CN101311177B - Method for preparing panipenem sodium chloride eutectic - Google Patents
Method for preparing panipenem sodium chloride eutectic Download PDFInfo
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- CN101311177B CN101311177B CN2007100412088A CN200710041208A CN101311177B CN 101311177 B CN101311177 B CN 101311177B CN 2007100412088 A CN2007100412088 A CN 2007100412088A CN 200710041208 A CN200710041208 A CN 200710041208A CN 101311177 B CN101311177 B CN 101311177B
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- sodium chloride
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Abstract
The invention discloses a preparation method for a panipenem sodium chloride eutecticum as shown in the formula II, which includes the following steps: (1) the compound as shown in the formula I reacts with H2 in buffer solution or the mixed liquor of the buffer solution and an organic solvent by taking a compound containing cesium or platinum as a catalyst; (2) sodium chloride and a solvent agent are added for reactive crystallization; wherein, R is phenmethyl or the phenmethyl substituted on a benzene ring; n is 0.5-3. The method of the invention has simple operation and does not need resinpurification or special equipment; after being refined, the obtained products have high purity and good stability.
Description
Technical field
The present invention relates to a kind of crystalline preparation method, be specifically related to method for preparing panipenem sodium chloride eutectic.
Background technology
Panipenem is a kind of carbapenem antibiotic, and its chemical name is: (5R, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-[[(3S)-1-(1-imines ethyl)-3-pyrrolidyl]-sulfo-]-7-oxo-1-azabicyclic [3.2.0]-hept-2-ene"-2-carboxylic acid.Panipenem has the pharmacologically active of general carbapenem antibiotic, has a broad antifungal spectrum, and anti-microbial activity is similar to imipenum.Activity to staphylococcus aureus and streptococcus aureus is better than imipenum, the activity of and negative Bacillus proteus, citrobacter, husky thunder bacterium, genera bacillus positive to intestinal bacteria, streptococcus pneumoniae, hemophilus influenza, enterobacter cloacae, indoles and imipenum is identical or strong slightly.In carbapenem antibiotic research, domestic research to panipenem is also relatively more blank.
At present, the preparation method of panipenem mainly contains two kinds: a kind of is first deprotection base, meets functional group again on pyrrole ring, as document and patent (J.Antibiot, 36,1034-1039,1983, JP5913757, EP0161546) reported method.Another kind is to remove protecting group at last, as the method for patent (JP5913757, EP0161546) disclosure.Two kinds of methods all need be used the resin desalting and purifying, and a large amount of elutriants need concentrate postlyophilization.
Patent (JP60115585) has disclosed the eutectiferous preparation of panipenem, and panipenem that this method is obtained by lyophilize and thiocarbamide or urea element induce eutectic to make the panipenem eutectic.And the solution of carbapenem compound is extremely unstable, easily part degraded in the concentration process, and complex operation, yield are not high.
Summary of the invention
The objective of the invention is in order to solve in the prior art, the eutectiferous preparation method's complex operation of panipenem, the problem that product stability is bad, and provide with a kind of simple, and the purity of product and stability are all higher, are more conducive to the method for preparing panipenem sodium chloride eutectic of fairly large application.
Preparation method of the present invention comprises the steps:
(1) in the mixed solution of damping fluid or damping fluid and organic solvent, be catalyzer to contain palladium or platiniferous compound, with compound shown by formula I and H
2Reaction removes protecting group;
(2) add sodium-chlor and solvent reagent,, collect product and get final product through reactive crystallization;
Wherein, R is the benzyl that replacement is arranged on benzyl or the phenyl ring; N is 0.5～3.
Wherein, the benzyl of replacement being arranged on the described phenyl ring is the preferable PhCH that is
2, 4-O
2NPhCH
2, 3-O
2NPhCH
2, CH
3OPhCH
2Or 2,4-(CH
3O)
2PhCH
2Among the present invention, Ph is a phenyl, and Me is a methyl.
In the step (1), what the pH value of described damping fluid was preferable is 5～9; That volumetric molar concentration is preferable is 0.2～3mol/L; Preferably zinc acetate damping fluid, magnesium chloride damping fluid, magnesium acetate damping fluid, ammonium acetate buffer, Potassium ethanoate damping fluid, sodium-acetate buffer, ammonium chloride buffer or N-methylmorpholine-acetate buffer.
In the step (1), described palladium or the platiniferous compound of containing can be palladium or platiniferous organism or the inorganics of containing commonly used in the hydrogenation, preferable palladium carbon, platinum, platinum dioxide or the palladium hydroxide of being selected from; The described consumption that contains palladium or platiniferous compound is preferable is 5～50% of the weight of compound shown by formula I.
In the step (1), described organic solvent is preferable is selected from ethyl acetate, acetone, tetrahydrofuran (THF), 1, one or more in 4-dioxane, ethanol, methyl alcohol, the trimethyl carbinol, isopropylcarbinol and the Virahol.
In the step (1), that the pressure of described reaction is preferable is 1～10Kg/m
2What the time of reaction was preferable is 0.5～5 hour; What the temperature of reaction was preferable is 0 ℃～40 ℃;
In the step (2), described amount of sodium chloride is preferable be compound shown by formula I weight 5～30%; What described solvent reagent was preferable is acetone, tetrahydrofuran (THF), 1, one or more in 4-dioxane, ethanol, the trimethyl carbinol, isopropylcarbinol and the Virahol; The time of described reaction can be 0.5～5 hour; The temperature of described reaction can be-10 ℃～20 ℃.
Among the present invention, for further purification panipenem sodium-chlor eutectic, the thick product that makes as stated above can be dissolved in sodium chloride aqueous solution, add gac and decolour, add solvent reagent again and carry out crystallization, the refining panipenem sodium-chlor eutectic that can make.What the mass concentration of described sodium chloride aqueous solution was preferable is 1～3%.Preferred solvent reagent is with aforementioned.
Among the present invention, compound shown by formula I can adopt the JP5913757 disclosed method to be prepared, and other agents useful for same and raw material are all commercially available to be got.
Positive progressive effect of the present invention is: compared with prior art; method of the present invention is simple to operate; do not need resin purification and specific installation; the purity height of product; good stability, after refining, yield can reach more than 35% usually; purity can reach more than 98%, is beneficial to the application of large-scale production more.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.
Embodiment 1
(R is 4-O with the compound shown in the 10g formula I
2NPhCH
2), adding the 100ml tetrahydrofuran (THF), N methylmorpholine-acetate buffer (pH=6.5) of 100ml1mol/L, the weight content of 2g palladium are 10% palladium carbon, control hydrogenation pressure 5Kg/m
2, react 2h down at 25 ℃, filter, separatory, water washs with ethyl acetate 50ml * 2, add 2g sodium-chlor, stirring and dissolving adds ethanol 200ml, drips the 400ml Virahol again, and-10 ℃ are stirred 2h, filter, solid washs with ethanol 10ml * 2, and drying under reduced pressure obtains the 3.60g light yellow solid.
The thick product of gained is dissolved in the 7.2ml2wt% sodium chloride solution, adds the 72mg activated carbon decolorizing, add tetrahydrofuran (THF) 140ml again ,-10 ℃ are stirred 2h, filter, solid washs with tetrahydrofuran (THF) 5ml * 2, drying under reduced pressure, obtain the 2.88g light yellow solid, yield: 43.3%, purity: 98.5%.
Analytical results (C
15H
21N
3O
4SNaCl2H
2O)
Calculated value: Cl% (8.17) H
2O% (8.30)
Measured value: Cl% (8.20) H
2O% (8.38)
Annotate: what of moisture content are relevant with time of drying.
Embodiment 2
(R is 4-O with the compound shown in the 10g formula I
2NPhCH
2), add the 50ml ethyl acetate, the 50ml trimethyl carbinol, the magnesium acetate damping fluid (pH=5.0) of 100ml0.5mol/L, the weight content of 6g palladium are 10% palladium carbon, control hydrogenation pressure 5Kg/m
2, react 5h down at 0 ℃, filter, separatory, water washs with ethyl acetate 50ml * 2, add 1g sodium-chlor, stirring and dissolving adds ethanol 200ml, drips the 400ml Virahol again, and-10 ℃ are stirred 2h, filter, solid washs with ethanol 10ml * 2, and drying under reduced pressure obtains the 2.12g light yellow solid.
The thick product of gained is dissolved in the 4.2ml1wt% sodium chloride solution, add the 40mg activated carbon decolorizing, add acetone 10ml again, drip the 20ml Virahol again ,-10 ℃ are stirred 2h, filter, solid washs with acetone 5ml * 2, and drying under reduced pressure obtains the 1.88g light yellow solid, yield: 27.2%, purity: 98.1%.
Analytical results (C
15H
21N
3O
4SNaCl3H
2O)
Calculated value: Cl% (7.86) H
2O% (11.96)
Measured value: Cl% (7.69) H
2O% (11.90)
Embodiment 3
(R is 4-O with the compound shown in the 10g formula I
2NPhCH
2), adding 100ml acetone, the Potassium ethanoate damping fluid (pH=9.0) of 100ml0.5mol/L, the weight content of 5g palladium are 10% palladium carbon, control hydrogenation pressure 8Kg/m
2, react 0.5h down at 25 ℃, filter, add the 100ml ethyl acetate, separatory, water washs with ethyl acetate 50ml * 2, add 3g sodium-chlor, stirring and dissolving adds acetone 200ml, drip the 400ml Virahol again,-10 ℃ are stirred 2h, filter, and solid washs with acetone 10ml * 2, drying under reduced pressure obtains the 2.6g light yellow solid.
The thick product of gained is dissolved in the 5.2ml2wt% sodium chloride solution, add the 52mg activated carbon decolorizing, add ethanol 10ml again, drip the 20ml tetrahydrofuran (THF) again ,-10 ℃ are stirred 2h, filter, solid washs with ethanol 5ml * 2, and drying under reduced pressure obtains the 2.28g light yellow solid, yield: 34.3%, purity: 98.5%.
Analytical results (C
15H
21N
3O
4SNaCl2H
2O)
Calculated value: Cl% (8.17) H
2O% (8.30)
Measured value: Cl% (8.20) H
2O% (8.38)
Embodiment 4
With the compound shown in the 10g formula I (R is a benzyl), add 100ml ethanol, add N methylmorpholine-acetate buffer (pH=7.0) of 100ml 3mol/L, the weight content that adds the 0.5g palladium hydroxide is 20% palladium hydroxide carbon, control hydrogenation pressure 10Kg/m
2, react 2.5h down at 40 ℃, filter, separatory, water washs with ethyl acetate 50ml * 2, add 0.5g sodium-chlor, stirring and dissolving adds tetrahydrofuran (THF) 500ml, and-10 ℃ are stirred 2h, filter, solid washs with ethanol 10ml * 2, and drying under reduced pressure obtains the 3.6g light yellow solid.
The thick product of gained is dissolved in the 7.2ml2wt% sodium chloride solution, add the 72mg activated carbon decolorizing, add ethanol 15ml again, drip the 30ml Virahol again ,-10 ℃ are stirred 2h, filter, solid washs with ethanol 5ml * 2, and drying under reduced pressure obtains the 2.98g light yellow solid, yield: 41.3%, purity: 98.7%.Analytical results (C
15H
21N
3O
4SNaCl1/2H
2O)
Calculated value: Cl% (8.73) H
2O% (2.21)
Measured value: Cl% (8.80) H
2O% (2.30)
Embodiment 5
(R is 3-O with the compound shown in the 10g formula I
2NPhCH
2), add 100ml1,4 dioxane, the ammonium chloride buffer of 100ml 0.20mol/L (pH=5.0) 100ml adds platinum dioxide carbon (5%) 3g, control hydrogenation pressure 1Kg/m
2, react 4h down at 10 ℃, filter, add the 100ml ethyl acetate, separatory, water washs with ethyl acetate 50ml * 2, add 2g sodium-chlor, stirring and dissolving adds acetone 200ml, drip the 400ml trimethyl carbinol again,-10 ℃ are stirred 2h, filter, and solid washs with ethanol 10ml * 2, drying under reduced pressure obtains the 3.2g light yellow solid.
The thick product of gained is dissolved in the 6.4ml2wt% sodium chloride solution, add the 64mg activated carbon decolorizing, add acetone 13ml again, drip 25ml1 again, the 4-dioxane,-10 ℃ are stirred 2h, filter, and solid washs with acetone 5ml * 2, drying under reduced pressure, obtain the 2.57g light yellow solid, yield: 38.7%, purity: 98.6%.
Analytical results (C
15H
21N
3O
4SNaCl2H
2O)
Calculated value: Cl% (8.17) H
2O% (8.30)
Measured value: Cl% (8.21) H
2O% (8.35)
Embodiment 6
(R is 3-CH with the compound shown in the 10g formula I
3OPhCH
2), adding the 100ml isopropylcarbinol, N methylmorpholine-acetate buffer (pH=7.0) of 100ml1mol/L, the weight content of 9g palladium are 10% palladium carbon, control hydrogenation pressure 3Kg/m
2, react 2h down at 30 ℃, filter, separatory, water washs with ethyl acetate 50ml * 2, add 2g sodium-chlor, stirring and dissolving adds ethanol 200ml, tetrahydrofuran (THF) 400ml, and-10 ℃ are stirred 2h, filter, solid washs with ethanol 10ml * 2, and drying under reduced pressure obtains the 3.3g light yellow solid.
The thick product of gained is dissolved in the 6.6ml2wt% sodium chloride solution, add the 66mg activated carbon decolorizing, add ethanol 13ml again, drip the 25ml isopropylcarbinol again ,-10 ℃ are stirred 2h, filter, solid washs with ethanol 5ml * 2, and drying under reduced pressure obtains the 2.77g light yellow solid, yield: 38.2%, purity: 97.9%.
Analytical results (C
15H
21N
3O
4SNaCl3H
2O)
Calculated value: Cl% (7.86) H
2O% (11.96)
Measured value: Cl% (7.79) H
2O% (11.70)
Embodiment 7
(R is 4-O with the compound shown in the 10g formula I
2NPhCH
2), adding the 100ml Virahol, the damping fluid of the zinc acetate of 100ml0.5mol/L (pH=6.0), the weight content of 8g palladium are 10% palladium carbon, control hydrogenation pressure 6Kg/m
2, react 1.5h down at 20 ℃, filter, with ethyl acetate 100ml * 2 washings, add 2g sodium-chlor, stirring and dissolving adds ethanol 200ml, tetrahydrofuran (THF) 400ml, and-10 ℃ are stirred 2h, filter, solid washs with ethanol 10ml * 2, and drying under reduced pressure obtains the 3.3g light yellow solid.
The thick product of gained is dissolved in the 6.6ml3wt% sodium chloride solution, adds the 66mg activated carbon decolorizing, add ethanol 130ml again ,-10 ℃ are stirred 2h, filter, solid washs with ethanol 5ml * 2, drying under reduced pressure, obtain the 2.80g light yellow solid, yield: 40.5%, purity: 98.3%.
Analytical results (C
15H
21N
3O
4SNaCl3H
2O)
Calculated value: Cl% (7.86) H
2O% (11.96)
Measured value: Cl% (7.78) H
2O% (11.82)
Embodiment 8
(R is 2,4-(CH with the compound shown in the 10g formula I
3O)
2PhCH
2), adding the 100ml ethyl acetate, N methylmorpholine-acetate buffer (pH=7.0) of 100ml2mol/L, the weight content of 5g platinum are 10% platinum carbon, control hydrogenation pressure 5Kg/m
2, react 2h down at 30 ℃, filter, separatory, water adds 2g sodium-chlor with ethyl acetate 50ml * 2 washings, stirring and dissolving adds Virahol 400ml, and-10 ℃ are stirred 2h, filter, solid washs with ethanol 10ml * 2, and drying under reduced pressure obtains the 2.76g light yellow solid, yield: 40.8%, purity: 97.5%.
Analytical results (C
15H
21N
3O
4SNaCl3H
2O)
Calculated value: Cl% (7.86) H
2O% (11.96)
Measured value: Cl% (7.79) H
2O% (11.70)
Claims (13)
1. one kind suc as formula the method for preparing panipenem sodium chloride eutectic shown in the II, it is characterized in that comprising the steps:
(1) in the mixed solution of damping fluid or damping fluid and organic solvent, be catalyzer to contain palladium or platiniferous compound, with compound shown by formula I and H
2Reaction;
(2) add sodium-chlor and solvent reagent, get final product through reactive crystallization;
Wherein, R is the benzyl that replacement is arranged on benzyl or the phenyl ring; N is 0.5～3; The benzyl that replacement is arranged on the described phenyl ring is 4-nitrobenzyl, 3-nitrobenzyl, methoxy-benzyl or 2, the 4-dimethoxy-benzyl.
2. the method for claim 1, it is characterized in that: in the step (1), the pH value of described damping fluid is 5～9.
3. the method for claim 1, it is characterized in that: in the step (1), the volumetric molar concentration of described damping fluid is 0.2～3mol/L.
4. the method for claim 1 is characterized in that: in the step (1), describedly contain palladium or the platiniferous compound is palladium carbon, platinum, platinum dioxide or palladium hydroxide.
5. the method for claim 1 is characterized in that: in the step (1), and 5～50% of the weight that the described consumption that contains palladium or platiniferous compound is a compound shown by formula I.
6. the method for claim 1, it is characterized in that: in the step (1), the pressure of described reaction is 1～10Kg/m
2
7. the method for claim 1, it is characterized in that: in the step (1), the time of described reaction is 0.5～5 hour.
8. the method for claim 1, it is characterized in that: in the step (1), the temperature of described reaction is 0 ℃～40 ℃.
9. the method for claim 1, it is characterized in that: in the step (1), described organic solvent is selected from one or more in ethyl acetate, acetone, tetrahydrofuran (THF), 1,4 dioxane, ethanol, methyl alcohol, the trimethyl carbinol, isopropylcarbinol and the Virahol.
10. the method for claim 1 is characterized in that: in the step (2), described amount of sodium chloride be compound shown by formula I weight 5～30%.
11. the method for claim 1, it is characterized in that: the panipenem sodium-chlor eutectic crude product suc as formula shown in the II that will make is dissolved in sodium chloride aqueous solution, add gac and decolour, add solvent reagent again and carry out crystallization, promptly make refining panipenem sodium-chlor eutectic.
12. method as claimed in claim 11 is characterized in that: the mass concentration of described sodium chloride aqueous solution is 1～3%.
13. as claim 1 or 11 described methods, it is characterized in that: described solvent reagent is acetone, tetrahydrofuran (THF), 1, one or more in 4-dioxane, ethanol, the trimethyl carbinol, isopropylcarbinol and the Virahol.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100412088A CN101311177B (en) | 2007-05-24 | 2007-05-24 | Method for preparing panipenem sodium chloride eutectic |
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|---|---|---|---|
| CN2007100412088A CN101311177B (en) | 2007-05-24 | 2007-05-24 | Method for preparing panipenem sodium chloride eutectic |
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| CN101311177B true CN101311177B (en) | 2010-10-27 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0161546A1 (en) * | 1984-04-30 | 1985-11-21 | Merck & Co. Inc. | Combination of 2-substituted carbapenems with dipeptidase inhibitors |
-
2007
- 2007-05-24 CN CN2007100412088A patent/CN101311177B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0161546A1 (en) * | 1984-04-30 | 1985-11-21 | Merck & Co. Inc. | Combination of 2-substituted carbapenems with dipeptidase inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| JP昭60-115585A 1985.06.22 |
| JP昭61-172878A 1986.08.04 |
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