CN103772459A - Tulathromycin intermediate, preparation method of tulathromycin intermediate and preparation method of tulathromycin - Google Patents
Tulathromycin intermediate, preparation method of tulathromycin intermediate and preparation method of tulathromycin Download PDFInfo
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Abstract
The invention provides a tulathromycin intermediate, a preparation method of the tulathromycin intermediate and a preparation method of tulathromycin. According to the preparation method, Erythromycin A (E) oxime used as a starting material is subjected to acetyl protection, Albright-Goldman oxidation, Corey-Chaykovsky epoxidation, deprotection, Beckmann rearrangement, reduction and hydrolysis, and n-propylamine ring opening to synthesize tulathromycin. The preparation method has mild conditions, has the advantages of convenient operation, high yield and low cost and is beneficial to industrial production, and the raw materials are easily available.
Description
Technical field
The invention belongs to field of antibiotics for animals, specifically, relate to the preparation method of a kind of Tulathromycin intermediate and preparation method thereof and Tulathromycin.
Background technology
Respiratory tract infection is one of epidemic disease more rambunctious in livestock industry, serious to livestock industry disserve to produce.At present, macrolide antibiotics is a class common drug that is used for the treatment of the respiratory tract infection of pig, ox, for example, at the widely used tylosin of China and tilmicosin.Although the use of these two kinds of medicines has all obtained good effect, but along with the prolongation of duration of service, occurred resistance in various degree in a lot of areas, and these two kinds of medicines adopt spice or drinking-water administering mode, the general repeatedly repeat administration competence exertion drug effect that needs conventionally.Therefore, on market, be badly in need of the novel antibacterial medicine of, safety efficient to respiratory tract infection, wide spectrum, low residue.Tulathromycin is strong with its anti-microbial activity, has a broad antifungal spectrum, animal specific, overlength transformation period and single-dose just can complete the many merits such as whole therapeutic process, just causes people's extensive concern once coming out.
Tulathromycin (Tulathromycin), claim again soil to draw mycin, Tulathromycin, be the semi-synthetic macrolide antibiotics by the exploitation of Pfizer animal health company in 2002, the 10% Tulathromycin injection liquid that its commodity are called Rui Kexin (Draxxin) went on the market in European Union and the U.S. in 2004.The Ministry of Agriculture of China allows first Tulathromycin to use in animal produces in 2008 No. 957 bulletin.At present, Tulathromycin is mainly used in the respiratory infectious disease by the microbial pig of sensitivity and ox.
At present, the Tulathromycin of patent and bibliographical information synthetic is mainly (conventional to have carbobenzoxy-(Cbz), an ethanoyl take demethyl Azythromycin as raw material through selectivity hydroxyl protection.Tertbutyloxycarbonyl), selective oxidation (Swern oxidation, Albright-Goldman oxidation), Corey-Chaykovsky epoxidation, deprotection, Tri N-Propyl Amine open loop obtain Tulathromycin compound.(EP 0988310, WO9856802, EP1253153, CN102260306, CN102786569); but these methods are raw materials used expensive; operation harshness; need utmost point low temperature; what have also needs high-pressure hydrogenation; and intermediate is difficult for separation and purification, these synthesis techniques have limited the large-scale industrial production of Tulathromycin.
Summary of the invention
The invention provides the preparation method of a kind of Tulathromycin intermediate and preparation method thereof and Tulathromycin, can solve the expensive raw material price of existing method employing, the problem of severe reaction conditions, the object of the present invention is to provide a kind of simple, cheap method of synthesizing Tulathromycin.
For solving the problems of the technologies described above, the present invention is achieved by the following technical solutions:
A kind of Tulathromycin intermediate, the structural formula of this intermediate is as follows:
A preparation method for Tulathromycin intermediate, specifically adopts following steps:
A, protect 2 '-hydroxyl and the 9-position oxime of Erythromycin A (E) oxime with ethanoyl, make intermediate 1;
B, adopt Albright-Goldman oxidation style to intermediate 14 ' ' a position hydroxyl carries out selective oxidation synthetic intermediate 2;
C, adopt Corey-Chaykovsky epoxidation reaction to intermediate 24 ' ' position carries out epoxidation, makes intermediate 3;
D, intermediate 3 remove ethanoyl under methyl alcohol-sodium bicarbonate condition, obtain intermediate 4;
E, intermediate 4 are by Beckmann rearrangement synthetic intermediate 5;
F, employing hydroborate carry out reductive hydrolysis to intermediate 5 and can obtain intermediate 6, and intermediate 6 is described Tulathromycin intermediate.
The present invention is take Erythromycin A (E) oxime as starting raw material, first by simple ethanoyl protection synthetic intermediate 1, then adopt Albright-Goldman oxidation synthetic intermediate 2, again by the synthetic intermediate 3 of Corey-Chaykovsky epoxidation, under methyl alcohol-sodium bicarbonate system de-Ac synthetic intermediate 4 and then by Beckmann rearrangement synthetic intermediate 5, finally adopt sodium borohydride reduction hydrolysis intermediate 6.
The preparation method's of above-mentioned Tulathromycin intermediate concrete operation step:
A, in solvent, add Erythromycin A (E) oxime, acid binding agent, ethanoyl protective material, 25-40 ℃ of reaction, reaction finish after, separate to obtain intermediate 1; Described reaction solvent is methylene dichloride or chloroform; Described acid binding agent is triethylamine, diethylamine, diisopropyl ethyl amine or pyridine; Described ethanoyl protecting group is ethanoyl or Acetyl Chloride 98Min., with the mol ratio of Erythromycin A (E) oxime be 1.0:2.0 ~ 3.0;
B, step (1) gained intermediate 1 is dissolved in reaction solvent, at 40 ~ 60 ℃, carries out Albright-Goldman oxidation, after reaction finishes, separate and obtain intermediate 2; Described reaction solvent is methylene dichloride or chloroform; Described Albright-Goldman is oxidized to DMSO-Ac
2o system, wherein intermediate 2:DMSO:Ac
2o mol ratio is 1:40:20;
C, by the intermediate 2 of step (2) gained at-20 ℃ ~-80 ℃, under alkaline condition, carry out cyclization with Corey-Chaykovsky epoxidation, separation and purification obtains intermediate 3; Described Corey-Chaykovsky reagent is sulfur ylide reagent, is mainly wherein trimethylammonium bromination sulfonium; Described reaction solvent is methylene dichloride or tetrahydrofuran (THF); Described alkali is potassium tert.-butoxide, potassium hydroxide, the silica-based potassium amide of hexamethyl two or sodium hydride;
D, by intermediate deprotection base in alkaline alcohol solution of step (3) gained, separation and purification obtains intermediate 4; Described alkali is sodium methylate, sodium bicarbonate; Described solvent is methyl alcohol, ethanol or Virahol;
E, by step (4) gained intermediate 4 in solvent, under base catalysis, there is Beckmann rearrangement, separation and purification obtains intermediate 5; Described solvent is acetone, methyl alcohol, water; Described alkali is sodium hydroxide or sodium bicarbonate; Described Beckman activation base is Tosyl chloride or formyl chloride;
F, by the intermediate 5 of step (5) gained in solvent, reduce by hydroborating agents, after hydrolysis, obtain Tulathromycin intermediate; Described solvent is water, methyl alcohol; Described hydroborating agents is sodium borohydride, POTASSIUM BOROHYDRIDE or cyano group POTASSIUM BOROHYDRIDE; Described hydrolysising condition is hydrochloric acid or 20% sulfuric acid of mass percent 18%, pH=1 ~ 2.
Preferably, in the preparation method of above-mentioned Tulathromycin intermediate, preferred Ac in step a
2o is as acylating reagent, and methylene dichloride makees solvent, and pyridine is alkali, Erythromycin A (E) oxime: acetic anhydride: pyridine=1:2.5:0.5, and temperature of reaction is 0 ℃, the reaction times is 6h, has reacted and has had solid to separate out, and is directly used in next step reaction.
Preferably, in the preparation method of above-mentioned Tulathromycin intermediate, step b adopts DMSO-Ac
2o reaction, reaction ratio is intermediate 1:DMSO:Ac
2o=1:40:20,60 ℃ of preferred temperature of reaction, the reaction times is 2h.
Preferably, in the preparation method of above-mentioned Tulathromycin intermediate, in step c, alkali adopts sodium hydride (potassium tert.-butoxide is perishable), and preferred sodium hydride interval adds for five minutes in three batches, intermediate 2: trimethylammonium bromination sulfonium: sodium hydride=1:2:4;
Preferably, in the preparation method of above-mentioned Tulathromycin intermediate, in steps d, solvent adopts methyl alcohol, and alkali adopts sodium bicarbonate, reaction times 24h;
Preferably, in the preparation method of above-mentioned Tulathromycin intermediate, in step e, directly in upper step methanol-water-sodium bicarbonate system, add methylsulfonyl chloride, 0-5 ℃ of reaction 2h in batches; Intermediate 4: methylsulfonyl chloride=1:1.5;
Preferably, in the preparation method of above-mentioned Tulathromycin intermediate, in step f, adopt sodium borohydride better as reductive agent effect, intermediate 5: sodium borohydride=1:7, solvent is water, it is good that reaction finishes rear employing 18%HCl hydrolysis effect.
A preparation method for Tulathromycin reacts Tulathromycin intermediate can synthesize Tulathromycin with Tri N-Propyl Amine in alcoholic solution; Described alcoholic solution is methyl alcohol, ethanol, Virahol; The mol ratio of Tulathromycin intermediate and Tri N-Propyl Amine is 1:20, and temperature of reaction is 25 ~ 60.
Preferably, in the preparation method of above-mentioned Tulathromycin, solvent is Virahol, preferably 55 ℃ of temperature of reaction, and reaction density is 6 mol/L, preferably adds Louis acid catalyst as effectively Reaction time shorten of magnesium bromide.
Compared with prior art, advantage of the present invention and positively effect are:
(1) existing method all adopts demethyl Azythromycin to be starting raw material, expensive, and manufacturer is less, is unfavorable for scale operation, is starting raw material and the present invention adopts Erythromycin A (E) oxime, cheap and easy to get; The present invention uses Ac
2o replaces and has irritating CbzCl reagent, and when last deprotection base, does not need to use expensive Pd/C hydrogenation, has avoided heavy-metal residual, has improved safety operation, has reduced production cost;
(2) the present invention adopts gentle Albright-Goldman oxidation to replace the Swern oxidation of low temperature harshness, reduces costs, and has simplified operation, is easy to suitability for industrialized production;
(3) intermediate of the present invention is easy to separation, purifying, has avoided column chromatography.
Accompanying drawing explanation
Fig. 1 is the reaction scheme schematic diagram of Tulathromycin of the present invention.
Embodiment
Below in conjunction with the drawings and specific embodiments, the present invention is further detailed explanation.
In the present invention, the synthetic method step of Tulathromycin intermediate and Tulathromycin is as follows:
1, Erythromycin A (E) oxime is synthesized to key intermediate through overprotection, oxidation, epoxidation, deprotection, Beckmann rearrangement, reductive hydrolysis;
2, in Virahol, use magnesium bromide as catalyzer in Tulathromycin intermediate and Tri N-Propyl Amine, can obtain the Tulathromycin that meets quality standard.Shown in its concrete reaction scheme Fig. 1.
Embodiment
In 1L round-bottomed flask, add Erythromycin A (E) oxime (50g, 0.067 mol), pyridine (5g,), methylene dichloride (500 mL), vigorous stirring under ice-water bath, slowly drips acetic anhydride (16 mL, 0.17 mol) approximately 45 min, after TLC detection reaction 6 h, suction filtration, is dried to obtain white solid, make intermediate 1, yield 100%.
In 2L there-necked flask, add intermediate 1(50 g, 0.06 mol), nitrogen protection; inject DMSO(170 mL), be heated to 60 ℃, slowly drip acetic anhydride (110 mL; 1.2 mol) about 1h; maintain 60 ℃ of reaction 2h, add 100mL methyl alcohol cancellation reaction after cooling, concentrating under reduced pressure has solid to separate out; dry; obtain white solid, make intermediate 2, productive rate 90%.
In 1L there-necked flask, add trimethylammonium bromination sulfonium (16.5 g, 0.11 mol), anhydrous tetrahydro furan (200 mL), be cooled to-20 ℃, add in three batches sodium hydride (7g, 0.16 mol), maintain-20 ℃ of reaction 1.5h, be cooled to-80 ℃, dropwise drip the dichloromethane solution (35 g/100 mL) of compound intermediate 2, TLC detects 3h and reacts completely.Add saturated ammonium chloride solution, separatory, organic phase is evaporated to 1/3rd, adds acetone, and methylene dichloride is removed in decompression, is chilled to 10 ℃ of crystallizations, and suction filtration is dry, obtains white powder solid (3), makes intermediate 3, yield 80%.
In 3L round-bottomed flask, add compound intermediate 3 (40g), sodium methylate (2g), methyl alcohol 2.5L, 20 ℃ of reaction 10h.Then underpressure distillation obtains white solid, makes intermediate 4, the not purified the next step that is directly used in.
40g intermediate 4 is added to acetone 200 mL, and water 200 mL, are cooled to 0-5 ℃, dropwise drip the acetone soln that contains methylsulfonyl chloride, adjust pH=10 left and right simultaneously with 20% sodium hydroxide solution, reaction 2h finishes, add a large amount of water, 20% sodium hydroxide solution is adjusted pH=11 left and right, has a large amount of white solids to separate out, suction filtration, washing, dry, obtain white powder solid, make intermediate 5, two step total recoverys 73%.
In 1L there-necked flask, add intermediate 5(100g, 0.28 mol), methyl alcohol (300 mL) distilled water (300 mL), be chilled to 0 ℃, dropwise drip 20% sodium borohydride solution, stirring reaction 2h, adds Iso Butyl Acetate extraction, and organic phase is chilled to 0 ℃, add water 100mL, 18%HCl adjusts pH=2,, continue to maintain 0 ℃ of reaction 90 min.20% sodium hydroxide solution is adjusted pH=12, separatory, and Iso Butyl Acetate extracting and washing three times, merges organic phase, and removal of solvent under reduced pressure, obtains white crystal, makes intermediate 6, i.e. crucial Tulathromycin intermediate, yield 78%.
Electric stirring, thermometer, reflux condensing tube are installed in 1L four-hole bottle, are added intermediate 6(64g) magnesium bromide (3g), Virahol (500 mL), be heated with stirring to 55 ℃ reaction 24h, naturally cooling.Removal of solvent under reduced pressure, dries, and obtains white powder, i.e. Tulathromycin, yield 82%.
The Tulathromycin of synthesized is compared with the Tulathromycin standard substance that extract from the product Rui Kexin of Pfizer, and its liquid phase appearance time is consistent, and HPLC shows purity 96%.HPLC testing conditions is: Kromasil C18,150 mm x 4.6 mm 3.5 um mobile phase methanols: acetonitrile: 0.075 mol/L potassium primary phosphate=45:25:30, flow velocity 1.0 mL/min.
The above, be only preferred embodiment of the present invention, is not the restriction of the present invention being made to other form, and any those skilled in the art may utilize the technology contents of above-mentioned announcement to be changed or be modified as the equivalent embodiment of equivalent variations.But every technical solution of the present invention content that do not depart from, any simple modification, equivalent variations and the remodeling above embodiment done according to technical spirit of the present invention, still belong to the protection domain of technical solution of the present invention.
Claims (10)
1. a Tulathromycin intermediate, is characterized in that, the structural formula of this intermediate is as follows:
2. a preparation method for Tulathromycin intermediate, is characterized in that adopting following steps:
A, protect 2 '-hydroxyl and the 9-position oxime of Erythromycin A (E) oxime with ethanoyl, make intermediate 1;
B, adopt Albright-Goldman oxidation style to intermediate 14 ' ' a position hydroxyl carries out selective oxidation synthetic intermediate 2;
C, adopt Corey-Chakovsky epoxidation reaction to intermediate 24 ' ' position carries out epoxidation, makes intermediate 3;
D, intermediate 3 remove ethanoyl under methyl alcohol-sodium bicarbonate condition, obtain intermediate 4;
E, intermediate 4 are by Beckmann rearrangement synthetic intermediate 5;
F, employing hydroborate carry out reductive hydrolysis to intermediate 5 and can obtain intermediate 6, and intermediate 6 is described Tulathromycin intermediate.
3. the preparation method of Tulathromycin intermediate according to claim 2, is characterized in that concrete operation step is as follows:
A, in solvent, add Erythromycin A (E) oxime, acid binding agent, ethanoyl protective material, 25-40 ℃ of reaction, reaction finish after, separate to obtain intermediate 1; Described reaction solvent is methylene dichloride or chloroform; Described acid binding agent is triethylamine, diethylamine, diisopropyl ethyl amine or pyridine; Described ethanoyl protecting group is ethanoyl or Acetyl Chloride 98Min., with the mol ratio of Erythromycin A (E) oxime be 1.0:2.0～3.0;
B, step (1) gained intermediate 1 is dissolved in reaction solvent, at 40～60 ℃, carries out Albright-Goldman oxidation, after reaction finishes, separate and obtain intermediate 2; Described reaction solvent is methylene dichloride or chloroform; Described Albright-Goldman is oxidized to DMSO-Ac
2o system, wherein intermediate 2:DMSO:Ac
2o mol ratio is 1:40:20;
C, by the intermediate 2 of step (2) gained at-20 ℃～-80 ℃, under alkaline condition, carry out cyclization with Corey-Chaykovsky epoxidation, separation and purification obtains intermediate 3; Described Corey-Chaykovsky reagent is sulfur ylide reagent, is mainly wherein trimethylammonium bromination sulfonium; Described reaction solvent is methylene dichloride or tetrahydrofuran (THF); Described alkali is potassium tert.-butoxide, potassium hydroxide, the silica-based potassium amide of hexamethyl two or sodium hydride;
D, by intermediate deprotection base in alkaline alcohol solution of step (3) gained, separation and purification obtains intermediate 4; Described alkali is sodium methylate, sodium bicarbonate; Described solvent is methyl alcohol, ethanol or Virahol;
E, by step (4) gained intermediate 4 in solvent, under base catalysis, there is Beckmann rearrangement, separation and purification obtains intermediate 5; Described solvent is acetone, methyl alcohol, water; Described alkali is sodium hydroxide or sodium bicarbonate; Described Beckman activation base is Tosyl chloride or formyl chloride;
F, by the intermediate 5 of step (5) gained in solvent, reduce by hydroborating agents, after hydrolysis, obtain Tulathromycin intermediate; Described solvent is water, methyl alcohol; Described hydroborating agents is sodium borohydride, POTASSIUM BOROHYDRIDE or cyano group POTASSIUM BOROHYDRIDE; Described hydrolysising condition is hydrochloric acid or 20% sulfuric acid of mass percent 18%, pH=1～2.
4. the preparation method of Tulathromycin intermediate according to claim 3, is characterized in that: preferred Ac in step a
2o is as acylating reagent, and methylene dichloride makees solvent, and pyridine is alkali, Erythromycin A (E) oxime: acetic anhydride: pyridine=1:2.5:0.5, and temperature of reaction is 0 ℃, the reaction times is 6h, has reacted and has had solid to separate out, and is directly used in next step reaction.
5. the preparation method of Tulathromycin intermediate according to claim 3, is characterized in that: step b adopts DMSO-Ac
2o reaction, reaction ratio is intermediate 1:DMSO:Ac
2o=1:40:20,60 ℃ of preferred temperature of reaction, the reaction times is 2h.
6. the preparation method of Tulathromycin intermediate according to claim 3, is characterized in that: in step c, alkali adopts sodium hydride, and preferred sodium hydride interval adds for five minutes in three batches, intermediate 2: trimethylammonium bromination sulfonium: sodium hydride=1:2:4.
7. the preparation method of Tulathromycin intermediate according to claim 3, is characterized in that: in steps d, solvent adopts methyl alcohol, and alkali adopts sodium bicarbonate, reaction times 24h.
8. the preparation method of Tulathromycin intermediate according to claim 3, is characterized in that: in step e, directly in upper step methanol-water-sodium bicarbonate system, add methylsulfonyl chloride, 0-5 ℃ of reaction 2h in batches; Intermediate 4: methylsulfonyl chloride=1:1.5.
9. the preparation method of Tulathromycin intermediate according to claim 3, is characterized in that: in step f, adopt sodium borohydride as reductive agent, and intermediate 5: sodium borohydride=1:7, solvent is water, reaction finishes rear employings 18%HCl and is hydrolyzed.
10. a preparation method for Tulathromycin, is characterized in that, Tulathromycin intermediate is reacted and can synthesize Tulathromycin with Tri N-Propyl Amine in alcoholic solution; Described alcoholic solution is methyl alcohol, ethanol, Virahol; The mol ratio of Tulathromycin intermediate and Tri N-Propyl Amine is 1:20, and temperature of reaction is 25～60 ℃.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104861018A (en) * | 2015-06-17 | 2015-08-26 | 瑞普（天津）生物药业有限公司 | Preparation method of draxxin |
| CN106153740A (en) * | 2015-03-25 | 2016-11-23 | 上海医药工业研究院 | A kind of Tulathromycin have related substance, its be enriched with preparation method and application |
| CN109456372A (en) * | 2018-12-19 | 2019-03-12 | 江苏威凌生化科技有限公司 | A kind of separation method of the Tulathromycin in relation to substance |
| CN110317236A (en) * | 2019-08-15 | 2019-10-11 | 齐鲁动物保健品有限公司 | A method of Tulathromycin is prepared using micro passage reaction continous way |
| CN111253447A (en) * | 2020-03-26 | 2020-06-09 | 苏州正永生物医药有限公司 | Preparation method of tulathromycin |
| CN112745370A (en) * | 2021-02-23 | 2021-05-04 | 枣庄市润安制药新材料有限公司 | Preparation method of tulathromycin |
| 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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| WO2003011266A2 (en) * | 2001-08-01 | 2003-02-13 | Pfizer Products Inc. | Azalide antibiotic compositions |
| CN102786569A (en) * | 2012-09-07 | 2012-11-21 | 安徽中升药业有限公司 | Tulathromycin intermediate and preparation method thereof, as well as preparation method of tulathromycin |
| CN103080121A (en) * | 2010-09-20 | 2013-05-01 | 诺瓦提斯公司 | Novel process for the preparation of 9-deoxo-9a-aza- 9a-homoerythromycin a modified in the c-4'' of the cladinose ring by an epoxide group |
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| WO2003011266A2 (en) * | 2001-08-01 | 2003-02-13 | Pfizer Products Inc. | Azalide antibiotic compositions |
| CN103080121A (en) * | 2010-09-20 | 2013-05-01 | 诺瓦提斯公司 | Novel process for the preparation of 9-deoxo-9a-aza- 9a-homoerythromycin a modified in the c-4'' of the cladinose ring by an epoxide group |
| CN102786569A (en) * | 2012-09-07 | 2012-11-21 | 安徽中升药业有限公司 | Tulathromycin intermediate and preparation method thereof, as well as preparation method of tulathromycin |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106153740A (en) * | 2015-03-25 | 2016-11-23 | 上海医药工业研究院 | A kind of Tulathromycin have related substance, its be enriched with preparation method and application |
| CN106153740B (en) * | 2015-03-25 | 2019-01-01 | 上海医药工业研究院 | A kind of related substance of Tulathromycin, its be enriched with preparation method and application |
| CN104861018A (en) * | 2015-06-17 | 2015-08-26 | 瑞普（天津）生物药业有限公司 | Preparation method of draxxin |
| CN109456372A (en) * | 2018-12-19 | 2019-03-12 | 江苏威凌生化科技有限公司 | A kind of separation method of the Tulathromycin in relation to substance |
| CN110317236A (en) * | 2019-08-15 | 2019-10-11 | 齐鲁动物保健品有限公司 | A method of Tulathromycin is prepared using micro passage reaction continous way |
| CN111253447A (en) * | 2020-03-26 | 2020-06-09 | 苏州正永生物医药有限公司 | Preparation 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 |
| CN112745370A (en) * | 2021-02-23 | 2021-05-04 | 枣庄市润安制药新材料有限公司 | Preparation method of tulathromycin |
| 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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Application publication date: 20140507 |