CN105753885B - A kind of technique synthesizing aspoxicillin - Google Patents
A kind of technique synthesizing aspoxicillin Download PDFInfo
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- CN105753885B CN105753885B CN201610164838.3A CN201610164838A CN105753885B CN 105753885 B CN105753885 B CN 105753885B CN 201610164838 A CN201610164838 A CN 201610164838A CN 105753885 B CN105753885 B CN 105753885B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
- C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/18—Separation; Purification
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Abstract
The invention discloses a kind of techniques for synthesizing aspoxicillin, it include: that dane potassium salts (II) react to obtain compound (IV) with chloride compounds (III), compound (IV) is reacted with Amoxicillin (V) again, reaction terminates that acid is added, obtain aspoxicillin at salt product, aspoxicillin product is obtained after purification；The acid is selected from one of p-methyl benzenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid, trifluoracetic acid, oxalic acid, benzoic acid or a variety of.Method of the invention has originality, in entire reaction process, do not need to post-process, and there is easy to operate, convenient post-treatment, reaction time to shorten, the features such as intermediate increases addition salts, washes and starches removal of impurities measure, and impurity is few, high income, is suitable for industrial mass production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, are specifically related to a kind of new process for synthesizing aspoxicillin.
Background technique
Aspoxicillin, chemical name: (2S, 5R, 6R) -6- [(2R) -2- [(2R) -2- amino -3- (N- methylamino formyl) third
Amide groups] -2- (p- hydroxyphenyl) acetylamino] -3,3- dimethyl -7- oxo -4- thia -1- azabicyclo [3,2,0]-heptan
Alkane -2- carboxylic acid trihydrate, English name: Aspoxicillin foreign countries trade name: Doyle Chinese phonetic alphabet name: APu Xi Lin,
Structure is as follows:
Aspoxicillin is day first semi-synthetic mould of injection amino acid pattern in the world of Honda side drugmaker exploitation
Plain drug, 1987 in Japanese Initial Public Offering.Can be clinically used for treatment septicemia, infectious endocarditis, wound, scald,
The secondary infection of surgical wound etc., sphagitis, tonsillitis, acute bronchitis, pneumonia, pulmonary abscess, chronic respiratory system disease
The secondary infection of disease, peritonitis, cholecystitis, cholangitis, tympanitis, paranasal sinusitis, lower ganathitis.The medicine is at present in China
The new drug development stage, with good development and application prospects.
Currently, the synthesis technology of aspoxicillin is broadly divided into three kinds by raw material difference:
(1) D-Asp-β-formamide and amido protecting agent 2- nitrobenzene sulphur chlorine (abbreviation NPS-Cl) reaction, then
Under the action of DCC, by activated carboxylic, using condensation, deprotection, six-step process, finally passes through pillar layer separation method altogether,
Obtain target compound (The Journal of antibiotics 1983,36 (2), 147-154.).2- nitro in this route
Benzene sulphur chlorine toxicity is very big, there is dense stink, big to human injury.
(2) acyl chlorides synthetic method (US4053609) reacts to obtain 2- aminomethylamine carbon propionic using thionyl chloride,
Aspoxicillin is obtained using acylation, condensation plus hydrogen Deprotection.This route makes to pacify due to thionyl chloride and the use for adding hydrogen
Full property reduces.
(3) activity anhydride method (Tang Guangan, perhaps inspired, the synthesis of Zou Qiao root semi-synthetic penicillins antibiotic aspoxicillin
Improve, Chinese Journal of New Drugs, 2009, volume 18, the 10th phase), it is original with D-ASP and Utimox
Material, using 2- nitrobenzene sulphur chlorine as amino protecting group, is prepared into acid anhydrides with pivaloyl chloride, using condensation, deprotection preparation Ah flutterring
XiLin.This route, which still needs, uses 2- nitrobenzene sulphur chlorine, this reagent needs are prepared separately, and which increase the periods of preparation, and
And toxicity is very big, last deprotection is also inconvenient, and yield is not high.
Summary of the invention
The present invention is unstable for the synthesis technology of existing aspoxicillin, and poor repeatability is not suitable for industrial ask
Topic, it is simple to provide a kind of technological operation, is easy to pure without the use of toxic agents, high income, intermediates such as 2- nitrobenzene sulphur chlorine
Change operation, product purity is high, and impurity is few, is suitble to industrial aspoxicillin new synthetic method.
The purpose of the present invention is achieved through the following technical solution:
A kind of technique synthesizing aspoxicillin, comprising: dane potassium salts (II) react to obtain compound with chloride compounds (III)
(IV), compound (IV) is reacted with Amoxicillin (V) again, and reaction terminates that acid is added, obtain aspoxicillin at salt product, purification
After obtain aspoxicillin product；
The acid is selected from p-methyl benzenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid, trifluoro
One of acetic acid, oxalic acid, benzoic acid are a variety of；
Above-mentioned reaction process is as follows:
R is selected from alkyl, alkoxy；The further preferably alkoxy of the alkyl of C1-C5, C1-C5；As further excellent
Choosing, R are ethyoxyl, tertiary butyl.
Preferably, specific steps include:
(1) it configures solution A: Amoxicillin or Utimox (compound shown in Formula V) and triethylamine is dissolved
In organic solvent I, 5 DEG C of heat preservation a period of times stirred below obtain solution A, 5 DEG C or less preservations；
(2) solution B is configured: in organic solvent II, dane potassium salts (compound shown in Formula II) and chloride compounds (formula III
Shown compound), N-methylmorpholine obtains solution B in -10 DEG C or less low-temp reactions (containing formula IV compound represented)；
(3) at -10 DEG C hereinafter, solution B is added dropwise in solution A, reaction terminates, and solvent is evaporated off, and it is molten that acetonitrile stirring is added
Acid is added at salting out to obtain the crude product of aspoxicillin one time in solution；
(4) by the crude product refining of aspoxicillin one time, desalination obtains aspoxicillin final products.
The organic solvent I, organic solvent II can individually select methylene chloride, chloroform etc., preferably, organic solvent
I and organic solvent II select methylene chloride.
In step (1), preferably, the molar ratio of the triethylamine and Amoxicillin or Utimox is
(2-5): 1, further preferably (2.25-2.5): 1.
Step (1) and step (2) can carry out simultaneously or other any sequences carry out, it is therefore an objective to obtain solution A and solution
B。
In step (2), the chloride compounds are alkyl acyl chloride compound or alcoxyl chloride compounds；Further preferably
The alcoxyl chloride compounds of the alkyl acyl chloride compound of C1-C5, C1-C5；As still more preferably, the chloride compounds are
Chloro-formate or pivaloyl chloride.
In step (2), the dane potassium salts are (1-5) with the molar ratio of Amoxicillin or Utimox: 1；Into
One step is preferably (1.5-2.5): 1；It is still more preferably 1.5:1.The chloride compounds and Amoxicillin or Amoxicillin
The molar ratio of trihydrate is (1-2.5): 1；Further preferably (1.5-2.5): 1.The N-methylmorpholine and Amoxicillin
Or the molar ratio of Utimox is (0.05-1): 1, further preferably (0.05-0.08): 1.
In step (2), the chloro-formate is added by the way of being added dropwise, and dropping temperature is -30~-10 DEG C, guarantees drop
During adding, system temperature is lower than -15 DEG C, avoids the generation of side reaction.After being added dropwise, reaction temperature is -25~-10 DEG C.
As further preferred, dropping temperature is -25~-15 DEG C, after being added dropwise, and reaction temperature is -25~-15 DEG C.
In step (3), solution B is added dropwise in solution A, dropping temperature is -30~-15 DEG C.Guarantee during being added dropwise, body
It is temperature lower than -15 DEG C, avoids the generation of side reaction；The time for adding of solution B is 1-3h.After being added dropwise, HPLC can be passed through
Tracking reaction process.The acid is preferably p-methyl benzenesulfonic acid, fumaric acid, salicylic acid, citric acid, trifluoracetic acid, oxalic acid, benzene first
Acid；Further preferably p-methyl benzenesulfonic acid, fumaric acid, salicylic acid, citric acid.It is -20 DEG C to 20 DEG C at salt crystallization temperature, at
The salt time is 1-3h.
In step (4), the crude product refining process of aspoxicillin one time is as follows:
(4-1) washes and starches the crude product of aspoxicillin one time in organic solvent II I, is improved the secondary crude product of content；One
Secondary crude product and secondary crude product are aspoxicillin into salt product；
Under (4-2) alkaline condition, secondary crude product is dissolved into water, is decolourized, pH=3.5~5.5, crystallization are adjusted after decoloration
Obtain final aspoxicillin product.
In above-mentioned steps (4-1), the organic solvent II I be selected from acetonitrile, ethyl alcohol, isopropanol, one of n-butanol or
A variety of, the volume ratio of further preferably isopropanol, the crude product of aspoxicillin one time and organic solvent II I is 1:4~5, washes and starches temperature
Degree is -10 DEG C to 30 DEG C, time 1-3h.In step (4-2), alkaline condition is supplied by following alkali carries, sodium carbonate, sodium hydroxide,
Ammonium hydroxide, sodium bicarbonate, potassium carbonate.Acid used is hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid.Use acid mass percent concentration for
10-30%.PH range is adjusted between 4-6, further preferably 4-5, crystallization temperature is preferably 5~10 DEG C.
This technique is reacted the activity anhydride to be formed with dane potassium salts and chloro-formate with Utimox and is reacted
The crude product of aspoxicillin one time is obtained, then washes and starches raising content with organic solvent and obtains secondary crude product, finally by secondary crude product in alkali
Under the action of solvent, the direct crystallization of acid adding obtains the aspoxicillin of high-purity.
Compared with prior art, the beneficial effects of the present invention are embodied in:
Method of the invention has originality, in entire reaction process, do not need to post-process, can directly by reaction solution A and
Reaction solution B is reacted, and by the way that acid is added, directly purpose product crude product can be precipitated, do not need complicated last handling process, tool
There are easy to operate, convenient post-treatment, reaction time to shorten, intermediate increasing addition salts, wash and starch removal of impurities measure, impurity is few, high income
The features such as, it is suitable for industrial mass production.
Detailed description of the invention
Fig. 1 is the HPLC spectrogram for the product that embodiment 1 is prepared.
Fig. 2 is the nuclear magnetic spectrogram for the product that embodiment 1 is prepared.
Specific embodiment
The present invention is further described by the following examples, but these embodiments are merely illustrative, not to this hair
Bright protection scope constitutes any restrictions, it will be apparent to a skilled person that the replacement that spirit is done according to the present invention,
Modification each falls within protection scope of the present invention.
Embodiment 1:
Utimox 20g's, anhydrous DCM 120g, 2.25eq (being calculated with the amount of Utimox)
TEA, cools to 0 DEG C, and stirring heat preservation 1h obtains solution A.
By the N-methylmorpholine of dane potassium salts (1.5eq of Amoxicillin), methylene chloride and catalytic amount (Amoxicillin
0.05eq), -20 DEG C of stirring cooling, (1.05eq of dane potassium salts, is added dropwise -15 DEG C to -15 DEG C of temperature control or less dropwise addition chloro-formates
Reaction 3 hours, obtains solution B.
- 15 DEG C hereinafter, solution B is added dropwise to solution A, time for adding 1.5h, HPLC tracking reaction, after, revolving
Dichloromethane solvent is removed, 50ml acetonitrile is added, stirring and dissolving is added p-methyl benzenesulfonic acid monohydrate (2.2eq), is precipitated solid
Body filters to obtain the crude product of aspoxicillin one time.At 0 DEG C, by the crude product of above-mentioned aspoxicillin one time and organic solvent isopropanol with 1:5 into
Row washes and starches 2h, filters to obtain secondary crude product.By secondary crude product and water according to 1:5, then be added dropwise 2N sodium hydroxide dissolution after, be added activity
Carbon decoloring is that 20%HCl aqueous solution adjusts aqueous pH values to pH=4.5 with mass percent concentration, 5~10 DEG C of temperature control, crystallization
6h, product yield 89%, product meet JP standard, and purity is greater than 99%, sees Fig. 1；Nuclear magnetic spectrogram is shown in Fig. 2.
Embodiment 2:
P-methyl benzenesulfonic acid monohydrate is changed into citric acid into salt, equivalent is constant, and product yield 85%, purity is greater than
99%.
Embodiment 3:
P-methyl benzenesulfonic acid monohydrate is changed into salicylic acid into salt, equivalent is constant, and product yield 94%, purity is greater than
99%.
Embodiment 4:
P-methyl benzenesulfonic acid monohydrate is changed into HCl/ ethyl acetate into salt, equivalent is constant, product yield 83%, purity
Greater than 99%.
Embodiment 5:
P-methyl benzenesulfonic acid monohydrate is changed into oxalic acid into salt, equivalent is constant, and product yield 87%, purity is greater than
99%.
Claims (7)
1. a kind of technique for synthesizing aspoxicillin characterized by comprising dane potassium salts react to obtain compound with chloride compounds
(IV), compound (IV) is reacted with Amoxicillin again, reaction terminate be added acid, obtain aspoxicillin at salt product, after purification
Obtain aspoxicillin product；
Compound Compound (IV) structure is as follows:
R is selected from alkyl, alkoxy；
Specific steps include:
(1) configure solution A: Amoxicillin or Utimox and triethylamine are dissolved in organic solvent I, 5 DEG C with
Under stir to obtain solution A；
(2) configure solution B: in organic solvent II, dane potassium salts and chloride compounds, N-methylmorpholine is in -10 DEG C or less low temperature
Reaction obtains solution B；
(3) at -10 DEG C hereinafter, solution B is added dropwise in solution A, reaction terminates, and acid is added at salting out to obtain aspoxicillin one
Secondary crude product；
(4) crude product refining of aspoxicillin one time, desalination are obtained into aspoxicillin final products.
In step (4), the crude product refining process of aspoxicillin one time is as follows:
(4-1) washes and starches the crude product of aspoxicillin one time in organic solvent II I, obtains secondary crude product；The organic solvent II I choosing
From acetonitrile, ethyl alcohol, isopropanol, one of n-butanol or a variety of；
Under (4-2) alkaline condition, secondary crude product is dissolved into water, is decolourized, pH=3.5~5.5 are adjusted after decoloration, crystallization obtains
Final aspoxicillin product；
The acid is p-methyl benzenesulfonic acid, fumaric acid, salicylic acid, citric acid, trifluoracetic acid, oxalic acid, benzoic acid, at salt crystallization temperature
Degree is -20 DEG C to 20 DEG C, salt time 1-3h.
2. the technique of synthesis aspoxicillin according to claim 1, which is characterized in that the triethylamine and Amoxicillin or
The molar ratio of Utimox is (2-5): 1.
3. the technique of synthesis aspoxicillin according to claim 1, which is characterized in that the chloride compounds are C1-C5
Alkyl acyl chloride compound, C1-C5 alcoxyl chloride compounds.
4. the technique of synthesis aspoxicillin according to claim 1 or 3, which is characterized in that the dane potassium salts and A Moxi
The molar ratio of woods or Utimox is (1-5): 1；The chloride compounds and three water of Amoxicillin or Amoxicillin
The molar ratio for closing object is (1-2.5): 1；The molar ratio of the N-methylmorpholine and Amoxicillin or Utimox is
(0.05-1):1。
5. the technique of synthesis aspoxicillin according to claim 1, which is characterized in that in step (2), the acyl chlorides chemical combination
Object is added by the way of being added dropwise, and dropping temperature is -30~-10 DEG C, after being added dropwise, and reaction temperature is -25~-10 DEG C.
6. the technique of synthesis aspoxicillin according to claim 1, which is characterized in that in step (3), solution B is added dropwise
Enter in solution A, dropping temperature is -30~-15 DEG C.
7. the technique of synthesis aspoxicillin according to claim 1, which is characterized in that the organic solvent II I is isopropyl
The volume ratio of alcohol, the crude product of aspoxicillin one time and organic solvent II I are 1:4~5.
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| CN102408437A (en) * | 2011-10-21 | 2012-04-11 | 西南交通大学 | Preparation method for Aspoxicillin |
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| CN103467496A (en) * | 2013-09-29 | 2013-12-25 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Preparing method of 7-((thiazolyl hydroxyl imino group) acetamido)-3-methyl cephalosporanic acid and another purpose |
| CN103570747A (en) * | 2013-11-15 | 2014-02-12 | 安徽悦康凯悦制药有限公司 | Preparation technology for cefbuperazone sodium |
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| CN102408437A (en) * | 2011-10-21 | 2012-04-11 | 西南交通大学 | Preparation method for Aspoxicillin |
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| 阿扑西林合成新工艺研究;张峥等;《中国抗生素杂志》;20121031;第37卷(第10期);第770-772页 |
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