CN108997327A - The preparation method of aztreonam ethyl ester - Google Patents
The preparation method of aztreonam ethyl ester Download PDFInfo
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- CN108997327A CN108997327A CN201810764301.XA CN201810764301A CN108997327A CN 108997327 A CN108997327 A CN 108997327A CN 201810764301 A CN201810764301 A CN 201810764301A CN 108997327 A CN108997327 A CN 108997327A
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- C07—ORGANIC CHEMISTRY
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention belongs to pharmaceutical technology fields, and in particular to a kind of preparation method of aztreonam ethyl ester.Aztreonam triethylamine (TEA) is added to dissolve in ethyl alcohol and clarify, add acylating agent and catalyst and reacting by the preparation method the following steps are included: using aztreonam as raw material；After completion of the reaction, the reactant aqueous solution of glacial acetic acid is added in aztreonam, 0~-5 DEG C of filterings is cooled to after reaction, filtrate is added ethanol solution hydrochloride and obtains aztreonam ethyl ester through crystallization, growing the grain.It is raw material that the preparation method of aztreonam ethyl ester provided by the invention, which has used technical maturity, purity is high, the aztreonam being easy to get, avoid the complicated technology that impurity is synthesized since side chain, the disadvantages of avoiding HPLC preparation the inefficient of chromatography, low yield, aztreonam ethyl ester is prepared using simple process, purity is high, yield are big, at low cost, suitable for mass industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of preparation method of aztreonam ethyl ester.
Background technique
Aztreonam (Aztreonarn) is a kind of novel ss-lactam antibiotics of monoamides ring class.Suitable for urinary tract sense
The abdominal cavity infections such as dye, lower respiratory tract infection, bloodstream infection, skin soft-tissue infection, peritonitis and reproductive tract infection.Aztreonam
Have the characteristics that weak renal toxicity, immunogenicity and penicillins, cephalosporins cross allergy are few, therefore can be used for substituting ammonia
Base glycoside drug treats the aerobic Gram-negative bacteria infections of kidney function damage patient；And it can be used in close observation
To the patient of penicillin, cephalosporin allergy.In the synthesis process of aztreonam, some by-products can be generated, wherein aztreonam
Ethyl ester is exactly one such.In order to preferably control the quality of product, guarantee the drug safety of aztreonam, needs to ammonia song
The impurity in south does method validation, therefore, it is necessary to do in-depth study to the synthesis technology of aztreonam impurity.
The preparation for the aztreonam ethyl ester mentioned in document at present is to be concentrated from aztreonam mother liquor, then purified by HPLC
It arrives, the method is time-consuming and laborious, and yield is lower；There are also use tert-butyl acetoacetate, 2- isobutyl ethyl bromide, thiocarbamide and two thio
Benzothiazole etc. is starting material, preferential to synthesize ethyl ester side chain, then is condensed to yield aztreonam ethyl ester with main ring.Specific synthesis road
Line sees below reaction equation:
The synthesis technology is complicated, needs six-step process that aztreonam ethyl ester could be made, and intermediate reaction controlling factor is more,
Influence the yield and purity of aztreonam ethyl ester.
Therefore a kind of method for developing simple process and big, the at low cost preparation aztreonam ethyl ester of purity is high, yield.
Summary of the invention
In view of this, the purpose of the present invention is to provide a kind of preparation method of aztreonam ethyl ester, preparation side of the invention
It is raw material that method, which has used technical maturity, purity is high, the aztreonam being easy to get, and preparation process is simple, at low cost.
To achieve the above object, the technical solution of the present invention is as follows:
The preparation method of aztreonam ethyl ester, comprising the following steps:
1) using aztreonam as raw material, aztreonam triethylamine (TEA) is added to dissolve in ethyl alcohol and is clarified, acylating agent is added
It is reacting with catalyst；
2) aztreonam after completion of the reaction, is added the reactant aqueous solution of glacial acetic acid, 0~-5 DEG C is cooled to after reaction in step 1)
Filtering, filtrate are added ethanol solution hydrochloride and obtain aztreonam ethyl ester through crystallization, growing the grain.
Further, the acylating agent be include dicyclohexylcarbodiimide (DCC), N, N- diisopropylcarbodiimide
(DIC), one kind of acetic anhydride, chloroacetic chloride.
As a preference, the acylating agent is N, N- diisopropylcarbodiimide.
DIC is liquid, is easy to use, the N of generation, N'- diisopropyl urea dissolves in most of organic solvents, it is easy to logical
Solvent extraction removing is crossed, therefore DIC is also commonly used in solid-state synthesis.
As a preference, the acylating agent is dicyclohexylcarbodiimide.
DCC is bi-functional cross-linking agent, chemical formula C13H22N2, it is a kind of reactions such as esterification, amidation commonly dehydrating agent,
It can also be used for the synthesis of acid anhydrides, aldehyde, ketone, isocyanates.
Further, the catalyst be include 4-dimethylaminopyridine (DMAP), it is 4- pyrollidinopyridine (4-PPY), right
One kind of toluenesulfonic acid.
As a preference, the catalyst is 4-dimethylaminopyridine.DMAP is a kind of acylation of superpower nucleophilic
Catalyst.DMAP is to be widely used in chemically synthesized efficient catalyst in recent years, the dimethylamino of supplied for electronic in structure
With the resonance of female ring (pyridine ring), can the nitrogen-atoms on strong activation ring carry out nucleophilic displacement of fluorine, be catalyzed high steric-hindrance amino significantly, it is low anti-
The acylation (phosphorylated, sulfonylation, phosphinylidyne) of the alkohol and amine of answering property is reacted, and activity is about the 10 of pyridine4~106Times.Use 4-
Dimethylamino naphthyridine not only has the advantages that reaction condition is mild, dosage is few, moreover it is possible to improve high steric-hindrance amino, low work as catalyst
The speed and yield of the alcohol of property, phenol acylation reaction.
As a preference, the catalyst is 4- pyrollidinopyridine.When bad with DMAP catalytic effect, it can be used
4-PPY, catalytic capability ratio DMAP high.
As a preference, acylating agent is N in the present invention, N- diisopropylcarbodiimide, catalyst is 4- pyrrolidinyl
Pyridine.
As a preference, acylating agent is dicyclohexylcarbodiimide in the present invention, catalyst is 4-dimethylaminopyridine.
The following are reaction routes:
It is acylating agent that dicyclohexylcarbodiimide is selected in the present invention, and 4-dimethylaminopyridine is catalyst, dicyclohexyl
Carbodiimide with activated carboxyl and can play dehydration, 4-dimethylaminopyridine, can the nitrogen-atoms on strong activation ring carry out
Nucleophilic displacement of fluorine is catalyzed high steric-hindrance amino, the acylation reaction of the alkohol and amine of hypoergia significantly；During the preparation process, the two is combined energy
Reaction rate is improved, and high income, reaction condition are mild, it is easily controllable.
Further, aztreonam and the molar ratio of triethylamine are 1~1.5:1~2.5 in step 1)；The matter of aztreonam and ethyl alcohol
Amount is than being 1:1.5~2.5.
As a preference, aztreonam and the molar ratio of triethylamine are 1~1.5:1~2 in step 1)；Aztreonam and ethyl alcohol
Mass ratio be 1:1.5~2.
The clear temperature of dissolution is 25~35 DEG C in step 1)；It is preferred that dissolving clear temperature is 25~32 DEG C.
Further, in step 1) acylating agent, catalyst and aztreonam molar ratio be 1~2:0.025~0.035:1~
1.5。
As a preference, the molar ratio of acylating agent, catalyst and aztreonam is 1.5:0.03~0.035:1 in step 1)
~1.5.
As a preference, the time reacted in step 1) is 38~50h.It is preferred that the time reacted is 48h.
Further, the mass percent of glacial acetic acid is 12%~17% in the aqueous solution of glacial acetic acid in step 2)；Step 2)
The molar ratio of aztreonam is 0.3~0.5:1~1.5 in middle glacial acetic acid and step 1).
As a preference, the mass percent of glacial acetic acid is 15%~17% in the aqueous solution of glacial acetic acid in step 2)；
The molar ratio of glacial acetic acid and aztreonam in step 1) is 0.3~0.5:1~1.15 in step 2).
Further, ethanol solution hydrochloride and the mass ratio of aztreonam in step 1) are 2:4~6 in step 2).
As a preference, ethanol solution hydrochloride and the mass ratio of aztreonam in step 1) are 2:5 in step 2).
As a preference, the reaction time in step 2) is 2~3h.
Further, rear adjusting filtrate pH2.5~3.0 after ethanol solution hydrochloride is added in step 2), keep the temperature 0~-10 DEG C and support
Brilliant 48h or more obtains aztreonam ethyl ester in 40~50 DEG C of dry 15h after filtering.
Further, detecting step 1) in aztreonam end of reaction method are as follows: detected with TLC method, mobile phase is second
The volume ratio of the mixed solvent of alcohol and methylene chloride, ethyl alcohol and methylene chloride is 1:5.
TLC method monitoring aztreonam of the invention whether fully reacting, testing result is accurate, sensitive, this is for realizing ammonia
Quality control, the yield guarantee of bent south ethyl ester are extremely important.
Further, the preparation method further includes step 3): aztreonam ethyl ester obtained is added at room temperature
DMSO is dissolved to clarification, adds ethyl alcohol, is cooled to 0~-10 DEG C of growing the grain 48h or more, and the solid was filtered, obtains aztreonam after dry
Ethyl ester product.
The beneficial effects of the present invention are: the preparation method of aztreonam ethyl ester provided by the invention used technical maturity,
Purity is high, the aztreonam being easy to get are raw material, avoid the complicated technology for synthesizing impurity since side chain, avoid HPLC system
Aztreonam ethyl ester is prepared using simple process in the disadvantages of standby the inefficient of chromatography, low yield, and purity is high, yield is big, cost
It is low, it is suitable for mass industrialized production.
Specific embodiment
It detailed description of a preferred embodiment of the present invention will be given below.The reality of actual conditions is not specified in preferred embodiment
Proved recipe method, usually according to normal condition, illustrated embodiment are but not to be to preferably be illustrated to the contents of the present invention
The contents of the present invention are only limitted to illustrated embodiment.So those skilled in the art are according to foregoing invention content to embodiment party
Case carries out nonessential modifications and adaptations, still falls within protection scope of the present invention.
Embodiment 1
500g (1.15mol) aztreonam, 156g (1.54mol) TEA are added in 1000g ethyl alcohol, in temperature 25~32
Clarification is dissolved under the conditions of DEG C.It is cooled to 0~5 DEG C after dissolved clarification, DCC310g (1.5mol), DMAP 4g (0.0327mol) is added, delays
Slowly it is warming up to room temperature reaction 48h, TLC contact plate (mobile phase ethyl alcohol: methylene chloride=1:5) judges aztreonam end of reaction, is added
Glacial acetic acid 27.5g (0.458mol), water 150g react 2.5h, are cooled to 0~-5 DEG C, are filtered to remove by-product, filtrate temperature control 0
~-5 DEG C, ethanol solution hydrochloride 200g is added, adjusts filtrate pH2.5~3.0, keeps the temperature 0~-10 DEG C of growing the grain 48h or more, filters
Aztreonam ethyl ester is obtained in 40~50 DEG C of dry 15h to aztreonam ethyl ester wet-milling.Obtained aztreonam ethyl ester is thick
750g DMSO is added at room temperature and is dissolved to clarification, 5000g ethyl alcohol is added, is cooled to 0~-10 DEG C of growing the grain 48h or more, mistake for product
Solid is filtered to obtain, in 40~50 DEG C of dry 15h, obtains 354g aztreonam ethyl ester, yield 70.8%, purity 99.5%.
Embodiment 2
500g (1.15mol) aztreonam, 156g (1.54mol) TEA are added in 1000g ethyl alcohol, in temperature 25~32
Clarification is dissolved under the conditions of DEG C.It is cooled to 0~5 DEG C after dissolved clarification, DIC189.3g (1.5mol), DMAP 4g (0.0327mol) is added,
It is to slowly warm up to room temperature reaction 48h, TLC contact plate (mobile phase ethyl alcohol: methylene chloride=1:5) judges aztreonam end of reaction, adds
Enter glacial acetic acid 27.5g (0.458mol), water 150g, reacts 2.5h, be cooled to 0~-5 DEG C, be filtered to remove by-product, filtrate temperature control
0~-5 DEG C, ethanol solution hydrochloride 200g is added, adjusts filtrate pH2.5~3.0, keeps the temperature 0~-10 DEG C of growing the grain 48h or more, filtering
Aztreonam ethyl ester wet-milling is obtained, in 40~50 DEG C of dry 15h, obtains aztreonam ethyl ester.The aztreonam ethyl ester that will be obtained
750g DMSO is added at room temperature and is dissolved to clarification, 5000g ethyl alcohol is added, is cooled to 0~-10 DEG C of growing the grain 48h or more for crude product,
The solid was filtered, in 40~50 DEG C of dry 15h, obtains 342g aztreonam ethyl ester, yield 68.4%, purity 99.4%.
Embodiment 3
500g (1.15mol) aztreonam, 156g (1.54mol) TEA are added in 1000g ethyl alcohol, in temperature 25~32
Clarification is dissolved under the conditions of DEG C.It is cooled to 0~5 DEG C after dissolved clarification, DIC189.3g (1.5mol), 4-PPY 4.45g is added
(0.03mol), is to slowly warm up to room temperature reaction 48h, and TLC contact plate (mobile phase ethyl alcohol: methylene chloride=1:5) judges that aztreonam is anti-
It should finish, glacial acetic acid 27.5g (0.458mol), water 150g is added, react 2.5h, be cooled to 0~-5 DEG C, be filtered to remove by-product
Object 0~-5 DEG C of filtrate temperature control, is added ethanol solution hydrochloride 200g, adjusts filtrate pH2.5~3.0, keeps the temperature 0~-10 DEG C of growing the grains
Aztreonam ethyl ester wet-milling is obtained by filtration in 48h or more, in 40~50 DEG C of dry 15h, obtains aztreonam ethyl ester.It will obtain
Aztreonam ethyl ester, 750g DMSO is added at room temperature and is dissolved to clarification, addition 5000g ethyl alcohol is cooled to 0~-10 DEG C
Growing the grain 48h or more, the solid was filtered, in 40~50 DEG C of dry 15h, obtains 358g aztreonam ethyl ester, yield 71.6%, purity
99.4%.
Embodiment 4
500g (1.15mol) aztreonam, 156g (1.54mol) TEA are added in 1000g ethyl alcohol, in temperature 25~32
Clarification is dissolved under the conditions of DEG C.It is cooled to 0~5 DEG C after dissolved clarification, DCC206.2g (1mol), DMAP 4g (0.0327mol) is added, delays
Slowly it is warming up to room temperature reaction 48h, TLC contact plate (mobile phase ethyl alcohol: methylene chloride=1:5) judges aztreonam end of reaction, is added
Glacial acetic acid 27.5g (0.458mol), water 150g react 2.5h, are cooled to 0~-5 DEG C, are filtered to remove by-product, filtrate temperature control 0
~-5 DEG C, ethanol solution hydrochloride 200g is added, adjusts filtrate pH2.5~3.0, keeps the temperature 0~-10 DEG C of growing the grain 48h or more, filters
Aztreonam ethyl ester is obtained in 40~50 DEG C of dry 15h to aztreonam ethyl ester wet-milling.Obtained aztreonam ethyl ester is thick
750g DMSO is added at room temperature and is dissolved to clarification, 5000g ethyl alcohol is added, is cooled to 0~-10 DEG C of growing the grain 48h or more, mistake for product
Solid is filtered to obtain, in 40~50 DEG C of dry 15h, obtains 306g aztreonam ethyl ester, yield 61.2%, purity 97.6%.
Embodiment 5
500g (1.15mol) aztreonam, 156g (1.54mol) TEA are added in 1000g ethyl alcohol, in temperature 25~32
Clarification is dissolved under the conditions of DEG C.It is cooled to 0~5 DEG C after dissolved clarification, DCC310g (1.5mol), DMAP 2.4g (0.02mol) is added, delays
Slowly it is warming up to room temperature reaction 48h, TLC contact plate (mobile phase ethyl alcohol: methylene chloride=1:5) judges aztreonam end of reaction, is added
Glacial acetic acid 27.5g (0.458mol), water 150g react 2.5h, are cooled to 0~-5 DEG C, are filtered to remove by-product, filtrate temperature control 0
~-5 DEG C, ethanol solution hydrochloride 200g is added, adjusts filtrate pH2.5~3.0, keeps the temperature 0~-10 DEG C of growing the grain 48h or more, filters
Aztreonam ethyl ester is obtained in 40~50 DEG C of dry 15h to aztreonam ethyl ester wet-milling.Obtained aztreonam ethyl ester is thick
750g DMSO is added at room temperature and is dissolved to clarification, 5000g ethyl alcohol is added, is cooled to 0~-10 DEG C of growing the grain 48h or more, mistake for product
Solid is filtered to obtain, in 40~50 DEG C of dry 15h, obtains 298g aztreonam ethyl ester, yield 59.4%, purity 97.2%.
Finally, it is stated that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to compared with
Good embodiment describes the invention in detail, those skilled in the art should understand that, it can be to skill of the invention
Art scheme is modified or replaced equivalently, and without departing from the objective and range of technical solution of the present invention, should all be covered at this
In the scope of the claims of invention.
Claims (10)
1. the preparation method of aztreonam ethyl ester, which comprises the following steps:
1) using aztreonam as raw material, aztreonam triethylamine (TEA) is added to dissolve in ethyl alcohol and is clarified, acylating agent is added and urges
Agent is reacting；
2) after completion of the reaction, the reactant aqueous solution of glacial acetic acid is added in aztreonam in step 1), and 0~-5 DEG C of mistakes are cooled to after reaction
Filter, filtrate are added ethanol solution hydrochloride and obtain aztreonam ethyl ester through crystallization, growing the grain.
2. preparation method according to claim 1, which is characterized in that the acylating agent be include dicyclohexylcarbodiimide
(DCC), N, N- diisopropylcarbodiimide (DIC), one kind of acetic anhydride, chloroacetic chloride.
3. preparation method according to claim 1, which is characterized in that the catalyst be include 4-dimethylaminopyridine
(DMAP), one kind of 4- pyrollidinopyridine, p-methyl benzenesulfonic acid.
4. preparation method according to claim 1, which is characterized in that in step 1) aztreonam and triethylamine and molar ratio
For 1~1.5:1~2.5；The mass ratio of aztreonam and ethyl alcohol is 1:1.5~2.5.
5. preparation method according to claim 1, which is characterized in that acylating agent in step 1), catalyst and aztreonam
Molar ratio is 1~2:0.025~0.035:1~1.5.
6. preparation method according to claim 1, which is characterized in that glacial acetic acid in the aqueous solution of glacial acetic acid in step 2)
Mass percent is 12%~17%；In step 2) in glacial acetic acid and step 1) molar ratio of aztreonam be 0.3~0.5:1~
1.5。
7. preparation method according to claim 1, which is characterized in that ethanol solution hydrochloride and ammonia in step 1) in step 2)
The mass ratio of Qu Nan is 2:4~6.
8. preparation method according to claim 1, which is characterized in that adjusted after ethanol solution hydrochloride is added after in step 2)
Filtrate pH2.5~3.0 keep the temperature 0~-10 DEG C of growing the grain 48h or more in 40~50 DEG C of dry 15h after filtering and it is thick to obtain aztreonam ethyl ester
Product.
9. preparation method according to claim 1, which is characterized in that detecting step 1) in aztreonam end of reaction method
Are as follows: it is detected with TLC method, mobile phase is the mixed solvent of ethyl alcohol and methylene chloride, and the volume ratio of ethyl alcohol and methylene chloride is
1:5。
10. preparation method according to claim 1, which is characterized in that the preparation method further includes step 3): will be made
Aztreonam ethyl ester DMSO be added at room temperature be dissolved to clarification, add ethyl alcohol, be cooled to 0~-10 DEG C of growing the grain 48h with
On, the solid was filtered, obtains aztreonam ethyl ester product after dry.
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| CN102086196A (en) * | 2011-01-28 | 2011-06-08 | 海南灵康制药有限公司 | Novel method for refining aztreonam |
| CN102584811A (en) * | 2011-12-29 | 2012-07-18 | 蚌埠丰原涂山制药有限公司 | Method for preparing aztreonam |
| CN103570707A (en) * | 2012-07-21 | 2014-02-12 | 重庆圣华曦药业股份有限公司 | Improved synthetic method of aztreonam |
| CN103910721A (en) * | 2013-01-06 | 2014-07-09 | 重庆福安药业(集团)股份有限公司 | Aztreonam preparation method |
-
2018
- 2018-07-12 CN CN201810764301.XA patent/CN108997327A/en active Pending
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| CN102086196A (en) * | 2011-01-28 | 2011-06-08 | 海南灵康制药有限公司 | Novel method for refining aztreonam |
| CN102584811A (en) * | 2011-12-29 | 2012-07-18 | 蚌埠丰原涂山制药有限公司 | Method for preparing aztreonam |
| CN103570707A (en) * | 2012-07-21 | 2014-02-12 | 重庆圣华曦药业股份有限公司 | Improved synthetic method of aztreonam |
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