CN102190690B - Convenient high-yield Arbekacin synthesis method - Google Patents
Convenient high-yield Arbekacin synthesis method Download PDFInfo
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- CN102190690B CN102190690B CN201110082052.4A CN201110082052A CN102190690B CN 102190690 B CN102190690 B CN 102190690B CN 201110082052 A CN201110082052 A CN 201110082052A CN 102190690 B CN102190690 B CN 102190690B
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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 easy and Arbekacin synthetic method of high yield.
[background technology]
Arbekacin (Arbekacin 1) is the semi-synthetic aminoglycosides antibiotics that a kind of dual chemical is modified, and is developed, and go on the market in nineteen ninety by Japanese Meiji Seika Kaisha.This treatment agent is mainly used in treatment by the microbial infection of various resistance, is particularly useful for treatment Methicillin-resistant Staphylococcus aureus (MRSA) and infects, paid close attention to widely clinically and use.
The synthesis of Arbekacin is with 3 '; 4 '-dibekacin B and dibekacin (Debekacin 2) are raw material, and dibekacin itself has been a semisynthetic antibiotics product gone on the market; By various means, optionally at the C of dibekacin molecule
1bit amino is introduced S (-)-4-amino-1-maloyl group base side chain Arbekacin.The pharmacologically active of its uniqueness produces shielding by the action site that the side chain space steric hindrance on molecular structure is mould to passivation and realizes.
3 '; 4 '-dibekacin B molecule has 5 amino, C1 bit amino introduces side chain, must first optionally protect at all the other amino.Meanwhile, due to connected side chain, in acid, facile hydrolysis under alkali environment, selected blocking group must be easy to removal of dissociating again.These are difficult point places of Arbekacin synthesis.
The people Tetrahedron Lett.51:4951-4954 such as Tsutomo Tsuchiya, 1979 synthetic methods disclosing a kind of Arbekacin.They are using benzyloxy carbonyl acyl ester compound as protection reagent, at Zn
2+complexing under, to 3 ', 4 '-dibekacin B (dibekacin) selective protection, obtains 3,2 ', 6 '-triamino benzyl formate-3 ', 4 '-dibekacin B." there are 2 hydroxyls in amino adjacent bit, to the special selectivity that trifluoroacetylation has, with Trifluoroacetic Acid Ethyl Ester, to C3, " amino is protected to utilize C3.Then with the pendant reactive ester made condensation amino with the C1 only deposited, then trifluoroacetylation protection is removed through ammonia solution; Hydrogenolysis removes carbobenzoxy-(Cbz) protection; Arbekacin is obtained again through separation and purification.
Aforesaid method, be one very successful, full guard synthesis example, be not only applicable to the synthesis of Arbekacin, be equally applicable to amikacin (Kanamycin A Sulfate) yet.But, still have many weak points.
First, the method selects benzyloxy carbonyl acyl ester compound as protection reagent, and object is to go protection by hydrogenolysis thereafter, other carbamates can be avoided so usually to need (F under comparatively strongly-acid
3cCOOH) protection is gone in hydrolysis, and the side chain connected is hydrolyzed.But in fact due to the difficulty that suitable solvents is selected, hydrogenolysis be often difficult to carry out or hydrogenolysis not thorough.Hydrogenolysis needs high pressure, noble metal catalyst simultaneously; Higher requirement is all had to equipment, operation and environment.
Secondly, with trifluoroacetylation to C3, " amino is protected, and has very high selectivity.But when ammonia solution goes protection, the ammoniacal liquor of higher concentration often makes the pendant moiety connected by ammonia solution, thus affects product yield.
Moreover, with the active ester made and protection condensation, make building-up process too complicated.
[summary of the invention]
The present invention is directed to the weak point in above-mentioned technology and provide a kind of whole process simple, being easy to control and recovery rate is high, being applicable to the Arbekacin synthetic method of suitability for industrialized production.
The present invention realizes in the following way:
With 2-formyl mercaptobenzothiazole for protection reagent, to 3 ', the C3 of 4 '-dibekacin B, three amino on C2 ', C6 ' position carry out formylation protection; " amino activity difference, directly optionally introduces side chain at 1 bit amino to utilize all the other free 1 bit aminos and 3; (S)-4-formamido group-2-hydroxybutyric acid after direct amido protecting is as the acylating reagent to 1 bit amino; Formyl radical protection is removed with the acid hydrolysis of gentleness.
Comprise the following steps:
(a) 3,2 ', 6 '-three formamido group-3 ', the synthesis of 4 '-dibekacin B
By 3 ', 4 '-dibekacin B (dibekacin), with methyl-sulphoxide (DMSO), dimethyl formamide (DMF) or N,N-DIMETHYLACETAMIDE (DME) etc. " aprotic polar solvent " dissolve, add the divalent transition metal salt of C1-5 carboxylic acid as zinc acetate, venus crystals, nickelous acetate, trimethylacetic acid zinc etc., between control pH 8-10, it is complete that abundant stirring makes it complexing; By the amount of mol ratio 1: 3-4, drop into 2-formyl mercaptobenzothiazole, react 3 hours under room temperature, thin layer detects and judges reaction end;
Reaction solution dilute with water, filtrate is adsorbed on cationic exchange [NH
4 +] in type resin column, massive laundering washs rear ammoniacal liquor wash-out, collects the component with three protection, is evaporated to dry, obtains 3,2 ', 6 '-three formamido group-3 ', 4 '-dibekacin B is a light yellow solid;
The synthesis of (b) (S)-4-formamido group-2-hydroxybutyric acid
In water-lower alcohol (C1-C5) solution of sodium carbonate, add (S)-4-amino-2-hydroxybutyric acid (HABA); Slowly instill 2-formyl mercaptobenzothiazole (mol ratio 1: 1-1.5) lower alcohol (C1-C5) solution, under room temperature, continue stirring reaction a few hours, check the completely dissolve of HABA spot to thin layer;
Reaction solution is concentrated boils off Organic Alcohol; Raffinate ethyl acetate is washed; Aqueous phase 6N HCl regulates PH 2-3, then with ethyl acetate repeatedly extracting; Concentrating under reduced pressure, boils off ethyl acetate; Residue tetrahydrofuran (THF) dissolves, constant volume; Take phenolphthalein as indicator, NaOH standardized solution is demarcated, stand-by;
The synthesis of (c) Arbekacin
3,2 ', 6 '-three formamido group-3 ', 4 '-dibekacin B appropriate lower alcohol (C1-C5) dissolves, and add 1-hydroxy benzo triazole and a small amount of triethylamine, stirred at ambient temperature is to dissolving completely; Add the tetrahydrofuran solution of (S)-4-formamido group-2-hydroxybutyric acid again; Be cooled to 0-20 DEG C, preferably 5-10 DEG C; Slowly drip the solution that DCCI is dissolved in appropriate lower alcohol (C1-C5) under stirring, stirring reaction a few hours at same temperature, TCL checks to the completely dissolve of raw material spot;
Reaction solution is concentrated into dry, adds a small amount of water, and lower alcohol, and stirring at room temperature is dissolved; At 0--5 DEG C, slowly add 0.5MHCl; Then outer bath temperature 15-20 DEG C is warming up to gradually, stirring reaction 2-4 hour; PH to 6-7 is regulated, thin up, elimination insolubles with 2N NaOH;
Filtrate with weak-type macroporosity ion exchange resin column as; The absorption such as CD-180 [NH4+], Amberliter CG-50 [NH4+], with gradient ammoniacal liquor wash-out after water washing, collecting the flow point with Abbe, be concentrated into dry, obtain Arbekacin free alkali, is a white solid.
The invention has the advantages that:
Come off because the side chain on Arbekacin molecule is easily hydrolyzed in the basic conditions, then less sensitive in acid condition, 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, obtains 3,2 ', 6 '-three formamido group-3 ', 4 '-dibekacin B.This protection complete with side chain condensation after, protection can be removed smoothly under room temperature and 0.5M hydrochloric acid.Eliminate the de-protected many difficulties of hydrogenolysis using benzyloxy carbonyl acyl blocking group to run into like this.
" amino may due to sterically hindered cause, to the reactive behavior of side chain condensation than C for C3
1amino weak many; Therefore the present invention can by controlling charge ratio, and the method lowering speed of response makes side chain condensation be oriented in C1 amino position; Thus save trifluoroacetylation protection C3 " amino, and ammonia solution removes the step of trifluoroacetyl protection.
Protection and side chain condensation; can directly at HOBt; under DCCI exists; be raw material with (the S)-4-amino-2-hydroxybutyric acid after amido protecting; without the need to first (the S)-4-amino-2-hydroxybutyric acid after amido protecting being made active ester; use active ester and protection condensation again, part operation and equipment can be simplified like this.
[accompanying drawing explanation]
Fig. 1 the present invention synthesizes the poly-route map of 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 for protection reagent, to 3 ', the C3 of 4 '-dibekacin B, three amino on C2 ', C6 ' position carry out formylation protection; " amino activity difference, directly optionally introduces side chain at 1 bit amino to utilize all the other free C1 bit amino and C3; (S)-4-formamido group-2-hydroxybutyric acid after direct amido protecting is as the acylating reagent to 1 bit amino; Formyl radical protection is removed with the acid hydrolysis of gentleness.
As shown in Figure 1, comprise the following steps:
(a) 3,2 ', 6 '-three formamido group-3 ', the synthesis of 4 '-dibekacin B
By 3 ', 4 '-dibekacin B (dibekacin), with methyl-sulphoxide (DMSO), dimethyl formamide (DMF) or N,N-DIMETHYLACETAMIDE (DME) etc. " aprotic polar solvent " dissolve, add the divalent transition metal salt of C1-5 carboxylic acid as zinc acetate, venus crystals, nickelous acetate, trimethylacetic acid zinc etc., between control pH 8-10, it is complete that abundant stirring makes it complexing; By the amount of mol ratio 1: 3-4, drop into 2-formyl mercaptobenzothiazole, react 3 hours under room temperature, thin layer detects and judges reaction end;
Reaction solution dilute with water, filtrate is adsorbed on cationic exchange [NH
4 +] in type resin column, massive laundering washs rear ammoniacal liquor wash-out, collects the component with three protection, is evaporated to dry, obtains 3,2 ', 6 '-three formamido group-3 ', 4 '-dibekacin B is a light yellow solid;
The synthesis of (b) (S)-4-formamido group-2-hydroxybutyric acid
In water-lower alcohol (C1-C5) solution of sodium carbonate, add (S)-4-amino-2-hydroxybutyric acid (HABA); Slowly instill 2-formyl mercaptobenzothiazole (mol ratio 1: 1-1.5) lower alcohol (C1-C5) solution, under room temperature, continue stirring reaction a few hours, check the completely dissolve of HABA spot to thin layer;
Reaction solution is concentrated boils off Organic Alcohol; Raffinate ethyl acetate is washed; Aqueous phase 6N HCl regulates PH 2-3, then with ethyl acetate repeatedly extracting; Concentrating under reduced pressure, boils off ethyl acetate; Residue tetrahydrofuran (THF) dissolves, constant volume; Take phenolphthalein as indicator, NaOH standardized solution is demarcated, stand-by;
The synthesis of (c) Arbekacin
3,2 ', 6 '-three formamido group-3 ', 4 '-dibekacin B appropriate lower alcohol (C1-C5) dissolves, and add 1-hydroxy benzo triazole and a small amount of triethylamine, stirred at ambient temperature is to dissolving completely; Add the tetrahydrofuran solution of (S)-4-formamido group-2-hydroxybutyric acid again; Be cooled to 0-20 DEG C, preferably 5-10 DEG C; Slowly drip the solution that DCCI is dissolved in appropriate lower alcohol (C1-C5) under stirring, stirring reaction a few hours at same temperature, TCL checks to the completely dissolve of raw material spot;
Reaction solution is concentrated into dry, adds a small amount of water, and lower alcohol, and stirring at room temperature is dissolved; At 0--5 DEG C, slowly add 0.5MHCl; Then outer bath temperature 15-20 DEG C is warming up to gradually, stirring reaction 2-4 hour; PH to 6-7 is regulated, thin up, elimination insolubles with 2N NaOH;
Filtrate with weak-type macroporosity ion exchange resin column as; The absorption such as CD-180 [NH4+], Amberliter CG-50 [NH4+], with gradient ammoniacal liquor wash-out after water washing, collecting the flow point with Abbe, be concentrated into dry, obtain Arbekacin free alkali, is a white solid.
Following instance is further described in detail the present invention, but the present invention is not limited only to the process parameters range in following instance and example.
Embodiment 1,2 ', 6 '-three formamido group-3 ', the preparation of 4 '-dibekacin B
In 500ml tri-neck round-bottomed flask, add 3 ', 4 '-dibekacin B (9.02 grams, 0.02mol), DMSO 150ml, stir 10min, add zinc acetate 13.2 grams, under room temperature, airtight stirring 5 hours, clarifies to solution.Drop into 2-formyl mercaptobenzothiazole (12.88 grams, 0.066mol), continue stirring reaction 3 hours under room temperature, thin layer detects and judges reaction end.
Reaction solution is slowly poured in 400ml water, and adularescent precipitation generates, and stir about 0.5 hour adjusts pH to 6 ~ 7 with ammoniacal liquor, elimination insolubles, the appropriate water repetitive scrubbing of filter residue, merging filtrate.
Filtrate is adsorbed on 800ml 732 [NH
4 +] in type resin, massive laundering washs rear 0.3N ammoniacal liquor wash-out, collects the component with three protection, is evaporated to dry.Obtain 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 about 0.35, developping agent: chloroform-methanol-ammoniacal liquor (25%): 10-10-1 (V/V/V), triketohydrindene hydrate develops the color.
The preparation of embodiment two (S)-4-formamido group-2-hydroxybutyric acid
In the three neck round-bottomed flasks of 250ml, add sodium carbonate (15.9 grams, 0.15mol), water 120ml, is stirred to and dissolves completely.Add (S)-4-amino-2-hydroxybutyric acid (HABA) (11.9 grams, 0.1mol) in above-mentioned solution, stirring and dissolving, to clarifying completely, checks that pH is more than 10.Add methanol solution 20ml, continue to stir 30min.Slowly instill 2-formyl mercaptobenzothiazole (self-control, 21.5 grams, 0.11mol) to be dissolved in 10ml methanol solution, about 15min adds.Continue stirring reaction hour under 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.
Above-mentioned reaction solution elimination white solid, filtrate is concentrated boils off methyl alcohol.Raffinate ethyl acetate 100ml washs.The water layer 6N HCl separated regulates PH 2-3, then uses ethyl acetate 100ml × 3 time extracting, combined ethyl acetate layer, and concentrating under reduced pressure, boils off ethyl acetate.Gained solid tetrahydrofuran (THF) dissolves, and is settled to 100ml.Take phenolphthalein as indicator, 0.1M NaOH standardized solution is demarcated, and is 0.00085mol/ml, yield: 85%
The preparation of embodiment three Arbekacin
In 250ml tri-neck round-bottomed flask, add 3,2 ', 6 '-three formamido group-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, stirred at ambient temperature is to dissolving completely.Add the tetrahydrofuran solution (12.94ml of (S)-4-formamido group-2-hydroxybutyric acid again, 0.00085mol/ml), ice-water bath 5-10 DEG C, slowly drips DCCI (3.12 grams under stirring, 0.015mol) be dissolved in 30ml methanol solution, within about 45 minutes, add.Stirring reaction 6 hours at same temperature, 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 dry, adds H
2o 10ml, methyl alcohol 10ml, stirring at room temperature is dissolved.At 0--5 DEG C, slowly drip 0.5MHCl 50ml, control to add for 30 minutes.Then outer bath temperature 15-20 DEG C is warming up to gradually, stirring reaction 1.5 hours.Regulate PH to 6-7 with 2N NaOH, be diluted with water to 500ml, elimination insolubles.
Filtrate is adsorbed with 500ml CD-180 [NH4+] type resin column.Use 0.5N successively after water washing, 0.65N ammoniacal liquor wash-out, collects the flow point with Abbe, is concentrated into dry, obtain a white solid (3.52 grams, yield: 63.76%).
Claims (1)
1. an easy and Arbekacin synthetic method for high yield, is characterized in that: concrete steps are as follows:
(a) 3,2 ', 6 '-three formamido group-3 ', the synthesis of 4 '-dibekacin B
By 3 ', 4 '-dibekacin B, with methyl-sulphoxide, dimethyl formamide or dimethylacetamide amine solvent, add the divalent transition metal salt zinc acetate of C1-5 carboxylic acid, venus crystals, nickelous acetate or trimethylacetic acid zinc, between control pH 8-10, it is complete that abundant stirring makes it complexing; By the amount of mol ratio 1: 3-4, drop into 2-formyl mercaptobenzothiazole, react 3 hours under room temperature, thin layer detects and judges reaction end;
Reaction solution dilute with water, filtrate is adsorbed on cationic exchange [NH
4 +] in type resin column, massive laundering washs rear ammoniacal liquor wash-out, collects the component with three protection, is evaporated to dry, obtains 3,2 ', 6 '-three formamido group-3 ', 4 '-dibekacin B is a light yellow solid;
The synthesis of (b) (S)-4-formamido group-2-hydroxybutyric acid
In the water-methanol solution of sodium carbonate, add (S)-4-amino-2-hydroxybutyric acid; Slowly instill 2-formyl mercaptobenzothiazole methanol solution, its mol ratio is 1: 1-1.5, continues stirring reaction a few hours under room temperature, to the completely dissolve of thin layer inspection (S)-4-amino-2-hydroxybutyric acid spot;
Reaction solution is concentrated boils off Organic Alcohol; Raffinate ethyl acetate is washed; Aqueous phase 6N HCl regulates PH 2-3, then with ethyl acetate repeatedly extracting; Concentrating under reduced pressure, boils off ethyl acetate; Residue tetrahydrofuran (THF) dissolves, constant volume; Take phenolphthalein as indicator, NaOH standardized solution is demarcated, stand-by;
The synthesis of (c) Arbekacin
3,2 ', 6 '-three formamido group-3 ', 4 '-dibekacin B proper amount of methanol is dissolved, and add 1-hydroxy benzo triazole and a small amount of triethylamine, stirred at ambient temperature is to dissolving completely; Add the tetrahydrofuran solution of (S)-4-formamido group-2-hydroxybutyric acid again; Be cooled to 0-20 DEG C, slowly drip the solution that DCCI is dissolved in proper amount of methanol under stirring, stirring reaction a few hours at same temperature, TLC checks to the completely dissolve of raw material spot;
Reaction solution is concentrated into dry, adds a small amount of water, and methyl alcohol, and stirring at room temperature is dissolved; At 0--5 DEG C, slowly add 0.5MHCl; Then outer bath temperature 15-20 DEG C is warming up to gradually, stirring reaction 2-4 hour; PH to 6-7 is regulated, thin up, elimination insolubles with 2N NaOH;
Filtrate is adsorbed with weak-type macroporosity ion exchange resin column CD-180 [NH4+] or Amberliter CG-50 [NH4+], with gradient ammoniacal liquor wash-out after water washing, collect the flow point with Abbe, be concentrated into dry, obtaining Arbekacin free alkali, is a white solid.
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| 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 |
| 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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