• 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:
    Crystallized cephalosporin salts, particularly crystalline addition salt of pivaloyloxymethyl 7 beta -[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoethyl)-1H-t etrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylate with hydrochloric acid, tartaric acid or citric acid, which is very stable and is readily adsorbable through intestinal tract, with little individual differences, when the salt is applied orally.
    公开号:SU973024A3
    申请号:SU802921250
    申请日:1980-05-14
    公开日:1982-11-07
    发明作者:Есимура Есинобу；Морикава Нобухиде；Таканохаси Кунио
    申请人:Такеда Кемикал Индастриз,Лтд (Фирма)；
    IPC主号:
    专利说明:

    Crystallization can be carried out by concentrating or cooling the reaction mixture in the presence of ethanol or by concentrating or cooling the reaction mixture in the presence of sodium chloride. The reaction is carried out in an aqueous medium (water or mixture, water with an aqueous Li-hydrophilic solvent). Compound 1 can be added to the aqueous solution of the acid for the reaction or acid to the aqueous suspension containing the compound 1 for the reaction, or compound 1 and the acid can be added to the water immediately for the reaction. The amount of Compound I used varies depending on the solubility of the resulting acid addition salt and may be about 1-30%, preferably 3-20% (w / v) based on aqueous medium or water. The amount of acid used may be typically 2-10 mol per 1 mol of compound 1, although excess amounts may be used. The reaction of the compound 1 with the acid can usually be carried out at room temperature, although it can also be carried out at an elevated temperature, if necessary. After concentration or cooling of the reaction mixture, namely an aqueous, additive solution (salt of compound 1. with the acid obtained by the indicated / isolated method acid addition salt crystals. If there are insoluble substances in the reaction mixture, it is desirable to remove them beforehand, for example, by filtration. Concentration of the reaction mixture is usually carried out In order to cool in general, it is sufficient to lower the temperature of the reaction mixture from room temperature to about. In some cases, the crystallization process as described above can be carried out in the presence of crystallization, as indicated above, can be carried out in the presence of one or hydrophilic a solvent other than water and / or salts, whereby the properties of the separated crystals are improved and the yield is increased. Such aqueous or hydrophilic solvents may: for example, alcohol (such as methane, tanol and isopropyl alcohol) ketone ,. (such as acetone and methyl ethyl ketone), dioxane, tetrahydrofuran, acetonitrile, or others, among which it is convenient to use acetone and ethanol. The amount of added aqueous or hydrophilic solvent is preferably up to 40% i (v / v) relative to the amount of the reaction mixture. The added salt may be, for example, sodium chloride, sodium bromide, calcium chloride, among which it is convenient to use sodium chloride. The amount of salt used can usually be up to about 30% (w / v, preferably up to 15% (w / v; relative to the total amount). Such an aqueous solvent or salt does not necessarily require low cooling temperatures. The aqueous solvent and salt can be used Together, the crystallization can be carried out repeatedly. Thus, once formed crystals can be separated, dissolved in water or an aqueous acidic solution of the indicated acid and recrystallized in the manner described above. The acid additive salt of compound 1 with the acid thus obtained can be separated and separated from the reaction mixture by known techniques such as filtration, washing, and drying. Filtration and drying should preferably be carried out under reduced pressure and low strain E for a short period of time .. The crystalline salts of the compound I. with hydrochloric, citric or tartaric acid, thus obtained, can be of the hydrate type. For example, they are formed as anhydrous dihydrate crystals or hexa- or heptahydrate. Alla dihydrate are most stable. The crystalline acid addition salts can be administered orally, for example, in the form of tablets, capsules, granules, or other preparations. Example 1. Obtaining crystalline dihydrochloride. A. 2.9 .g (2-aminothiazol-4-and-ladetamido-3-d-2-dimethylaminoethyl. 1H-tetrazol-5-ylthiomethyl cef-3-em-4 carboxylate a. Potassium is dissolved in 30 ml of dimethylacetamide) and the solution is cooled to -15 ° C. To the solution, with stirring, 4 ml of dimethylacetamide solution containing 1.3 g of iodomethyl pivalate are added dropwise over 5 minutes, and stirring is continued for another 5 minutes. The reaction mixture is poured into 100 ml of ice-water, extracted with 1QO ml of dichloromethane and then extracted with 50 ml of the same solvent. The combined organic layer is washed with water and then with saturated After evaporation of the solvent in vacuo, 2.0 g of colorless powdered 7f) - p- (2-aminothiazol-4-yl) acetamido-3-1-2-dimethylaminoethyl-Sh-tetrazole is obtained. 3-iltiomethyl def-3-em-4-carboxylate pivaloylonsyme-, tyla. 2 g of Compound 1 are dissolved in 7.5 ml of 0.5N. hydrochloric acid. After addition and dissolving the chlorine chloride, the solution is cooled to isolate the colorless dihydrochloride of compound 1 as needles. B.- The crystals obtained in step A are dissolved in 10 ml of 0.5N. hydrochloric acid and insoluble matter is filtered off. Adding 0.5 ml of ethanol to the filtrate, followed by cooling, makes it possible to isolate colorless crystals that are filtered, washed with a small amount of cold 0.5 hydrochloric acid, and then dried in vacuo to obtain 1.7 g of needles dihydrochlo compound 1. M.p. 132-134C. IR (KBG), cm: 1775 -1730. NMR (100 MHz, c) (f; 1.24 (S, C (CH5) 5) -; 3.11 (S, N (CH.)); 3.6 4, 1 (m, CH, CO and H); 3.91 (t, 3 6Hz, N. CHa); 4.24 and 4.42 {ABqf, U 14 Hz, Cj-HB 4.99 (t, 3 6 Hz, NCHa); 5.20 (d, 3, 4.5 Hz, Cj-H); 5.73 (d, D (, 5 .Hz, Cj.H); 5.80 and 5.97 (ABq.r3 6 Hz., o-OCH2 0 -); 6.74 (S, thiazole 5-H) "Elemental analysis: Found,%: C 38.02; H 5.07; N 17,02 C5.4HJ3 2HC-2HiO (contains 0.79% NaC) Calculated,%: C 38.20; H 5.21; And 16.70 From the results of X-ray powder diffraction and observations using a polarization microscope, it was proved that the product is crystalline. B. In 600 ml of water, 53.6 moist crystals are dissolved, obtained in stage A. The insoluble substances are filtered. When adding 100 chloride colorless crystals are obtained and separated out to the filtrate with stirring.After 2 hours, the crystals in the form of needles are collected by filtration and dried under vacuum to obtain 16 g of the desired product. IR (KBg), cm: 1775, 1730. NMR (100 MHz, c), tf: 1.26 (S, C (CH) h), 1b (S, N (CHj) / ;.); 3.74, 1 (m, CH2.CO and C-b - H); 3.93 (t, and 6 Hz, NCHa); 4.26 and 4.44 (ABq, 3 13 4, Hz); 5.00 (t, 3 6 Hz, NCH2.); 5.23 (d, D 4.5 Hz, H); 5.74 (d, 3 4.5Hz, Cy- H); 5.81 and 6.00 (ABq, Hz.); 6.77 (S, thiazole-5-H). Found,%: C 38.08; H 5.14; N 16.75 019.70. NhObS ,. 2HCt 2H, gO Calculated, PO: C 38.50; H 5.25, N 16. Ci9.47. From the results of powder X-ray diffraction and observations through a polarization microscope, it was proved that the product is crystalline. Example 2 „Preparation of crystalline monohydrochloride. 0.8 g of the dihydrochloride of compound 1 is dissolved in 10 ml of water. While cooling and stirring, 0.1 N is added dropwise to the solution. NaOH to adjust pH to 4.5. After further cooling and stirring, a precipitate is formed from the solution, which is collected by filtration, washed with a small amount of cold water and dried in vacuum to obtain 0.45 g of the intended product. IR (KBr), cm-: 1780, 1745. NMR (90 MHz, in dg-DMSO), rf: 1.16 (S, C (CH5) a); 2.75 (S, N (CH,)); 3.36 (s, CHjCO); 3.53. (T, 3 6 Hz, NCH); 3.67 and 3.88 (ABq, 3 16.5 Hz, 0.2, - H); 4.20 and 4.53 (ABq, d 13.5 Hz, Cs-H); 4.72 (t, 3 6 Hz, NCH); 5.08 (d, L 4.5 Hz, Cg-H); 5.6 5, 8 (m, C-y-H); 5.73 and 5.90 (ABq, J 6 Hz, -QCHj.0-); 6.27 (Z. thiazol-5-H): 6.9-7.5 (b-s, VH.); 8.88 (d, D 9 Hz, CONH). Found.%: C 40.95, H 5.05, N 18.08 / S 13.78; C I 5.48 HCt-H20 Calculated,%: C 41.58; H 5.09, N 18.19. S13.87; Ct5, ll From the results of powder X-ray diffraction and observations through a polarization microscope, it was proved that the product is crystalline. Example 3. Getting allist tartrate cristae. A. In F, 5 ml of water dissolve 0.31 g of tartaric acid. While stirring, 0.65 g of compound 1 is added to the solution. Insoluble matters are filtered off. 0.3 ml of ethanol is added to the filtrate and cooled, by means of which colorless crystals are precipitated, which are collected by filtration and dried under vacuum to obtain O, 40 g of the intended product. M.p. 106-108С. IR (KBG), 1780, .1740. NMR (90 MHz, 0., 0), D: 1.30 (S, C (CH, h)); 3.17 (S, N (CH) a); 3.7-4.15 (m,., And H); 3.95 (t, P 6 Hz, NCH /); 4.25 and 4.50 (ABq, O 13.5 Hz, 03-H); 4.60 (S, CH-CH), 5.06 (t, and 6 Hz, NCH2); 5.25 ,, (d, I 4,5 HZ, Sat-H) ;; 5.75 (d, 3 4., 5Hz, C -; - H); 5.86 and 6.03 (ABq, 3. 6 Hz, -OCH,); 6.75 (S, thiazole 5-H) o Found: C 40.27; H 5.19 / N 13.13, S10.92 c j Hg NgOeSy aCdNYAb-Hjp Calculated: С 40.12; H, N 13.16 S10.04, From the results of x-ray diffraction on the powder and observation through a polarization microscope, it was proved that the product is crystalline. B. 0.10 tartaric acid is dissolved in 10 ml of water, 0.65 g of compound 1 is dissolved in the solution with stirring. The insoluble substances are filtered off and 70 g of sodium chloride are dissolved in the filtrate. After protection, colorless crystals are collected, which are collected by filtration and dried in vacuo. 1.50 g of the desired product IR (KW), 1780, 1740. NMR (90 MMz, at 02.0), cG: 1.31 ( S, C (CH5) -); 3.18 (S, N (CH) 5i); 3, 8 -. 4.1 (tn, and Ca-H); 3.97 (t, Hz,); 4.26 and 4.51 (ABq, 3 13.5 Hz, H); 4.66 (S, CH-CH 5.07 (t, I "6 Hz, NCH); 5.28 (d, 3 4 , 5 Hz, Cg- H); 5.79 (d, 3 4.5 Hz, C -, - H); 5.89 And 6.01 (ABq, 3 6 Hz, -bCH.O-); 6 , 77 (S, thiazol 5tN). Found: C 33.65, H 4.57 / N 12.45 58.90 C2.4 Ag C% H- 2 C4 Nb Og - 2 H2.0 Calc.,% : C 34.22, I-4.39 / N 11, S 8.56 o The product is crystalline in accordance with the results of X-ray diffraction and observations using a polarization microscope, Example 4. Preparation of crystalline citrate 0.38 g of citric acid is dissolved in 12 ml of water. 0.65 g of Compound 1 is dissolved in the solution with stirring, after which the crystals immediately precipitate. After cooling waiting, the crystals are collected by filtration, washed with small amounts of cold water and dried under vacuum t: obtaining 0.46 g of the desired crystalline product, mp 103-106 ° C. IR (KBr),, 1750-1730. NMR (90 MHz , in d.; - OMSO) cr: 1.14 (S, C (CH3)); 2.29 (S, (,,) t) 2.63 and i66 (two S, CH2COOH X2); 2, 83 (t, and b, NCHyj.); 3.3 (S, HiCO); 3.57 and 3.82 (ABq, 3 18.0 Hz, Cv H); 3.98 and 4.32 ftBq, 3 13.5 Hz, Cs-H); i, t | 0 (t, 3 6 Hz, NCH); 5.04 (d, 3 4.5 Hz, C.- H); 5.6 5, 8 (m, D-H); 5.73 and 5.89 (ABq, Hz, -OCHj O-); 6, A - ;, 2 (d-s, MND COOH and OH); 8.80 (d, 3 9 liz, CONH). Found,, 87, H5.35, N1lt, 71: 511.27. C..H ,, zN90b5z. , 1, 5 .O Calculated,%: with 41.95, H 5.16; N 14.75, 511.20. From the results of x-ray diffraction and observations through a polarization microscope, it was proved that the product is crystalline. A mixture of 178 h of pivaloyloxymethyl 7P-E2 -. (2-aminothiazol-4-yl) acetamido3-3-fl- (2-dimethyl) butethyl -1 H-tetrazole-5-ylthiomethyl 3-cef-3-em-4-carboxylate dihydrochloride (125 mg by potency calculated as free carboxylic acid), 19 parts of crystalline cellulose (AviceJ), a small amount of magnesium stearate as a lubricant is converted into tablets and coated with hydroxypropyl lulose. The resulting tablets have a potency of 125 mg (tablet; take two tablets after eating) 1. The table shows the data of X-ray diffraction analysis of the powder add active salts of Compound 1.
    0.5
    14.0
    13.8 0.5 11.6 0.4
    OV5
    6.2
    0.2
    5.5 0.4
    12.3 0.9
    8.2 0.5
    5.2 0.6
    4.5 1.0
    1.0
    4.3
    0.3
    3.2
    权利要求:
    Claims (5)
    [1]
    .-- gp-- The distance between the plane ks Relative intensity The claims of the invention 1. Method of obtaining additive: salts of 7ji-f 2- (2-aminothiaol-4-yl) acetamido pivoyloxymethyl ester - -3-tl- (2-dimethylaminvethyl) salts 1H-tetrazol-5-ylthiomethyl-3-cephem-4- to arboxylic acid with psaltic, tartaric or monoic acid, characterized in that pivaloyloxymethyl ester 7 (2-aminothiazol-4-yl) Achwtamido-3-C1-2 -dimethylaminoethyl) -1H-tetrazol-5-ylthiomethyl3-3-Cephem-4-carboxylic acid is reacted with hydrochloric or tartaric or citric acid in water The desired product crystallizes from the medium and from the reaction mixture.
    [2]
    2. The method according to claim 1, characterized in that pivaloyloxymethyl ether 7p- | 2-K2-aminothiases-4-. IL) acetamido-3-1-2-dimethylaminoethyl) -1H-tetrazol-5-ylthiomethyl-3 Continuation of the table
    4.30,9
    0.3
    0.5
    3,80,9
    0.4-cepheme-4-carboxylic acid is reacted with hydrochloric acid.
    [3]
    3. The method of claim 1, wherein the crystallization is carried out in the presence of acetone.
    [4]
    4. The method according to claim 1, characterized by the fact that crystallization is carried out by concentrating or cooling the reaction mixture in the presence of ethanol. G.
    [5]
    5. Method POP1, characterized in that the crystallization is carried out by concentrating or cooling the reaction mixture in the presence of sodium chloride. - Sources of information taken into account during the examination 1. Listed with the cue of the Federal Republic of Germany 2738711, cl, С 071) 501- / 36, published. 1978
    类似技术:
    公开号 | 公开日 | 专利标题
    DE2713272C2|1983-01-20|Derivatives of 7-aminothiazolyl-acetamido-cephalosporanic acid, their preparation and pharmaceutical compositions
    DE2812625C2|1990-08-23|
    LU82452A1|1980-12-16|METHANEDIOL BIS-ESTERS WITH PENICILLINS AND PENICILLANIC ACID 1,1-DIOXIDE, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITION CONTAINING THEM
    EP0340677A2|1989-11-08|Gabapentin monohydrate and a process for producing the same
    CH634578A5|1983-02-15|METHOD FOR PRODUCING NEW CEPHALOSPORINE DERIVATIVES.
    DK155525B|1989-04-17|METHOD FOR PREPARING | -7-OE | -2- | -2- | -ACETAMIDOAA-3- | ceph-3-em-4-carboxylate pentahydrate
    FR2503712A1|1982-10-15|CEPHALOSPORINE COMPOUNDS AND PROCESS FOR THEIR PREPARATION
    DK164508B|1992-07-06|PROCEDURE FOR THE PREPARATION OF SODIUM CEFUROXIM
    TW202454B|1993-03-21|
    SU973024A3|1982-11-07|Process for producing acid-additive salts of pivaloylhydroxymethyl ester of 7-beta-|-acetamido)-3-|-1h-tetrazol-5-ylthiomethyl)-3-cephem-1-carboxylic acid with hydrochloric, tartaric or citric acid
    SU845789A3|1981-07-07|Method of preparing d-7-/alpha-|-alpha-|-acetamido/-3-| thiomethyl-3-cephem-4-carboxylic acid
    US4496562A|1985-01-29|7-Substituted-3-cephem-4-carboxylic acid esters
    FR2496106A1|1982-06-18|7-ACYLAMINOCEPHALOSPORANIC ACID DERIVATIVES AND PROCESS FOR THEIR PREPARATION
    JPH10511377A|1998-11-04|Manufacture of cefotaxime
    JP3317649B2|2002-08-26|Carbapenem compounds in crystalline form
    US5182383A|1993-01-26|Stable, crystalline form of a cephalosporin intermediate product
    FR2482104A1|1981-11-13|PROCESS FOR THE PREPARATION OF SODIUM CEFUROXIME AND SOLVATE OF SODIUM CEFUROXIME AND TETRAHYDROFURAN OBTAINED BY THIS PROCESS
    CS195746B2|1980-02-29|Process for preparing crystalline methanolate of natrium salt of cephamandole
    US20070191602A1|2007-08-16|Crystalline form of cefdinir cesium salt
    JPH05194404A|1993-08-03|Carbostyril derivative
    CS202056B2|1980-12-31|Process for preparing derivatives for preparing 7-aminocephalosporanic acid and ester thereof
    JPH0680065B2|1994-10-12|Crystalline acid addition salt of diastereomerically pure 1- | -ethyl 3-cephem-4-carboxylate
    JP2575590B2|1997-01-29|Triazolylthiomethylthiocephalosporin hydrochloride and its hydrate crystals and their preparation
    EP0068403B1|1986-08-13|Cephalosporin compound
    US4959469A|1990-09-25|Crystalline cephalosporin compounds
    同族专利:
    公开号 | 公开日
    GR68203B|1981-11-10|
    ES491386A0|1980-12-16|
    GB2052483A|1981-01-28|
    ES8102132A1|1980-12-16|
    FR2456746A1|1980-12-12|
    IT1132053B|1986-06-25|
    DE3018340A1|1980-11-27|
    PT71241B|1982-06-08|
    IT8022020D0|1980-05-13|
    ATA259180A|1981-11-15|
    BE883250A|1980-11-13|
    PT71241A|1980-06-01|
    US4316018A|1982-02-16|
    JPS55151588A|1980-11-26|
    NZ193634A|1982-05-25|
    FI801563A|1980-11-15|
    AT367427B|1982-07-12|
    NO801428L|1980-11-17|
    DK209380A|1980-11-15|
    SE8003548L|1980-11-15|
    NL8002758A|1980-11-18|
    AU5838080A|1980-11-20|
    ZA802874B|1980-12-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    JPS603314B2|1976-08-31|1985-01-26|Takeda Chemical Industries Ltd|
    US4189479A|1977-12-22|1980-02-19|Takeda Chemical Industries, Ltd.|Cephalosporin esters|GR78221B|1980-02-01|1984-09-26|Ciba Geigy Ag|
    US4616008A|1984-05-02|1986-10-07|Takeda Chemical Industries, Ltd.|Antibacterial solid composition for oral administration|
    US5244891A|1985-08-05|1993-09-14|Bristol-Myers Squibb Company|Injectable compositions of cefepime dihydrochloride hydrate|
    US4910301A|1985-08-05|1990-03-20|Bristol-Myers Company|Cefepime cephalosporin salts|
    FR2585705B1|1985-08-05|1989-01-13|Bristol Myers Co|CEPHALOSPORIN SALTS AND INJECTABLE COMPOSITIONS|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP5948179A|JPS55151588A|1979-05-14|1979-05-14|Preparation of cephalosporin salt crystal|
    [返回顶部]