CN102190690A - Convenient high-yield Arbekacin synthesis method - Google Patents
Convenient high-yield Arbekacin synthesis method Download PDFInfo
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Abstract
The invention discloses a convenient high-yield Arbekacin synthesis method which comprises the following steps: using 2-formyl mercaptobenzothiazole as the protection reagent to carry out formylation protection on three amino groups on the C3 site, C2' site and C6' site of 3',4'-dibekacin B; based on the difference between other free amino groups on the C1 site and the amino group on the C3'' site in activity, directly introducing side chains to the amino groups on the C1 site optionally; directly using (S)-4-formylamino-2-hydroxy-butanoic acid with the protected amino groups as the acylation reagent for the amino groups on C1 site; and hydrolyzing with moderate acid to remove the formacyl protection. In the whole process, the yield is more than 50%. The whole process is simple, easy to control and high in yield, thereby being applicable to industrial production.
Description
[technical field]
The present invention relates to a kind of methodology of organic synthesis, refer more particularly to a kind of Arbekacin synthetic method of easy and high yield.
[background technology]
Arbekacin (Arbekacin 1) is the semi-synthetic aminoglycosides antibiotics that a kind of dual chemical is modified, and is developed by Japanese Meiji Seika Kaisha, and goes on the market in nineteen ninety.This treatment agent is mainly used in treatment by the microbial infection of various resistances, is particularly useful for treating methicillin-resistant gold Portugal bacterium (MRSA) and infects, and is paid close attention to widely clinically and uses.
Arbekacin synthetic be with 3 '; 4 '-dibekacin B is that dibekacin (Debekacin 2) is a raw material, dibekacin itself has been a semisynthetic antibiotics product that has gone on the market; By various means, optionally at the C of dibekacin molecule
1Introduce on the bit amino S (-)-4-amino-1-maloyl group base side chain Arbekacin.Its unique pharmacologically active is realized the mould action site generation shielding of passivation by the side chain on the molecular structure is sterically hindered.
3 '; 4 '-dibekacin B molecule has 5 amino, to introduce side chain on the C1 bit amino, must optionally protect earlier at all the other amino.Simultaneously, because the side chain that is connected, in acid, facile hydrolysis under the alkali environment, selected blocking group must be easy to the removal of dissociating again.These are Arbekacin synthetic difficult point places.
People Tetrahedron Lett.51:4951-4954 such as Tsutomo Tsuchiya, 1979 have disclosed a kind of synthetic method of Arbekacin.They with benzyloxy carbonyl acyl ester compound as the protection reagent, at Zn
2+Complexing under, to 3 ', 4 '-dibekacin B (dibekacin) selective protection, obtain 3,2 ', 6 '-triamino benzyl formate-3 ', 4 '-dibekacin B." there are 2 hydroxyls in amino phase ortho position, and to the special selectivity that trifluoroacetylation has, " amino is protected to C3 with Trifluoroacetic Acid Ethyl Ester to utilize C3.With side chain active ester of making and the amino condensation of the C1 that only deposits, separate through ammonia again and remove the trifluoroacetylation protection then; Hydrogenolysis is removed the carbobenzoxy-(Cbz) protection; Obtain Arbekacin through separation and purification again.
Aforesaid method, be one very successful, full guard is synthesized example, is not only applicable to the synthetic of Arbekacin, equally also is applicable to amikacin (Kanamycin A Sulfate).But, still have many weak points.
At first, this method selects for use benzyloxy carbonyl acyl ester compound as protection reagent, and purpose is in order to go protection with hydrogenolysis thereafter, can avoid other carbamates usually need be than (F under the strongly-acid like this
3CCOOH) protection is gone in hydrolysis, and the side chain that has connected is hydrolyzed.But in fact because the difficulty that suitable solvents is selected, hydrogenolysis often be difficult to carry out or hydrogenolysis not thorough.Hydrogenolysis needs high pressure, noble metal catalyst simultaneously; To equipment, operation, and environment higher requirement is all arranged.
Secondly, " amino is protected, and has very high selectivity to C3 with trifluoroacetylation.But separate when protecting at ammonia, the ammoniacal liquor of higher concentration tends to make the pendant moiety that has connected to be separated by ammonia, thereby influences the product yield.
Moreover, with active ester of making and the condensation of protection thing, make building-up process too complicated.
[summary of the invention]
The present invention is directed to the weak point in the above-mentioned technology and provide a kind of whole process simple, be easy to control and recovery rate height, be applicable to the Arbekacin synthetic method of suitability for industrialized production.
The present invention realizes in the following way:
With 2-formyl mercaptobenzothiazole is protection reagent, to 3 ', 4 '-C3 of dibekacin B, C2 ', three amino on C6 ' position carry out formylation protection; " amino activity difference is directly optionally introduced side chain at 1 bit amino to utilize all the other free 1 bit aminos and 3; Directly with the acylating reagent of (the S)-4-formamido group behind the amido protecting-2-hydroxybutyric acid conduct to 1 bit amino; Remove the formyl radical protection with the acid hydrolysis of gentleness.
May further comprise the steps:
(a) 3,2 ', 6 '-three formamido groups-3 ', 4 '-dibekacin B synthetic
With 3 ', 4 '-dibekacin B (dibekacin), with methyl-sulphoxide (DMSO), dimethyl formamide (DMF) or N,N-DIMETHYLACETAMIDE " non-proton property polar solvents " such as (DME) dissolving, the divalent transition metal salt of adding C1-5 carboxylic acid such as zinc acetate, venus crystals, nickelous acetate, trimethylacetic acid zinc etc., between the control pH 8-10, it is complete that abundant stirring makes it complexing; By the amount of mole proportioning 1: 3-4, drop into 2-formyl mercaptobenzothiazole, reaction is 3 hours under the room temperature, and thin layer detects judges reaction end;
Reaction solution dilute with water, filtrate are adsorbed on cationic exchange [NH
4 +] in the type resin column, massive laundering is washed back ammoniacal liquor wash-out, collects to have three components of protecting things, is evaporated to driedly, obtain 3,2 ', 6 '-three formamido groups-3 ', 4 '-dibekacin B, be a light yellow solid;
(b) (S)-4-formamido group-2-hydroxybutyric acid synthetic
In water-lower alcohol (C1-C5) solution of yellow soda ash, add (S)-4-amino-2-hydroxybutyric acid (HABA); Slowly splash into 2-formyl mercaptobenzothiazole (mole proportioning 1: 1-1.5) lower alcohol (C1-C5) solution, continue stirring reaction a few hours under the room temperature, check the completely dissolve of HABA spot to thin layer;
Reaction solution concentrates and boils off organic alcohol; Raffinate washs with ethyl acetate; Water is regulated PH 2-3 with 6N HCl, again with repeatedly extracting of ethyl acetate; Concentrating under reduced pressure boils off ethyl acetate; Residue dissolves with tetrahydrofuran (THF), constant volume; With phenolphthalein is indicator, and the NaOH standardized solution is demarcated, and is stand-by;
(c) Arbekacin is synthetic
3,2 ', 6 '-three formamido groups-3 ', 4 '-dibekacin B is with an amount of lower alcohol (C1-C5) dissolving, adds 1-hydroxy benzo triazole and a small amount of triethylamine, is stirred to dissolving fully under the room temperature; The tetrahydrofuran solution that adds (S)-4-formamido group-2-hydroxybutyric acid again; Be cooled to 0-20 ℃, preferably 5-10 ℃; Stir and slowly to drip the solution that DCCI is dissolved in an amount of lower alcohol (C1-C5) down, stirring reaction a few hours under the same temperature, TCL checks to the completely dissolve of raw material spot;
Reaction solution is concentrated into dried, adds less water, and lower alcohol, the stirring at room dissolving; Under 0--5 ℃, slowly add 0.5MHCl; Be warming up to outer bath temperature 15-20 ℃ then gradually, stirring reaction 2-4 hour; Regulate PH to 6-7, thin up, elimination insolubles with 2N NaOH;
Filtrate with weak-type macroporosity ion exchange resin column as; CD-180[NH4+], Amberliter CG-50[NH4+] etc. absorption, with gradient ammoniacal liquor wash-out, collect the flow point that has Abbe after the water washing, be concentrated into driedly, obtain the Arbekacin free alkali, be a white solid.
The invention has the advantages that:
Since the side chain on the Arbekacin molecule under alkaline condition easily hydrolysis come off, next less sensitive at acidic conditions, under room temperature and 1M concentration of hydrochloric acid, almost have no impact in 24 hours.Therefore the present invention adopts 2-formyl mercaptobenzothiazole as protection reagent, at Zn
2+Complexing under, to 3 ', 4 '-dibekacin B (dibekacin) selective protection, obtain 3,2 ', 6 '-three formamido groups-3 ', 4 '-dibekacin B.This protection thing finish with the side chain condensation after, under room temperature and 0.5M hydrochloric acid, can remove protection smoothly.The de-protected many difficulties of hydrogenolysis of using benzyloxy carbonyl acyl blocking group to be run into have been exempted like this.
C3 " amino may be because sterically hindered cause, to the reactive behavior of side chain condensation than C
1Amino weak is many; Therefore the present invention can be by the control charge ratio, and the method that lowers speed of response is oriented on the C1 amino position side chain condensation; Thereby save trifluoroacetylation protection C3 " amino, and ammonia is separated the step of removing the trifluoroacetyl protection.
Protection thing and side chain condensation; can be directly at HOBt; DCCI exists down; with (the S)-4-amino-2-hydroxybutyric acid behind the amido protecting is raw material; need not earlier (the S)-4-amino-2-hydroxybutyric acid behind the amido protecting to be made active ester; with active ester and the condensation of protection thing, can simplify part operation and equipment so again.
[description of drawings]
Fig. 1 the present invention poly-route map of synthetic step;
Wherein:
(1): zinc acetate/DMSO, triethylamine;
(2): S-formyl mercaptobenzothiazole;
(3): (S)-4-formamido group-2-hydroxybutyric acid, hydroxy benzo triazole, DCCI, methyl alcohol;
(4):0.5M?HCl;
[embodiment]
The present invention realizes in the following way:
With 2-formyl mercaptobenzothiazole is protection reagent, to 3 ', 4 '-C3 of dibekacin B, C2 ', three amino on C6 ' position carry out formylation protection; " amino activity difference is directly optionally introduced side chain at 1 bit amino to utilize all the other free C1 bit amino and C3; Directly with the acylating reagent of (the S)-4-formamido group behind the amido protecting-2-hydroxybutyric acid conduct to 1 bit amino; Remove the formyl radical protection with the acid hydrolysis of gentleness.
As shown in Figure 1, may further comprise the steps:
(a) 3,2 ', 6 '-three formamido groups-3 ', 4 '-dibekacin B synthetic
With 3 ', 4 '-dibekacin B (dibekacin), with methyl-sulphoxide (DMSO), dimethyl formamide (DMF) or N,N-DIMETHYLACETAMIDE " non-proton property polar solvents " such as (DME) dissolving, the divalent transition metal salt of adding C1-5 carboxylic acid such as zinc acetate, venus crystals, nickelous acetate, trimethylacetic acid zinc etc., between the control pH 8-10, it is complete that abundant stirring makes it complexing; By the amount of mole proportioning 1: 3-4, drop into 2-formyl mercaptobenzothiazole, reaction is 3 hours under the room temperature, and thin layer detects judges reaction end;
Reaction solution dilute with water, filtrate are adsorbed on cationic exchange [NH
4 +] in the type resin column, massive laundering is washed back ammoniacal liquor wash-out, collects to have three components of protecting things, is evaporated to driedly, obtain 3,2 ', 6 '-three formamido groups-3 ', 4 '-dibekacin B, be a light yellow solid;
(b) (S)-4-formamido group-2-hydroxybutyric acid synthetic
In water-lower alcohol (C1-C5) solution of yellow soda ash, add (S)-4-amino-2-hydroxybutyric acid (HABA); Slowly splash into 2-formyl mercaptobenzothiazole (mole proportioning 1: 1-1.5) lower alcohol (C1-C5) solution, continue stirring reaction a few hours under the room temperature, check the completely dissolve of HABA spot to thin layer;
Reaction solution concentrates and boils off organic alcohol; Raffinate washs with ethyl acetate; Water is regulated PH 2-3 with 6N HCl, again with repeatedly extracting of ethyl acetate; Concentrating under reduced pressure boils off ethyl acetate; Residue dissolves with tetrahydrofuran (THF), constant volume; With phenolphthalein is indicator, and the NaOH standardized solution is demarcated, and is stand-by;
(c) Arbekacin is synthetic
3,2 ', 6 '-three formamido groups-3 ', 4 '-dibekacin B is with an amount of lower alcohol (C1-C5) dissolving, adds 1-hydroxy benzo triazole and a small amount of triethylamine, is stirred to dissolving fully under the room temperature; The tetrahydrofuran solution that adds (S)-4-formamido group-2-hydroxybutyric acid again; Be cooled to 0-20 ℃, preferably 5-10 ℃; Stir and slowly to drip the solution that DCCI is dissolved in an amount of lower alcohol (C1-C5) down, stirring reaction a few hours under the same temperature, TCL checks to the completely dissolve of raw material spot;
Reaction solution is concentrated into dried, adds less water, and lower alcohol, the stirring at room dissolving; Under 0--5 ℃, slowly add 0.5MHCl; Be warming up to outer bath temperature 15-20 ℃ then gradually, stirring reaction 2-4 hour; Regulate PH to 6-7, thin up, elimination insolubles with 2N NaOH;
Filtrate with weak-type macroporosity ion exchange resin column as; CD-180[NH4+], Amberliter CG-50[NH4+] etc. absorption, with gradient ammoniacal liquor wash-out, collect the flow point that has Abbe after the water washing, be concentrated into driedly, obtain the Arbekacin free alkali, be a white solid.
Following example is further described in detail the present invention, but the present invention is not limited only to the process parameters range in following example and the example.
In the 500ml three neck round-bottomed flasks, add 3 ', 4 '-dibekacin B (9.02 grams, 0.02mol), DMSO 150ml stirs 10min, adds zinc acetate 13.2 grams, and airtight stirring is 5 hours under the room temperature, clarifies to solution.(12.88 grams 0.066mol), continued stirring reaction 3 hours under the room temperature, and thin layer detects judges reaction end to drop into 2-formyl mercaptobenzothiazole.
Reaction solution is slowly poured in the 400ml water, and adularescent precipitation generates, and stir about 0.5 hour is transferred pH to 6~7 with ammoniacal liquor, the elimination insolubles, and filter residue is with an amount of water repetitive scrubbing, merging filtrate.
Filtrate is adsorbed on 800ml 732[NH
4 +] in the type resin, massive laundering is washed the back with 0.3N ammoniacal liquor wash-out, collects the component that has three protection things, is evaporated to dried.Get light yellow solid 8.8 grams, yield 82.2%.ESI-MS(m/z):(558)[M+Na]
+,(536)[M+H]
+,
Silica gel G thin-layer chromatography: Rf is about 0.35, developping agent: chloroform-methanol-ammoniacal liquor (25%): 10-10-1 (V/V/V), triketohydrindene hydrate colour developing.
The preparation of embodiment two (S)-4-formamido group-2-hydroxybutyric acid
In the three neck round-bottomed flasks of 250ml, (15.9 grams, 0.15mol), water 120ml is stirred to dissolving fully to add yellow soda ash.(11.9 grams, 0.1mol) in above-mentioned solution, stirring and dissolving checks that to clarification fully pH is more than 10 to add (S)-4-amino-2-hydroxybutyric acid (HABA).Add methanol solution 20ml, continue to stir 30min.(make by oneself, 21.5 grams 0.11mol) are dissolved in the 10ml methanol solution, and about 15min adds slowly to splash into 2-formyl mercaptobenzothiazole.Continue stirring reaction hour under the room temperature, check the completely dissolve of HABA spot to thin layer.Developping agent: CHCl
3-MeOH-NH
4OH (25%) 4: 4: 1 (V/V/V), developer: 5% phospho-molybdic acid ethanol liquid.
Above-mentioned reaction solution elimination white solid, filtrate concentrating boils off methyl alcohol.Raffinate washs with ethyl acetate 100ml.The water layer of telling is regulated PH 2-3 with 6N HCl, uses ethyl acetate 100ml * 3 time extracting again, the combined ethyl acetate layer, and concentrating under reduced pressure boils off ethyl acetate.The gained solid dissolves with tetrahydrofuran (THF), is settled to 100ml.With phenolphthalein is indicator, and 0.1M NaOH standardized solution is demarcated, and is 0.00085mol/ml, yield: 85%
The preparation of embodiment three Arbekacins
In the 250ml three neck round-bottomed flasks, adding 3,2 ', 6 '-three formamido groups-3 ', 4 '-dibekacin B (5.35 grams, 0.01mol), methyl alcohol 40ml, 1-hydroxy benzo triazole (HOBT 2.03 grams, 0.015mol), TEA 0.5ml is stirred to dissolving fully under the room temperature.(12.94ml, 0.00085mol/ml), ice-water bath 5-10 ℃, (3.12 grams 0.015mol) are dissolved in the 30ml methanol solution to the tetrahydrofuran solution of adding (S)-4-formamido group-2-hydroxybutyric acid, add in about 45 minutes slowly to drip DCCI under stirring again.Stirring reaction is 6 hours under the same temperature, and TCL checks to the completely dissolve of raw material spot.Developping agent: CH
2Cl
2-MeOH-NH
4OH (25%) 50: 35: 5 (V/V/V), iodo steam displaing color.
Reaction solution is concentrated into dried, adds H
2O 10ml, methyl alcohol 10ml, stirring at room dissolving.Under 0--5 ℃, slowly drip 0.5MHCl 50ml, control 30 minutes and add.Be warming up to outer bath temperature 15-20 ℃ then gradually, stirring reaction 1.5 hours.Regulate PH to 6-7 with 2N NaOH, thin up is to 500ml, the elimination insolubles.
Filtrate is used 500ml CD-180[NH4+] absorption of type resin column.Use 0.5N after the water washing successively, 0.65N ammoniacal liquor wash-out is collected the flow point have Abbe, be concentrated into dried, a white solid (3.52 grams, yield: 63.76%).
Claims (2)
1. the Arbekacin synthetic method of an easy and high yield is characterized in that:
(1) serve as protection reagent with 2-formyl mercaptobenzothiazole, to 3 ', 4 '-C3 of dibekacin B, C2 ', three amino on C6 ' position carry out formylation protection;
(2) " amino activity difference is directly optionally introduced side chain at 1 bit amino to utilize all the other free C1 bit amino and C3; Directly with the acylating reagent of (the S)-4-formamido group behind the amido protecting-2-hydroxybutyric acid conduct to 1 bit amino;
(3) remove the formyl radical protection with gentle acid hydrolysis.
2. the Arbekacin synthetic method of a kind of easy and high yield according to claim 1 may further comprise the steps:
(a) 3,2 ', 6 '-three formamido groups-3 ', 4 '-dibekacin B synthetic
With 3 ', 4 '-dibekacin B (dibekacin), with methyl-sulphoxide (DMSO), dimethyl formamide (DMF) or N,N-DIMETHYLACETAMIDE " non-proton property polar solvents " such as (DME) dissolving, the divalent transition metal salt of adding C1-5 carboxylic acid such as zinc acetate, venus crystals, nickelous acetate, trimethylacetic acid zinc etc., between the control pH 8-10, it is complete that abundant stirring makes it complexing; By the amount of mole proportioning 1: 3-4, drop into 2-formyl mercaptobenzothiazole, reaction is 3 hours under the room temperature, and thin layer detects judges reaction end;
Reaction solution dilute with water, filtrate are adsorbed on cationic exchange [NH
4 +] in the type resin column, massive laundering is washed back ammoniacal liquor wash-out, collects to have three components of protecting things, is evaporated to driedly, obtain 3,2 ', 6 '-three formamido groups-3 ', 4 '-dibekacin B, be a light yellow solid;
(b) (S)-4-formamido group-2-hydroxybutyric acid synthetic
In water-lower alcohol (C1-C5) solution of yellow soda ash, add (S)-4-amino-2-hydroxybutyric acid (HABA); Slowly splash into 2-formyl mercaptobenzothiazole (mole proportioning 1: 1-1.5) lower alcohol (C1-C5) solution, continue stirring reaction a few hours under the room temperature, check the completely dissolve of HABA spot to thin layer;
Reaction solution concentrates and boils off organic alcohol; Raffinate washs with ethyl acetate; Water is regulated PH 2-3 with 6N HCl, again with repeatedly extracting of ethyl acetate; Concentrating under reduced pressure boils off ethyl acetate; Residue dissolves with tetrahydrofuran (THF), constant volume; With phenolphthalein is indicator, and the NaOH standardized solution is demarcated, and is stand-by;
(c) Arbekacin is synthetic
3,2 ', 6 '-three formamido groups-3 ', 4 '-dibekacin B is with an amount of lower alcohol (C1-C5) dissolving, adds 1-hydroxy benzo triazole and a small amount of triethylamine, is stirred to dissolving fully under the room temperature; The tetrahydrofuran solution that adds (S)-4-formamido group-2-hydroxybutyric acid again; Be cooled to 0-20 ℃, preferably 5-10 ℃; Stir and slowly to drip the solution that DCCI is dissolved in an amount of lower alcohol (C1-C5) down, stirring reaction a few hours under the same temperature, TCL checks to the completely dissolve of raw material spot;
Reaction solution is concentrated into dried, adds less water, and lower alcohol, the stirring at room dissolving; Under 0--5 ℃, slowly add 0.5MHCl; Be warming up to outer bath temperature 15-20 ℃ then gradually, stirring reaction 2-4 hour; Regulate PH to 6-7, thin up, elimination insolubles with 2N NaOH;
Filtrate with weak-type macroporosity ion exchange resin column as; CD-180[NH4+], Amberliter CG-50[NH4+] etc. absorption, with gradient ammoniacal liquor wash-out, collect the flow point that has Abbe after the water washing, be concentrated into driedly, obtain the Arbekacin free alkali, be a white solid.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104447732A (en) * | 2014-11-27 | 2015-03-25 | 齐鲁天和惠世制药有限公司 | Preparation method of amikacin and intermediate activated thioester thereof |
CN106916192A (en) * | 2017-04-20 | 2017-07-04 | 齐鲁天和惠世制药有限公司 | The method that one kettle way continuous stream produces Arbekacin |
CN108358983A (en) * | 2018-04-11 | 2018-08-03 | 常州方圆制药有限公司 | A kind of amide side chain derivative compounds at Arbekacin method |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0547031A1 (en) * | 1989-06-21 | 1993-06-16 | Schering Corporation | N-protected-(S)-isoserine compounds |
CN101139371A (en) * | 2007-10-09 | 2008-03-12 | 无锡苏科生物科技有限公司 | Aminoglycoside antibiotics |
CN101152195A (en) * | 2007-10-09 | 2008-04-02 | 无锡苏科生物科技有限公司 | Application of aminoglycoside antibiotic in preparing pharmaceutical composition for treating drug-fast bacteria infection |
CN101575354A (en) * | 2009-05-26 | 2009-11-11 | 北京化工大学 | Method for synthesizing Arbekacin and intermediate dibekacin thereof |
CN101723994A (en) * | 2007-10-09 | 2010-06-09 | 常州方圆制药有限公司 | Method for preparing aminoglycoside antibiotic |
-
2011
- 2011-04-01 CN CN201110082052.4A patent/CN102190690B/en not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0547031A1 (en) * | 1989-06-21 | 1993-06-16 | Schering Corporation | N-protected-(S)-isoserine compounds |
CN101139371A (en) * | 2007-10-09 | 2008-03-12 | 无锡苏科生物科技有限公司 | Aminoglycoside antibiotics |
CN101152195A (en) * | 2007-10-09 | 2008-04-02 | 无锡苏科生物科技有限公司 | Application of aminoglycoside antibiotic in preparing pharmaceutical composition for treating drug-fast bacteria infection |
CN101723994A (en) * | 2007-10-09 | 2010-06-09 | 常州方圆制药有限公司 | Method for preparing aminoglycoside antibiotic |
CN101575354A (en) * | 2009-05-26 | 2009-11-11 | 北京化工大学 | Method for synthesizing Arbekacin and intermediate dibekacin thereof |
Non-Patent Citations (2)
Title |
---|
《Synthetic Communications》 20071019 Konstantin Doktorova,等 New Convenient Reagents for Chemoselective N-Alkoxycarbonylation of (S)-Isoserine: Application in the Isepamicin Synthesis 3709-3718 1-2 第37卷, 第21期 * |
KONSTANTIN DOKTOROVA,等: "New Convenient Reagents for Chemoselective N‐Alkoxycarbonylation of (S)‐Isoserine: Application in the Isepamicin Synthesis", 《SYNTHETIC COMMUNICATIONS》 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104447732A (en) * | 2014-11-27 | 2015-03-25 | 齐鲁天和惠世制药有限公司 | Preparation method of amikacin and intermediate activated thioester thereof |
CN104447732B (en) * | 2014-11-27 | 2016-12-07 | 齐鲁天和惠世制药有限公司 | A kind of amikacin and the preparation method of intermediate activity thioesters thereof |
CN106916192A (en) * | 2017-04-20 | 2017-07-04 | 齐鲁天和惠世制药有限公司 | The method that one kettle way continuous stream produces Arbekacin |
CN106916192B (en) * | 2017-04-20 | 2019-05-07 | 齐鲁天和惠世制药有限公司 | The method of one kettle way continuous flow production Arbekacin |
CN108358983A (en) * | 2018-04-11 | 2018-08-03 | 常州方圆制药有限公司 | A kind of amide side chain derivative compounds at Arbekacin method |
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