• 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 a new process for the preparation of N-sulfamyl-3-(2-guanidinothiazol-4-yl-methylthio)-propionitrile (famotidine) of the formula (I) <IMAGE> (I) by S-alkylation of 2-guanidino-thiazol-4-yl-methanethiol obtained from S-(2-guanidino-thiazol-4-yl-methyl)-isothiourea dihydrochloride of the formula (III) <IMAGE> (III) by in situ treatment with a base, which comprises carrying out S-alkylation with a N-sulfamyl-3-halopropionamidine of the formula (II) <IMAGE> (II) wherein X stands for halogen.
    公开号:SU1450743A3
    申请号:SU864028107
    申请日:1986-09-09
    公开日:1989-01-07
    发明作者:Дод Петер；Харшаньи Кальман；Агаи Ева；Богш Эрик；Фекеч Ева；Тришлер Ференц；Домани Дьердь；Сабадкаи Иштван；Хегедюш Бела
    申请人:Рихтер Гедеон Ведьесети Дьяр Рт (Инопредприятие)；
    IPC主号:
    专利说明:


    sn
    This invention relates to an improved process for the preparation of N-sulfamyl-3- (2-guanidino-thiazole-4-S1 methylthio) -propionamidine (famotidine), which has the property of blocking histamine H receptors and which is used in medicine as a drug: inhibiting development of tumors of the stomach and intestines.
    The aim of the invention is to increase the yield of the target product and simplify the process technology.
    The goal is achieved by the fact that S- (2- -guanidinothiazol-4-ylmethyl) -isothiocarbamide-dihydrochloride is treated with an excess of alkali in an aqueous-alcoholic medium using ethanol as the alcohol, which forms (2-guanidino-thiazol-4-yl a) methyl mercaptan is S-alkylated with N-sulfamyl-3-chloropropionamidine hydrochloride as an S-alkylating agent and the process is injected at a molar ratio of 8- (2-guanidinothiazol-4-ylmethyl) -isothiocarbamide hydrochloride N-sulfa-mil-3-chloropropionamidine and alkali 1: (1.0-1.1) :( 4.1 ± 0.2), respectively at 25 -.
    Sodium hydroxide is usually taken as the alkali, which is introduced at a temperature of from room temperature to, or a 40% aqueous solution of sodium hydroxide, which is introduced at 20,
    Example 1. To a prepared solution of 3.04 g (0.01 mol) of S- (2-guanidino-thiazol-4-ylmethyl) -isothiocarbamide-dihydrochloride and 2.22 g (0.01 mol) of L-sulfamyl-3- Clorpropionamidine hydrochloride in 8 ml of deionized water is added dropwise at 25-30 ° C. a mixture of 40 ml of 10 n.
    ten
    IR spectrum (KBr-Partille, Park Elmer 257), cm-:, 3400 NH 3360, 3240, 1635, (horse 1590 wide; SO 1288, 1Sh7.
    Proton NMR spectrum (DMSO d ,, Varian EM 360): 2.6 multiplet, Ar-CH -S 3.6 ppm, si years, Ar-H 6.5 MD, singlet, NH, N 3.5} 6.8} 7.4; 8.3 ppm wide.
    Approximately 2. To prepared in 100 ml of non-ionized water and 40 ml of isopropanol and a solution of 32.1 (0.1 mol) of 5- (2-guanidinodinothiaz-4-sh1methyl) -isothiocarbamide-dihydr chloride-monohydrate and 24.4 g (011 . mol) N-sulfamyl-3-chloroprop onamidine hydrochloride is added by stirring 43 ml of 10N sodium hydrochloride (0.43 mol), after which the temperature of the reaction mixture is set to 50 ° C, held for 2 h. After that I cool before. The precipitated product is filtered out and washed first with water, then with isopropanol. Get 27, (82.5%) famotidine. T. pl. 160-16
    15
    20
    25
    thirty
    35
    40
    Example 3. In a reaction vessel with a capacity of 1000 l, we weigh 80.3 kg (250 mol) of 5- (2-guanidino-thiazol-4-ylmethyl) -isothiourea-dihydrochloride monohydrate, 55.5 (250 mol) of N- sulfamyl-3-chloropropamine-hydrochloride, 200 liters of non-ionized water and 150 liters of technical ethanol. After that, a cooled solution of 40 kg (1000 mo of solid sodium hydroxide and 100 liters of non-ionized water) is added to the reaction mixture for 15–20 minutes, and the internal temperature is kept between 25 and 30 C with strong cooling. After the addition, the mixture is stirred for half a day.
    a solution (0.04 mol) of sodium hydroxide at 40–3 ° С. After ohri and 6.0 ml of ethanol. The resulting homogeneous reaction mixture with pH 11 is stirred for another 1.5 h and then cooled for one hour with ice water. The precipitated product is filtered off, washed twice with deionized water, twice with isopropanol and dried to constant weight. The result is 2.40 g (71.2%) of famotidine. T. pl. (159) -160-162 ° С, decomposition at 165 ° С.
    Spectroscopic characteristics of the product.
    50
    55
    At 10-15 ° C, the resulting suspension of crystals is centrifuged, and the product is rinsed in a centrifuge with water and then peptized with isopanol. After drying, 69, (82%) famotidine are obtained. T. pl. 160-162 Decomposition at 165-166 C.
    Thus, the proposed method allows to double the yield of the target product, simplify the technology of its isolation and purification, since the target product is in the form of crystals, which eliminates the need for purification by column chromatography

    ten
    50743. 2
    IR spectrum (KBr-Partille, Parkin-Elmer 257), cm-: 3400} NH 3360, 3240, 1635, (conjugate), 1590 is wide; SO 1288, 1SH7.
    Proton NMR spectrum (DMSO d ,, Varian EM 360): 2.6 ppm multiplet, Ar-CH -S 3.6 ppm, singlet, Ar-H 6.5 MD, singlet, NH, NH2 3.5} 6.8} 7.4; 8.3 ppm wide.
    Approximately 2. To a solution prepared in 100 ml of non-ionized water and 40 ml of isopropanol, 32.1 g (0.1 mol) of 5- (2-guanidinodinothiazol-4-sh1methyl) -isothiocarbamide dihydrochloride monohydrate and 24.4 g ( 011. mol) N-sulfamyl-3-chloropropionamidine hydrochloride is added with stirring 43 ml of 10N sodium hydrochloride (0.43 mol), after which the temperature of the reaction mixture is adjusted to 50 ° C, held for 2 h and After that cool until. The precipitated product is filtered and washed first with water and then with isopropanol. 27.8 g (82.5%) of famotidine are obtained. T. pl. 160-161 C.
    15
    20
    25
    Example 3. In the reaction apparatus with a capacity of 1000 l weighed. 80.3 kg (250 mol) of 5- (2-guanidino-thiazol-4-ylmethyl) -isothiourea-dihydrochloride monohydrate, 55.5 g (250 mol) of N-sulfamyl-3-chloropropionamidine hydrochloride, 200 l of non-ionized water and 150 liters of technical ethanol. Thereafter, a cooled solution of 40 kg (1000 mol) of solid sodium hydroxide and 100 liters is added to the reaction mixture over 15-20 minutes. non-ionized water, and with strong cooling, the internal temperature is kept at 25 - 30 ° C. After the addition, stir for one and a half hours at 40 - 3 ° C. After oh
    After waiting up to 10-15 ° C, the resulting suspension of crystals is centrifuged and the product in the centrifuge is washed with water and then during peptization with isopropanol. After drying, 69.2 g (82%) of famotidine are obtained. T. pl. 160-162 0. Decomposition at 165-166 C.
    Thus, the proposed method allows to double the yield of the target product, to simplify the technology of its isolation and purification, since the target product is in the form of crystals, which eliminates the stage of purification by column chromatography.
    in addition, it can be used to produce famotidine on an industrial scale.
    权利要求:
    Claims (3)
    [1]
    1. A method for preparing N-sulfafamI-3- (2-guanidino-thiazol-4-ylmetx-thio) -propionamidine of the formula
    NH,
    H2N H, -N
    X,
    N-,
    .kl /
    S
    treatment of dihydrochloride 8- (2-guanidinothiazol-4-ylmethyl) -isothiocarbamide formula
    NH) I
    .-J-S-NHtci®
    n, k
    an excess of alkali in a water-alcohol medium and S-alkylation directly in the reaction medium of the resulting (2-guanidinothiazol-4-yl) .- methyl-mercaptan of the formula
    1450743
    ten
    0
    Hnn.
    -tg
    .l: g
    SH
    15
    25
    0
    (It is different from the fact that, in order to increase the yield of the target product and simplify the process technology, 3-alkols are carried out with L-sulfamyl-3-chloropropionamidine hydrochloride of the formula
    Shg.
    C Cl NS02MH2-HC1
    f
    at the molar ratio of the compound
    of formula II, compounds of formula IV and alkali 1: 1.0-1.1: 4.1 + 0.2, respectively, 0.3 -alkanol is taken as the alcohol and the process will be carried out at 25 - 50 ° C.
    [2]
    2. A method according to claim 1, characterized in that sodium hydroxide is taken as alkali and is introduced at a temperature of from room temperature to 50 ° C.
    [3]
    3. A method according to claim 2, characterized in that it takes a 40% aqueous solution of sodium hydroxide and is injected with a temperature of 20-40 ° C.
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    同族专利:
    公开号 | 公开日
    KR910000237B1|1991-01-23|
    DD249479A5|1987-09-09|
    CN1013674B|1991-08-28|
    NO163010B|1989-12-11|
    GB2180237B|1989-09-06|
    FI86423C|1992-08-25|
    FI863657A0|1986-09-10|
    AT386824B|1988-10-25|
    FI863657A|1987-03-12|
    NO163010C|1990-03-21|
    DK434586D0|1986-09-10|
    GB8621742D0|1986-10-15|
    BE905409A|1986-12-31|
    JPS6296481A|1987-05-02|
    US4835281A|1989-05-30|
    FI86423B|1992-05-15|
    PT83348B|1988-07-29|
    NO863616D0|1986-09-10|
    JPH0645609B2|1994-06-15|
    AU587279B2|1989-08-10|
    SE8603797L|1987-03-12|
    ES2001677A6|1988-06-01|
    ATA243486A|1988-03-15|
    NL8602225A|1987-04-01|
    KR870003078A|1987-04-15|
    AU6256986A|1987-03-12|
    AR240319A1|1990-03-30|
    NO863616L|1987-03-12|
    GR862308B|1987-01-02|
    DK169920B1|1995-04-03|
    GB2180237A|1987-03-25|
    CN86105909A|1987-05-13|
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    HU194845B|1988-03-28|
    PT83348A|1986-10-01|
    DK434586A|1987-03-12|
    CA1263120A|1989-11-21|
    SE8603797D0|1986-09-10|
    引用文献:
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    JPS6056143B2|1979-08-02|1985-12-09|Yamanouchi Pharma Co Ltd|
    US4808589A|1982-02-20|1989-02-28|Smith Kline & French Laboratories Limited|Pyrimidone derivatives|
    US4496737A|1982-09-27|1985-01-29|Merck & Co., Inc.|Process for preparing sulfamylamidine antisecretory agents|
    ES8504157A1|1983-10-07|1985-04-01|Inke Sa|Prepn. of antiulcer sulphamide cpd.|
    ES8506665A1|1984-05-07|1985-08-01|Inke Sa|Methylene-amino-thiazolyl:methyl-thio-propylidene-sulphamide|
    ES536322A0|1984-09-27|1985-08-01|Bioiberica|PROCEDURE FOR OBTAINING N-AMINOSOLPHENYL-3 - METHYL) THIO) PROPIONAMIDINE|
    ES536803A0|1984-10-17|1985-08-01|Inke Sa|PROCEDURE FOR THE OBTAINING OF AMINO) -4-TIAZOLIL) METHYL) TIO) PROPILIDEN) SULFAMIDE|
    HU194845B|1985-09-11|1988-03-28|Richter Gedeon Vegyeszet|Process for production of n-sulphamil-3-/2-guanidintiazolil-4-methil-tio/-propion-amidin|
    HU193608B|1985-09-11|1987-11-30|Richter Gedeon Vegyeszet|Process for production of new dervatives of n-sulphanol-propion-amidine|
    JP3751649B2|1994-12-01|2006-03-01|関西ペイント株式会社|Temporary protection method for automotive skin coating|HU194845B|1985-09-11|1988-03-28|Richter Gedeon Vegyeszet|Process for production of n-sulphamil-3-/2-guanidintiazolil-4-methil-tio/-propion-amidin|
    HU196775B|1986-08-05|1989-01-30|Richter Gedeon Vegyeszet|Process for production of morfologically unique new modifications of famotidin and medical compositions containing such substances|
    IL86330D0|1987-06-22|1988-11-15|Marga Investigacion|Famotidine polymorphic forms and their preparation|
    US5731442A|1997-03-11|1998-03-24|Albemarle Corporation|Synthesis of thiazole derivatives|
    US5856500A|1997-03-11|1999-01-05|Albemarle Corporation|Synthesis of thiazole derivatives|
    CA2349575A1|1998-11-17|2000-05-25|Nitromed, Inc.|Nitrosated and nitrosylated h2 receptor antagonist compounds, compositions and methods of use|
    WO2009058997A2|2007-11-01|2009-05-07|Biocept Inc.|Non-invasive isolation of fetal nucleic acid|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU853424A|HU194845B|1985-09-11|1985-09-11|Process for production of n-sulphamil-3-/2-guanidintiazolil-4-methil-tio/-propion-amidin|LV930049A| LV5248A3|1985-09-11|1993-01-18|Extraction yield of N-sulfamyl-3--propionamidine|
    LTRP907A| LT2233B|1985-09-11|1993-08-30|N-SULFAMIL-3--PROPIONAMIDIN|
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