 ° C to obtain 2.2 g of a crude product, which, after recrystallization from 95% ethanol, gives pure (+) (1-oxo 2 isoindolinyl) phenyl propionic acid (2 g), TgS 207-208 ° C , Vf t77,41 ° (С 1%, DMF) „
    Example 40 A suspension (i) of 2- (4-aminophenyl) butyric acid (100 and L (+) tartaric acid (83.7 g) is heated under reflux in anhydrous ethanol (2000 ml) until complete dissolution and the resulting salt is crystallized for at room temperature. The precipitate is filtered and repeatedly crystallized from anhydrous ethanol.
    The salt obtained is dried under vacuum at 50 ° С to obtain 70 g of the right
    common salt of tartrate, fo (J + 57 ° (C 1%, DMF) o To isolate the optically active acid, the salt is suspended in water and then sodium hydroxide is added until the pH is equal to #: 4 - 5 "The resulting suspension filter and wash the solid with water and dry under vacuum at 60 ° C to obtain (+) 2- (4-aminophenyl) butyric acid, (35 g), Topl, 157-158 ° C, oQ, 0 + 75 ° (C 0 , 1%, MeOH) s All mother liquors after the initial filtration and recrystallization of the tartrate salt are collected and distilled to dryness under vacuum. The obtained solid residue is dissolved in water (60 0 ml, 5 volumes) and calcium hydroxide (40 g) is added. The suspension is heated with stirring at 50 ° C. After 5 hours, the precipitated calcium tartrate is filtered and the L (+) tartaric acid is separated by acidification and recycled “The filtered aqueous solution is treated with 35% sodium hydroxide (200 g), evaporated at normal pressure to half the original volume and then heated under reflux.
    After 24 hours, the solution is acidified and the precipitate is collected by filtration, washed with water and dried under vacuum at 60. To obtain 50 g of the isolated racemic (+) 2- (4-aminophenyl) butyric acid, mp 143-144 ° C, ( XJ P ° (C 0.1%, MeOH).
    Example 5. A mixture of phthalic anhydride (8.5 g) and (+) 2- (4-aminophenyl) butyric acid (9 g) in ice-cold





    five
    0
    0
    five
    0
    acetic acid (140 ml) is heated under reflux for 8 h, then cooled at about
    LO
    20 C. The resulting precipitate is filtered, washed with water (100 ml) and dried under vacuum at 50 ° C to obtain (+) 2-Ј4- (1; 3-dioxo -2-isoindolinyl) phenyl butyric acid (13.4 g ), so pl. 234 - 237 ° С, Ы;} Ј + 71 ° (С 1%, DMF).
    EXAMPLE 6 A mixture of phthalic anhydride (17.9 g), 35% sodium hydroxide (15 g) and tartrate salt (+) 2- (4-aminophenyl) butyric acid (12.7 g) is heated with a reflux cooler for 6 hours and then cooled at K. 50 ° Co
    The resulting precipitate is filtered, washed with water at 50 ° C (100 ml) and dried under vacuum at 50 ° C to obtain (+) (1,3-dioxo 2 isoindoyl and nyl) phenyl butyric acid (10 g),
    - LCH-l CL. .G
    + 7.1 ° (C
    m.p. 234 - 237 ° С, ООД 5 1%, DMF)
    Example 7 A mixture (Ј) (1-oxo-2-isoindolinyl) phenyl butyric acid (18 g), ethanol (20 ml) and sulfuric acid (1 ml) is chemically reacted for 4 hours at room temperature. Then the mixture is vaporized. is evaporated to dryness and the evaporation residue is dissolved in chloroform (200 ml). Sodium bicarbonate is extracted and the organic phase is washed with water and evaporated to dryness, resulting in (+) ethyl ester (1-oxo-2-isoindolinyl / phenyl butyric acid (13 g), with a TopPLo of 124.5 - 125.5 ° C,
    five
    0
    five
    Example 8 Compound (+) 2-4 / 1-oxo-2-isoindolinyl / phenylpropionic acid (11 g) is suspended in a dilute solution of 35% NaOH (4.37 g) in water (85 ml) and the mixture is stirred at 22 ° C for 1.5 hours. The suspension is filtered and the filtrate is evaporated in vacuo to remove water. The evaporation residue is dissolved in ethanol. It is heated to 50 ° C until a complete solution is obtained. Then the solution is slowly cooled to 20 ° C, filtered and the filter cake is washed with ethanol and dried, the result is the sodium salt (+) (1-oxo-2-isoindolinyl) fe -
    Editor A.Dolinich
    mil li I | 1ts1 | 11 I. .1 | i I I..I li li Ulil.J.
    Compiled by I. Bocharova
    Tehred M. Morgen ta l Corrector -I. Beskids
    I | | | | B i -... i ..-.
    权利要求:
    Claims (1)
    [1]
    Claim.
    The method of obtaining dextrorotatory derivatives of oxyisoindolinyl of the general formula (I)
    O ^ -0-ch-coor,, 0 OK where R is C ^ -C. Alkyl;
    R | - hydrogen or C ^ -C ^ -alkyl, 'or their pharmaceutically acceptable salts, by reacting a compound 06— of the general formula (II)' R where R and R <have the indicated meanings, * с'о-phthalic anhydride followed by 2 to 5 reduction the resulting compound of "General" formula (III) using the stage of separation of the racemate into optical isomers, characterized in that, in order to increase the yield of the target product, the compounds of general formula (II) in the form of a racemate are preliminarily separated into optical isomers and interaction of o — phthalic anhydride with the dextrorotatory isomer of the compound of general formula (II) followed by reduction of the optically active compound of general formula (III) and isolation of the desired product in its free form or in the form of a pharmaceutically acceptable salt, or, when hydrogen is used, the compound of general formula I is ester-), and the levorotatory isomer of COE — the compounds of general formula II, if necessary, racemize.
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    同族专利:
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    PH26254A|1992-04-01|
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    BE1003280A3|1992-02-18|
    NL8800575A|1988-10-03|
    IE60565B1|1994-07-27|
    SE8800846L|1988-09-11|
    JPS63238058A|1988-10-04|
    AU1267988A|1988-09-08|
    GB2204579B|1991-01-30|
    KR880011096A|1988-10-26|
    GR880100137A|1989-01-31|
    JPH0759555B2|1995-06-28|
    CN88101200A|1988-10-26|
    NO881055L|1988-09-12|
    DK128988A|1988-09-11|
    GB8805631D0|1988-04-07|
    FI881075A0|1988-03-09|
    FR2612185A1|1988-09-16|
    FR2612185B1|1992-08-28|
    PT86933A|1988-04-01|
    DK168568B1|1994-04-25|
    AU605253B2|1991-01-10|
    ATA58988A|1990-07-15|
    NO174666C|1994-06-15|
    NZ223805A|1990-11-27|
    DK128988D0|1988-03-09|
    GB8705601D0|1987-04-15|
    UA12840A1|1997-02-28|
    YU46565B|1993-11-16|
    ES2006361A6|1989-04-16|
    FI881075A|1988-09-11|
    HU201011B|1990-09-28|
    FI93725C|1995-05-26|
    IL85651D0|1988-08-31|
    ZA881686B|1989-11-29|
    SE500710C2|1994-08-15|
    FI93725B|1995-02-15|
    AT392068B|1991-01-25|
    IT1227787B|1991-05-07|
    IL85651A|1991-07-18|
    HUT47247A|1989-02-28|
    IE880648L|1988-09-10|
    DE3807595A1|1988-09-22|
    CN1017527B|1992-07-22|
    IT8819683D0|1988-03-08|
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    MY103898A|1993-10-30|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE2154525A1|1970-11-05|1972-06-15|Carlo Erba S.P.A., Mailand |Isoindoline derivatives and processes for their preparation|
    GB1344663A|1970-11-10|1974-01-23|Erba Carlo Spa|Isoindoline compounds|
    US4010274A|1973-07-27|1977-03-01|Carlo Erba|Isoindoline derivatives having platelet anti-aggregating activity|
    JPS5336467B2|1974-07-04|1978-10-03|
    US4400520A|1980-09-10|1983-08-23|Hisamitsu Pharmaceutical Co., Inc.|Novel process for preparing isoindoline derivatives|
    IT1201408B|1985-03-22|1989-02-02|Montedison Spa|PROCESS FOR THE BIOTECHNOLOGICAL PREPARATION OF OPTICALLY ACTIVE ALFA-ARILALCANOIC ACIDS|
    JPH07120969B2|1989-03-30|1995-12-20|クラリオン株式会社|Spread spectrum modulator|US5272158A|1991-10-29|1993-12-21|Merck & Co., Inc.|Fibrinogen receptor antagonists|
    IT1256450B|1992-11-26|1995-12-05|Soldato Piero Del|NITRIC ESTERS WITH PHARMACOLOGICAL ACTIVITY AND PROCEDURE FOR THEIR PREPARATION|
    US5719144A|1995-02-22|1998-02-17|Merck & Co., Inc.|Fibrinogen receptor antagonists|
    US5981584A|1997-02-06|1999-11-09|Merck & Co., Inc.|Fibrinogen receptor antagonist prodrugs|
    CN100400633C|2006-03-30|2008-07-09|中国日用化学工业研究院|Detergent for washing dishware with hand and its preparation method|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB878705601A|GB8705601D0|1987-03-10|1987-03-10|Oxo-isoindolinyl derivatives|
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