CN109400495A - A kind of preparation method of acetochloroanilide - Google Patents
A kind of preparation method of acetochloroanilide Download PDFInfo
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- CN109400495A CN109400495A CN201811575537.5A CN201811575537A CN109400495A CN 109400495 A CN109400495 A CN 109400495A CN 201811575537 A CN201811575537 A CN 201811575537A CN 109400495 A CN109400495 A CN 109400495A
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- acetochloroanilide
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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Abstract
The present invention relates to veterinary drug technical fields, more particularly to a kind of preparation method of fortimicin synthesis process acetochloroanilide, the following steps are included: reaction dissolvent water is added in (1), keeping system temperature is 0~30 DEG C, put into reaction raw materials antifebrin, buffer reagent is put into after being stirred again, continues to be stirred；(2) reaction raw materials chlorine monoxide is passed through in step (1) according to the ratio that chlorine monoxide and antifebrin molar ratio are 0.55~0.8:1；(3) system temperature is kept to react 5~10h under conditions of 0-30 DEG C, reaction terminates, and filtering drying obtains acetochloroanilide.Preparation method generation abraum salt, wastewater flow rate is few, production cost is low, but also substantially increases the purity and yield of acetochloroanilide product.
Description
Technical field
The present invention relates to veterinary drug technical fields, and in particular to a kind of fortimicin synthesis process acetochloroanilide
Preparation method.
Background technique
Fortimicin is Tri-Biocin, and tetracycline medication can treat Chlamydia mycoplasma infection.It is mainly used for controlling
Treat respiratory tract, the urinary tract and infection of biliary tract caused by sensitive bacteria.Antimicrobial spectrum and tetracycline, terramycin are essentially identical, and body is inside and outside anti-
Bacterium power is strong compared with tetracycline.Microorganism has close cross resistance to this product and tetracycline, terramycin etc..Oral absorption is good
It is good.It is mainly used for the infection of the upper respiratory tract, tonsillitis, biliary tract sense caused by sensitive gram positive bacteria and gram negative bacilli
Dye, lymphnoditis, cellulitis, senile chronic bronchitis etc. are also used for treatment typhus, Qiang's parasitosis, Eaton agent pneumonia
Deng.Still for treating cholera, it can also be used to prevent pernicious malaria and leptospiral infection.This medicine is widely used in veterinary drug, city
Field is in great demand.
Fortimicin preparation at present generally comprises following two method: (1) " a kind of preparation process of doxycycline hydrochloride
(CN101786917；Publication date: 2010.07.28) ", processing step: by 11 α-chloro- 6- methine terramycin p-methyl benzenesulfonic acid
Salt is hydrogenated in the presence of catalyst-palladium, charcoal and adjuvant with pressurized with hydrogen, is then reacted again with 5-sulphosalicylic acid, and α-is obtained
Then 6- doxycycline 5-sulphosalicylic acid salt generates α -6- doxycycline alkali through alkalization, it is more finally to turn salt generation hydrochloric acid
Western ring element.This technique is using 11 α-chloro- 6- methine terramycin as Material synthesis fortimicin, and the raw material obtains in process of production
Approach is very limited, is realizing commercial process by limitation；(2) " a kind of preparation method of fortimicin
(CN107056641；Publication date: 2017.08.18) ", processing step: using Oxytetracycline Base as raw material, by Oxytetracycline Base NBS
(N-bromosuccinimide), at 11 α-bromo- 6,12- hemiketal terramycin, it is mould to be dehydrated into the bromo- 6 methine soil of 11 α-through bromo
Plain tosilate is hydrogenated in the presence of catalyst-palladium, charcoal and adjuvant with pressurized with hydrogen, then again with 5- sulfosalisylic
Acid reaction, obtains α -6- doxycycline 5-sulphosalicylic acid salt, then generates α -6- doxycycline alkali through alkalization, finally turns
Salt generates Doxycycline Hyclate.This technique is using terramycin as raw material, although terramycin raw material is easy to get, uses during chloro
NBS after bromo, in hydrotreating stage, there is hydrogen bromide generation, wastewater treatment is extremely difficult as bromo agent.In order to solve above-mentioned ask
Topic also has and uses chlorosuccinimide or nitrogen-chloro acetanilide as chloro agent in terramycin chloro process, and N- chloroacetyl
For aniline as chloro agent process, being is raw material, chloro again after being raw material chlorination with sodium hypochlorite by antifebrin.And sodium hypochlorite
For raw material process, mostly sodium chloride containing 1mol in technical grade sodium hypochlorite generates sodium hydroxide again after with antifebrin chlorination, needs
It further to neutralize, generation abraum salt (sodium chloride) is more, high production cost.Therefore the present invention is in view of the above-mentioned problems, establish one
The new process for being used to prepare acetochloroanilide of kind.
Summary of the invention
It is an object of the invention to: in view of the deficienciess of the prior art, providing a kind of preparation of acetochloroanilide
Method, preparation method generation abraum salt, wastewater flow rate is few, production cost is low, but also substantially increases acetochloroanilide production
The purity and yield of product.
To achieve the goals above, the technical scheme is that
A kind of preparation method of acetochloroanilide, the preparation method comprises the following steps:
(1) reaction dissolvent water is added, keeping system temperature is 0~30 DEG C, puts into reaction raw materials antifebrin, is stirred
It puts into buffer reagent again afterwards, continues to be stirred；
(2) it is passed through in step (1) instead according to the ratio that chlorine monoxide and antifebrin molar ratio are 0.55~0.8:1
Answer raw material chlorine monoxide；
(3) system temperature is kept to react 5~10h under conditions of 0-30 DEG C, reaction terminates, and filtering drying obtains N- chlorine
For antifebrin.
As an improvement technical solution, the buffer reagent in the step (1) is alkali metal hydroxide, alkali metal
Carbonate, alkali metal hydrogencarbonate or ammonium hydroxide.
As an improvement technical solution, the alkali metal hydroxide be sodium hydroxide or potassium hydroxide；The alkali
Metal carbonate is sodium carbonate or potassium carbonate；The alkali metal hydrogencarbonate is sodium bicarbonate or saleratus.
As a kind of perferred technical scheme, the step (1) and the middle holding system temperature of step (3) are 15~30 DEG C.
As a kind of perferred technical scheme, buffer reagent is sodium hydroxide or ammonium hydroxide in the step (1).
As a kind of further preferred technical solution, buffer reagent is sodium hydroxide in the step (1).
As a kind of perferred technical scheme, the molar ratio of chlorine monoxide and antifebrin is in the step (2)
0.65~0.75:1.
As a kind of perferred technical scheme, the reaction time is 5-6h in the step (3).
The invention adopts the above technical scheme, compared with prior art, has the advantage that
Using antifebrin and chlorine monoxide as reaction raw materials, antifebrin is partly dissolved the present invention in aqueous systems, is led to
When entering chlorine monoxide, chlorine monoxide reacts into hypochlorous acid in water, and the hydrogen being connected on antifebrin with N is replaced by chlorine, obtains
To nitrogen-chloro acetanilide product；Buffer reagent, buffer reagent is added in antifebrin of the present invention and chlorine monoxide reaction system
Addition system can be made to maintain in certain alkaline environment, avoid reaction mass from decomposing, be more conducive to material and sufficiently react, and
And buffer reagent is selected as sodium hydroxide, temperature of reaction system control is at 15-30 DEG C, and reaction time control is in 5-6h, an oxidation two
On the one hand the control of the molar ratio of chlorine and antifebrin substantially increases product yield in 0.65~0.75:1, according to this process conditions
And purity；On the other hand also solving has a large amount of abraum salts and waste water to lead to the problem of present in prior art preparation method, and
And greatly reduce production cost.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, the present invention is carried out further detailed
Explanation.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not intended to limit the present invention.
Embodiment 1
Purified water 300.15g is added in equipped with thermometer and churned mechanically 500ml reaction flask, ammonia is added in reaction flask
Water 7.54g is added antifebrin 50.04g, chlorine monoxide gas is passed through into reaction flask, being passed through chlorine monoxide amount is
18.14g.0~30 DEG C of heat preservation is reacted 5 hours, is filtered to obtain acetochloroanilide, is dried to obtain solid 49.27g, solid purity
88.4%, molar yield 69.1%.
Embodiment 2
Purified water 299.98g is added in equipped with thermometer and churned mechanically 500ml reaction flask, hydrogen is added in reaction flask
Sodium oxide molybdena 4.41g is added antifebrin 50.01g, chlorine monoxide gas is passed through into reaction flask, is passed through chlorine monoxide amount
For 18.03g.0~30 DEG C of heat preservation is reacted 5 hours, is filtered to obtain acetochloroanilide, is dried to obtain solid 56.40g, solid purity
93.2%, molar yield 83.6%.
Embodiment 3
Purified water 300.11g is added in equipped with thermometer and churned mechanically 500ml reaction flask, carbon is added in reaction flask
Sour sodium 11.76g is added antifebrin 50.05g, chlorine monoxide gas is passed through into reaction flask, being passed through chlorine monoxide amount is
18.09g.0~30 DEG C of heat preservation is reacted 5 hours, is filtered to obtain acetochloroanilide, is dried to obtain solid 55.34g, solid purity
93.8%, molar yield 82.1%.
Embodiment 4
Purified water 300.21g is added in equipped with thermometer and churned mechanically 500ml reaction flask, hydrogen is added in reaction flask
Sodium oxide molybdena 4.43g is added antifebrin 50.14g, chlorine monoxide gas is passed through into reaction flask, is passed through chlorine monoxide amount
For 18.13g.15~30 DEG C of heat preservation are reacted 5 hours, are filtered to obtain acetochloroanilide, are dried to obtain solid 57.8g, solid purity
92.4%, molar yield 85.7%.
Embodiment 5
Purified water 300.14g is added in equipped with thermometer and churned mechanically 500ml reaction flask, hydrogen is added in reaction flask
Sodium oxide molybdena 4.42g is added antifebrin 50.02g, chlorine monoxide gas is passed through into reaction flask, is passed through chlorine monoxide amount
For 20.9g.15~30 DEG C of heat preservation are reacted 5 hours, are filtered to obtain acetochloroanilide, are dried to obtain solid 62.92g, solid purity
98.7%, molar yield 98.9%.
Embodiment 6
Purified water 299.75g is added in equipped with thermometer and churned mechanically 500ml reaction flask, hydrogen is added in reaction flask
Sodium oxide molybdena 4.42g is added antifebrin 49.97g, chlorine monoxide gas is passed through into reaction flask, is passed through chlorine monoxide amount
For 24.12g.15~30 DEG C of heat preservation are reacted 5 hours, are filtered to obtain acetochloroanilide, are dried to obtain solid 63.42g, solid purity
98.2%, molar yield 99.2%.
In order to preferably prove that the yield and purity of product can be improved in preparation method of the invention, following present several
Comparative example.
Comparative example 1
As different from Example 5, buffer reagent is not put into reaction system, remaining operation is identical.
Comparative example 2
As different from Example 5, the molar ratio of chlorine monoxide and antifebrin is 0.85:1, remaining operation is identical.
Comparative example 3
As different from Example 5, the temperature of reaction system is maintained at 35-40 DEG C, remaining operation is identical.
Comparative example 4
According to water in four-hole bottle: antifebrin: sodium hypochlorite is that the mass ratio of 6:1:7 feeds intake, small in 0-30 DEG C of reaction 5
When, filtering product, purity 94.5%, yield 96.2%.
Embodiment 1-6 and acetochloroanilide purity under comparative example 1-4 process conditions and acetochloroanilide rub
You are shown in Table 1 by the yield of yield.
Table 1
By 1 data of table, it can be concluded that, the present invention is under the conditions of 15-30 DEG C, using sodium hydroxide as buffer reagent, produces
Object yield and purity are apparently higher than in embodiment 1-3 under the conditions of 0-30 DEG C, using ammonium hydroxide or carbonic acid sodium as the product of buffer reagent
Yield and purity；And compared by the product yield and purity and abraum salt yield with comparative example 1-4, it can be deduced that this hair
It is bright under the conditions of 15-30 DEG C, using sodium hydroxide as buffer reagent, the molar ratio of reaction mass is the condition of 0.65-0.75:1
Under, for the optimum reaction condition for preparing acetochloroanilide, the yield and purity of product are substantially increased under this process conditions,
And reduce abraum salt yield.
Chloro agent (acetochloroanilide) will be reacted to obtain as soil through chlorine monoxide and antifebrin in the present invention
Mycin chloro agent carries out obtaining yield indifference with NBS bromo in chlorination and patent CN107056641.
Anhydrous methanol 350.12g, 5% methanol ammonia is added in equipped with thermometer and churned mechanically 500ml reaction flask
5.12g puts into Oxytetracycline Base 35.11g, reaction flask is cooled to -5 DEG C hereinafter, the N- chloro second being added at one time in embodiment 8
Anilide 15.14g.It is stirred to react 15min, is filtered, cold methanol rinses up to 11 α-chloro- 6,12- hemiketal terramycin, dries
Solid 37.46g, solid purity 96.4%, molar yield 97.2%.
This patent is not limited to above-mentioned specific embodiment, those skilled in the art from the above idea,
Without creative labor, made various transformation are all fallen within the protection scope of this patent.
Claims (9)
1. a kind of preparation method of acetochloroanilide, it is characterised in that the preparation method comprises the following steps:
(1) reaction dissolvent water is added, keeping system temperature is 0~30 DEG C, puts into reaction raw materials antifebrin, is stirred and throws again
Enter buffer reagent, continues to be stirred；
(2) reaction original is passed through in step (1) according to the ratio that chlorine monoxide and antifebrin molar ratio are 0.55~0.8:1
Expect chlorine monoxide；
(3) system temperature is kept to react 5~10h under conditions of 0-30 DEG C, reaction terminates, filtering drying, obtains N- chloro second
Anilide.
2. a kind of preparation method of acetochloroanilide according to claim 1, it is characterised in that: the step (1)
In buffer reagent be alkali metal hydroxide, alkali carbonate, alkali metal hydrogencarbonate or ammonium hydroxide.
3. a kind of preparation method of acetochloroanilide according to claim 1, it is characterised in that: the alkali metal hydrogen
Oxide is sodium hydroxide or potassium hydroxide；The alkali carbonate is sodium carbonate or potassium carbonate；The alkali metal hydrogen carbonate
Salt is sodium bicarbonate or saleratus.
4. a kind of preparation method of acetochloroanilide according to claim 1, it is characterised in that: the step (1)
It is 15~30 DEG C with holding system temperature in step (3).
5. a kind of preparation method of acetochloroanilide according to claim 1, it is characterised in that: the step (1)
Middle buffer reagent is sodium hydroxide or ammonium hydroxide.
6. a kind of preparation method of acetochloroanilide according to claim 5, it is characterised in that: the step (1)
Middle buffer reagent is sodium hydroxide.
7. a kind of preparation method of acetochloroanilide according to claim 1, it is characterised in that: the step (1)
The molar ratio of middle buffer reagent and antifebrin is 0.3-0.6:1.
8. a kind of preparation method of acetochloroanilide according to claim 1, it is characterised in that: the step (2)
The molar ratio of middle chlorine monoxide and antifebrin is 0.65~0.75:1.
9. a kind of preparation method of acetochloroanilide according to claim 1, it is characterised in that: the step (3)
The middle reaction time is 5-6h.
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| CN201811575537.5A CN109400495A (en) | 2018-12-22 | 2018-12-22 | A kind of preparation method of acetochloroanilide |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358413A (en) * | 2020-11-09 | 2021-02-12 | 扬州联博药业有限公司 | Preparation method of N-chloroacetanilide |
| CN112875727A (en) * | 2021-02-22 | 2021-06-01 | 扬州联博药业有限公司 | Method for recovering sodium carbonate and sodium chloride from chloroacetanilide mother liquor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101525304A (en) * | 2009-04-08 | 2009-09-09 | 武汉大学 | Preparation method for nitrogen-chloro acetanilide containing halogenated functional group |
| CN106496051A (en) * | 2016-08-31 | 2017-03-15 | 浙江沙星药业有限公司 | A kind of synthetic method of 4 chlorine, 2 trifluoroacetyl aniline hydrochloride hydrate |
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2018
- 2018-12-22 CN CN201811575537.5A patent/CN109400495A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101525304A (en) * | 2009-04-08 | 2009-09-09 | 武汉大学 | Preparation method for nitrogen-chloro acetanilide containing halogenated functional group |
| CN106496051A (en) * | 2016-08-31 | 2017-03-15 | 浙江沙星药业有限公司 | A kind of synthetic method of 4 chlorine, 2 trifluoroacetyl aniline hydrochloride hydrate |
Non-Patent Citations (1)
| Title |
|---|
| F.D.CHATTAWAY ET AL: "CIV. - A series of substituted nitrogen chlorides and their relation to the substitution of halogen in anilides and anilines", 《JOURNAL OF THE CHEMICAL SOCIETY, TRANSACTIONS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358413A (en) * | 2020-11-09 | 2021-02-12 | 扬州联博药业有限公司 | Preparation method of N-chloroacetanilide |
| CN112875727A (en) * | 2021-02-22 | 2021-06-01 | 扬州联博药业有限公司 | Method for recovering sodium carbonate and sodium chloride from chloroacetanilide mother liquor |
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