CN106905397B - A method of Tilmicosin is prepared using tylosin D as raw material - Google Patents
A method of Tilmicosin is prepared using tylosin D as raw material Download PDFInfo
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- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The present invention relates to a kind of methods for preparing Tilmicosin as raw material using tylosin D, this method is using tylosin D as raw material, 20 primary hydroxy groups are obtained into intermediate 1 for aldehyde radical by selective oxidant, de- mycaminose is hydrolyzed again obtains intermediate 2, by formic acid and 3,5 lupetidine reduction aminations obtain product Tilmicosin.The present invention is using tylosin D as raw material, by specific selective oxidant make tylosin D be changed into synthesis Tilmicosin effective component, it avoids being changed into impurity, a new way is opened for the preparation of Tilmicosin, solves the problems, such as that the existing impurity residual for preparing Tilmicosin using tylosin as starting material is high relatively low with yield.
Description
Technical field
The present invention relates to a kind of methods for preparing Tilmicosin as raw material using tylosin D, belong to pharmaceutical synthesis field.
Background technique
Tilmicosin is a kind of dedicated macrolide antibiotics of livestock and poultry, is mainly used for preventing domestic animal pneumonia, avian mycoplasmas
Disease and the mazoitis of lactating mammal etc..The preparation method of Tilmicosin is mainly with the phosphate or tartaric acid of tylosin at present
Salt is raw material, takes off mycaminose through acidic hydrolysis, then react with 3,5- lupetidine and generate Tilmicosin, or change reaction time
Sequence first hydrolyzes generation Tilmicosin with the reaction of 3,5- lupetidine again.Such as, disclosed in Chinese patent literature CN102382159
A kind of preparation method of Tilmicosin, using Tylosin phosphate as raw material, alcohol is solvent, is with anhydrous formic acid at 65-97 DEG C
Catalyst and 3,5- lupetidine reaction, obtains intermediate 20- dihydro -20- deoxidation-(3,5- dimethyl piperazines after fully reacting
Pyridine -1- base) tylosin, concentrated solvent, residue is added 0.1N sulfuric acid solution and hydrolyzes to obtain Tilmicosin, for another example, Chinese special
Sharp document CN105837648A discloses a kind of preparation method of tilmicosin phosphate, using Tylosin Tartrate as raw material, passes through
Hydrolyzed under acidic conditions, alkalization extraction, amination, be added phosphorus pentoxide and a small amount of water progress phosphorylation, be sufficiently stirred make its at
Salt is dried in vacuo to obtain tilmicosin phosphate until solid is centrifugated after being precipitated completely.
Such preparation method, raw material Tylosin phosphate or Tylosin Tartrate are grouped as by four kinds of groups, and structure is such as
Under,
Wherein Tylosin A, B component are that effective component can synthesize Tilmicosin, C, and D component then changes during the reaction
For impurity.Tylosin C component is because content is very low smaller to Tilmicosin yield and impurities affect, and tylosin D component (thunder
Promise rhzomorph) the content about 8%-10% in tylosin in the synthesis process produces the yield of Tilmicosin with purity
Larger impact.
Therefore, the tylosin D component that how will affect Tilmicosin yield and purity efficiently uses, and makes synthesis
The effective component of Tilmicosin avoids being changed into impurity, influences the yield and purity of Tilmicosin, become at present have it is to be solved
Technical problem.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of method for preparing Tilmicosin as raw material using tylosin D.
This method solve impurity residual height and the relatively low problem of yield that Tilmicosin is prepared using tylosin as starting material.
Term explanation:
TEMPO: being is that 2,2,6,6- the general of tetramethyl piperidine nitrogen oxides are write a Chinese character in simplified form, and structure is as shown in formula III:
The present invention is achieved through the following technical solutions:
A kind of preparation method of Tilmicosin, using tylosin D as raw material, comprising steps of
(1) tylosin D is dissolved in organic solvent, adjusts the temperature to 0-5 DEG C, selective oxidant is added, react 4-
The organic solution of I intermediate 1 of formula is obtained after 6h；
The selective oxidant is the mixture of sodium bicarbonate, NaClO, KBr and TEMPO or TEMPO derivative composition；
(2) water, acid will be added in the organic solution of intermediate 1 obtained in step (1), static layering removes organic phase,
Retain water phase, then 0.5~3h of hydrolysis under conditions of 50~100 DEG C of temperature, the aqueous solution of II intermediate 2 of formula is made；
(3) organic solvent will be added in the aqueous solution for the intermediate 2 that step (2) obtains, is layered to have under alkaline condition
Machine phase, Xiang Youji are added to 3,5- lupetidine, formic acid, are warming up to 50-80 DEG C of reaction 4-8h, and reaction is completed to be down to room temperature,
It is washed out, is dehydrated, is concentrated, obtain Tilmicosin.
It is preferred according to the present invention, organic solvent described in step (1) be methylene chloride, ethyl acetate, chloroform or
Toluene one of which or two or more mixing, highly preferred, the organic solvent is ethyl acetate.
According to the present invention preferably, the mass ratio of step (1), the tylosin D and organic solvent is 1:(5-15).
It is preferred according to the present invention, in step (1), described NaClO, KBr and TEMPO or TEMPO derivative, sodium bicarbonate
Molar ratio with tylosin D is (5-10): (0.1-0.2): (2-4): (1-2): 1.
It is preferred according to the present invention, in step (1), the NaClO, KBr, TEMPO, sodium bicarbonate and tylosin D
Molar ratio is 5:0.1:2:1:1.
Preferred according to the present invention, the TEMPO derivative is 4- mesyl-TEMPO or 4- acetylaminohydroxyphenylarsonic acid TEMPO.
4- mesyl-TEMPO structure as shown in formula IV, 4- acetylaminohydroxyphenylarsonic acid TEMPO structure as shown in formula V,
Preferred according to the present invention, acid described in step (2) is hydrochloric acid, sulfuric acid, hydrobromic acid, p-methyl benzenesulfonic acid or trifluoro
Acetic acid one of which or two or more mixing, highly preferred, the acid is hydrochloric acid.
Preferred according to the present invention, in step (2), the additional amount of water is 3-10 times of 1 mass of intermediate, acid and intermediate
1 molar ratio is (1-3): 1.
Preferred according to the present invention, organic solvent described in step (3) is ethyl acetate, methyl acetate, isoamyl acetate
Or toluene, highly preferred, the organic solvent is ethyl acetate.
Preferred according to the present invention, the additional amount of step (3) organic solvent and the mass ratio of intermediate 2 are (5-10): 1.
Preferred according to the present invention, the pH value of step (3) neutral and alkali condition is 8.0-12.0, use mass concentration for
10%-30% sodium hydroxide solution is adjusted.
It is preferred according to the present invention, intermediate 2:3,5- lupetidine in the aqueous solution of intermediate 2 in step (3): first
The molar ratio of acid is 1:(1-1.8): (1-1.8)；Preferably, intermediate 2:3,5- lupetidine: the molar ratio of formic acid is 1:
1.2:1.2.
A currently preferred technical solution, a kind of preparation method of Tilmicosin, using tylosin D as raw material, packet
Include that steps are as follows:
(1) it is the ratio of 1:(5-15) in the mass ratio of tylosin D and organic solvent, tylosin D is dissolved in organic
In solvent, 0-5 DEG C is adjusted the temperature to, selective oxidant is added, obtains the organic solution of intermediate 1 after reacting 4-6h；
(2) in the organic solution for the intermediate 1 for obtaining step (1) be added 3-10 times of 1 mass of intermediate water, then plus
Entering acid, static layering removes organic phase, retain water phase, then 0.5~3h of hydrolysis under conditions of 50~100 DEG C of temperature,
The aqueous solution of intermediate 2 is made；
(3) organic solvent will be added in 2 aqueous solution of intermediate that step (2) obtains, adjusting pH value is 8.0-12.0, static
Layering removal water phase, Xiang Youji are added to 3,5- lupetidine, formic acid, and intermediate 2:3,5- lupetidine: formic acid rubs
You are than being 1:(1-1.8): (1-1.8) is warming up to 50-80 DEG C of reaction 4-8h, and reaction is completed to be down to room temperature, adds water washing, static
Layering discards water phase, and organic anhydrous sodium sulfate that is added to is dehydrated 3-12h, filter liquor, and filtrate is warming up to
40-70 DEG C, vacuum concentration obtains Tilmicosin.
Another preferred technical solution of the invention, a kind of preparation method of Tilmicosin are original with tylosin D
Material, comprises the following steps that
(1) tylosin D 91.8g is added in 459-1377g ethyl acetate, adjusts the temperature to 0-5 DEG C, be added
1.2gKBr, 0.8g TEMPO, 8.4g sodium bicarbonate, stir evenly, and 10%NaClO solution 373g is slowly added dropwise, and react 4-6h,
After the reaction was completed, layering removal water phase, obtains the ethyl acetate solution of intermediate 1；
(2) 500g water is added into the ethyl acetate solution of intermediate 1, hydrochloric acid 8.3g is added, static layering removal is organic
Phase, water phase are warming up to 50-100 DEG C of reaction, and the aqueous solution of intermediate 2 is made in 0.5~3h of hydrolysis；
(3) ethyl acetate is added to the aqueous solution of intermediate 2, uses sodium hydroxide solution adjusting pH value for 8.0-12.0,
Static layering removes water phase, organic to be added to 3,5- lupetidine 13.6g, formic acid 5.5g, is warming up to 50-80 DEG C of reaction 4-
8h, reaction are completed to be down to room temperature, purified water, agitator treating are added, static layering removes water phase, organic to be added to anhydrous sodium sulfate
It is dehydrated 3-12h, filter liquor, filtrate is warming up to 40-70 DEG C, and vacuum concentration obtains Tilmicosin.
Synthetic route of the invention is as follows:
Beneficial effect
1, method of the invention changes tylosin D by specific selective oxidant using tylosin D as raw material
It for the effective component for synthesizing Tilmicosin, avoids traditional handicraft and is changed into impurity, open one for the preparation of Tilmicosin
New way, solve the existing impurity residual for preparing Tilmicosin using tylosin as starting material it is high with yield is relatively low asks
Topic.
2,20 primary hydroxy groups of tylosin D are aldehyde radical by selective oxidant of the invention, can will make safe pleasure
Rhzomorph D is thoroughly converted into synthesis Tilmicosin effective component intermediate 1 (Tylosin A), provides for the yield of Tilmicosin
It ensures.
3, the present invention efficiently uses traditional route by component invalid in starting material of tylosin, improves Thailand
The utilization rate of happy rhzomorph.
Detailed description of the invention
Fig. 1 is Tilmicosin high-efficient liquid phase chromatogram made from embodiment 1.
Specific embodiment
Technical solution of the present invention is further elaborated below with reference to embodiment, the embodiment described is used only to illustrate
The present invention, and it is not considered as limitation of the present invention.
Embodiment 1
A method of Tilmicosin being prepared using tylosin D as raw material, steps are as follows:
(1) tylosin D 91.8g is added in 500g ethyl acetate, is kept for 0-5 DEG C of temperature, and 1.2gKBr, 0.8g is added
TEMPO, 8.4g sodium bicarbonate, stir evenly, and 10%NaClO solution 373g is slowly added dropwise, and react 4h, after the reaction was completed, static
Layering, water phase discard, and organic phase is 1 ethyl acetate solution of intermediate.
(2) by 1 solution of intermediate obtained in step (1) be added 500g purified water, be added hydrochloric acid 8.3g, static layering,
Organic phase is removed, water phase is warming up to 50 DEG C of reactions, and intermediate 2 is made in hydrolysis 1.0h；
(3) ethyl acetate is added in 2 aqueous solution of intermediate obtained in step (2), sodium hydroxide solution adjusts pH value and is
8.0, static layering discards water phase, organic to be added to 3,5- lupetidine 11.3g, and formic acid 4.6g is warming up to 50-80 DEG C
4h is reacted, reaction is completed to be down to room temperature, appropriate purified water is added, agitator treating, static layering, water phase discards, organic to be added to
Anhydrous sodium sulfate is dehydrated 3h, filter liquor, and filtrate is warming up to 50 DEG C, and vacuum concentration obtains product Tilmicosin 76.3g, yield
87.8%, Tilmicosin high-efficient liquid phase chromatogram is surveyed, as a result as shown in Figure 1, purity is 96.4% (cis- Tilmicosin, trans-
The sum of Tilmicosin, cis- -8- epimer).
Embodiment 2
A method of Tilmicosin being prepared using tylosin D as raw material, steps are as follows:
(1) tylosin D 91.8g is added in 1000g ethyl acetate, is kept for 0-5 DEG C of temperature, and 1.8gKBr, 1.2g is added
TEMPO, 12.6g sodium bicarbonate, stir evenly, and 10%NaClO solution 560g is slowly added dropwise, and react 5h, after the reaction was completed, static
Layering, water phase discard, and organic phase is 1 ethyl acetate solution of intermediate.
(2) by 1 solution of intermediate obtained in step (1) be added 500g purified water, be added hydrochloric acid 16.6g, static layering,
Organic phase is removed, water phase is warming up to 50 DEG C of reactions, and intermediate 2 is made in hydrolysis 0.5h；
(3) ethyl acetate is added in 2 aqueous solution of intermediate obtained in step (2), sodium hydroxide solution adjusts pH value and is
10.0, static layering discards water phase, organic to be added to 3,5- lupetidine 13.6g, and formic acid 5.5g is warming up to 50-80 DEG C
6h is reacted, reaction is completed to be down to room temperature, appropriate purified water is added, agitator treating, static layering, water phase discards, organic to be added to
Anhydrous sodium sulfate is dehydrated 6h, filter liquor, and filtrate is warming up to 60 DEG C, and vacuum concentration obtains product Tilmicosin 78.3g, yield
90.1%, purity 95.8%.
Embodiment 3
A method of Tilmicosin being prepared using tylosin D as raw material, steps are as follows:
(1) tylosin D 91.8g is added in 1500g ethyl acetate, is kept for 0-5 DEG C of temperature, and 2.4gKBr, 1.8g is added
TEMPO, 19.0g sodium bicarbonate, stir evenly, and 10%NaClO solution 746g is slowly added dropwise, and react 6h, after the reaction was completed, static
Layering, water phase discard, and organic phase is 1 ethyl acetate solution of intermediate.
(2) by 1 solution of intermediate obtained in step (1) be added 500g purified water, be added hydrochloric acid 24.9g, static layering,
Organic phase is removed, water phase is warming up to 50 DEG C of reactions, and intermediate 2 is made in hydrolysis 0.5h；
(3) ethyl acetate is added in 2 aqueous solution of intermediate obtained in step (2), sodium hydroxide solution adjusts pH value and is
12.0, static layering discards water phase, organic to be added to 3,5- lupetidine 20.4g, and formic acid 8.3g is warming up to 50-80 DEG C
6h is reacted, reaction is completed to be down to room temperature, appropriate purified water is added, agitator treating, static layering, water phase discards, organic to be added to
Anhydrous sodium sulfate is dehydrated 12h, filter liquor, and filtrate is warming up to 70 DEG C, and vacuum concentration obtains product Tilmicosin 78.9g, yield
90.8%, purity 96.2%.
Claims (5)
1. a kind of preparation method of Tilmicosin, using tylosin D as raw material, comprising steps of
(1) tylosin D is dissolved in organic solvent, adjusts the temperature to 0-5 DEG C, selective oxidant is added, after reacting 4-6h
Obtain the organic solvent of I intermediate 1 of formula；The organic solvent is methylene chloride, ethyl acetate, chloroform or toluene wherein one
Kind or two or more mixing；
The selective oxidant is the mixture of sodium bicarbonate, NaClO, KBr and TEMPO or TEMPO derivative composition；It is described
The molar ratio of NaClO, KBr and TEMPO or TEMPO derivative, sodium bicarbonate and tylosin D is (5-10): (0.1-0.2):
(2-4): (1-2): 1；, the TEMPO derivative is 4- mesyl-TEMPO or 4- acetylaminohydroxyphenylarsonic acid TEMPO；
Formula I
(2) water, acid will be added in the organic solvent of intermediate 1 obtained in step (1), static layering removes organic phase, retains
Water phase, then 0.5~3h of hydrolysis under conditions of 50~100 DEG C of temperature, is made the aqueous solution of II intermediate 2 of formula；
Formula II
(3) organic solvent will be added in the aqueous solution for the intermediate 2 that step (2) obtains, is layered to obtain organic phase under alkaline condition,
It is added to 3,5- lupetidine, formic acid to organic, is warming up to 50-80 DEG C of reaction 4-8h, reaction is completed to be down to room temperature, then be washed
It washs, be dehydrated, be concentrated, obtain Tilmicosin.
2. the preparation method of Tilmicosin according to claim 1, which is characterized in that the NaClO, KBr, TEMPO, carbon
The molar ratio of sour hydrogen sodium and tylosin D are 5:0.1:2:1:1.
3. the preparation method of Tilmicosin according to claim 1, which is characterized in that acid described in step (2) is salt
Acid, sulfuric acid, hydrobromic acid, p-methyl benzenesulfonic acid or trifluoroacetic acid one of which or two or more mixing；The additional amount of water is centre
The molar ratio of 3-10 times of 1 mass of body, acid and intermediate 1 is (1-3): 1.
4. the preparation method of Tilmicosin according to claim 1, which is characterized in that organic solvent described in step (3)
For ethyl acetate, methyl acetate, isoamyl acetate or toluene；The additional amount of organic solvent and the mass ratio of intermediate 2 are (5-
10): 1.
5. the preparation method of Tilmicosin according to claim 1, which is characterized in that in step (3), the pH of alkaline condition
Value is 8.0-12.0, uses mass concentration for the adjusting of 10%-30% sodium hydroxide solution；Intermediate 2 in the aqueous solution of intermediate 2:
3,5- lupetidine: the molar ratio of formic acid is 1:(1-1.8): (1-1.8).
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| CN111269275A (en) * | 2020-03-09 | 2020-06-12 | 浙江康牧药业有限公司 | Preparation method of tilmicosin |
| CN115925772B (en) * | 2022-12-20 | 2023-07-25 | 山东久隆恒信药业有限公司 | Synthesis method of tilmicosin |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101108866A (en) * | 2006-07-18 | 2008-01-23 | 洛阳普莱柯生物工程有限公司 | Method of preparing tilmicosin |
| CN102382159A (en) * | 2011-12-07 | 2012-03-21 | 齐鲁动物保健品有限公司 | Preparation method of tilmicosin |
| CN105837648A (en) * | 2015-11-02 | 2016-08-10 | 湖北龙翔药业科技股份有限公司 | Tilmicosin phosphate preparation method |
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2017
- 2017-04-26 CN CN201710284230.9A patent/CN106905397B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101108866A (en) * | 2006-07-18 | 2008-01-23 | 洛阳普莱柯生物工程有限公司 | Method of preparing tilmicosin |
| CN102382159A (en) * | 2011-12-07 | 2012-03-21 | 齐鲁动物保健品有限公司 | Preparation method of tilmicosin |
| CN105837648A (en) * | 2015-11-02 | 2016-08-10 | 湖北龙翔药业科技股份有限公司 | Tilmicosin phosphate preparation method |
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| Highly Stereoselective Total Synthesis of Tylonolide, the Aglycon of the 16-Membered Macrolide Antibiotic Tylosin. II. Total Synthesis of Tylonolide by Virtue of 4-Methoxybenzyl and 3,4-Dimethoxybenzyl Protection;TATSUYOSHI TANAKA，等;《Chem. Pharm. Bull.》;19871231;第35卷(第6期);第2222页 * |
| 一种制备高纯度替米考星的方法研究;渠继雷，等;《广州化工》;20130531;第41卷(第9期);第77页 * |
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