Method of preparing desoxyaminoglycoside antibiotics

专利摘要:
1460039 Silylated deoxyneomycins and deoxykanamycins TAKEDA YAKUHIN KOGYO KK 21 Dec 1973 [29 Dec 1972 (2) 24 May 1973 (2) 9 July 1973] 59635/73 Heading C3S [Also in Division C2] 31 - Chloro - 31 - dioxyneomycin A is acylated and silylated to obtain the tetra-N- acetyl - tri - O - trimethylsilyl derivative. 31 - Chloro - 3<SP>1</SP> - deoxy - kanamycin B is acylated and silylated to obtain the penta-N-acetylpenta-O-trimethylsilyl derivative.
公开号:SU873888A3
申请号:SU731983087
申请日:1973-12-27
公开日:1981-10-15
发明作者:Хирага Кентаро；Окутани Тецуя；Иосиока Коуити；Асако Цунехико
申请人:Такеда Кемикал Индастриз Лтд(Фирма)；
IPC主号:

专利说明:

 one , . .
The invention relates to the synthesis of biologically active compounds, specifically to an improved method for the preparation of deoxyaminoglycoside an-, tibiotics with valuable pharmacological properties.
A known method for producing deoxyaminoglycoside antibiotics by dehydroxylation of aminoglycogenic antibiotics. The method consists in the fact that in the source of non-phosphorus aminoglycoside antibiotic and sequential protection of all fugesional groups (YH), the red heart groups (XH) did not protect the fugitive groups (YH), the target heart (XH) was protected by all fugesionic groups (YH), the target heart (XH) was protected by all fugesionic groups (YH), the target heart (XH) was protected by all fugesionic groups (YH), the target heart (XH) was protected by all fugitive groups (YH), the target heart (XH) was protected by all fugesionic groups (YH). dehydroxylation, and this group is transformed into a new fuyk-rational group, which is subjected to transformation with replacement by H
atom 11 ...:
However, this method is microbial. staged (up to 9 stages), and the yield of the target product does not exceed 13-14%.
The aim of the invention is to control the process of obtaining deoxyaminoglycoside antibiotics and increase their yield .: The goal set is achieved, according to the method of producing deoox-. siaminoglycotic antibiotics ay nsg
glycosides containing the structural fragment of the formula
o-ro (he) r
 , 1 n NH-R
where R means a hydrogen atom, methyl,
ethyl, L-methoxyphenyl or P-metroxybenzyl;
or structural fragment of the formula
-s1Ng-ORO (OH) g
dehydrated by the they are also reacted with an acylating agent selected from the group: acetic anhydride, acetyl chloride, benzoyl chloride. The resultant silyl of phosphorus, oxasilyl chloro pibromide phosphorus, with the formation of the corresponding halo-derivative. At the final stage, the halogen derivative is reduced catalytically electrolytically using a metal hydride, a metal salt, zinc, amalgamated zinc, or Grignard reagent, followed by the removal of silyl or acyl groups.
The described method proceeds in stages 4-5 (including phosphorylation). If silylation and halogenation are carried out in one stage, the whole process takes place in 4 stages. The total yield is from 20 to 40%. Thus, the present method requires fewer stages for its implementation and gives greater yields compared with the known method.
Example. A mixture of 1.0 g of xylostasin-3-phosphate monohydrate, 0.7 g of triphenylphosphine, 9 ml of trimethylsilyl chloride, 4 ml of hexamethyldisilazane and 7.5 ml of pyridine is heated at 2 days. The reaction mixture is diluted with 200 ml of methanol and concentrated in vacuo to vacuum.
200 ml of water are added to the residue, the insoluble part is filtered off, dissolved in 100 ml of ethyl acetate and washed with 100 ml of water. The aqueous phase is concentrated in vacuo and chromatographed on a column of Amberlite resin (NHl-form).
Al} orate 1 and. . The eluate is concentrated and applied to a column with Amberlite CQ-SO resin (III-form).
It is washed with water and chromatographed in a concentration gradient from 0 to 0.3 n. fractions containing 3-chloro-3-deoxyxylostasin are combined, concentrated and lyophilized. An O. 505 g of 3-chloro-3-deoxy-xylostasin dihydrate is obtained.
Found,%: C 40.08; H 7.20; N 10.73; C1 6.55.
Ci-tH-5jN OgCl-2Hip.
Calculated,% t With 40,12; H 7.33; N 11.01, C1 6.97.
The original xylostasin-3-phosphate is obtained by enzymatic phosphorylation of xylostasin.
0.2 g of 3-chloro-3-deoxyxylostazine, 20 ml of water and 0.3 ml of triethylamine are shaken under a hydrogen atmosphere (normal conditions) in the presence of a skeletal nickel catalyst. After 6 h, the catalyst is filtered
and washed with 150 ml of 1N. ammonia water solution. The filtrate and wash water are combined and concentrated (20 ml). The formed precipitate was filtered off and the filtrate was applied to a column with Amberlite CQ-50 RESIN (NHt Form). .
The column is washed with water and chromatographed on an NH4OH gradient from 0 to 0.5 n. The fractions containing Z-dizoksilostazin,. combined, concentrated in vacuo. 0.152 g of 3-deoxixylostasin trihydrate is obtained.
Found%: C 41.23; H 7.95; N 11.08.
C Hj N40g-3Hi6,.
Calculated,%: C 41.54; H 8.18; N 11.37.
PRI mme R 2. A mixture of 0.3 g of neomycin-B-3-phosphate-pentahydrate, 2.7 ml of trimethylsilyl chloride, 1.2 ml of hexamethyldisilazane, 2.25 ml of dry pyridine and 0.21 g of triphenylphosphine are heated per mass. 44 hours. The reaction mixture was diluted with a 30 ml of methanol and concentrated in vacuo. 100 ml of water are added to the residue, the insoluble material is filtered off and 100 ml of ethyl acetate are added. The aqueous layer was separated, concentrated in vacuo, and applied to an Amberlite iRC-50 resin column (NHj-form).
The column was washed with water, eluted with aqueous ammonia, and the eluate was concentrated in vacuo. 0.25 g of crude product is obtained, which is dissolved in 50 ml of water and loaded onto a column with Amberlite CG resin (-50 (W-form). The column is washed with 100 ml of water, chromatographed over a concentration gradient of KNfOH from 0 to 0, 3 N. The crude product thus obtained is rechromatographed on Amberlite CQ-50 resin (NH-form) under the same conditions. After freeze-drying, 0.195 g of 3-chloro-3-deoxine neomycin-B dihydrate is obtained.
Found,%: with 41.03; H 7.29; N 12.41; every 5.35
CaoH; rN O -., iO. Calculated: C 41.28; H 7.38; N 12.55; From 5.29.
(Source eomycin-B-3-phosphate. 5H, iP is prepared by enzymatic phosphorylation of neomycin-B by a known method).
0.1 g of 3-chloro 3-deoxineomycin-B in 15 ml of water, .0.5 ml of triethyl calcium and 0.3 MP of the skeletal nickel catalyst are shaken in a hydrogen atmosphere (condition normal).
After 4 h, the catalyst is filtered off, washed with 100 ml of 1N. ammonia, the wash water is combined with the filtrate and concentrated.
0.085 g of crude product is obtained, which is dissolved in 20 ml of water and carried on a CQ column with Amberlite CQ-501 resin (NHt-form). Elute in an NH40H gradient from 0 to 0.5 n. After lyophilization, 0.06 g of 3-deeoxineomycin-B dihydrate is obtained (yield 42.2%; total yield 36%). Found,%: C 43.67 H, 7.75; N 13.05 .b fe ° ia l ° Calculated L: C 43.52 H 7, N 13.24. Example 3. A mixture of 0.1 g of zinc-A-3-phosphate trihydrate, 3 ml of trimethylsilyl chloride, 3 ml of bis (trimethylsilyl) acetamide and 3 ml of dry pyridine is heated on an oil tank at 15 hours. The reaction mixture is decomposed with methanol while cooling with ice and concentrate. The residue was diluted in 50 ml and applied to Amberlite IRC-50 column (LHD-form). The column is washed with 100 ml of water and eluted with 200 ml of 0.5N. aqueous ammonia the Eluate is concentrated, adjusted to N to 7.0 and applied to the column with Amberlite Cq-50 (LH4-form). 0.075 and water are eluted, and the resulting crude product is rechromatographed on a box with Amberlite cq-50 (NH-form). 0.035 g of 3-chloro-3-dez and n-omiCina-A are obtained. Found:% C 41.94} H 7.13 N 16.49; C | 10.12 C 2 H25N4.0, a Calculated,%: C 42.29 and 7.39 N 16.44; Ci 10.40. (The initial neomycin-A-3-phosphate is obtained by known means s farmer in phosphorylation carried “A and A-A). 0.15 g of 3-zhoro-3-de z-oxineoma is reduced in the usual way by the presence of a skeletal nickel catalyst. After chromatography on Amberlite CQrSOl (LH-form), 0.12 g of 3-disoxin-mycin-A monohydrate is obtained (yield 39.4%; total yield 29.6%). Found: C, 44.12; H 8.53; N 19.98. Hjo. Calculated: C 44.43; And 8,69; .N 17.27. Example 4. A mixture of 0.15 g Kanmitsin-B-3-phosphate. ZN, O, 7.5 ml of tr methylsilyl chloride, iS ml of hexa Silsane and 7.5 ml of dry pyridine are heated in an oil bath for 62 hours. According to the procedure of examples 1-3, 0.082 g of monohydrate is isolated; 3-chloro-3-Dee sycanamycin-B. Found,%: C 41.45; H 7.56 N 12.88; C1, 6.64: c. Calculated,%: C 41.57 — H, 7.36; N, 13.46; From 6.81. (The initial kanamycin-B-3-phosphate ZN, O is prepared in a known manner: enzymatic phosphorylation of Camicin-B). As described in the reduction of 0.03 g of 3-chloro-Zdezoksikanamitsya-B, 0.020 g of deoxycanamycin B is obtained (yield 44.7%; total yield 33.5%). Found,%: C 42.11; H 8.04; N 13.05 C gH TNgOg. 2HiO Calculated,%: C 42.93; H 8.20; N 13.90. Example 5. 1.2 g of kanamycin-B-3 phosphate trihydrate, 0.8 g of triphenylphosphine, 10 ml of trimethylsilyl chloride, 4 ml of hexamethyldisilazane and 4 ml of pyridine are heated at 130 with 48 hours. The reaction mixture is cooled with ice, decomposed 200 ml of methanol, concentrated to dryness, and the residue dissolved in 300 ml of water. The solution is extracted with 420 ml of methylene chloride, the aqueous layer is separated, diluted with water, 500 ml and chromatographed sequentially on a column with Amberlite iRC-50 (LH-form) and Amberlite CQ-50 (NH-form). 0.755 g of 3-chloro-3-deoxocanamycin B dihydrate is obtained. Similarly, by reducing 0.053 g of 3-chloro-3-deoxicanamycin-B, 0.033 g of 3-deoxycan mycin-B is obtained (yield 48%; total yield 36%). Approximately 6. A mixture of 0.63 g of kanamycin B-E-phosphate trihydrate, 5 ml of trimethylsilyl chloride, 2 ml of hexamethyldisylazane, 2 ml of pyridine, 0.4 g of three | Fensch1 phosphine and 0.1 g of zinc chloride are heated at 48 hours. The reaction mixture treated in the usual way. As a result, 0.425 g D-chloro-3 deoxycanamycin-B. To a solution of 0.1 g of 31-chloro-3-deoxycanamycin-B in 10 ml of water is added ©, 3 p palladium on carbon. Stir in hydrogen atmosphere for 5 hours. the catalyst is filtered off and washed with 50 ml 0/5 and. hydrochloric acid. The washing solution and the filtrate are combined, concentrated and neutralized with 1N. ammonia water. The neutralized solution is desalted on Amberlite 1RC-50 cation-exchange resin (NH-form), and then chromatographed on Amberlite cq-50i resin (Shf-form). 0.064 g of 3-decade of sycanamycin-B is obtained (yield 53%, total yield 39.6%). P Rome p 7. A mixture of 0.3 g of paromomycin-1-z-phosphate tetrahydrate, 2.7 ml of trimethylsilyl chloride, 1.2 ml of hexamethyldisilazane, 2.25 ml of dry pyridine, 0.21 g of triphenylphosphine are heated at 110 ° C for 48 hours After conventional treatment and sequential chromatography on Lumberlite iRC-50 and Amberlite CQ-501 and cq-SO (all LH-forms), 0.202 g of 3-chloro-3-deoxy-paro-mymycin-1 dihydrate is obtained. .
Found,%: C 40.97; H 7.09; N 10.63; CE 5.03
SPV, H44 "5013Се -IHiОВ $ automatically,%: 41,22; H 7,22;, N 10,45; С1 5-29.
(The initial paromomycin 1-3 phosphate is prepared in a known manner: by enzymatic phosphorylation of paramomycin-1),
0.1 g of 3-chloro-3-deoxyparomomycin-1 is reduced in the usual manner in the presence of a skeletal nickel catalyst. After ion exchange, ;; oja chromatography (Amberlite CQ-50 (LH-form)) 0.07 g of 3-deoxyparomycin-1 dihydrate is obtained (yield 56.7%; total yield 42.4%).
Found,%: C 43.29 ;, H, 7.65; N 10.91
Ci ,, H 5-N5 1i-2Ha.O.
Calculated,%: С43,45; H 7.76; N 11.01.
Example 8. A mixture of 0.6 g of ribostamycin-5-phosphate dihydrate, 0.6
, triphenylphosphine, 5 ml of trimethylsilyl chloride, 2 ml of hexamethyldisilazane; 2 ml of dry pyridine and 0.3 g of zinc chloride are heated at 100 ° C for 48 hours. The reaction mixture is decomposed by cooling with ice at 150 ml of methanol, evaporated to dryness, the residue is shaken with 150 m of ethyladetate, and the aqueous layer is chromatographed (Amberlite iRC-50p Amberlite SS; -50, NHD-form). Get 0,247 monohydrate 5 -cloo-5-deoxyribostamycin.
Found,%: C 41.43; H 7.35; N 11.25; ce 7.03,
From Ka9Y4Ozse.
Calculated,%: C 41.59; H 7.18; N 11.41; cr 7.22.
(The original ribostamidine-5-phosphate. Get a known method: enzymatic phosphorylation of ribostamycin).
0.15 g of 5-chloro-5-deoxyribostamycin is reduced in the usual manner in the presence of a skeletal nickel catalyst. Hollow ion exchange chromatography on Amberlite cq-50 (LHD-form) gives 0.081 g of 5-deoxyribostamycin dihydrate (yield 26.6%; total yield 20%),
Found,%: C 43.07; H 7.89; N 11.51. .
C. H.OgN42HiO
Calculated,%: C 43.03; H 8.07; N 11.81,
I'll try it on. A mixture of 0.5 g of ribostamycin-3-phosphate trihydrate, 2.7 ml of trimethylsilyl chloride, 1.2 ml of hexamethyldisilazane, 2.25 ml of dry pyridine and 0.21 g of triphenylphosphine are heated in an oil bath at 110 ° C for 44 hours. After the usual processing and chromatography on Amberlite CGi-50, Amberlite CGJ-501 and Amberlite CQ-50, (all NHj forms) get 0.191 g
z-chloro-3-deoxyribostamycin monohydrate.
Found,%: C 41.63; H 7.10; N 11.35; with; 7.01
Sc H9jN403C - H-ip
Calculated,%: C41,59; H 7.18; N 11.41; From 7.22.
0.1 g of s-chloro-3-deoxyribostamcin is reduced in the usual manner in the presence of a skeletal nickel catalyst. After ion exchange chromatography on Ambarlit CCJ-501 (L1 form), 0.068 g of 3-deoxyribostamycin monohydrate is obtained (yield 39%; total yield 29.2%).
Found,%: C 44.51; H 8.08; N 12.19
.
Calculated,%: C 44.72; H 7.94; N 12.27.

权利要求:
Claims (1)
[1]
Invention Formula
The method of producing deoxyaminoglycoside antibiotics by dehydroglylation of ag onoglycoside antibiotics, characterized in that, in order to simplify the process and increase the yield of the target product, aminoglycosides containing the structural fragment of the formula D are subjected to dehydroxylation.
(She is
  - V
H NH-R
where R denotes a hydrogen atom, methyl, ethyl, p-methoxyphenium or p-methoxybenzyl; or structural fragment of the formula IT
-:% - OPO (OH) j
by their interaction with the rest of the world; glycoelectrons undergo interaction with an acylidemic agent selected from the group including acetic anhydride, acetyl chloride, benzoyl chloride; resulting from a silync phosphorus tibromide, with the formation of the corresponding halogen derivative, which was recovered987388810
catalytically, electrolytically. 05/24/73 - a method for producing desokpri prysedi metal hydride, alkali and cosya aminoglycoside antibiotics - parometal, - metal salt, zinc, amalgamomycin iribostamicin, zinc or Gri-09 reagent. - a method of obtaining deoxidine, and removal; silyl or siaminoglycoside antibiotic - xyacyl groups are administered before or - lostasin. after the reduction reaction. Sources of information
Priority by featured. taken into account in the examination of 29.12.72 - method of preparation: deok- i. y Nlshimura et al. The synthemino-glycosytic antibiotic - cana-sis of t r deoxykanaroycln. Bull. Chem
No. 1 B, Soc. Japan, 45.2847, 1972 (prototype).

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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JP732167A|JPS5238557B2|1972-12-29|1972-12-29|

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JP216673A|JPS5652917B2|1972-12-29|1972-12-29|

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JP5828273A|JPS505303A|1973-05-24|1973-05-24|

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JP5828373A|JPS505304A|1973-05-24|1973-05-24|

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JP48077261A|JPS5025548A|1973-07-09|1973-07-09|

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