CN102260306A - Novel method for preparing tulathromycin - Google Patents

Novel method for preparing tulathromycin Download PDF

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CN102260306A
CN102260306A CN2011102063232A CN201110206323A CN102260306A CN 102260306 A CN102260306 A CN 102260306A CN 2011102063232 A CN2011102063232 A CN 2011102063232A CN 201110206323 A CN201110206323 A CN 201110206323A CN 102260306 A CN102260306 A CN 102260306A
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reaction
suc
methyl
mycin
temperature
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CN102260306B (en
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郭强
周妮妮
董坤
彭欣
颜丙春
桑艳丽
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SHANDONG LUKANG SHELILE PHARMACEUTICAL CO Ltd
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SHANDONG LUKANG SHELILE PHARMACEUTICAL CO Ltd
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    • 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

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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

A kind ofly prepare the novel method that mycin draws in Thailand
 
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 a class weakly alkaline microbiotic and the structural modification thing thereof that is produced by streptomycete, and they mostly are alkaline lipophilic compound, and are higher to the inhibition activity of gram-positive microorganism and mycoplasma.Nineteen fifty-two, gift comes company to release first-generation macrolide antibiotics product erythromycin, has nowadays released the s-generation even third generation macrolide antibiotics product.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 erythromycin.The semisynthetic macrolide antibiotics of the s-generation has the Azythromycin (azithromycin) etc. of clarithromycin (clarithromycin), Roxithromycin (roxithromycin), dirithromycin (dirithromycin), Flurithromycin (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 erythromycin (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 extensive use of gradually, and the gesture of medicines such as replacing tylosin and tilmicosin is arranged.
For the preparation that mycin draws in Thailand, the preparation method that Pfizer of the former unit of grinding adopts be with go the first Azythromycin (suc as formula
Figure 832503DEST_PATH_IMAGE001
Shown in) be raw material; 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 2 ' position hydroxyl); then successively in the cladinose 4 ' '-a position hydroxyl carries out oxidation, epoxidation; and catalytic hydrogenation removes protecting group benzyloxy acyl; at last with Tri N-Propyl Amine to 4 ' '-a position epoxy carries out nucleophilic substitution and promptly makes Thailand and draw mycin product (EP1253153A1; US6472371B1, US6420536B1).
But these preparation method's operating process are complicated, especially need to 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 at above-mentioned the deficiencies in the 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 draw mycin (suc as formula
Figure 561610DEST_PATH_IMAGE003
Shown in) concrete structure be: (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[[2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(Propylamino) methyl]-the pyrans glycosyl of 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).
Figure 754694DEST_PATH_IMAGE004
Technical assignment of the present invention is realized in the following manner: a kind ofly prepare the novel method that mycin draws in Thailand, be characterized in may further comprise the steps:
A, with ethanoyl protection suc as formula
Figure 955869DEST_PATH_IMAGE001
Shown go 2 in the first Azythromycin '-OH and 6a-amino make structural formula as
Figure 601614DEST_PATH_IMAGE005
Shown intermediate one (the two protections of ethanoyl go first Azythromycin);
B, with one reaction of Swern oxygenant and step a gained intermediate, to its 4 ' '-a position hydroxyl carries out oxidation, structural formula as
Figure 913646DEST_PATH_IMAGE006
Shown intermediate two (4 ' '-oxo, 2 '-the two protections of OH and 6a-N position ethanoyl remove the first Azythromycin);
C, with Corey-chaykovsky reagent to 4 of step b gained intermediate two ' '-position carbonyl carry out epoxidation, obtain structural formula as
Figure 961237DEST_PATH_IMAGE007
Shown intermediate three (4 ' '-epoxy-2 '-the two protections of OH and 6a-N position ethanoyl remove the first Azythromycin);
Figure 333312DEST_PATH_IMAGE008
D, in alkaline alcohol solution, remove the protecting group of step c gained intermediate three, and with Tri N-Propyl Amine to 4 ' '-a position epoxy carries out nucleophilic addition(Adn), " one kettle way " obtain structural formula as
Figure 466353DEST_PATH_IMAGE003
Mycin draws in shown target compound Thailand.
Intermediate one (structural formula as
Figure 582077DEST_PATH_IMAGE005
Shown in) concrete structure be: (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).
Intermediate two (structural formula as
Figure 484174DEST_PATH_IMAGE006
Shown in) concrete structure 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-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).
Intermediate three (structural formula as
Figure 27151DEST_PATH_IMAGE007
Shown in) concrete structure be: (2R, 3S, 4R, 5R; 8R, 10R, 11R, 12S; 13S, 14R)-13-[[2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[epoxy 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).
Specifically, the inventive method may further comprise the steps:
A, with formula
Figure 381908DEST_PATH_IMAGE001
The shown first Azythromycin that goes is dissolved in the reaction solvent, and adds an amount of acid binding agent, ethanoyl protective material successively, 10～45 ℃ of down reactions, after reaction finishes, separate, purifying, structural formula as
Figure 301323DEST_PATH_IMAGE005
Shown intermediate one (the two protections of ethanoyl go first Azythromycin),
Described reaction solvent is methylene dichloride or chloroform,
Described acid binding agent be diethylamine, triethylamine, diisopropyl ethyl amine or N-methylamino pyridine,
Described 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 intermediate one is dissolved in the reaction solvent, under-10～-45 ℃, carries out the Swern oxidizing reaction, add an amount of acid binding agent again, after reaction finishes, separate under the room temperature, purifying, structural formula as
Figure 52067DEST_PATH_IMAGE009
Shown intermediate two (4 ' '-oxo, 2 '-the two protections of OH and 6a-N position ethanoyl remove the first Azythromycin),
Described reaction solvent is methylene dichloride or chloroform,
The oxidation system of described Swern oxidizing reaction is methyl-sulphoxide-Vanadium Pentoxide in FLAKES, methyl-sulphoxide-trifluoroacetic anhydride or methyl-sulphoxide-oxalyl chloride, and intermediate two is 1.0:1.0～1.5 with the amount ratio of oxidation system,
Described acid binding agent is diethylamine, triethylamine or diisopropyl ethyl amine;
C, in reaction solvent ,-10～-78 ℃, under the alkaline environment,, after reaction finishes, separate under the room temperature, purifying with Corey-chaykovsky reagent epoxidation step b gained intermediate two, structural formula as
Figure 703628DEST_PATH_IMAGE007
Shown intermediate three (4 ' '-epoxy-2 '-the two protections of OH and 6a-N position ethanoyl remove the first Azythromycin),
Described reaction solvent is a tetrahydrofuran (THF),
Described Corey-chaykovsky reagent is sulfur ylide or sulphur oxygen ylide, and intermediate 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 protecting group of step c gained intermediate three, and with Tri N-Propyl Amine to 4 ' '-a position epoxy carries out nucleophilic addition(Adn), after reaction finishes, separates, purifying, obtain structural formula as
Figure 811261DEST_PATH_IMAGE003
Mycin draws in shown target compound Thailand,
Remove in the reaction of protecting group 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 intermediate four and Tri N-Propyl Amine, intermediate 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,
Intermediate 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,
Intermediate 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 protecting group 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 intermediate three and Tri N-Propyl Amine, intermediate 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 protecting group removes, production cost is low, and operation steps is few, industrial production is safe and feasible more, helps suitability for industrialized production;
(2) realized that " one kettle way " that remove protecting group and Tri N-Propyl Amine replacement two-step reaction prepares, method is simple, mild condition, yield height.
 
Embodiment
Explain 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; 14-vegolysen 1-[[3,4, the pyrans glycosyl of 6-three deoxidations-3-(dimethylamino)-2-O-ethanoyl-β-D-wood-] oxygen]-preparation of 1-oxa--6-nitrogen heterocyclic pentadecane (15-person encircles greatly) (intermediate one)
Adding 7.34 g(0.01 mol in the round-bottomed flask of 250ml) remove the first Azythromycin, be placed in the ice bath with the dissolving of 40 ml methylene dichloride, add 1.4 ml triethylamines (0.01mol) then, 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, 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, the sodium dihydrogen phosphate that adds 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 the organic phase anhydrous magnesium sulfate drying, filter, concentrate, resistates gets intermediate one with methylene dichloride and cyclohexane recrystallization.
It is as follows 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; 14-vegolysen 1-[[3,4, the pyrans glycosyl of 6-three deoxidations-3-(dimethylamino)-2-O-ethanoyl-β-D-wood-] oxygen]-preparation of 1-oxo-6-nitrogen heterocyclic pentadecane (15-person encircles greatly) (intermediate two)
In the single necked round bottom flask of 100 ml, add 2.05 g(25 mmol) intermediate formula II, room temperature condition adds 532 ul methyl-sulphoxides (75 mmol) with 25 ml exsiccant methylene dichloride dissolving back down, stir to be placed under the low temperature and reacted 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, add the saturated NaCl solution of 30 ml during closely to room temperature, after 30 minutes, tell organic phase, use chloroform extraction water 5 times, merge organic phase and use saturated NaCl solution washing again, the organic phase anhydrous magnesium sulfate drying filters, and concentrates, with sherwood oil: ethyl acetate: diethylamine=250:30:20 carries out silica gel column chromatography as eluent, intermediate two.
It is as follows 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-[[2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[epoxy methyl]-the pyrans glycosyl of 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)-2-O-ethanoyl-β-D-wood-] oxygen]-preparation of 1-oxa--6-nitrogen heterocyclic pentadecane (15-person encircles greatly) (intermediate three)
Adding 1.38 g(0.008 mol in the single necked round bottom flask of 100 ml) trimethylammonium sulfur bromide and the hexamethyl two silica-based potassium amides (0.008 mol) of 25 ml exsiccant tetrahydrofuran (THF)s and 8.8 ml1M; place under-15 ℃ of low temperature; argon shield is reacted after 1 hour down; add in the reaction system and be dissolved with 2.04 g(0.0025 mol) the 10ml tetrahydrofuran (THF) of intermediate three; low temperature reaction down changed under the room temperature after 30 minutes; go 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; merging organic phase washs 1 time with saturated nacl aqueous solution; get the organic phase anhydrous magnesium sulfate drying; filter; concentrate, resistates is with sherwood oil: ethyl acetate: diethylamine=170:30:20 carries out chromatographic silica gel as eluent, intermediate three.
It is as follows 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-[[2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(Propylamino) methyl]-the pyrans glycosyl of 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]-preparation of 1-oxa--6-nitrogen heterocyclic pentadecane (15-person encircles greatly) (mycin draws in Thailand)
Adding 2.07 g(0.0025 mol in the single necked round bottom flask of 100ml) intermediate four, 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 ethyl acetate, tell organic phase after fully stirring, wash water 4 times with ethyl acetate again, merging organic phase washs 1 time with saturated nacl aqueous solution, get the organic phase anhydrous magnesium sulfate drying, filter, concentrate, last sherwood oil: ethyl acetate: diethylamine=120:30:20 carries out silica gel column chromatography as eluent, De Taila mycin 1.4 g.
It is as follows 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 prepare structure suc as formula
    Figure 176350DEST_PATH_IMAGE001
    Thailand's novel method of drawing mycin,
    Figure 787460DEST_PATH_IMAGE002
    Formula
    Figure 937818DEST_PATH_IMAGE001
    It is characterized in that this method may further comprise the steps:
    A, with ethanoyl protection suc as formula
    Figure 267169DEST_PATH_IMAGE003
    Shown go 2 in the first Azythromycin '-OH and 6a-amino, make suc as formula Shown intermediate one;
    B, with one reaction of Swern oxygenant and step a gained intermediate, to its 4 ' '-a position hydroxyl carries out oxidation, must suc as formula Shown intermediate two;
    C, with Corey-chaykovsky reagent to 4 of step b gained intermediate two ' '-position carbonyl carry out epoxidation, obtain suc as formula
    Figure 315262DEST_PATH_IMAGE006
    Shown intermediate three;
    Figure 990963DEST_PATH_IMAGE007
    D, in alkaline alcohol solution, remove the protecting group of step c gained intermediate three, and with Tri N-Propyl Amine to 4 ' '-a position epoxy carries out nucleophilic addition(Adn), obtain suc as formula Mycin draws in shown target compound Thailand.
  2. 2. the safe novel method of drawing mycin of preparation according to claim 1 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, separate, purifying, must suc as formula
    Figure 585115DEST_PATH_IMAGE004
    Shown intermediate one,
    Described reaction solvent is methylene dichloride or chloroform;
    Described acid binding agent be diethylamine, triethylamine, diisopropyl ethyl amine or N-methylamino pyridine;
    Described 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 intermediate one is dissolved in the reaction solvent, under-10～-45 ℃, carries out the Swern oxidizing reaction, add an amount of acid binding agent again, after reaction finishes, separate under the room temperature, purifying, must suc as formula
    Figure 811697DEST_PATH_IMAGE005
    Shown intermediate two,
    Described reaction solvent is methylene dichloride or chloroform;
    The oxidation system of described Swern oxidizing reaction is methyl-sulphoxide-Vanadium Pentoxide in FLAKES, methyl-sulphoxide-trifluoroacetic anhydride or methyl-sulphoxide-oxalyl chloride, and wherein intermediate one is 1.0:1.0～1.5 with the amount ratio of oxidation system;
    Described acid binding agent is diethylamine, triethylamine or diisopropyl ethyl amine;
    C, step b gained intermediate two under the alkaline environment, carry out epoxidation reaction with Corey-chaykovsky reagent at-10～-78 ℃, separate, purifying must suc as formula
    Figure 115640DEST_PATH_IMAGE006
    Shown intermediate three,
    Described reaction solvent is a tetrahydrofuran (THF);
    Described Corey-chaykovsky reagent is sulfur ylide or sulphur oxygen ylide, and intermediate 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 protecting group of step c gained intermediate three, and with Tri N-Propyl Amine to 4 ' '-a position epoxy carries out nucleophilic addition(Adn), separate, purifying promptly get suc as formula
    Figure 718659DEST_PATH_IMAGE001
    Mycin draws in shown target compound Thailand,
    Remove in the reaction of protecting group 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 intermediate three and Tri N-Propyl Amine, intermediate 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. 3. the safe novel method of drawing mycin of preparation according to claim 2 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. 4. the safe novel method of drawing mycin of preparation according to claim 2 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,
    Intermediate one is 1.0:1.5 with the amount ratio of oxidation system,
    Temperature of reaction is-25～-15 ℃.
  5. 5. the safe novel method of drawing mycin of preparation according to claim 2 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,
    Intermediate two is 1.0:3.5 with Corey-chaykovsky reagent mass ratio,
    Temperature of reaction is-35～-15 ℃.
  6. 6. the safe novel method of drawing mycin of preparation according to claim 2 is characterized in that, in the steps d:
    Remove in the reaction of protecting group 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 intermediate three and Tri N-Propyl Amine, intermediate three is 1.0:4.0 with Tri N-Propyl Amine amount of substance ratio, and temperature of reaction is 55～60 ℃.
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CN103497227A (en) * 2013-09-13 2014-01-08 青岛科技大学 Preparation method for tulathromycin intermediate
CN103588833A (en) * 2013-10-30 2014-02-19 北京科技大学 Preparation method of animal antibiotic tulathromycin
CN106046077A (en) * 2016-08-04 2016-10-26 湖北美天生物科技股份有限公司 Tulathromycin A synthesis method
CN106939029A (en) * 2017-04-28 2017-07-11 艾美科健（中国）生物医药有限公司 A kind of preparation method of Tulathromycin
WO2017124222A1 (en) * 2016-01-18 2017-07-27 浙江海正药业股份有限公司 Method and intermediate for preparing tulathromycin
CN110128486A (en) * 2019-06-19 2019-08-16 常州齐晖药业有限公司 A kind of synthetic method of Tulathromycin
CN111253447A (en) * 2020-03-26 2020-06-09 苏州正永生物医药有限公司 Preparation method of tulathromycin
US11001604B2 (en) 2017-12-19 2021-05-11 Wisdom Pharmaceutical Co., Ltd. Method for preparing tulathromycin
CN113493483A (en) * 2021-07-05 2021-10-12 上海应用技术大学 Synthesis 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
CN113861252A (en) * 2021-11-08 2021-12-31 江苏君若药业有限公司 Synthesis of tulathromycin

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CN103497227A (en) * 2013-09-13 2014-01-08 青岛科技大学 Preparation method for tulathromycin intermediate
CN103588833A (en) * 2013-10-30 2014-02-19 北京科技大学 Preparation method of animal antibiotic tulathromycin
CN103588833B (en) * 2013-10-30 2016-08-17 北京科技大学 The preparation method of animal antibiotic tulathromycin
CN108473524A (en) * 2016-01-18 2018-08-31 浙江海正药业股份有限公司 A kind of Preparation Method And Their Intermediate of Tulathromycin
US10414746B2 (en) 2016-01-18 2019-09-17 Zhejiang Hisun Pharmaceutical Co., Ltd. Method and intermediate for preparing tulathromycin
WO2017124222A1 (en) * 2016-01-18 2017-07-27 浙江海正药业股份有限公司 Method and intermediate for preparing 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
CN106046077A (en) * 2016-08-04 2016-10-26 湖北美天生物科技股份有限公司 Tulathromycin A synthesis method
CN106939029A (en) * 2017-04-28 2017-07-11 艾美科健（中国）生物医药有限公司 A kind of preparation method of Tulathromycin
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
US11001604B2 (en) 2017-12-19 2021-05-11 Wisdom Pharmaceutical Co., Ltd. Method for preparing tulathromycin
CN110128486A (en) * 2019-06-19 2019-08-16 常州齐晖药业有限公司 A kind of synthetic method of Tulathromycin
CN110128486B (en) * 2019-06-19 2022-12-02 常州齐晖药业有限公司 Synthesis method of tulathromycin
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