• 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:
    A process for preparing a 7-halodeoxylincomycin or an analogue thereof, which comprises reacting lincomycin or an analogue thereof with a thionyl halide and dimethylformamide, under mild conditions.
    公开号:SU1405705A3
    申请号:SU853984283
    申请日:1985-11-28
    公开日:1988-06-23
    发明作者:Алэн Ливингстон Даглэс；Елизабет Пэтре Джанет
    申请人:Дзе Апджон Компани (Фирма)；
    IPC主号:
    专利说明:

    WITH
    with
    ate
    about ate

    s
    This invention relates to an improved process for the preparation of 7-chloro-deoxylin comicine hydrochloride, a known antibiotic.
    The purpose of the invention is to reduce the energy intensity of the process, which is achieved by using an excess of thionyl chloride in K, K-dimethylformamide, as well as in the order of addition of reagents.
    Example 1. In a kiln-dried round-bottomed flask, which is equipped with a magnetic stirrer, methylene chloride (53. ml, containing 1.5 volumes of thionyl chloride) and 35 ml (479 mmol) of thionyl chloride are charged in a stream of nitrogen. The resulting solution is cooled in an ice bath and Lincomycin Hydrochloride Monohydrate (35.0 g, 75.1 mmol, containing 3.90% water, as established by Karl Fisher titration) is added via a solids loading device, as determined by Karl Fischer titration. slowly over 30 min. The residual solid material is reduced by 4 ml of methylene chloride. The final mixture was stirred for 5 minutes to dissolve completely. While cooling with an acetone / ice mixture, 70 ml (900 mmol) of N, N-dimethylformamide was slowly added while maintaining the temperature below 5 ° C (it takes about 30 minutes). The cooling bath is then removed and the yellow solution is kept under vacuum. A trap with a mixture of dry ice and acetone is used. Within 2.25 hours, the reaction temperature rises to room temperature, while due to the weak exothermicity of the reaction, the temperature rises to 20 ° C with an increase in gas evolution. With the help of a water bath, the temperature is adjusted, and the gas release is stopped. At this stage, thin-layer chromatographic analysis points to very pure clindamycin (7-chloro-deoxylin comicin) and the presence of a very small amount of residual lincomycin. The water bath was removed and the reaction mixture was stirred in vacuo for one hour (total reaction time was 3.25 hours). The final solution, reddened, is cooled almost to and 40 ml of anhydrous methanol is gradually added to it. The reaction is abruptly stopped by entering the reaction mixture through the cannula.
    -
    with
    -. fO
    Ч5, 20 25 - ЗО. -. ds
    35
    50
    55
    into a mixture of 114 g of 50% sodium hydroxide in 200 g of ice, cooled to a temperature of about -10 C, maintaining the temperature below 37 s. At the end of the cessation of the reaction, an additional amount of 50% sodium hydroxide is used to bring the pH to above 11. The resulting mixture was stirred at 37 - ± 4 seconds for 45 minutes.
    This mixture is cooled to room temperature and adjusted to pH 7 by the addition of concentrated hydrochloric acid. The solution is concentrated in vacuo to about 1/2 volume, removing all of the methanol. Upon cooling with an ice bath, the pH of the solution was adjusted to 1.5 by the addition of concentrated hydrochloric acid, after which the mixture became homogeneous. Then 100 ml of methylene chloride are added and the phases are separated. The organic phase is subjected to sequential extraction treatment in three portions of 150 ml of aqueous phases with a pH of 1.5 (0.5 M buffer based on primary potassium phosphate, adjusted to pH 1.5 by addition of concentrated hydrochloric acid). All interfacial material is retained by the aqueous phase. Each aqueous phase is subjected to repeated extraction treatment in four portions of 150 ml of methylene chloride. The four aqueous phases are combined and the pH is adjusted to 10.2 by adding 50% sodium hydroxide, and then to 8.2 by adding concentrated hydrochloric acid (ice is added to maintain a temperature of about 25 ° C). Then add 100 ml of methylene chloride and the phases are separated. The organic phase is subjected to extraction treatment with two 1,00 ml portions of phosphate buffer of 0.5 M and pH 6.2. The aqueous phases with a pH of 8.2 and 6.2 are subjected to sequential repeated extraction treatments in four portions of 5 ml of methylene chloride. The combined organic structures are dried over sodium sulfate and evaporated to give an oil-like residue. The residual methylene chloride is removed by ethyl acetate azeotropes. The oil-like residue is dissolved in 158 ml of ethyl acetate and 47 ml of absolute ethanol. Clindamycin Hydrochloride Ethanol
    The solvate is obtained by introducing the clindamycin hydrochloride ethanol solvate into the solution as a seed, while adjusting the pH to 1.0-1.5 with concentrated hydrochloric acid. After stirring for 1 hour at room temperature and then at 0 ° C for 45 minutes, the slurry is filtered off and washed with ethyl acetate. After drying for 3 hours under vacuum, 17.04 g of product is obtained, which corresponds to a yield of 68.1% clindamycin hydrochloride ethanol solvate.
    Example2. In the dried c. methylene chloride. All four water round bottom flasks, supplied with phases, are combined and the pH is adjusted to
    with a magnetic stirrer, lincomycin hydrochloride 35.0 g (79 mmol, containing 0.974% of water, as determined by Karl Fischer titration) and 125 ml of NsN-di-formamide are charged in a stream of nitrogen. Slime 35 ml (474 mmol of thionyl chloride) are added to the mixture for 1 h. After 2 hours at room temperature, the reaction is complete. After cooling to approximately 0 ° C, 75 ml of anhydrous methanol are slowly added. The solution is stirred in for 1 h at room temperature. Next, the reaction is abruptly stopped by introducing the reaction mixture through a cannula into a mixture of 114 g of 50% sodium hydroxide with 200 g of ice and 200 ml of methylene chloride, previously cooled to about -10 ° C C, maintaining the temperature below 16 ° C. At the end of the abrupt cessation operation, an additional 50% sodium hydroxide is added to maintain the pH of the mixture at 10.5.
    With stirring at room temperature for 3 hours and a pH of 10.5, an additional I00 ml of methylene chloride is added. The pH is then adjusted to 7 and the reaction mixture is left overnight at room temperature. The mixture is concentrated in vacuo to about half the original volume, 100 ml of methylene chloride is added and the pH is adjusted to 1.5 with cooling with an ice bath and concentrated hydrochloric acid is added. The mixture is separated into layers, after which the organic phase is subjected to sequential extraction treatment.
    in three portions of 150 ml of the aqueous phase with a pH of 1.5 (0.5 M potassium hydrogen phosphate solution, the pH of which is adjusted to 1.5 by the addition of concentrated hydrochloric acid). The aqueous phase retains the entire interfacial layer. Each aqueous phase is subjected to repeated extraction treatment in four portions of 50 ml of methylene chloride.
    The last two aqueous phases are extracted with two additional 100 ml portions.
    five
    about
    10.5 by addition of 50% sodium hydroxide. Ice is used to maintain the solution at room temperature. Then 100 ml of methylene chloride are added and the phases are separated. The organic phase is subjected to extraction treatment in two portions of 130 ml of phosphate buffer with
    5 pH 6.2 (0.5 M). The aqueous phases, one with a pH of 10.5 and two with a pK of 6.2, are subjected to repeated extraction treatment in four portions of 50 ml each of methylene chloride. Organic
    The materials are dried over sodium sulfate and concentrated under vacuum to give an oil-like product. Residual methylene chloride is removed by two ethyl acetate azeotropes. The butter-like product is dissolved in 157 ml of ethyl acetate and 45 ml of absolute ethanol solvate.
    A clindamycin hydrochloride ethanol solvate is obtained by introducing a seed into a solution using clindamine cyrohydrochloride ethanol solvate, at the same time bringing the pH to 1.0-1.5 by adding concentrated
    g hydrochloric acid. After stirring at room temperature for 1 hour and then at 0 ° C for 45 minutes, the slots are filtered and washed with ethanol acetate. After drying the filter cake under vacuum for 1 hour, 26.65 g (yield: 66.5%) of clindamycinhydroch were injected. lridethanol solvate. Clindamycin - hydrochloride is separated from ethanolic polyol by known means.
    Example In a kiln-dried round bottom flask, stocked. with a magnetic stirrer, in a stream of nitrogen, 12.5 ml (1.5 v / v chloride)
    0
    0
    five
    five
    thionyl) methylene chloride and 8.25 ml (113 ml) of thion chloride; la. The solution is cooled on an ice bath with a device for adding solid material, 10 g (22.6 mmol, with 0.974% water) is added over 25 minutes, as determined by Karl Fischer titration or comicin hydrochloride. Formed


    the pale pink mixture is stirred at until it becomes homogeneous (15 min), then 4.8 g (113 mmol) of chloride is added
    lithium, dried for 7 hours at 15 and a residual pressure of 2 mm Hg. With cooling with a mixture of ice and acetone, 17.6 ml (226 mmol) of NjN-dimethylformamide are gradually added, maintaining the temperature below 5 ° C. The cooling bath is then removed and the mixture is kept in vacuum. Within 20 minutes, the reaction mixture becomes gelled. In order to simplify the stirring, 10 ml of 25 ml of dimethylformamide are added over 45 minutes. After 4.25 hours with 0.5 g of activated carbon (the variety reaction is terminated as defined - DARCOG - 60). After filtering
    The organic phase is subjected to a sequential extraction treatment with two 75 ml portions of phosphate buffer pH 6.210.1 (0.5 molar buffer). One aqueous phase with a pH of 10.5 and two phases with a pH of 6.2 are subjected to repeated extraction treatment: in four portions of 50 ml each of methylene chloride. The organic materials are dried over sodium sulfate and evaporated to give an oil-like residue. Residual methylene chloride is removed by two ethyl acetate azeotropes. The residual oil is dissolved in 25 ml of ethyl acetate and stirred with a thin layer chromatographic analysis, then 40 ml of methylene chloride is added and the reaction mixture is cooled to a temperature of about 0 ° C. The reaction is abruptly stopped by introducing the reaction mixture through a cannula into a mixture of 27.2 g of 50% sodium hydroxide with 100 g of ice, oh--. approximately to a temperature that is maintained below (at the end of the operation of the abrupt termination of the reaction to keep the pH above 1-1 using an additional amount of 50% sodium hydroxide. After stirring for 2 hours at room temperature and pH 10- The pH is adjusted to pH 7 by adding concentrated hydrochloric acid and the mixture is left overnight at room temperature. The pH is adjusted to pH 10 by the addition of 50% sodium hydroxide and the layers are separated. traction treatment in four portions of 75 ml of the aqueous phase with a pH of 1.5 (0.5 M potassium hydrogen phosphate, the pH of which is brought to 1.5 by the addition of concentrated hydrochloric acid). The aqueous phase with a pH of 10 is subjected to repeated sequential treatment with four in portions of 50 ml of methylene chloride, at a temperature of 45 minutes with 0.5 g of activated carbon (grade DARCOG - 60). After filtering
    start each wash liquid sequentially through four phases with a pH of 1.5. The aqueous phases are combined and the pH is adjusted to 10.5 with the addition of a 50% sodium oxide tridrate. Then 100 ml of methylene chloride are added and the resulting layers are separated.
    The organic phase is subjected to a sequential extraction treatment with two 75 ml portions of phosphate buffer with a pH of 6.210.1 (0.5 molar buffer). One aqueous phase with a pH of 10.5 and two phases with a pH of 6.2 are subjected to repeated extraction treatment: in four portions of 50 ml each of methylene chloride. The organic materials are dried over sodium sulfate and evaporated to give an oil-like residue. Residual methylene chloride is removed by two ethyl acetate azeotropes. The residual oil is dissolved in 25 ml of ethyl acetate and stirred, while stirring with Celite 545, the filtrate is evaporated to dryness. Residual Melt0
    five
    0
    The rial is dissolved in 45 ml of ethyl acetate and 12.9 ml of absolute ethanol.
    Clindamycinhydrochloride ethanol solvate is obtained by introducing clindamine-cytohydrochloride ethanol solvate into this solution as a seed, while adjusting the pH to 1.0-1.5 by adding concentrated hydrochloric acid. After stirring at room temperature for 1 hour and then at temperature for 30 minutes, the slurry is filtered and washed at room temperature with ethyl acetate. After drying for 1.5 hours under vacuum, 8.25 g of product is obtained, 5 which corresponds to the 72% yield of clindamycin hydrochloride ethanol solvate.
    Note 4. To a mixture of 1.5 ml; thionyl chloride in 24 ml of methylene chloride with stirring at 0 ° C in portions add 20 g of lyncomycin hydrochloride, and then 0.2 g of 3-tert-butyl-4-hydroxy-5-methyl-phenyl sulfide and 3 ml of methylene chloride .; The mixture is heated to 15 minutes and then cooled to 0 ° C, after which 40 ml of dimethylformamide and 6.3 ml of triethylamine are added successively. The mixture is kept in a vacuum.
    five
    and then give it to react for 6 h at. 80 ml of methylene chloride was added to the mixture, after which the reaction was abruptly stopped by introducing the reaction mixture into a mixture of 17 g of sodium hydroxide with 17 g of ice while maintaining the temperature below 15 ° C. After heating for 45 minutes to 37-41 ° C, the free base of clindamycin was isolated by extraction into methylene chloride. According to the described method, it is converted into the corresponding hydrochloride ethanol solvate. According to this thin-layer chromatographic analysis, the isolated product (yield 13.14 g) is similar to authentic material (anti-silica gel plates, displayed in a mixture of n-ammonium oxide, methanol and methylene chloride in a ratio of 1: 9: 90 ; RT 0.50).
    Example 5. To a solution of 9.82 g of lincomycin hydrochloride in 50 ml of dimethylformamide, 21.4 ml of thioinyl chloride was added dropwise with stirring. After heating for 1 hour, 150 ml of methanol was added to the mixture, maintaining the temperature. The mixture is then heated for 1 hour at and cooled down again, after which the reaction is abruptly stopped by introducing the reaction mixture into a mixture of 35 g of sodium hydroiso with 185 ml of water and 200 ml of methylene chloride, maintaining the temperature below. The pH is adjusted to more than 6.5 by adding an additional amount of aqueous sodium hydroxide solution. At pH 7, the solvents are vacuum embedded and the free base of clindamycin is isolated by extraction into methyl chloride. Then, according to the methods described, it is converted into the corresponding hydrochloride ethanol solvate (yield 7.86 g) and successively into the corresponding hydrochloride hydrate (yield 6.23 g). According to the data of thin-layer chromatographic analysis, the isolated clindamycingrnbhloride hydrate is similar to authentic standard materials. (Antech-silica gel plates, which are in a mixture of ammonium hydroxide, methanol, and methylene chloride in a ratio of 1: 9: 90;
     0.50).
    PRI me R 6. A solution of 8.44 g of lincomycin hydrochloride in 12 ml of s
    five
    0
    five
    0
    five
    0
    five
    0
    AT
    Dimethylformamide, with strong reagent at 50 s under nitrogen, is treated with 8.3 ml of thionyl chloride, added dropwise over 15 minutes. The mixture is cooled in an ice bath to maintain a temperature of 50-60 ° C. After the completion of the addition, the reaction mixture is stirred for 5 minutes at and then abruptly cooled, 20 ml of methanol are added dropwise, the mixture is cooled to keep the temperature below 20 C. At the end of the addition, the mixture is cooled to 0 ° C, after which it is introduced into a mixture of 19.4 g of sodium hydroxide f in 120 g of ice and water, keeping the temperature below. 25 ml of methylene chloride is added, and the pH is adjusted to 1i by the addition of a 6-molar solution of hydrochloric acid. The mixture is stirred for a week, after which it is subjected to extraction treatment in three portions of 30 ml of chlorine methylene each with a pH of 6.2. The combined extracts are dried over sodium sulfate, and the organic materials are evaporated to give an oily residue, which is decolorized with 1 g of activated carbon (Darco G-60) dissolved in 50 ml of ethyl acetate. After filtration on celite 845 and evaporation in vacuo, the residue is crystallized from a mixture of 38 ml of ethyladetate and 1 ml of ethanol by adding hydrochloric acid according to the described method. According to thin-layer chromatographic analysis, the isolated product (yield 4.64 g, 48%) corresponds to authentic clindamycin hydrochloride (analtec silica gel plates, displayed in ammonia, methanol, and methylene chloride hydroxide in a ratio of 1: 9: 90 ; R |, 0.50).
    Thus, the method allows the process to be carried out under mild conditions.
    权利要求:
    Claims (1)
    [1]
    1. A method for preparing 7-chloro-deoxy-lyncomycin in the form of its G schrochloride, and by chlorinating lincomycin hydrochloride with thionyl chloride S an organic solvent medium, characterized in that, to reduce the energy intensity of the process, lincomycin hydrochloride is treated with 3.5 to 13 thionylchloride9U0570510
    yes, and as organic rastionyl chloride to lincomitic hydrochloride, N, H-dimethylformachloride is used.
    Mamid and the process is carried out at 0-50 ° C. 3, Pop.1 method, differing with the addition of chlo2. The method according to Claim 1, of the distinctive thionyl in the reaction mixture using the fact that N is added after adding N, N-di-N-dimethylformamide to methylformamide in the reaction mixture to lincomycin, the hydromix is produced after adding chloride.
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1405705A3|1988-06-23|Method of producing 7-chloro-dioxylinecomycine in the form of its hydrochloride
    RU2066324C1|1996-09-10|Crystalline azithromycin dehydrate, and process for preparation thereof
    SU578887A3|1977-10-30|Method of preparing phthalide ester 6-|-|-penicillanoic acid or its additive salts
    SU613724A3|1978-06-30|Method of obtaining 8-thiomethyl-ergolines or salts thereof
    SU628822A3|1978-10-15|Method of producing 4'-epy-6'-oxyadriamycin hydrochloride
    SU837326A3|1981-06-07|Method of preparing 4"-desoxy-4"-oxoeritromycin a
    SU613725A3|1978-06-30|Method of obtaining 3-iminomethylrifamycin derivatives
    SU625612A3|1978-09-25|Method of producing ergoline compounds or their salts
    SU884572A3|1981-11-23|Method of preparing lysergol derivatives
    SU578865A3|1977-10-30|Method of preparing a-6-desoxy-5-oxytetracycline
    SU558644A3|1977-05-15|The method of obtaining imidazoles or their salts
    US4865765A|1989-09-12|Ursodeoxycholic acid derivatives and their inorganic and organic salts having therapeutic activity, and process for preparing the same
    SU543355A3|1977-01-15|The method of obtaining derivatives of glucose
    SU604497A3|1978-04-25|Method of preparing tetramyzole or salts thereof
    KR860000063B1|1986-02-06|Process for preparing a furan derivative
    US4110537A|1978-08-29|Method of producing N1 -|-5-fluorouracil
    SU1114677A1|1984-09-23|Process for preparing benzo-2,1,3-thiadiazole
    JP2578797B2|1997-02-05|Method for producing N- | formamides
    SU1080744A3|1984-03-15|Process for preparing derivatives of benzodiazepine
    US4070363A|1978-01-24|Manufacture of tetramisole
    SU650502A3|1979-02-28|Method of obtaining 4-|-benzylnicotinate or salts thereof
    SU1215622A3|1986-02-28|Method of producing derivatives of n-carbamoylbenzoic sulfimide
    SU1114336A3|1984-09-15|Process for preparing apovincaminic acid esters
    WO2001016115A1|2001-03-08|Process for synthesizing isoxazolidines
    SU436057A1|1974-07-15|METHOD OF OBTAINING ISOPROPYLIDENE DERIVATIVES OF PYRIDOXYN IN PT5FONM mmim
    同族专利:
    公开号 | 公开日
    JPH0649714B2|1994-06-29|
    FI78708B|1989-05-31|
    ZA858117B|1986-06-25|
    CN85101921A|1987-01-10|
    CN1016694B|1992-05-20|
    DK542785A|1986-05-30|
    JPS61137892A|1986-06-25|
    IL76778D0|1986-02-28|
    HU199497B|1990-02-28|
    AU574232B2|1988-06-30|
    FI854711A|1986-05-30|
    DK165010C|1993-02-22|
    CN1004002B|1989-04-26|
    DK542785D0|1985-11-22|
    CN85108244A|1986-08-20|
    IL76778A|1991-09-16|
    AU4883785A|1986-06-05|
    PT81496B|1987-11-11|
    KR860004077A|1986-06-16|
    FI854711A0|1985-11-28|
    EP0183505B1|1990-02-07|
    CA1238319A|1988-06-21|
    PT81496A|1985-12-01|
    EP0183505A2|1986-06-04|
    AT50265T|1990-02-15|
    GR852861B|1986-03-28|
    DE3575930D1|1990-03-15|
    DK165010B|1992-09-28|
    HUT40806A|1987-02-27|
    KR930003492B1|1993-05-01|
    US4710565A|1987-12-01|
    ES8605817A1|1986-04-01|
    FI78708C|1989-09-11|
    ES548152A0|1986-04-01|
    MX162251A|1991-04-17|
    EP0183505A3|1987-06-24|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3496163A|1965-02-08|1970-02-17|Upjohn Co|7-halo-7-deoxylincomycins and process for preparing the same|
    US3435025A|1966-03-18|1969-03-25|Upjohn Co|7-deoxylincomycin and analogs and isomers thereof and process for making the same|
    US3580904A|1969-04-03|1971-05-25|Upjohn Co|7-halo-7-deoxy-lincomycin derivatives|
    US3574186A|1969-10-08|1971-04-06|Upjohn Co|Process for making 7-chloro-7-deoxylincomycin and related compounds and novel intermediates produced therein|
    US4568741A|1984-05-15|1986-02-04|The Upjohn Company|Synthesis of 7-halo-7-deoxylincomycins|US4568741A|1984-05-15|1986-02-04|The Upjohn Company|Synthesis of 7-halo-7-deoxylincomycins|
    JP2531876Y2|1988-12-15|1997-04-09|日東工器株式会社|Magnet holder for electromagnetic diaphragm pump|
    JP2531877Y2|1988-12-15|1997-04-09|日東工器株式会社|Electromagnetic diaphragm pump|
    JP2544782Y2|1988-12-27|1997-08-20|日東工器株式会社|Magnet holder for electromagnetic diaphragm pump|
    US6565882B2|2000-02-24|2003-05-20|Advancis Pharmaceutical Corp|Antibiotic composition with inhibitor|
    US6544555B2|2000-02-24|2003-04-08|Advancis Pharmaceutical Corp.|Antibiotic product, use and formulation thereof|
    US6541014B2|2000-10-13|2003-04-01|Advancis Pharmaceutical Corp.|Antiviral product, use and formulation thereof|
    US20020068078A1|2000-10-13|2002-06-06|Rudnic Edward M.|Antifungal product, use and formulation thereof|
    US20030073647A1|2001-08-28|2003-04-17|Chao Robert S.|Crystaline clindamycin free base|
    US7361743B2|2004-02-11|2008-04-22|Pfizer Inc|Lincomycin derivatives possessing antibacterial activity|
    BR0313725A|2002-08-15|2006-06-13|Vicuron Pharm Inc|lincomycin derivatives that have antibacterial activity|
    US7256177B2|2003-06-17|2007-08-14|Vicuron Pharmaceuticals, Inc.|Lincomycin derivatives possessing antibacterial activity|
    US7199105B2|2002-08-15|2007-04-03|Vicuron Pharmaceuticals, Inc.|Lincomycin derivatives possessing antibacterial activity|
    US7199106B2|2003-06-17|2007-04-03|Vicuron Pharmaceuticals, Inc.|Lincomycin derivatives possessing antimicrobial activity|
    JP4828404B2|2003-01-24|2011-11-30|ステフェルリサーチオーストラリアプロプライエタリーリミティッド|Clindamycin phosphate foam|
    EP1648415A4|2003-07-21|2011-11-16|Middlebrook Pharmaceuticals Inc|Antibiotic product, use and formulation thereof|
    WO2005009368A2|2003-07-21|2005-02-03|Advancis Pharmaceutical Corporation|Antibiotic product, use and formulation thereof|
    JP2006528185A|2003-07-21|2006-12-14|アドバンシスファーマスーティカルコーポレイション|Antibiotic preparations, their use and preparation|
    US8758820B2|2003-08-11|2014-06-24|Shionogi Inc.|Robust pellet|
    US8062672B2|2003-08-12|2011-11-22|Shionogi Inc.|Antibiotic product, use and formulation thereof|
    CA2535780A1|2003-08-29|2005-03-17|Advancis Pharmaceuticals Corporation|Antibiotic product, use and formulation thereof|
    JP2007513869A|2003-09-15|2007-05-31|アドバンシスファーマスーティカルコーポレイション|Antibiotic preparations, their use and preparation|
    AU2005269981A1|2004-07-02|2006-02-09|Bonck, John A|Tablet for pulsed delivery|
    US8357394B2|2005-12-08|2013-01-22|Shionogi Inc.|Compositions and methods for improved efficacy of penicillin-type antibiotics|
    AU2007220123A1|2006-02-28|2007-09-07|V.B. Medicare Pvt. Ltd.|Process for the production of a chlorinating reagent and its use in the preparation of chlorinated sugars|
    PL2010133T3|2006-03-31|2017-08-31|Stiefel Research Australia Pty Ltd|Foamable suspension gel|
    US8299052B2|2006-05-05|2012-10-30|Shionogi Inc.|Pharmaceutical compositions and methods for improved bacterial eradication|
    US8778924B2|2006-12-04|2014-07-15|Shionogi Inc.|Modified release amoxicillin products|
    CN101205245B|2007-12-06|2011-04-06|河南天方药业股份有限公司|Method for preparing hydrochloric acid clindamycinum|
    CN102675146A|2012-05-22|2012-09-19|山东凯盛新材料股份有限公司|Method for preparing novel solid chlorating agentdimethyl ammonium chloride|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US67615784A| true| 1984-11-29|1984-11-29|
    [返回顶部]