CN105801443A - Synthesis method of dicloxacillin drug intermediate 2-amino-6-chlorobenzoic acid - Google Patents
Synthesis method of dicloxacillin drug intermediate 2-amino-6-chlorobenzoic acid Download PDFInfo
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- CN105801443A CN105801443A CN201610292940.1A CN201610292940A CN105801443A CN 105801443 A CN105801443 A CN 105801443A CN 201610292940 A CN201610292940 A CN 201610292940A CN 105801443 A CN105801443 A CN 105801443A
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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Abstract
The invention discloses a synthesis method of a dicloxacillin drug intermediate 2-amino-6-chlorobenzoic acid. The synthesis method comprises the following steps: carrying out reaction on 2-chloro-6-nitrobenzoic acid and cerium chloride under the heating condition in mixed solution of 4-hydroxyl-3-methoxyphenthyl alcohol, potassium chloride and potassium bisulfite, then lowering solution temperature for separating out solids, filtering, carrying out reduced-pressure concentration, dehydrating by adopting a dehydrating agent, washing, and recrystallizing, so that 2-amino-6-chlorobenzoic acid crystals are obtained. The whole reaction time can be controlled to be within 10 hours, reaction yield can reach up to more than 80%, and the invention provides a new synthesis route, so that a good foundation is laid for further increase of the reaction yield.
Description
Technical field
The present invention relates to the preparation method of a kind of medicine intermediate, belong to organic synthesis field, particularly relate to a kind of double chlorine
The synthetic method of XiLin pharmaceutical intermediate 2-amino-6-chlorobenzoic acid.
Background technology
Dicloxacillin is penbritin class antibiotic, and dicloxacillin is isoxazolyl penicillin, and the latter is difficult to by penicillin
Enzyme destroys.This product is external has antibacterial action to following antibacterial.Gram positive bacteria: staphylococcus aureus, A group and B group haemolysis
Property streptococcus, Streptococcus viridans, streptococcus faecalis, streptococcus pneumoniae etc..Gram negative bacteria: gonococcus, meningitis are double
Coccus, influenza and haemophilus parainfluenzae, escherichia coli, proteus mirabilis, Salmonella bacteria etc..Anaerobe: shuttle shape
Bacillus, actinomyces antibacterial etc..Dicloxacillin is stable under the conditions of gastric acid, and oral absorption is good.Food is to A Moxi
The absorption of woods has no effect, but can reduce the absorption of dicloxacillin.In oral 1-2 hour, blood drug level all can reach peak
Value, the half-life is 0.5-1.5 hour.The protein binding rate of amoxicillin is relatively low, and about 20%；And the protein binding of dicloxacillin
Rate is up to more than 97%.Both can be distributed widely in tissue and body fluid, but seldom enters cerebrospinal fluid.Both have by internal metabolism
Limit, original shape medicine and metabolite are all drained by glomerular filtration and tubular secretion mode., to staphylococcus and Grain-positive
Bacterium tool antibacterial activity.Amoxicillin-dicloxacillin has good antibacterial action to common pathogen, also has Salmonella typhi
Good antibacterial action, can be as treatment respiratory tract infection, pure skin soft-tissue infection and typhoid fever etc..2-amino-6-chlorobenzene
Formic acid is as dicloxacillin pharmaceutical intermediate, and its synthetic method is good and bad for improving pharmaceutical synthesis product quality, reduces by-product
Content has Important Economic meaning.
Yan Jie (synthesis [J] of Yan Jie, Zhu Min .2-amino-4-bromo-5-chlorobenzoic acid. fine chemistry industry, 1997,03:48-
50.) with Nitrobenzol as raw material, through bromination, reduce, be condensed, cyclization, chlorination etc. are synthesized 2-amino-6-chlorobenzoic acid, but
This synthetic method is the most complicated, and reaction intermediate link is many, and the response time is long, and more than 24 hours, and overall yield of reaction was the lowest,
It is 11.7%, therefore, for improving reaction yield, it is necessary to propose a kind of new synthetic method.
Summary of the invention
The technical problem existed based on background technology, the present invention propose a kind of dicloxacillin pharmaceutical intermediate 2-amino-
The synthetic method of 6-chlorobenzoic acid.
The synthetic method of a kind of dicloxacillin pharmaceutical intermediate 2-amino-6-chlorobenzoic acid, follows the steps below:
A, in the reaction vessel being provided with agitator, thermometer, reflux condenser, Dropping funnel, add cerium chloride
0.16mol, 4-hydroxy 3-methoxybenzene ethanol solution 0.19mol, Klorvess Liquid 400-500ml, control mixing speed and exist
160-190rpm, rising solution temperature, to 60-65 DEG C, is slowly added to 2-chloro-6-nitrobenzoyl acid solution 0.13mol, sulfurous acid
Hydrogen potassium solution 200ml, raises mixing speed to 260-310rpm, back flow reaction 5-7h；
B, reduction solution temperature, to 15-19 DEG C, separate out solid, filter, and add diammonium hydrogen citrate solution 150-in filtrate
180ml, concentrating under reduced pressure, separate out solid, filter, dehydrant is dehydrated, brine, and pyridine solution washs, ethyl acetate solution
Middle recrystallization, obtains crystal 2-amino-6-chlorobenzoic acid (molecular formula 1).
Preferably, described 4-hydroxy 3-methoxybenzene ethanol solution mass fraction is 15-23%.
Preferably, described Klorvess Liquid mass fraction is 20-28%.
Preferably, described Potassium acid sulfite liquid quality fraction is 30-41%.
Preferably, described diammonium hydrogen citrate liquid quality fraction is 40-49%.
Preferably, described dehydrant is any one in calcium oxide, potassium hydroxide.
Preferably, described saline solution is any one in sodium bromide, magnesium chloride.
Preferably, described pyridine solution mass fraction is 60-72%.
Preferably, described ethyl acetate solution mass fraction is 70-78%.
Whole course of reaction can represent with following reaction equation:
Compared to synthetic method disclosed in background technology, the dicloxacillin pharmaceutical intermediate 2-amino-6-that the present invention provides
The synthetic method of chlorobenzoic acid, the response time is greatly shortened, and reaction yield is greatly improved, and the invention provides a kind of new simultaneously
Synthetic route, lays a good foundation for promoting reaction yield further.
Accompanying drawing explanation
Fig. 1 is the mass fraction of the 4-hydroxy 3-methoxybenzene ethanol solution normal distribution on the impact of reaction yield.
Wherein, abscissa is the mass fraction of 4-hydroxy 3-methoxybenzene ethanol solution；Vertical coordinate is reaction yield；
Fig. 2 is the mass fraction of the Klorvess Liquid normal distribution on the impact of reaction yield.Wherein, abscissa is chlorine
Change the mass fraction of potassium solution；Vertical coordinate is reaction yield；
Fig. 3 is the mass fraction of the diammonium hydrogen citrate solution normal distribution on the impact of reaction yield.Wherein, horizontal seat
It is designated as the mass fraction of diammonium hydrogen citrate solution；Vertical coordinate is reaction yield；
Fig. 4 is the mass fraction of the pyridine solution normal distribution on the impact of reaction yield.Wherein, abscissa is pyridine
The mass fraction of solution；Vertical coordinate is reaction yield.
Detailed description of the invention
Embodiment 1:
The synthetic method of a kind of dicloxacillin pharmaceutical intermediate 2-amino-6-chlorobenzoic acid, follows the steps below:
A, in the reaction vessel being provided with agitator, thermometer, reflux condenser, Dropping funnel, add cerium chloride
0.16mol, mass fraction is the 4-hydroxy 3-methoxybenzene ethanol solution 0.19mol of 23%, and mass fraction is 28% potassium chloride
Solution 500ml, controls mixing speed and to 65 DEG C, is slowly added to 2-chloro-6-nitrobenzoic acid molten at 190rpm, rising solution temperature
Liquid 0.13mol, mass fraction is 41% bisulfite potassium solution 200ml, raises mixing speed to 310rpm, back flow reaction 5h；
B, reduction solution temperature, to 19 DEG C, separate out solid, filter, and adding mass fraction in filtrate is 49% hydrogen citrate two
Ammonium salt solution 180ml, concentrating under reduced pressure, separate out solid, filter, calcium oxide dehydrant is dehydrated, and sodium bromide solution washs, and mass fraction is
72% pyridine solution washing, mass fraction be 78% ethyl acetate solution in recrystallization, obtain crystal 2-amino-6-chlorobenzene first
Acid 19.82g, yield 89%.
Embodiment 2:
The synthetic method of a kind of dicloxacillin pharmaceutical intermediate 2-amino-6-chlorobenzoic acid, follows the steps below:
A, in the reaction vessel being provided with agitator, thermometer, reflux condenser, Dropping funnel, add cerium chloride
0.16mol, mass fraction is the 4-hydroxy 3-methoxybenzene ethanol solution 0.19mol of 15%, and mass fraction is the chlorination of 20%
Potassium solution 400ml, controls mixing speed and to 60 DEG C, is slowly added to 2-chloro-6-nitrobenzoic acid at 160rpm, rising solution temperature
Solution 0.13mol, mass fraction is the bisulfite potassium solution 200ml of 30%, raises mixing speed to 260rpm, back flow reaction
7h；
B, reduction solution temperature, to 15 DEG C, separate out solid, filter, and adding mass fraction in filtrate is the hydrogen citrate of 40%
Two ammonium salt solution 150ml, concentrating under reduced pressure, separate out solid, filter, calcium oxide dehydrant is dehydrated, and sodium bromide solution washs, mass fraction
Be 60% pyridine solution washing, mass fraction be 70% ethyl acetate solution in recrystallization, obtain crystal 2-amino-6-chlorobenzene
Formic acid 18.56g, yield 83%.
Embodiment 3:
The synthetic method of a kind of dicloxacillin pharmaceutical intermediate 2-amino-6-chlorobenzoic acid, follows the steps below:
A, in the reaction vessel being provided with agitator, thermometer, reflux condenser, Dropping funnel, add cerium chloride
0.16mol, mass fraction is the 4-hydroxy 3-methoxybenzene ethanol solution 0.19mol of 18%, and mass fraction is 23% potassium chloride
Solution 450ml, controls mixing speed and to 63 DEG C, is slowly added to 2-chloro-6-nitrobenzoic acid molten at 180rpm, rising solution temperature
Liquid 0.13mol, mass fraction is the bisulfite potassium solution 200ml of 35%, raises mixing speed to 280rpm, back flow reaction
6h；
B, reduction solution temperature, to 17 DEG C, separate out solid, filter, and adding mass fraction in filtrate is the hydrogen citrate of 45%
Two ammonium salt solution 170ml, concentrating under reduced pressure, separate out solid, filter, potassium hydroxide dehydration agent is dehydrated, and magnesium chloride solution washs, and quality is divided
Number is 67% pyridine solution washing, and mass fraction is recrystallization in 75% ethyl acetate solution, obtains crystal 2-amino-6-chlorobenzene first
Acid 19.01g, yield 85%.
From embodiment 1-3, the synthetic method of the 2-amino-6-chlorobenzoic acid that the present invention provides, in preferred scope
In, the response time can control within 10 hours, and reaction yield is more than 80%.
Below embodiment 4-9 is contrasted with embodiment 1, the percent mass comparison yield of each solution in research reaction
Impact.
Embodiment 4:
The mass fraction of the 4-hydroxy 3-methoxybenzene ethanol solution in embodiment 1 is adjusted, remaining preparation condition
Same as in Example 1 with proportioning raw materials, obtain reaction yield as follows:
The impact on reaction yield of the mass fraction of table one: 4-hydroxy 3-methoxybenzene ethanol solution
| 4-hydroxy 3-methoxybenzene ethanol solution mass fraction % | 7 | 10 | 12 | 15 | 19 | 23 | 25 | 30 | 34 |
| Reaction yield % | 70 | 74 | 78 | 87 | 89 | 88 | 79 | 76 | 74 |
From embodiment 4, the mass fraction of 4-hydroxy 3-methoxybenzene ethanol solution is too high or too low all can be affected instead
Answering yield, it becomes normal distribution (Fig. 1) with reaction yield, and it is 15-23% that peak value occurs in mass fraction.
Embodiment 5:
The mass fraction of the Klorvess Liquid in embodiment 1 is adjusted, remaining preparation condition and proportioning raw materials and reality
Execute example 1 identical, obtain reaction yield as follows:
Table two: the mass fraction of the Klorvess Liquid impact on reaction yield
| Klorvess Liquid mass fraction % | 10 | 15 | 18 | 20 | 24 | 28 | 31 | 36 | 40 |
| Reaction yield % | 67 | 70 | 79 | 88 | 89 | 87 | 78 | 77 | 74 |
From embodiment 5, the mass fraction of Klorvess Liquid is too high or too low all can affect reaction yield, itself and reaction
Yield becomes normal distribution (Fig. 2), and it is 20-28% that peak value occurs in mass fraction.
Embodiment 6:
The mass fraction of the bisulfite potassium solution in embodiment 1 is adjusted, remaining preparation condition and proportioning raw materials
Same as in Example 1, obtain reaction yield as follows:
Table three: the mass fraction of the bisulfite potassium solution impact on reaction yield
| Potassium acid sulfite liquid quality fraction % | 20 | 23 | 28 | 30 | 36 | 41 | 48 | 50 | 53 |
| Reaction yield % | 87 | 87 | 88 | 88 | 89 | 89 | 89 | 90 | 90 |
| Reflux time h | 5.5 | 6 | 7.5 | 8 | 8 | 8 | 8 | 8 | 8 |
From embodiment 6, the too high or too low impact on reaction yield of mass fraction of bisulfite potassium solution is the least,
But it is relatively big on reflux time impact, for reducing cost, the mass fraction of the bisulfite potassium solution of selection is 30-
41%.
Embodiment 7:
Being adjusted by the mass fraction of the diammonium hydrogen citrate solution in embodiment 1, remaining preparation condition is joined with raw material
Ratio is same as in Example 1, obtains reaction yield as follows:
Table four: the mass fraction of the diammonium hydrogen citrate solution impact on reaction yield
| Diammonium hydrogen citrate liquid quality fraction % | 34 | 35 | 37 | 40 | 45 | 49 | 54 | 60 | 62 |
| Reaction yield % | 71 | 75 | 79 | 86 | 89 | 85 | 77 | 73 | 70 |
From embodiment 7, the mass fraction of diammonium hydrogen citrate solution is too high or too low all can affect reaction yield, its
Become normal distribution (Fig. 3) with reaction yield, it is 40-49% that peak value occurs in mass fraction.
Embodiment 8:
The mass fraction of the pyridine solution in embodiment 1 is adjusted, remaining preparation condition and proportioning raw materials and enforcement
Example 8 is identical, obtains reaction yield as follows:
Table five: the mass fraction of the pyridine solution impact on reaction yield
| Pyridine solution mass fraction % | 50 | 55 | 58 | 60 | 67 | 72 | 75 | 77 | 80 |
| Reaction yield % | 74 | 75 | 78 | 86 | 89 | 87 | 79 | 75 | 73 |
From embodiment 8, the mass fraction of pyridine solution is too high or too low all can affect reaction yield, and it is received with reaction
Rate becomes normal distribution (Fig. 4), and it is 60-72% that peak value occurs in mass fraction.
Embodiment 9:
The mass fraction of the ethyl acetate solution in embodiment 1 is adjusted, remaining preparation condition and proportioning raw materials with
Embodiment 1 is identical, obtains reaction yield as follows:
Table six: the mass fraction of the ethyl acetate solution impact on reaction yield
| Ethyl acetate solution mass fraction % | 60 | 63 | 68 | 70 | 74 | 78 | 82 | 85 | 89 |
| Reaction yield % | 82 | 83 | 83 | 85 | 89 | 87 | 87 | 85 | 85 |
| Recrystallization time h | 2.0 | 1.5 | 1.2 | 0.8 | 0.7 | 0.8 | 1.0 | 1.2 | 1.5 |
From embodiment 9, the mass fraction of ethyl acetate solution is little on the impact of reaction yield, but it is to recrystallization
Time effects relatively big, it is 70-78% that the minima of recrystallization time occurs in the mass fraction of ethyl acetate solution.
Described in above example, the only present invention preferably detailed description of the invention, but protection scope of the present invention not office
Being limited to this, any those familiar with the art is in the technical scope that the invention discloses, according to the technology of the present invention
Scheme and inventive concept equivalent or change in addition thereof, all should contain within protection scope of the present invention.
Claims (9)
1. the synthetic method of a dicloxacillin pharmaceutical intermediate 2-amino-6-chlorobenzoic acid, it is characterised in that according to following step
Suddenly carry out:
A, in the reaction vessel being provided with agitator, thermometer, reflux condenser, Dropping funnel, add cerium chloride
0.16mol, 4-hydroxy 3-methoxybenzene ethanol solution 0.19mol, Klorvess Liquid 400-500ml, control mixing speed and exist
160-190rpm, rising solution temperature, to 60-65 DEG C, is slowly added to 2-chloro-6-nitrobenzoyl acid solution 0.13mol, sulfurous acid
Hydrogen potassium solution 200ml, raises mixing speed to 260-310rpm, back flow reaction 5-7h；
B, reduction solution temperature, to 15-19 DEG C, separate out solid, filter, and add diammonium hydrogen citrate solution 150-in filtrate
180ml, concentrating under reduced pressure, separate out solid, filter, dehydrant is dehydrated, brine, and pyridine solution washs, ethyl acetate solution
Middle recrystallization, obtains crystal 2-amino-6-chlorobenzoic acid.
2. the synthetic method of dicloxacillin pharmaceutical intermediate 2-amino-6-chlorobenzoic acid as claimed in claim 1, its feature exists
In, described 4-hydroxy 3-methoxybenzene ethanol solution mass fraction is 15-23%.
3. the synthetic method of dicloxacillin pharmaceutical intermediate 2-amino-6-chlorobenzoic acid as claimed in claim 1, its feature exists
In, described Klorvess Liquid mass fraction is 20-28%.
4. the synthetic method of dicloxacillin pharmaceutical intermediate 2-amino-6-chlorobenzoic acid as claimed in claim 1, its feature exists
In, described Potassium acid sulfite liquid quality fraction is 30-41%.
5. the synthetic method of dicloxacillin pharmaceutical intermediate 2-amino-6-chlorobenzoic acid as claimed in claim 1, its feature exists
In, described diammonium hydrogen citrate liquid quality fraction is 40-49%.
6. the synthetic method of dicloxacillin pharmaceutical intermediate 2-amino-6-chlorobenzoic acid as claimed in claim 1, its feature exists
In, described dehydrant is any one in calcium oxide, potassium hydroxide.
7. the synthetic method of dicloxacillin pharmaceutical intermediate 2-amino-6-chlorobenzoic acid as claimed in claim 1, its feature exists
In, described saline solution is any one in sodium bromide, magnesium chloride.
8. the synthetic method of dicloxacillin pharmaceutical intermediate 2-amino-6-chlorobenzoic acid as claimed in claim 1, its feature exists
In, described pyridine solution mass fraction is 60-72%.
9. the synthetic method of dicloxacillin pharmaceutical intermediate 2-amino-6-chlorobenzoic acid as claimed in claim 1, its feature exists
In, described ethyl acetate solution mass fraction is 70-78%.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3409244A1 (en) * | 1984-03-14 | 1985-09-19 | Basf Ag, 6700 Ludwigshafen | Process for the preparation of haloanthranilic acids |
| CN102603718A (en) * | 2012-02-08 | 2012-07-25 | 武汉嘉特利佰联创科技有限公司 | Synthesis method of cediranib |
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2016
- 2016-05-05 CN CN201610292940.1A patent/CN105801443A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3409244A1 (en) * | 1984-03-14 | 1985-09-19 | Basf Ag, 6700 Ludwigshafen | Process for the preparation of haloanthranilic acids |
| CN102603718A (en) * | 2012-02-08 | 2012-07-25 | 武汉嘉特利佰联创科技有限公司 | Synthesis method of cediranib |
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Application publication date: 20160727 |