• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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    • 专利摘要:
    A process for production of esters of antibiotics from the group of polyene macrolides and of N-substituted derivatives thereof, having the general Formula 1, wherein R denotes the radical of antibiotic or of its R-COOR, I N-substituted derivative, and R1 denotes an alkyl with the chain length of C1 through C5, or an aryl, consisting therein that an antibiotic from the group of polyene macrolides or its N-substituted derivative is dissolved or suspended in alcohol and/or neutral organic solvent, or in a mixture of organic solvents, in presence of dicyclohexylcarbodiimide and/or hydrocybenzotriazole, the whole is allowed to stand at room temperature, or at temperature elevated to 40 DEG C., and then the obtained product is isolated from the reaction medium after known methods.
    公开号:SU1052154A3
    申请号:SU802945106
    申请日:1980-07-07
    公开日:1983-10-30
    发明作者:Фальковски Лэонард；Стэфаньска Барбара；Трока Элжбета；Голик Ежи；Боровски Эдвард
    申请人:Политехника Гданьска (Инопредприятие)；
    IPC主号:
    专利说明:

    The invention relates to an improved method for producing esters of antibiotics from the field of new macrolides or their N-substituted derivatives, which can be used in medical practice. A known method of producing antibiotic esters from, for example, nystatin methyl ester, pimaricin amphotericin, candicidin, a group of polyene macrolides, which involves the interaction of the corresponding | 11 polyene macrolide in tetrahydrof; a wound with diazmethane in tetrahydrofuran and room temperature 13. polyene macrolide esters are used for the alkylation reaction of diazoalkanes, explosive and toxic substances. The purpose of the invention is to simplify the process and asshirenie target product assortment. This goal is achieved in that according to the method for producing esters of antibiotics from the group of polyene macrolides or their N-substituted derivatives of the general formula. where R is the residue of the polyene macroli. Yes, such, as pimaricin, nystatin, polyfungin, amphotericin B, aureofacin, or its N-substituted derivative, and the substituent. is N-acetyl, N- (N, N-dimethylamino) -methylene, M-penten-2-he-4-yl-2, N- (1-carboalkoxy) propen-1-yl::. -2,;, /: - -; -. , R - C-C-alkyl, phenyl, p-nitrophenyl, benzyl, methoxyben .- .:. zil, . , Ma, the corresponding polyene macrolide, or its N-substituted derivative, is treated with an alcohol of formula (II). where R. has the indicated values in an organic organic solvent such as N, N-dimethylacetamide, M, K-dim1 tilformamide, pyridine or tetrahydrofuran in the presence of dicyclohexylcarbodiimide or dicyclohexylcarbodiimide with the addition of hydroxybenzotriazole at 20 ° -40 ° A number of compounds prepared by this route are new. The structures of the obtained derivatives were proved by comparing with the initial antibiotic from the group of polyene macromolnds, as well as on the basis of spectroscopic analysis in the ultraviolet, visible light and infrared radiation and mass spectrometry, performed by field desorption technique. The absorption spectra in the region of visible and ultraviolet light of the ethers obtained and the initial antibiotics differ only slightly in intensity, and the position of the absorption maxima and the oscillation structure are odinak1. This indicates the unchanged structure of the polyene chromophore in the obtained derivatives. Evidence of the presence of an ether bond in the molecule of an antibiotic derivative is the presence of an intense absorption band in the infra. the red spectrum at cm (ap aliphatic and aromatic ethers) with the simultaneous absence of the band of carboxilane ion characteristic of the original antibiotic at 1590 cm-,. Example. 1 g of nystatin (E, °, 800 at 304 nm) and 1 g of dicyclohexylcarbodiimide (DCGC) are dissolved in 200 cm of anhydrous methanol and mixed for 15 minutes. During this time, almost the entire antibiotic will react. The progress of the reaction is monitored by thin layer chromatography of the composition ethyl acetate: acetic acid: water (4: 1: 1). Then methanol is evaporated with a decrease of -. pressure to a volume of several cubic centimeters and precipitated with ethyl ether. After cleaning, the product is centrifuged, washed alternately with ethyl alcohol and hexane and dried under reduced pressure. 0.9 g of crude nystatin methyl ester is obtained at 304 nm. after purification by column chromatography on Sephadex.e 20 consisting of chloroform: methanol (5: 1), 0.8 g of nystatin methyl ester 720 (304 nm) is obtained, which is 80% of the theoretical value. Example 2. To 1 g of nystatin (E, -800 at 304 nm) and 1 DCGC, 20 ml of freshly distilled benzyl ester are added, mixed until dissolved, and left overnight. Additive 300 ml of a mixture of ethyl alcohol: hexane (2: 1) precipitate the product, centrifuged, washed alternately with ethyl alcohol and hexane and dried under reduced pressure. About 75 g of crude product ether is obtained with 670 at 304 nm, which is purified by chloroform-methanol (10: 1) using a column chromatography method on Sephadexe.20. 0.65 g of nystatin benzyl ester is obtained with 760 at 304 nm, which is bb% of theoretical. Froze O, 4 g of nystatin, 0.3 g of DCCA, and O, 5 g of p-nitrophenol
    dissolved in a mixture of 3 cm of N, N-dimethylacetamide and pyridine (1: 1). and left goth overnight at. After precipitating with ethyl ether and repeatedly washing with ether and hexane, 0.35 g of raw product (. 630 with 304 im) is obtained. It is purified by the method of column chromatography on Silica gel, precondensed with water, consisting of chloroform: butanol: gvod (20: 20: 1) and 0.3 g of the nystatin ester phenyl ester is obtained. (with E.dm fiPH 304 nm), which is 65% of the theoretical. EXAMPLE 4 0.5 g of nystatin and 0.5 g of DCC are dissolved in 3 cm of saturated solution of phenol in M, N-dimethyl acetamide and left overnight at. The product is precipitated with ethyl ether and purified by column chromatography on silica gel, which is preliminarily saturated with water, in the composition of chloroform: methanol: water (20: 10: O, 5). , 0.3 g of phenyl ester of nystatin is obtained (700 at 304 nm), which is 55% of the theoretical value.
    PRI me R 5 H- (1-carboalkoxy) - propent1-yl-2-LPA derivative. 1 g of NPA-derived aureofacin at 373 and 0.5 g of CTC was dissolved in 20 cm of a mixture of g-yantanol and tetratadrofuray (1: 1) and left overnight at 40 ° C. Then thicken; with reduced pressure to a few cubic centimeters and precipitated, the product is ethanol.
    The floor is 0.9 g of the methyl ether of the LRA-derivative of aureofacin (EP 500 at 378 im). An example of b. 0.5 g of NPA-npOK3 iodine candicidin (Et, 503 prc 383 im) and g of dagK are dissolved in 10 cm of a mixture of methanol and tetradhydrrfuran (1: 1) and left overnight at a temperature. The selection is analogous to Example 5. 0.45 g (Е1Й, "400), which is 80% of the theoretical value, is produced. . -. ..;
    Example 7. 0.3 g of N-acetylpium maricium with 110 at 304 nm and 0.2 g are dissolved in 2 wi of freshly distilled benzyl alcohol and left overnight at room temperature. :
    The precipitate, seen with an ethyl ethyl mixture, ether: hexane (2: 1), is applied to a mat filled with Sephadex LH 20 gel and chromatographed in a chlorine form: itachach system (5: 1). Obtain 0.2 g of benzyl efkra and N-acetylpiratshtsina (, 1000 at 304 nm), which compares 60% of theoretical.
    Example 8. 0.5 g of L-ace ± ilamphotericin B with 1, 1200, at 383 NM and 0.4 g of DCCA are dissolved in 5 14 L of newly distilled benzyl alcohol and left overnight at xiatum
    temperature The isolation method is similar to Example 7.
    0.45 g of N-acetylamphotericin B benzyl ester is obtained from 1200 at 383 nm, which is 85% of the theoretical.
    PRI me R. 9. 0.5 g of N-acetylnistatin (, 900 at 304 nm) and 0.4 g of DdGK solution in 3 mp of freshly candy; benzyl alcohol and left overnight at room temperature. The method of isolation is analog to Example 7. 0.4 g of N-acetylnistatin benzyl ester (or 304 nm) is obtained, which accounts for 75% of the theoretical.
    EXAMPLE 10: 1 g of polyfungin (at 304 nm) is dissolved in 10 uci of anhydrous methanol, 1 g of dicyclohexylcarbodiyletd is added and mixed for 24 hours at a coarse tag. The progress of the reaction is controlled by thin-layer chromatography consisting of ethyl acetate: acetic acid:: water (4: 1: 1). Then 5 1lp of butanol is added, methanol is evaporated with a decrease in pressure and oca} Jc is added with ethyl ether and a precipitate of polyfungin methyl ester. The wasp; kdenny product is spilled; about three times and dried under reduced pressure. 580 g of polyfungin methyl ester are obtained with an E of 760 at 304 nm, which is about 70% of the theoretical. 1C 0.25 µg / ml.
    Example 11. 0.5 g of the NPA-derivative of amphotericin B with E 1550 at 382 nm is dissolved in 5 ml of anhydrous ethanol, 0.5 g of alkali halide is added and weighed at room temperature for 24 hours. The reaction is controlled by thin layer chromatography ethyl whey: acetic acid: water (4: 1: 1). Then, 1 mp of pyridine is added and After 4 hours, precipitate of ethyl ether of NPA-derivative of amphotericin B is precipitated with ethyl ether from the solution and then doused twice with ethyl ether and dried under reduced pressure. Obtain 0.4 g of ethyl ester NPA-PrR derivative of amphotericin B. iCgQ 0.05 µg / m) 1, which is 80% of theoretical with El | l 1260 at 382 of them. The precipitate of ethyl ester of the NpA-derivative of amphotericin B is dissolved in chloroform: methanol: water (lOOtlO :) and applied to cope Sephadex L1I. 20. After the column, 250 g of ether are isolated with E 1400.
    EXAMPLE 12: 0.5 g of NPA-n-y derivative of nystatin with E, dissolved in 100 MP of ethanol, 0.4 g of DGHA are added and left at room temperature for 24 hours. The resulting ethyl ether product The nytitin NPA-derivative is precipitated with ethyl ether, twice with ethyl ether and dried under reduced pressure. O Obtain 0.5 g of NPA7npo ethyl ether and aqueous nystatin with El5 ° 500, iCcr,. . rCWvt f "0.5 µg / ml. P, p, and m e p 13. 100 mg of NPA-npoH3 VOL) Noah is amphotrich with 382 of it dissolved in 20 mp of butanol, 100 mg of DCC is added and left for 24 hours at. After checking with the absorption of thin layer chromatography composed of ethyl acetate: acetic acid: that: water (4.1: 1) and the reaction from the reaction mixture, it is precipitated with ethyl ether: the precipitate, which is washed twice with ethyl ether and dried under reduced pressure. Get it. 85 mg of the NPA-derivative of amphotericin B at 304 nm, which is 80% of the theoretical. Example 14, 0.4 g of NPA-specific pyramicin at 304 nm was dissolved in 20 ml of anhydrous methanol. 100 mg of DCGC was added. After reaction for 20 hours at room temperature, the progress of this reaction was checked by thin layer chromatography (the PAA derivative was practically reacted). A precipitate is precipitated from methanol with ethyl ether, washed twice with ethyl ether and dried under reduced pressure. Get 14 mg of methyl ester J PA-derivative of piramycin s, Sd mcg / g-sh. P R: th measures 15. 50 mg of candicidin with E. | 600 Dissolve in 1 ml of pyridine, 50 mg of dicyclohexylcarbodiimide and 50 mg of hexamethylbenetriazole are added. After mixing for 1 hour, 3 ml of methanol was added and left at room temperature for 24 hours. The reaction product was precipitated with ethyl ether, washed twice with ethyl ether and dried under reduced pressure. 35 mg of candicidin methyl ester are obtained with 0.001 μg / mp. Example: 16. To 50 mg of polyfungin are added 1 ml of anisic alcohol and 50 mg of DCC. The reaction lasts 30 hours at. The progress of the reaction is controlled by the method of thin-layer chromats 11} aphium in the composition of chlorbform: methanol: water (100: 25: 3). At the end of the reaction, the product is precipitated with ethyl ether, washed twice with ethyl ether and dried under reduced pressure. 30 mg of polyfungin anise ester are obtained, Cd = 1.0 μg / ml. Alkhod 65% of theoretical. The antifungal activity of the antibiotic esters of the invention is presented in the table. Thus, the invention makes it possible to obtain esters of antibiotics from the group of polyene macrolides and their N-substituted derivatives without the use of explosive and toxic and eioalkanes and allows expanding the range of the target product.
    p-Nitrophenyl Ether
    Phenyl ether
    Aureofacin
    Methyl ester Candicidin
    N-acetylnistatin benzyl ester N- (penten-2-he-4-ylo-2) -nistatin ethyl ester
    Methyl ester of N- (penten-2-one-4-ylo-2) -aurieofacin
    N- (neHTeH72-one-4-ylo-2) candecydin methyl ester
    Amphotericin B
    ttiilpuiMriitMfi
    PsmMfuyty Methyl ether
    Anise ether
    lh
    1 11 "act ester
    Continuation of the table
    Ben-ester N-acetylamphoteric B
    Ethyl ester (4- (peiten-2-one -4-11Lb-2 -) - amphotoacrya B
    Butyl ether Y- (peiten-2-it 4gilo-2) -amphote1r Itcin / B
    {N-Acetylpicin Vonyl Ester
    methyl ester of H- (peiten-on-4-ylo 2) -pimeration
    权利要求:
    Claims (1)
    [1]
    The method of obtaining esters of antibiotics from the group of polyene macrolides or their N-substituted derivatives of the General formula
    RC-0K1, where R is the residue of a polyene macrolide such as pimaricin, nystatin, polyfungia, amphotericin b, aureofacin, or ! its N-substituted derivative, the substituent being N-acetyl, N- (N, N * -dimethylamino) -methylene, N-penten-2-one-4-yl-2, N- (1-carboalkoxy) propene- 1-yl-2;
    R 4 - C - ^ - C ^ -alkyl, phenyl, p-nitrophenyl, benzyl, methoxybeneyl, characterized in that, in order to simplify the process and expand the assortment of the target product, they act on the corresponding polyene macrolide or its N-substituted derivative formulas ι он-he,.
    where R n has the indicated meanings, in an organic solvent such as Ν, Ν-dimethylacetamide, Ν, Ν'-dimethylformamide, pyridine or tetrahydrrfuran in the presence of dicyclohexylcarbodiimide or dicyclohexylcarbodiimide with the addition of hydroxybenetriearol at 20-40 ° С.
    类似技术:
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    同族专利:
    公开号 | 公开日
    PL124710B1|1983-02-28|
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    FI69472C|1986-02-10|
    PL217239A1|1981-03-13|
    DE3026045A1|1981-01-29|
    US4365058A|1982-12-21|
    FI802216A|1981-01-19|
    FI69472B|1985-10-31|
    GB2055812A|1981-03-11|
    DE3026045C2|1983-12-15|
    GB2055812B|1983-11-23|
    FR2461717B1|1983-12-02|
    引用文献:
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    RU2488590C2|2007-07-03|2013-07-27|Биосерген АС|Derivatives of nystatin and their application as antifungal agents|US2628249A|1951-01-03|1953-02-10|Pittsburgh Coke & Chemical Co|Esterification process|
    GB1359473A|1970-11-03|1974-07-10|Prodotti Antibiotici Spa|Polyenic antibiotic|
    US4035568A|1971-06-07|1977-07-12|Rutgers Research And Educational Foundation|Derivatives of polyene macrolide antibiotics|ZA807892B|1979-12-24|1981-12-30|Dumex Ltd As|Water soluble guanidine derivatives of polyene marcrolides and the esters thereof|
    EP0431874A1|1989-12-08|1991-06-12|Beecham Group p.l.c.|Novel compounds|
    WO2001051061A1|2000-01-14|2001-07-19|Intrabiotics Pharmaceuticals, Inc.|Derivatives of polyene macrolides and preparation and use thereof|
    US6664241B2|2000-05-31|2003-12-16|Micrologix Biotech Inc.|Water-soluble amide derivatives of polyene macrolides and preparation and uses thereof|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    PL21723979A|PL124710B1|1979-07-18|1979-07-18|Process for preparing esters of antibiotics from polyene macrolids group and their n-substituted derivatives|
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