CN102260306B - Novel method for preparing tulathromycin - Google Patents
Novel method for preparing tulathromycin Download PDFInfo
- Publication number
- CN102260306B CN102260306B CN201110206323A CN201110206323A CN102260306B CN 102260306 B CN102260306 B CN 102260306B CN 201110206323 A CN201110206323 A CN 201110206323A CN 201110206323 A CN201110206323 A CN 201110206323A CN 102260306 B CN102260306 B CN 102260306B
- Authority
- CN
- China
- Prior art keywords
- reaction
- midbody
- formula
- suc
- amount
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- MLOAQRNDXHEWGO-BJMCJPPVSA-N C[C@H](C1OC11OC)OC1[O]=C Chemical compound C[C@H](C1OC11OC)OC1[O]=C MLOAQRNDXHEWGO-BJMCJPPVSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a novel method for preparing tulathromycin and relates to a semi-synthetic macrolide antibiotic. The method comprises the following steps: simultaneously protecting 2'-hydroxyl and 6a-amino of desmethyl azithromycin with acetyl, then carrying out oxidation and epoxidation on 4''-hydroxy, then removing the protecting groups under alkaline alcohol solution conditions, and carrying out nucleophilic addition on 4''-epoxy group with n-propylamine to obtain the target compound tulathromycin. Compared with the prior art, the method for preparing tulathromycin has the advantages of simple process, mild conditions, high yield and the like, and is beneficial to industrial production.
Description
Technical field
The present invention relates to a kind of Macrolide semisynthetic antibiotics, specifically a kind ofly prepare the novel method that mycin draws in Thailand.
Background technology
Macrolide antibiotics is one type of weakly alkaline microbiotic and the structural modification thing thereof that is produced by streptomycete, and mostly they are alkaline lipophilic compound, higher to the inhibition activity of gram-positive microorganism and mycoplasma.Nineteen fifty-two, gift comes company to release first-generation macrolide antibiotics product Oxacyclotetradecane,erythromycin deriv, the existing s-generation even the third generation macrolide antibiotics product nowadays released.Wherein Erythromycin A (erythromycin A) is representative clinically first-generation macrolide antibiotics; It is to separate and get from Streptothrix (S. erythreus); Gram-positive bacteria is had powerful anti-microbial effect, and gram-negative bacteria such as meningococcus, gonococcus, hemophilus influenza, bordetella pertussis, Brucella etc. and legionella (Legionella) are also all extremely sensitive to Oxacyclotetradecane,erythromycin deriv.The semisynthetic macrolide antibiotics of the s-generation has the Azythromycin (azithromycin) etc. of clarithromycin (clarithromycin), Roxithromycin (roxithromycin), dirithromycin (dirithromycin), P 80206 (flurithromycin) and 15 yuan of rings of 14 yuan of ring systems row.The third generation comprises the effective Ketek of resistant organism (telithromycin), match Oxacyclotetradecane,erythromycin deriv (cethromycin) etc., and its 3 for taking off cladinose, and is the ketone carbonyl, so be called ketolide (ketolide) microbiotic again.These macrolides compounds and cephalosporin analog antibiotic and fluoroquinolone etc. have formed the antibiotic tripartite balance of forces (external medicine, microbiotic fascicle, 2002,23 (3): 129-131).
Mycin draws in Thailand, and (rhzomorph draws in dilatory rhzomorph or Thailand; Tulathromycin) be a kind of exploitation listing recently and be the Macrolide semisynthetic antibiotics of animal specific; It is mainly used in the pig that is caused by actinobacillus pleuropneumoniae, mycoplasma, pasteurellosis bacillus, secondary influenzae, bordetella bronchiseptica etc., the control of ox respiratory system disease, especially ox, respiratory diseases in pigs transmissible disease is had fairly obvious result of treatment.Thailand draws mycin to have to absorb rapidly, high and low residual, the long half time of bioavailability, lasting medicine, parenteral single-dose can provide advantages (Chinese veterinary drug magazine, 2008,12,51 – 54) such as whole-course treatment.The rhzomorph commodity draw in Thailand--and auspiciously newly be made up of 2 isomerss when injection liquid reaches balance in the aqueous solution, 90% is 15 Yuans azalactones rings, and 10% is 13 Yuans azalactones rings (J. Chromatography B, 2007,1,464 – 470).
At present, the widely used Macrolide veterinary drug of China is tylosin and tilmicosin, though the result of use of these two kinds of medicines is good, along with the prolongation of duration of service, resistance in various degree occurred in a lot of areas; Thailand draws the drug effect of mycin to be better than widely used Macrocyclolactone lactone kind medicine (external medical microbiotic fascicle, 2003,24 (3): 115) on the markets such as tylosin and tilmicosin simultaneously.Because safe plurality of advantages of drawing mycin, domestic aquaculture begin to be widely used gradually, and the gesture of medicines such as replacing tylosin and tilmicosin is arranged.
Draw the preparation of mycin for Thailand; The preparation method that Pfizer of the former unit of grinding adopts is to be raw material to remove first Azythromycin (shown in
); At first with the simultaneously two protections of benzyloxy acyl chloride go in the first Azythromycin 2 '-position hydroxyl and 6a bit amino (or optionally protecting a 2 ' hydroxyl); Then successively in the cladinose 4 ' '-a position hydroxyl carries out oxidation, epoxidation; And catalytic hydrogenation removes the basic benzyloxy acyl of protection; At last with Tri N-Propyl Amine to 4 ' '-a position epoxy carry out nucleophilic substitution promptly make Thailand draw the mycin product (EP1253153A1, US6472371B1, US6420536B1).
But these preparing method's operating process are complicated, especially need use high-pressure hydrogenation device and deep cooling condition, are unfavorable for industrial production.
Summary of the invention
Technical assignment of the present invention is the deficiency to above-mentioned prior art, provides a kind of method simple, mild condition, and the higher one kettle way of yield prepares safe method of drawing mycin.
Thailand draws the concrete structure of mycin (shown in
) to be: (2R, 3S, 4R, 5R; 8R, 10R, 11R, 12S; 13S, 14R)-13-[[2, the pyrans glycosyl of 6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(Propylamino) methyl]-α-L-nuclear-]-oxygen]-2-ethyl-3; 4,10-trihydroxy--3,5; 8,10,12; 14-vegolysen 1-[[3,4, the pyrans glycosyl of 6-three deoxidations-3-(dimethylamino)-β-D-wood-] oxygen]-1-oxa--6-nitrogen heterocyclic pentadecane (15-person encircles greatly).
Technical assignment of the present invention is realized by following mode: a kind ofly prepare the novel method that mycin draws in Thailand, be characterized in may further comprise the steps:
a, protected with an acetyl group as formula
azithromycin norepinephrine shown in 2'-OH and 6a-amino obtain structural formula
intermediates shown in a (acetyl-protected norepinephrine dual azithromycin);
B, with one reaction of Swern oxygenant and step a gained midbody; To its 4 ' '-position hydroxyl carry out oxidation; The midbody two of structural formula shown in
(4 ' '-oxo, 2 '-OH and 6a-N position ethanoyl two protect remove the first Azythromycin);
C, with Corey-chaykovsky reagent to 4 of step b gained midbody two ' '-a position carbonyl carries out epoxidation, obtain the midbody three of structural formula shown in
(4 ' '-epoxy-2 '-OH and 6a-N position ethanoyl two protect remove the first Azythromycin);
D, in alkaline alcohol solution, remove the protection base of step c gained midbody three; And with Tri N-Propyl Amine to 4 ' '-a position epoxy carries out nucleophilic addition(Adn), " one kettle way " obtains the target compound Thailand of structural formula shown in
and draws mycin.
The concrete structure of midbody one (structural formula is shown in
) is: (2R, 3S, 4R, 5R; 8R, 10R, 11R, 12S; 13S, 14R)-13-[[2,6-dideoxy-3-C-methyl-3-O-methyl--the pyrans glycosyl of α-L-nuclear-]-oxygen]-2-ethyl-3; 4,10-trihydroxy acid-3,5; 8,10,12; 14-vegolysen 1-[[3,4, the pyrans glycosyl of 6-three deoxidations-3-(dimethylamino)-2-O-ethanoyl-β-D-wood-] oxygen]-1-oxa--6-nitrogen heterocyclic pentadecane (15-person encircles greatly).
The concrete structure of midbody two (structural formula is shown in
) is: (2R, 3S, 4R, 5R; 8R, 10R, 11R, 12S; 13S, 14R)-13-[[2, the pyrans glycosyl of 6-dideoxy-3-C-methyl-3-O-methyl-4-oxo-α-L-nuclear-]-oxygen]-2-ethyl-3; 4,10-trihydroxy acid-3,5; 8,10,12; 14-vegolysen 1-[[3,4, the pyrans glycosyl of 6-three deoxidations-3-(dimethylamino)-2-O-ethanoyl-β-D-wood-] oxygen]-1-oxo-6-nitrogen heterocyclic pentadecane (15-person encircles greatly).
The concrete structure of midbody three (structural formula is shown in
) is: (2R, 3S, 4R, 5R; 8R, 10R, 11R, 12S; 13S, 14R)-13-[[2, the pyrans glycosyl of 6-dideoxy-3-C-methyl-3-O-methyl-4-C-[epoxy methyl]-α-L-nuclear-]-oxygen] 2-ethyl-3; 4,10-trihydroxy acid-3,5; 8,10,12; 14-vegolysen 1-[[3,4, the pyrans glycosyl of 6-three deoxidations-3-(dimethylamino)-2-O-ethanoyl-β-D-wood-] oxygen]-1-oxa--6-nitrogen heterocyclic pentadecane (15-person encircles greatly).
Specifically, the inventive method may further comprise the steps:
A; The first Azythromycin that goes shown in the formula
is dissolved in the reaction solvent; And add an amount of acid binding agent successively; The ethanoyl protective material; 10～45 ℃ of reactions down; After reaction finishes; Separate; Purifying; The midbody one of structural formula shown in
(the two protections of ethanoyl go first Azythromycin)
Said reaction solvent is methylene dichloride or chloroform,
Said acid binding agent be diethylamine, triethylamine, diisopropyl ethyl amine or
N-methylamino pyridine,
Said ethanoyl protective material is diacetyl oxide or Acetyl Chloride 98Min., goes first Azythromycin and protective material amount of substance ratio to be 1.0:2.0～3.0;
B, step a gained midbody one is dissolved in the reaction solvent; Under-10～-45 ℃, carry out the Swern oxidizing reaction; Add an amount of acid binding agent again; After reaction finishes, separate under the room temperature, purifying, the midbody two of structural formula shown in
(4 ' '-oxo; 2 '-the two protections of OH and 6a-N position ethanoyl remove the first Azythromycin)
Said reaction solvent is methylene dichloride or chloroform,
The oxidation system of said Swern oxidizing reaction is methyl-sulphoxide-Vanadium Pentoxide in FLAKES, methyl-sulphoxide-trifluoroacetic anhydride or methyl-sulphoxide-oxalyl chloride, and midbody two is 1.0:1.0～1.5 with the amount ratio of oxidation system,
Said acid binding agent is diethylamine, triethylamine or diisopropyl ethyl amine;
C, in reaction solvent;-10～-78 ℃; Under the alkaline environment; With Corey-chaykovsky reagent epoxidation step b gained midbody two, after reaction finishes, separation, purifying under the room temperature; The midbody three of structural formula shown in
(4 ' '-epoxy-2 '-OH and 6a-N position ethanoyl two protect remove the first Azythromycin)
Said reaction solvent is a THF,
Said Corey-chaykovsky reagent is sulfur ylide or sulphur oxygen ylide, and midbody three is 1.0:2.0～3.5 with Corey-chaykovsky reagent mass ratio,
Used alkali is potassium tert.-butoxide, hexamethyl two silica-based potassium amide or sodium hydrides in the epoxidation process;
D, utilize alkaline alcohol solution to remove the protection base of step c gained midbody three; And with Tri N-Propyl Amine to 4 ' '-a position epoxy carries out nucleophilic addition(Adn); After reaction finishes; Separation, purifying obtain the target compound Thailand of structural formula shown in
and draw mycin
Remove in the reaction of protection radical reaction, the alkaline matter in the alkaline alcohol solution is K
2CO
3-MeOH, Cs
2CO
3-MeOH, Na
2CO
3-MeOH or K
2CO
3-EtOH, the solvent that uses be methyl alcohol, propyl alcohol, Virahol or propyl carbinol, temperature of reaction is 10～75 ℃,
In the reaction of midbody four and Tri N-Propyl Amine, midbody four is 1.0:3.0～5.0 with Tri N-Propyl Amine amount of substance ratio, and temperature of reaction is 45～85 ℃.
Further:
Among the step a:
Reaction solvent is preferably methylene dichloride, and acid binding agent is preferably triethylamine, and protective material is preferably diacetyl oxide,
Go first Azythromycin and protective material amount of substance ratio to be preferably 1.0:2.5,
Temperature of reaction is preferably 20～30 ℃.
Among the step b:
Reaction solvent is preferably methylene dichloride, and the oxidation system of Swern oxidizing reaction is preferably methyl-sulphoxide-trifluoroacetic anhydride, and acid binding agent is preferably triethylamine,
Midbody one is preferably 1.0:1.5 with the amount ratio of oxidation system,
Temperature of reaction is preferably-25～-15 ℃.
Among the step c:
Corey-chaykovsky reagent is preferably sulfur ylide, and used alkali is preferably hexamethyl two silica-based potassium amides in the epoxidation process,
Midbody two is preferably 1.0:3.5 with Corey-chaykovsky reagent mass ratio,
Temperature of reaction is preferably-35～-15 ℃.
In the steps d:
Remove in the reaction of protection radical reaction, the alkaline matter in the alkaline alcohol solution is preferably K
2CO
3-MeOH, the solvent that uses is preferably methyl alcohol, and temperature of reaction is preferably 25～35 ℃,
In the reaction of midbody three and Tri N-Propyl Amine, midbody three is preferably 1.0:4.0 with Tri N-Propyl Amine amount of substance ratio, and temperature of reaction is preferably 55～60 ℃.
Preparation of the present invention is safe draws the novel method of mycin compared with prior art to have following outstanding beneficial effect:
(1) ethanoyl with cheapness is a protection reagent; Avoided using the benzyloxy acyl group to do the catalytic hydrogenation of using when the protection base removes, production cost is low, and operation steps is few; Industrial production is safe and feasible more, helps suitability for industrialized production;
(2) realized removing the protection base and prepared with " one kettle way " that Tri N-Propyl Amine replaces two-step reaction, method is simple, mild condition, and yield is high.
Embodiment
Explanation at length below with specific embodiment the safe novel method of drawing mycin of preparation of the present invention being done.
Embodiment one
(2R, 3S, 4R, 5R, 8R; 10R, 11R, 12S, 13S, 14R)-13-[[2; The pyrans glycosyl of 6-dideoxy-3-C-methyl-3-O-methyl-α-L-nuclear-]-oxygen] 2-ethyl-3,4,10-trihydroxy--3,5,8; 10,12, the preparation of 14-vegolysen 1-[[3,4, the pyrans glycosyl of 6-three deoxidations-3-(dimethylamino)-2-O-ethanoyl-β-D-wood-] oxygen]-1-oxa--6-nitrogen heterocyclic pentadecane (15-person encircles greatly) (midbody one)
In the round-bottomed flask of 250ml, add 7.34 g (0.01 mol) and remove the first Azythromycin, be placed in the ice bath, add 1.4 ml triethylamines (0.01mol) then with the dissolving of 40 ml methylene dichloride; Add 1.5 ml diacetyl oxides (0.015 mol) after 20 minutes again, reaction removes ice bath after 20 minutes again in the ice bath, and reaction adds 1.0 ml diacetyl oxides (0.01 mol) after 10 hours again under the room temperature; React again after 8 hours reaction is stopped, adding the sodium dihydrogen phosphate of the 1M of 50 ml in the reaction system, stir after 30 minutes under the room temperature; Tell organic phase, use the chloroform extraction water again 3 times, merge organic phase and use anhydrous magnesium sulfate drying; Filter; Concentrate, resistates gets midbody one with methylene dichloride and cyclohexane recrystallization.
It is following that product detects data:
White powder 5.6 g, yield 88%, purity 98%.
1H?NMR?(400?MHz,?CDCl
3)?δ?5.03?(s,?1H),?4.88(d,?
J?=?4.4?Hz,?1?H),?4.81?(t,?1?H),?4.56?(s,?1?H),?4.00-3.93?(m,?2?H),?3.47?(d,?
J?=?31.4?Hz,?3?H),?3.35?(s,?3?H),?3.05?(d,?
J?=?9.5Hz,?1?H),?2.91?(s,?2?H),?2.73-2.67?(m,?3?H),?2.34?(d,?
J?=7.2?Hz,?2?H),?2.28?(s,?6?H),?2.08?(s,?3?H),?2.03?(?s,?3?H),?1.85?(s,?1?H),?1.74?(d,?
J?=12.8?Hz,?2?H),?1.59?(d,?
J?=4.4?Hz,?1?H),?1.50-1.47?(m,?3?H),?1.42?(s,?5?H),?1.35?(d,?
J?=?11.9?Hz,?5?H),?1.29?(d,?
J?=6.4?Hz,?5?H),?1.26?(s,?5?H),?1.21-1.19?(m,?9?H),?1.02?(s,?3?H),?0.90-0.82?(m,?6?H);?
13C?NMR?(100.6?MHz,?CDCl
3)?δ?175.9,?171.7,?169.8,?100.0,?95.3,?84.6,?79.0,?77.7,?75.7,?75.2,?74.5,?72.6,?71.6,?67.9,?65.4,?62.8,?53.4,?50.9(2C),?49.3,?44.9,?40.6(2C),?39.9,?34.8,?34.5,?31.2,?28.6,?27.1,?23.3,?21.9,?21.5,?21.4,?21.1,?20.3,?18.4,?17.4,?16.1,?12.5,?10.7,?9.1;?MS?(ESI)?m/z:?819.6?[M+H]
+。
Embodiment two
(2R, 3S, 4R, 5R, 8R; 10R, 11R, 12S, 13S, 14R)-13-[[2; The pyrans glycosyl of 6-dideoxy-3-C-methyl-3-O-methyl-4-oxo-α-L-nuclear-]-oxygen] 2-ethyl-3,4,10-trihydroxy acid-3,5,8; 10,12, the preparation of 14-vegolysen 1-[[3,4, the pyrans glycosyl of 6-three deoxidations-3-(dimethylamino)-2-O-ethanoyl-β-D-wood-] oxygen]-1-oxo-6-nitrogen heterocyclic pentadecane (15-person encircles greatly) (midbody two)
Adding 2.05 g (25 mmol) midbody formula II in the single necked round bottom flask of 100 ml, room temperature condition adds 532 ul methyl-sulphoxides (75 mmol) with 25 ml exsiccant methylene dichloride dissolving back down, stirs to be placed under the low temperature and reacts 15 minutes; Splash into 1.5 ml trifluoroacetic anhydrides (0.0106 mol) afterwards, continue reaction 1 hour, add 3 ml triethylamines (0.021 mol); Low temperature stirs after 30 minutes down and is warming up to room temperature naturally, adds the saturated NaCl solution of 30 ml during closely to room temperature, after 30 minutes; Tell organic phase,, merge organic phase and use saturated NaCl solution washing again with chloroform extraction water 5 times; Organic phase is used anhydrous magnesium sulfate drying, filters, and concentrates; With sherwood oil: ETHYLE ACETATE: diethylamine=250:30:20 carries out silica gel column chromatography as eluent, midbody two.
It is following that product detects data:
Faint yellow solid 1.6 g, yield 78%.
1H?NMR?(400?MHz,?CDCl
3)?δ?5.18?(s,1H),?4.80-4.76?(m,?2?H),?4.50?(s,?1?H),?4.43-4.38?(m,?2?H),?4.08?(d,?
J?=?9.2?Hz,?1?H),?3.95?(s,?1?H),?3.46?(d,?
J?=?5.2?Hz,?2?H),?3.32?(s,?3?H),?3.08?(s,?1?H),?2.90?(s,?1?H),?2.76?(s,?1?H),?2.70-2.63?(m,?1?H),?2.41-2.30?(m,?3?H),?2.24?(s,?6?H),?2.07?(s,?3?H),?2.03(?s,?3?H),?1.74(s,?1?H),?1.66?(d,?
J?=?10.4?Hz,?2?H),?1.36-1.30?(m,?17?H),?1.20-1.10?(m,?9?H),?0.98?(s,?3?H),?0.79?(d,?
J?=?5.0?Hz,?6?H);?
13C?NMR?(100.6?MHz,?CDCl
3)?δ?211.1,?175.4,?171.7,?169.8,?100.4,?96.3,?84.9,?79.7,?75.6,?75.1,?72.2(2C),?71.4,?68.4,?62.6,?51.2(2C),?51.0,?44.4,?40.5(2C),?39.0,?37.4,?34.8,?30.9,?28.5,?27.1,?23.4(2C),?21.9,?21.4(2C),?21.1,?20.6,?20.1,?17.8,?16.2,?16.0,?12.6,?10.5,?9.0;?MS?(ESI)?m/z:?817.5?[M+H]
+?。
Embodiment three
(2R, 3S, 4R, 5R, 8R; 10R, 11R, 12S, 13S, 14R)-13-[[2; The pyrans glycosyl of 6-dideoxy-3-C-methyl-3-O-methyl-4-C-[epoxy methyl]-α-L-nuclear-]-oxygen] 2-ethyl-3,4,10-trihydroxy--3,5,8; 10,12, the preparation of 14-vegolysen 1-[[3,4, the pyrans glycosyl of 6-three deoxidations-3-(dimethylamino)-2-O-ethanoyl-β-D-wood-] oxygen]-1-oxa--6-nitrogen heterocyclic pentadecane (15-person encircles greatly) (midbody three)
In the single necked round bottom flask of 100 ml, add the trimethylammonium sulfur bromide of 1.38 g (0.008 mol) and the hexamethyl two silica-based potassium amides (0.008 mol) of 25 ml exsiccant THFs and 8.8 ml1M, place under-15 ℃ of low temperature, argon shield is reacted after 1 hour down; In reaction system, add the 10ml THF that is dissolved with 2.04 g (0.0025 mol) midbody three, low temperature reaction down changed under the room temperature after 30 minutes, went out with 20 ml saturated ammonium chloride solutions collection; Stir after 30 minutes under the room temperature and tell organic phase; With chloroform extraction water 5 times, merge organic phase with saturated nacl aqueous solution washing 1 time, get organic phase and use anhydrous magnesium sulfate drying; Filter; Concentrate, resistates is with sherwood oil: ETHYLE ACETATE: diethylamine=170:30:20 carries out chromatographic silica gel as eluent, midbody three.
It is following that product detects data:
Faint yellow solid 1.7 g, yield 76%.
1H?NMR?(400?MHz,?CDCl
3)?δ?5.10?(d,?
J?=?9.6?Hz,?1?H),?4.93?(d,?
J?=?20.0?Hz,?1?H),?4.74?(s,?2?H),?4.62?(d,?
J?=?17.2?Hz,?2?H),?3.98-3.92?(m,?1?H),?3.49?(s,?1?H),?3.40?(s,?2?H),?3.30?(s,?2?H),?3.28-3.19?(m,?1?H),?3.08?(d,?
J?=?12.6?Hz,?1?H),?2.88-2.67?(m,?6?H),?2.38-2.19?(m,?2?H),?2.18?(s,?2?H),?2.02?(s,?3?H),?1.96?(s,?3?H),?1.82-1.68?(m,?4?H),?1.43?(s,?3?H),?1.36?(s,?4?H),?1.26?(d,?
J?=?6.0?Hz,?4?H),?1.12?(d,?
J?=?22.5?Hz,?8?H),?1.00?(d,?
J?=?20.7?Hz,?10?H),?0.81?(d,?
J?=?20.7?Hz,?6?H);?
13C?NMR?(100.6?MHz,?CDCl
3)?δ?175.6,?171.6,?169.8,?99.7,?95.8,?84.6,?79.5,?75.5,?75.2,?74.8,?73.6,?73.2,?71.7,?71.6,?67.6,?63.6,?62.6,?62.5,?61.5,?50.9(2C),?50.0,?45.0,?44.7,?40.5,?39.5,?38.4,?34.6,?31.1,?28.5,?27.0,?23.3,?21.8,?21.4,?21.2,?20.3,?18.1,?17.6,?16.1,?14.6,?13.9,?12.6,?10.6,?9.2;?MS?(ESI)?m/z:?831.6?[M+H]
+。
Embodiment four
(2R, 3S, 4R, 5R, 8R; 10R, 11R, 12S, 13S, 14R)-13-[[2; The pyrans glycosyl of 6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(Propylamino) methyl]-α-L-nuclear-]-oxygen] 2-ethyl-3,4,10-trihydroxy--3,5,8; 10,12, the preparation of 14-vegolysen 1-[[3,4, the pyrans glycosyl of 6-three deoxidations-3-(dimethylamino)-β-D-wood-] oxygen]-1-oxa--6-nitrogen heterocyclic pentadecane (15-person encircles greatly) (mycin draws in Thailand)
In the single necked round bottom flask of 100ml, add the midbody four of 2.07 g (0.0025 mol), add 40 ml methyl alcohol then, stir complete molten back under the room temperature and add the Tri N-Propyl Amine (0.07 mol) of 5.9 ml and the solution of potassium carbonate of 5 ml1M; Add material and be placed on back flow reaction in the oil bath, finish reaction after 48 hours, reaction solution is concentrated into dried; Add entry and ETHYLE ACETATE, tell organic phase after fully stirring, wash water 4 times with ETHYLE ACETATE again; Merge organic phase with saturated nacl aqueous solution washing 1 time; Get organic phase and use anhydrous magnesium sulfate drying, filter, concentrate; Last sherwood oil: ETHYLE ACETATE: diethylamine=120:30:20 carries out silica gel column chromatography as eluent, De Taila mycin 1.4 g.
It is following that product detects data:
White solid, productive rate 68%.
1H NMR (400 MHz, CDCl
3) δ 4.95 (d,
J=3.2 Hz, 1 H), 4.75 (d,
J=2.0 Hz, 1 H), 4.50 (d,
J=7.5 Hz, 1 H), 4.42 (q, 1 H), 3.47 (s, 1 H), 3.35 (s, 3 H), 3.23 (t, 1 H), 3.03 (d,
J=11.3 Hz, 1 H), 2.81-2.69 (m, 3 H), 2.61-2.47 (m, 5 H), 2.29 (s, 6 H), 2.17-2.14 (m, 2 H), 1.98-1.95 (m, 1 H), 1.89-1.83 (m, 2 H), 1.73 (d,
J=14.2 Hz, 2 H), 1.66 (d,
J=12.8 Hz, 1 H), 1.53-1.44 (m, 3 H), 1.41-1.34 (m, 2 H), 1.31 (s, 4 H), 1.25-1.20 (m, 18 H), 1.06 (d,
J=5.5 Hz, 6 H), 0.95-0.87 (m, 10 H);
13C NMR (100.6 MHz, CDCl
3) δ 178.2,102.9,95.4,83.6,78.6,77.6,76.2,73.9,73.6,73.4,72.3; 70.9,68.4,67.6,65.4,57.0,56.3,52.5,49.6,48.9,45.1; 42.0,41.5,40.2,33.8,29.7,28.8,27.1,22.8,21.8,21.3; 20.9,17.2,16.1,15.2,15.0,14.1,14.0,11.6,11.0,9.2; LRMS (ESI) m/z:806.6 [M+H]
+LRMS (ESI) m/z:806.5749 [M+H] (C
41H
80N
3O
12Calculated value: 806.5737).
Claims (6)
1. one kind prepares the method that structure is drawn mycin suc as formula the Thailand of
Formula
It is characterized in that this method may further comprise the steps:
A, with ethanoyl protection suc as formula shown in
go 2 in the first Azythromycin '-OH and 6a-amino, make suc as formula the midbody one shown in
;
B, with one reaction of Swern oxygenant and step a gained midbody; To its 4 ' '-position hydroxyl carry out oxidation, must be suc as formula the midbody two shown in
;
C, with Corey-chaykovsky reagent to 4 of step b gained midbody two ' '-position carbonyl carry out epoxidation, obtain suc as formula the midbody three shown in
;
D, in alkaline alcohol solution, remove the protection base of step c gained midbody three; And with Tri N-Propyl Amine to 4 ' '-a position epoxy carries out nucleophilic addition(Adn), obtains drawing mycin suc as formula the target compound Thailand shown in
.
2. according to claim 1ly prepare safe method of drawing mycin, it is characterized in that this method may further comprise the steps:
A, will go first Azythromycin material dissolution in reaction solvent; And add an amount of acid binding agent, ethanoyl protective material successively; 10～45 ℃ of reactions down, after reaction finishes, separation, purifying; Must be suc as formula the midbody one shown in
Said reaction solvent is methylene dichloride or chloroform;
Said acid binding agent be diethylamine, triethylamine, diisopropyl ethyl amine or
N-methylamino pyridine;
Said ethanoyl protective material is diacetyl oxide or Acetyl Chloride 98Min., goes first Azythromycin and protectant amount of substance ratio to be 1.0:2.0～3.0;
B, step a gained midbody one is dissolved in the reaction solvent; Under-10～-45 ℃, carry out the Swern oxidizing reaction; Add an amount of acid binding agent again, after reaction finishes, separation, purifying under the room temperature; Must be suc as formula the midbody two shown in
Said reaction solvent is methylene dichloride or chloroform;
The oxidation system of said Swern oxidizing reaction is methyl-sulphoxide-Vanadium Pentoxide in FLAKES, methyl-sulphoxide-trifluoroacetic anhydride or methyl-sulphoxide-oxalyl chloride, and wherein midbody one is 1.0:1.0～1.5 with the amount of substance ratio of oxidation system;
Said acid binding agent is diethylamine, triethylamine or diisopropyl ethyl amine;
C, step b gained midbody two are at-10～-78 ℃; Under the alkaline environment; Carry out epoxidation reaction with Corey-chaykovsky reagent; Separate, purifying must be suc as formula the midbody three shown in
The reaction solvent of epoxidation reaction is a THF;
Said Corey-chaykovsky reagent is sulfur ylide or sulphur oxygen ylide, and midbody two is 1.0:2.0～3.5 with Corey-chaykovsky reagent amount of substance ratio;
Used alkali is potassium tert.-butoxide, hexamethyl two silica-based potassium amide or sodium hydrides in the epoxidation process;
D, utilize alkaline alcohol solution to remove the protection base of step c gained midbody three; And with Tri N-Propyl Amine to 4 ' '-a position epoxy carries out nucleophilic addition(Adn); Separation, purifying promptly get suc as formula the target compound Thailand shown in
and draw mycin
Remove in the reaction of protection radical reaction, the alkaline matter in the alkaline alcohol solution is K
2CO
3-MeOH, Cs
2CO
3-MeOH, Na
2CO
3-MeOH or K
2CO
3-EtOH, the solvent that uses be methyl alcohol, propyl alcohol, Virahol or propyl carbinol, temperature of reaction is 10～75 ℃;
In the reaction of midbody three and Tri N-Propyl Amine, midbody three is 1.0:3.0～5.0 with Tri N-Propyl Amine amount of substance ratio, and temperature of reaction is 45～85 ℃.
3. according to claim 2ly prepare safe method of drawing mycin, it is characterized in that, among the step a:
Reaction solvent is a methylene dichloride, and acid binding agent is a triethylamine, and protective material is a diacetyl oxide,
Go first Azythromycin and protective material amount of substance ratio to be 1.0:2.5,
Temperature of reaction is 20～30 ℃.
4. according to claim 2ly prepare safe method of drawing mycin, it is characterized in that, among the step b:
Reaction solvent is a methylene dichloride, and the oxidation system of Swern oxidizing reaction is methyl-sulphoxide-trifluoroacetic anhydride, and acid binding agent is a triethylamine,
Midbody one is 1.0:1.5 with the amount of substance ratio of oxidation system,
Temperature of reaction is-25～-15 ℃.
5. according to claim 2ly prepare safe method of drawing mycin, it is characterized in that, among the step c:
Corey-chaykovsky reagent is sulfur ylide, and used alkali is hexamethyl two silica-based potassium amides in the epoxidation process,
Midbody two is 1.0:3.5 with Corey-chaykovsky reagent amount of substance ratio,
Temperature of reaction is-35～-15 ℃.
6. according to claim 2ly prepare safe method of drawing mycin, it is characterized in that, in the steps d:
Remove in the reaction of protection radical reaction, the alkaline matter in the alkaline alcohol solution is K
2CO
3-MeOH, the solvent that uses is methyl alcohol, temperature of reaction is 25～35 ℃,
In the reaction of midbody three and Tri N-Propyl Amine, midbody three is 1.0:4.0 with Tri N-Propyl Amine amount of substance ratio, and temperature of reaction is 55～60 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110206323A CN102260306B (en) | 2011-07-22 | 2011-07-22 | Novel method for preparing tulathromycin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110206323A CN102260306B (en) | 2011-07-22 | 2011-07-22 | Novel method for preparing tulathromycin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102260306A CN102260306A (en) | 2011-11-30 |
| CN102260306B true CN102260306B (en) | 2012-07-18 |
Family
ID=45007166
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110206323A Active CN102260306B (en) | 2011-07-22 | 2011-07-22 | Novel method for preparing tulathromycin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102260306B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497227B (en) * | 2013-09-13 | 2015-09-30 | 青岛科技大学 | A kind of preparation method of tulathromycin intermediate |
| CN103588833B (en) * | 2013-10-30 | 2016-08-17 | 北京科技大学 | The preparation method of animal antibiotic tulathromycin |
| ES2858585T3 (en) | 2016-01-18 | 2021-09-30 | Zhejiang Hisun Pharm Co Ltd | Method and intermediate product to prepare tulathromycin |
| CN106046077B (en) * | 2016-08-04 | 2019-07-26 | 湖北美天生物科技股份有限公司 | A kind of synthetic method of Tulathromycin A |
| CN106939029B (en) * | 2017-04-28 | 2020-10-13 | 艾美科健（中国）生物医药有限公司 | Preparation method of tulathromycin |
| CN108003207B (en) | 2017-12-19 | 2019-05-10 | 海门慧聚药业有限公司 | Method for preparing tulathromycin |
| CN110128486B (en) * | 2019-06-19 | 2022-12-02 | 常州齐晖药业有限公司 | Synthesis method of tulathromycin |
| CN111253447B (en) * | 2020-03-26 | 2021-03-02 | 苏州正永生物医药有限公司 | Preparation method of tulathromycin |
| CN113666978A (en) * | 2020-05-14 | 2021-11-19 | 洛阳惠中兽药有限公司 | Preparation method of macrolide compound and intermediate used by same |
| CN113493483A (en) * | 2021-07-05 | 2021-10-12 | 上海应用技术大学 | Synthesis method of tulathromycin |
| CN113861252A (en) * | 2021-11-08 | 2021-12-31 | 江苏君若药业有限公司 | Synthesis of tulathromycin |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| YU43116B (en) * | 1979-04-02 | 1989-04-30 | Pliva Pharm & Chem Works | Process for preparing 11-aza-4-o-cladinosyl-6-o-desosaminyl-15-ethyl-7,13,14-trihydroxy-3,5,7,9,12,14-hexamethyl-oxacyclopentadecane-2-one(11-aza-10-deox |
| HN1998000086A (en) * | 1997-06-11 | 1999-03-08 | Pfizer Prod Inc | DERIVATIVES OF 9 - DESOFO - 9 AZA - 9A - HOMOERITROMICINA A - C - 4 SUBSTITUTED. |
| AP9801420A0 (en) * | 1998-01-02 | 1998-12-31 | Pfizer Prod Inc | Novel macrolides. |
| CN100413879C (en) * | 2001-04-27 | 2008-08-27 | 辉瑞产品公司 | Process for preparing 4''-substituted-9-deoxo-9A-AZA-9A-homoerythromycin a derivatives |
-
2011
- 2011-07-22 CN CN201110206323A patent/CN102260306B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN102260306A (en) | 2011-11-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102260306B (en) | Novel method for preparing tulathromycin | |
| JP3262806B2 (en) | C-4 "substituted macrolide derivative | |
| CA2293823C (en) | 4"-substituted-9-deoxo-9a-aza-9a-homoerythromycin a derivatives | |
| CN102786569B (en) | The preparation method of Tulathromycin intermediate and preparation method thereof and Tulathromycin | |
| Sugawara et al. | Novel 12-membered non-antibiotic macrolides from erythromycin A; EM900 series as novel leads for anti-inflammatory and/or immunomodulatory agents | |
| NO330249B1 (en) | Azalides and their uses and preparations, and pharmaceutical compositions | |
| Fajdetić et al. | 4 ″-O-(ω-Quinolylamino-alkylamino) propionyl derivatives of selected macrolides with the activity against the key erythromycin resistant respiratory pathogens | |
| CN1141312C (en) | 15-membered lactams ketolides with antibacterial activity | |
| OA11753A (en) | Ketolide antibiotics. | |
| CN102260305B (en) | 4''-((substituted benzamido)alkyl)carbamate azithromycin11-carbamate derivatives and intermediates thereof | |
| JP2001139591A (en) | New macrolide | |
| Ma et al. | Novel C-4 ″modified azithromycin analogs with remarkably enhanced activity against erythromycin-resistant Streptococcus pneumoniae: The synthesis and antimicrobial evaluation | |
| Yan et al. | Synthesis and antibacterial activity of 4 ″-O-(trans-β-arylacrylamido) carbamoyl azithromycin analogs | |
| Ma et al. | Synthesis and antibacterial activity of novel 15-membered macrolide derivatives: 4 ″-Carbamate, 11, 12-cyclic carbonate-4 ″-carbamate and 11, 4 ″-di-O-arylcarbamoyl analogs of azithromycin | |
| EP1181298B1 (en) | Novel 8a- and 9a-15-membered lactams | |
| Zhang et al. | Synthesis and antibacterial activity of new 4 ″-O-carbamates of 11, 12-cyclic carbonate erythromycin A 6, 9-imino ether | |
| CN104119413A (en) | Synthesis method of tulathromycin residue marker | |
| WO2012105562A1 (en) | Novel macrolide derivative | |
| Alihodzic et al. | Synthesis and antibacterial activity of isomeric 15-membered azalides | |
| Wu et al. | Synthesis and antibacterial activity of 3-O-carbamoyl derivatives of 6, 11-di-O-methylerythromycin A: A novel class of acylides | |
| CN104876983B (en) | A kind of variation route for synthesizing Tulathromycin | |
| CN105418706B (en) | A kind of macrolides antimicrobial compound and the preparation method and application thereof | |
| Liang et al. | Synthesis and antibacterial activity of 2, 3-dehydro-3-O-(3-aryl-E-prop-2-enyl)-10, 11-anhydroclarithromycin derivatives | |
| US20070259822A1 (en) | 8a,11-bicyclic 8a-azalide derivatives | |
| Yan et al. | Synthesis and Antibacterial Activity of Novel 11-O-Phenethylcarbamoylazithromycin Derivatives with 4 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP02 | Change in the address of a patent holder |
Address after: Taibai Road 272021 in Shandong province Jining City District No. 173 Patentee after: Shandong Lukang Shelile Pharmaceutical Co., Ltd. Address before: 272021 No. 173 Taibai West Road, Shandong, Jining Patentee before: Shandong Lukang Shelile Pharmaceutical Co., Ltd. |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 273517 No. 50, Hualu Road, Zoucheng Industrial Park, Zoucheng City, Jining City, Shandong Province Patentee after: SHANDONG LUKANG SHELILE PHARMACEUTICAL Co.,Ltd. Address before: 272021 No. 173, Taibai West Road, Rencheng District, Jining City, Shandong Province Patentee before: SHANDONG LUKANG SHELILE PHARMACEUTICAL Co.,Ltd. |