CN100344635C - 7-phenylacetylamino-3-pyridinylmethyl-3-cephalosporin-4-carboxyl acid p-methoxybenzyl ester crystal and its preparation method - Google Patents
7-phenylacetylamino-3-pyridinylmethyl-3-cephalosporin-4-carboxyl acid p-methoxybenzyl ester crystal and its preparation method Download PDFInfo
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- CN100344635C CN100344635C CNB2005101126154A CN200510112615A CN100344635C CN 100344635 C CN100344635 C CN 100344635C CN B2005101126154 A CNB2005101126154 A CN B2005101126154A CN 200510112615 A CN200510112615 A CN 200510112615A CN 100344635 C CN100344635 C CN 100344635C
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- cephalosporin
- phenylacetylamino
- carboxyl acid
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Abstract
The present invention relates to a stable and high-purity 7-phenacetylamino-3-pyridyl methyl-3-cephalosporin-4-p-methoxybenzyl carboxylic ester crystal and a preparation method thereof. The crystal form of a 7-phenacetylamino-3-pyridyl methyl-3-cephalosporin-4-p-methoxybenzyl carboxylic ester is expressed in a corresponding X-ray diffraction pattern. The preparation method of the crystal comprises the steps that the 7-phenacetylamino-3-pyridyl methyl-3-cephalosporin-4-p-methoxybenzyl carboxylic ester is used as an initial raw material; under the existence of an organic solvent, the 7-phenacetylamino-3-pyridyl methyl-3-cephalosporin-4-p-methoxybenzyl carboxylic ester reacts with pyridine and/or an iodide; after reaction, a crystal is crystallized and separated by adopting alkane, an ether solvent or a mixture of alkane and the ether solvent and a mixed solvent of alcohol. The crystal can exist in a stable state for a long time and is difficult to decompose, which is very favorable to industrialized production. In addition, the preparation method has the advantages of easy operation, low cost and high safety.
Description
Related application
The application is one and divides an application that the application number of original application is 03146092.5, and the applying date is on July 22nd, 2003, and invention and created name is " 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid is to methoxybenzyl ester crystal and preparation method thereof ".
Technical field
The present invention relates to 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester crystal and preparation method thereof.
Background technology
7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid is the important intermediate of synthetic ceftazime and some other cephalosporin analog antibiotic to methoxybenzyl ester, and its structural formula is as follows:
Wherein X is iodine or chlorine.
In the prior art, existing about the report of 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to the similar intermediates preparation of methoxybenzyl ester, as Journal ofAntibiotics, XXXIX (8), the following method of 1090 reports:
R ' is a hydroxyl protecting group in the formula; Tr is a trityl; DPM is a diphenyl-methyl;
Be alkylamine or aromatic amine; R is an alkyl.
In the method, at first, in butanone solvent, the 3-chloromethyl derivative of structural formula (IV) and sodium iodide reaction; After the reaction, boil off solvent, the gained resistates is dissolved in the ethyl acetate, and water and hypo solution washing, and organic phase pressure reducing and steaming solvent obtains unbodied iodide; Then, these unbodied iodide add alkylamine or aromatic amine in ether solvent, obtain quarternary ammonium salt compound (VI) after the reaction.
Zhi Bei 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid is an oily matter to the amino methyl benzyl ester in this way, purity difference; Stability is very poor, and for example period of storage is short at ambient temperature, easily decomposes.As intermediate, if will further synthesize ceftazime and some other cephalosporin analog antibiotic, it must can be used for the next step through the column chromatography purification rear to the 7-phenylacetylamino that makes like this-3-picolyl-3-cephalosporin-4-carboxyl acid to the amino methyl benzyl ester.
Summary of the invention
Therefore, the objective of the invention is to, 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid that a kind of crystalline form of stable existence for a long time is provided is defined as α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to the methoxybenzyl ester crystal hereinafter to methoxybenzyl ester.
Another object of the present invention is to, 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid that the better crystalline form of another kind of stability is provided is defined as β type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to the methoxybenzyl ester crystal hereinafter to methoxybenzyl ester.
A further object of the present invention is, the method for a kind of 7-of preparation phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester is provided.
An also purpose of the present invention is, provides a kind of preparation α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester crystalline method.
Another object of the present invention is, provides a kind of preparation β type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester crystalline method.
The following 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid of structural formula provided by the invention is to the alpha type crystal of methoxybenzyl ester,
Wherein X is iodine or chlorine;
This crystal has following X-ray powder diffraction pattern, and this collection of illustrative plates passes monochromator silk filter by the copper ray of λ=1.5406 dusts and obtains:
d I/I
0
23.3-23.5 55-58
11.65-11.85 23-25
5.35-5.45 35-38
4.62-4.65 35-38
4.50-4.55 66-69
4.28-4.33 60-65
4.12-4.18 56-59
3.90-3.94 60-62
3.87-3.89 70-73
3.80-3.82 50-52
3.61-3.63 25-28
3.51-3.53 30-33
3.27-3.29 20-22
2.81-2.83 100
1.99-2.00 58-60
1.62-1.63 20-25
Wherein d is a spacing, I/I
0Be relative intensity.
β type 7-phenylacetylamino provided by the invention-3-picolyl-3-cephalosporin-4-carboxyl acid is to the methoxybenzyl ester crystal, and this crystal has following X-ray powder diffraction pattern, and this collection of illustrative plates passes monochromator silk filter by the copper ray of λ=1.5406 dusts and obtains:
d I/I
0
14.80-15.00 50-55
9.50-9.60 80-98
7.40-7.50 30-35
6.20-6.30 28-30
5.60-5.70 28-30
5.10-5.20 30-32
4.90-5.00 66-76
4.70-4.80 25-28
4.55-4.60 60-71
4.30-4.32 25-28
4.17-4.20 100
4.05-4.08 27-32
3.80-3.83 55-65
3.70-3.73 70-80
3.60-3.63 85-95
3.53-3.55 22-26
3.46-3.49 28-32
3.40-3.42 55-70
3.28-3.29 65-75
3.17-3.19 47-50
2.98-3.00 25-35
2.87-2.89 30-35
2.82-2.83 92-95
2.62-2.63 25-28
2.56-2.57 25-28
2.22-2.23 23-25
2.11-2.12 23-25
1.99-2.00 51-53
Wherein d is a spacing, I/I
0Be relative intensity.
The method for preparing 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester of the present invention, it is characterized in that be starting raw material with 7-phenylacetylamino-3-monochloromethyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester, wherein halogen atom is chlorine or iodine;
At starting raw material is that 7-phenylacetylamino-3-chloromethyl-3-cephalosporin-4-carboxyl acid is during to methoxybenzyl ester, 7-phenylacetylamino-3-chloromethyl-3-cephalosporin-4-carboxyl acid is added in the organic solvent methoxybenzyl ester, iodide, add pyridine again, reaction is after separation obtains 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester;
Be that 7-phenylacetylamino-3-iodomethyl-3-cephalosporin-4-carboxyl acid is during to methoxybenzyl ester perhaps at starting raw material, 7-phenylacetylamino-3-iodomethyl-3-cephalosporin-4-carboxyl acid is reacted in organic solvent methoxybenzyl ester and pyridine, obtain 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester through separation then.
In preparation method of the present invention, when so that the 7-phenylacetylamino-when 3-methyl fluoride-3-cephalosporin-4-carboxyl acid was starting raw material to methoxybenzyl ester, entire reaction course can be represented with following equation:
Wherein X is iodine or chlorine.
Because in preparation method of the present invention, the negatively charged ion that exists in this reaction system has iodide ion and/or chlorion, and 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid has cation group N to methoxybenzyl ester
+, combine with negatively charged ion (iodide ion and/or chlorion) in the reaction system and to form ionic compound.
In the method, at starting raw material is 7-phenylacetylamino-3-chloromethyl-3-cephalosporin-4-carboxyl acid during to methoxybenzyl ester, and preferred the 7-phenylacetylamino-3-chloromethyl-3-cephalosporin-4-carboxyl acid is 1 to the mol ratio of methoxybenzyl ester, iodide and pyridine add-on: 1-3: 1-3;
At starting raw material is 7-phenylacetylamino-3-iodomethyl-3-cephalosporin-4-carboxyl acid during to methoxybenzyl ester, and preferred the 7-phenylacetylamino-3-iodomethyl-3-cephalosporin-4-carboxyl acid is 1 to the mol ratio of methoxybenzyl ester and pyridine add-on: 1-3.
Organic solvent and 7-phenylacetylamino-3-monochloromethyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester preferably by weight 1-50: 1 amount is used, more preferably 2-30: 1,5-15 most preferably: 1.
In preparation method provided by the present invention, temperature of reaction preferably is controlled at-30-100 ℃ in reaction process, more preferably 0-50 ℃; Reaction times preferably was controlled at 0.5-48 hour.
The starting raw material that is used for the present invention, 7-phenylacetylamino-3-monochloromethyl-3-cephalosporin-4-carboxyl acid is the compound of a known easy purchase to methoxybenzyl ester, also can be according to Torri etc. at Tetrahedron Lett., reported method preparation in 23,2187 (1982).
Employed organic solvent is preferably ketone, ester class, halogenated hydrocarbon, nitrile solvents or its mixture among the present invention, wherein said ketone, for example acetone, butanone or diethyl ketone etc.; Ester class, for example methyl-formiate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, butylacetate, methyl propionate or ethyl propionate etc.; Halogenated hydrocarbon, for example methylene dichloride, ethylene dichloride, chloroform or tetracol phenixin etc.; Nitrile, for example acetonitrile, propionitrile, butyronitrile or valeronitrile etc.The present invention more preferably uses ketone or halogenated hydrocarbon solvent as reaction solvent.
Described iodide can be alkaline metal iodide, alkaline earth metal iodide or quaternary ammonium iodide, wherein for example lithium iodide, sodium iodide or potassiumiodide of alkaline metal iodide; Alkaline earth metal iodide, for example calcium iodide; Quaternary ammonium iodide, for example tetraethyl-iodate amine.
Resulting reaction mixture after reaction is finished, available ordinary method is separated and purifying, obtains 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester.For example can distill and desolventize, obtain an oily matter, then adopt column chromatography to carry out purifying reaction mixture.
Phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid is as follows to methoxybenzyl ester crystalline method for preparation α type 7-of the present invention:
In the 7-phenylacetylamino-3-picolyl-solution of 3-cephalosporin-4-carboxyl acid, add alkanes, ether solvent or its mixture, α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid is separated out the methoxybenzyl ester crystal structure methoxybenzyl ester.
Wherein, described 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to the solution of methoxybenzyl ester can for, according to the inventive method, the reaction solution that 7-phenylacetylamino-3-chloromethyl-3-cephalosporin-4-carboxyl acid obtains after methoxybenzyl ester, iodide and pyridine are reacted in organic solvent, the perhaps reaction solution that obtains after methoxybenzyl ester and pyridine are reacted in organic solvent for 7-phenylacetylamino-3-iodomethyl-3-cephalosporin-4-carboxyl acid; Also can be dissolved in the solution that obtains in the solvent to methoxybenzyl ester for 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid.
Being used to dissolve 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid can be to dissolve the solvent of 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester to the solvent of methoxybenzyl ester, for example ketone, ester class, halogenated hydrocarbon, nitrile solvents or its mixture, wherein said ketone, for example acetone, butanone or diethyl ketone etc.; Ester class, for example methyl-formiate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, butylacetate, methyl propionate or ethyl propionate etc.; Halogenated hydrocarbon, for example methylene dichloride, ethylene dichloride, chloroform or tetracol phenixin etc.; Nitrile, for example acetonitrile, propionitrile, butyronitrile or valeronitrile etc.; Preferred ketone or the halogenated hydrocarbon solvent of using.
Described alkanes, ether solvent or its mixture, wherein ethers, for example ether, isopropyl ether or dibutyl ether etc.; Alkanes, for example normal hexane or sherwood oil etc.
In the 7-phenylacetylamino-3-picolyl-solution of 3-cephalosporin-4-carboxyl acid, add alkanes, ether solvent or its mixture to methoxybenzyl ester, the add-on of alkanes, ether solvent or its mixture is unrestricted, as long as alpha type crystal can be separated out in crystallization.Usually 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid is preferably 1 to the solution of methoxybenzyl ester with alkanes, ether solvent or its mixture weight ratio: 1-20.
In the 7-phenylacetylamino-3-picolyl-solution of 3-cephalosporin-4-carboxyl acid, adding alkanes, ether solvent or its mixture, making in the process that the alpha type crystal crystallization separates out methoxybenzyl ester, preferred temperature is controlled at-10-40 ℃, more preferably 0-25 ℃.
After crystal is separated out, after filtration, obtain α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to the methoxybenzyl ester crystal after solvent wash and the drying.
The α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid that obtains by the inventive method is to the methoxybenzyl ester crystal, through HPLC test purity is 95-98%, color and luster is the 5-7 look, stability better, deposit at least one month at ambient temperature, just decompose, color and luster is deepened the 1-2 look.
Preparation β type 7-phenylacetylamino of the present invention-3-picolyl-3-cephalosporin-4-carboxyl acid is to methoxybenzyl ester crystalline method, above-mentioned preparation α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester crystalline method in, change when making the solvent that crystal separates out, adopt alkanes, during the mixed solvent of ether solvent or its mixture and alcohols, the β type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid that then obtains excellent stability is to the methoxybenzyl ester crystal, promptly in the 7-phenylacetylamino-3-picolyl-solution of 3-cephalosporin-4-carboxyl acid, add alkanes to methoxybenzyl ester, the mixed solvent of ether solvent or its mixture and alcohols makes β type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid separate out the methoxybenzyl ester crystal structure.
Described alkanes, ether solvent or its mixture and the mixed solvent of alcohols be alkanes, ether solvent or its mixture and alcoholic solvent by weight 1: 0.01-0.5 mixes and obtains, wherein alkanes, for example normal hexane or sherwood oil etc.; Ethers, for example ether, isopropyl ether or dibutyl ether etc.; Alcohols, for example methyl alcohol, ethanol, Virahol, butanols, isopropylcarbinol, primary isoamyl alcohol or its mixture etc.
The mixed solvent that in the 7-phenylacetylamino-3-picolyl-solution of 3-cephalosporin-4-carboxyl acid, adds alkanes, ether solvent or its mixture and alcohols to methoxybenzyl ester, the add-on of mixed solvent is unrestricted, as long as the β N-type waferN can be separated out in crystallization.Usually 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid is preferably 1 to the solution of methoxybenzyl ester and the weight ratio of this mixed solvent: 1-20.
β type 7-phenylacetylamino of the present invention-3-picolyl-3-cephalosporin-4-carboxyl acid is to the methoxybenzyl ester crystal, purity higher (＞98%), and color and luster is generally less than look No. 2, stability is strong, deposited at least 2 months under the room temperature condition, do not see to decompose to produce, be convenient to suitability for industrialized production.
α type provided by the invention and β type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid are to the methoxybenzyl ester crystal, good stability, the purity height, be difficult for decomposing, crystalline structure is stable, so these two kinds of cephalosporin crystals can be stored for a long time under economic condition, are beneficial to very much suitability for industrialized production.And 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid of pressing former bibliographical information method preparation is oily matter to methoxybenzyl ester, and purity is very poor, and stability is very poor, and necessary column chromatography for separation just can be used for the next step.
α type provided by the invention and β type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid can be used for synthetic widely used cephalosporin analog antibiotic to methoxybenzyl ester, for example be used for synthetic third generation wide spectrum cephalosporin analog antibiotic-ceftazime, first-generation cephalosporin analog antibiotic-Cephaloridine.
The invention has the advantages that and adopt short-cut method to make 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid the methoxybenzyl ester crystal, the purity height, good stability, method is easy to operate, and cost is low, and security is good, is very beneficial for suitability for industrialized production.
Embodiment
The embodiment that provides below is used for specifically describing embodiment of the present invention, and these embodiment do not limit the scope of the invention.Institute's symbolically is as follows among the embodiment:
S: unimodal; Br: broad peak; D: bimodal; Two groups of doublets of dd; T: triplet;
M: multiplet; D
2O: heavy water; DMSO-d6: hexadeuterated dimethyl sulfoxide.
Nucleus magnetic resonance is made interior mark all with chemical shift (ppm) expression with tetramethylsilane (DMSO-d6 is a solvent).
Embodiment 1
α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid prepares the methoxybenzyl ester crystalline:
7-phenylacetylamino-3-chloromethyl-3-cephalosporin-4-carboxyl acid is added in the reaction flask methoxybenzyl ester 10g, potassiumiodide 4.9g and acetone 120ml, stir and be heated to 30 ℃ then, add pyridine 2.5ml after 2 hours, proceed to react 5 hours; In reaction flask, drip isopropyl ether 200ml then, stir after 3 hours suction filtration, and use the isopropyl ether washing leaching cake, obtain α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid after the drying to methoxybenzyl ester crystal 14.9g, HPLC test purity is 97.4%, and yield is 95.8%.
1H-NMR(DMSO-d6)δ(ppm)：
3.46(1H，J＝13.8Hz)；3.53(1H，J＝13.8Hz)；3.49(2H，m)；3.74(3H，s)；5.13(1H，d，J＝4.8Hz)；5.18(1H，J＝12.0Hz)；5.22(1H，J＝12.0Hz)；5.5，5.8(2H，J＝15.6Hz)；5.78(1H，dd，J＝4.8，8.4Hz)；6.90(2H，m)；7.32(2H，m)；7.1-7.3(7H，m)；8.18(2H，m)；8.64(2H，m)；8.99(2H，m)；9.12(1H，d，J＝8.4Hz)。
This crystal X-ray powder diffraction pattern is as follows, and this collection of illustrative plates passes monochromator silk filter by the copper ray of λ=1.5406 dusts and obtains:
d I/I
0
23.48 57
11.81 24
5.44 37
4.63 36
4.51 69
4.31 62
4.13 58
3.93 61
3.89 73
3.81 52
3.62 27
3.53 32
3.29 22
2.83 100
1.99 59
1.63 22
Wherein d is a spacing; I/I
0Be relative intensity.
Embodiment 2
β type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid is to the preparation of methoxybenzyl ester:
7-phenylacetylamino-3-chloromethyl-3-cephalosporin-4-carboxyl acid is added in the reaction flask methoxybenzyl ester 10g, potassiumiodide 4.9g and acetone 120ml, stir and be heated to 30 ℃ then, add pyridine 2.5ml after 2 hours, proceed to react 5 hours; In reaction flask, drip the mixed solvent of methyl alcohol 5ml and isopropyl ether 250ml then, stir after 2 hours, suction filtration, and use the isopropyl ether washing leaching cake, obtain β type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid after the drying to methoxybenzyl ester crystal 15.1g, purity is 98.3%; Yield is 97.1%.
1H-NMR(DMSO-d6)δ(ppm)：
3.46(1H，J＝13.8Hz)；3.53(1H，J＝13.8Hz)；3.49(2H，m)；3.74(3H，s)；5.13(1H，d，J＝4.8Hz)；5.18(1H，J＝12.0Hz)；5.22(1H，J＝12.0Hz)；5.5，5.8(2H，J＝15.6Hz)；5.78(1H，dd，J＝4.8，8.4Hz)；6.90(2H，m)；7.32(2H，m)；7.1-7.3(7H，m)；8.18(2H，m)；8.64(2H，m)；8.99(2H，m)；9.12(1H，d，J＝8.4Hz)。
This crystal X-ray powder diffraction pattern is as follows, and this collection of illustrative plates passes monochromator silk filter by the copper ray of λ=1.5406 dusts and obtains:
d I/I
0
14.87 52
9.54 98
7.42 32
6.21 29
5.66 29
5.16 32
4.95 66
4.79 26
4.59 71
4.31 27
4.18 100
4.07 27
3.81 59
3.71 75
3.61 89
3.54 26
3.48 31
3.41 58
3.29 70
3.18 47
2.98 26
2.88 35
2.82 92
2.63 25
2.56 25
2.22 23
2.12 24
1.99 53
Wherein d is a spacing, I/I
0Be relative intensity.
α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid that the embodiment of the invention 1 is made is to the methoxybenzyl ester crystal, β type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid that embodiment 2 makes is to the methoxybenzyl ester crystal, and by the 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid of former literature method preparation to methoxybenzyl ester, place under room temperature (20-25 ℃) condition, stable testing, data are as follows:
| Period of storage (moon) | Storage temperature | The alpha type crystal that embodiment 1 makes | The β N-type waferN that embodiment 2 makes | Prepared by former literature method | ||
| Purity (%) | Color and luster | Purity (%) | Color and luster | Purity (%) | ||
| 0 | 20-25℃ | 97.4 | 5# | 98.3 | 1# | 73 |
| After 1 month | 20-25℃ | 96.1 | 6# | 98.2 | 1# | 61 |
| After 2 months | 20-25℃ | 94.5 | 8# | 98.3 | 1# | 45 |
| After 3 months | 20-25℃ | 92.5 | ＞10# | 97.8 | 2# | 32 |
| After 6 months | 20-25℃ | 89.3 | ＞10# | 97.1 | 3# | 18 |
Embodiment 3
α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid prepares the methoxybenzyl ester crystalline:
7-phenylacetylamino-3-iodomethyl-3-cephalosporin-4-carboxyl acid is added in the reaction flask methoxybenzyl ester 17.7g and acetone 120ml, stir also temperature adjustment then, add pyridine 3.0ml after 5 hours, continued stirring reaction 24 hours to-5 ℃; In 0 ℃ of downhill reaction bottle, drip isopropyl ether 100ml then, stir after 1 hour suction filtration, and use the isopropyl ether washing leaching cake, obtain α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid after the drying to methoxybenzyl ester crystal 15.0g, purity is 97.3%, and yield is 96.4%.
Embodiment 4
α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid prepares the methoxybenzyl ester crystalline:
The reaction solvent acetone 120ml that replaces embodiment 1 with methylene dichloride 150ml, other condition is with embodiment 1, make α type 7-phenylacetylamino-3-picolyl-3-cynnematin-4-carboxyl to methoxybenzyl ester crystal 14.7g, purity is 96.6%, and yield is 94.5%.
Embodiment 5
α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid prepares the methoxybenzyl ester crystalline:
7-phenylacetylamino-3-chloromethyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester 10g, potassiumiodide 4.9g and acetone 120ml, is added in the reaction flask, and 0～5 ℃ of following stirring adds pyridine 2.5ml simultaneously, stirs reaction down 15 hours; In reaction flask, drip normal hexane 300ml then, stir after 2 hours, suction filtration, the normal hexane washing obtains α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester crystal 15.1g, purity 97.3%, yield 97.1% after the drying.
Embodiment 6
α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid prepares the methoxybenzyl ester crystalline:
7-phenylacetylamino-3-chloromethyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester 10g, potassiumiodide 4.9g and acetone 120ml, is added in the reaction flask, stir and be heated to 50 ℃, add pyridine 2.8ml, stirring reaction 12 hours after 1 hour; In reaction flask, drip sherwood oil 500ml then, stir after 5 hours, suction filtration, petroleum ether obtains α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester crystal 14.6g, purity 96.3%, yield 93.9% after the drying.
Embodiment 7
β type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid prepares the methoxybenzyl ester crystalline:
7-phenylacetylamino-3-chloromethyl-3-cephalosporin-4-carboxyl acid is added in the reaction flask methoxybenzyl ester 10g, potassiumiodide 4.9g and acetone 320ml, stir and be heated to 50 ℃, add pyridine 3.5ml, stirring reaction 2 hours after 1 hour; In reaction flask, drip ethanol 50ml and isopropyl ether 400ml mixed solvent then, stir after 4 hours suction filtration, the isopropyl ether washing, obtain β type 7-phenylacetylamino-3-picolyl-3-cynnematin-4-carboxyl after the drying to methoxybenzyl ester crystal 14.8g, purity 98.6%, yield 95.1%.
Embodiment 8
β type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid prepares the methoxybenzyl ester crystalline:
7-phenylacetylamino-3-chloromethyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester 10g, potassiumiodide 4.9g and acetone 80ml, is added in the reaction flask, and 0～5 ℃ of stirring adds pyridine 2.8ml, stirring reaction 15 hours; In reaction flask, drip Virahol 22ml and sherwood oil 300ml mixed solvent then, stir after 2 hours suction filtration, petroleum ether, obtain β type 7-phenylacetylamino-3-picolyl-3-cynnematin-4-carboxyl after the drying to methoxybenzyl ester crystal 15.3g, purity 98.7%, yield 98.3%.
Embodiment 9
α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid prepares the methoxybenzyl ester crystalline:
The 50ml methylene dichloride is added to 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid in the methoxybenzyl ester 10g oily matter, stir, temperature adjustment 0-5 ℃, add the 600ml isopropyl ether, stir after 5 hours suction filtration, and use the isopropyl ether washing leaching cake, obtain α type 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid after the drying to methoxybenzyl ester crystal 8.9g, HPLC test purity is 97.2%, and yield is 91.8%.
Claims (8)
1, the following 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid of a kind of structural formula is to the crystal of methoxybenzyl ester,
Wherein X is iodine or chlorine;
It is characterized in that this crystal has following X-ray powder diffraction pattern, this collection of illustrative plates passes monochromator silk filter by the copper ray of λ=1.5406 dusts and obtains:
d I/I
0
14.80-15.00 50-55
9.50-9.60 80-98
7.40-7.50 30-35
6.20-6.30 28-30
5.60-5.70 28-30
5.10-5.20 30-32
4.90-5.00 66-76
4.70-4.80 25-28
4.55-4.60 60-71
4.30-4.32 25-28
4.17-4.20 100
4.05-4.08 27-32
3.80-3.83 55-65
3.70-3.73 70-80
3.60-3.63 85-95
3.53-3.55 22-26
3.46-3.49 28-32
3.40-3.42 55-70
3.28-3.29 65-75
3.17-3.19 47-50
2.98-3.00 25-35
2.87-2.89 30-35
2.82-2.83 92-95
2.62-2.63 25-28
2.56-2.57 25-28
2.22-2.23 23-25
2.11-2.12 23-25
1.99-2.00 51-53
Wherein d is a spacing, I/I
0Be relative intensity.
2, the described 7-phenylacetylamino of a kind of preparation claim 1-3-picolyl-3-cephalosporin-4-carboxyl acid is to methoxybenzyl ester crystalline method, it is characterized in that, the mixed solvent that adds alkanes, ether solvent or its mixture and alcohols in the 7-phenylacetylamino-3-picolyl-solution of 3-cephalosporin-4-carboxyl acid to methoxybenzyl ester makes 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid separate out the methoxybenzyl ester crystal structure.
3, method according to claim 2, it is characterized in that, described 7-phenylacetylamino-3-picolyl-3-cynnematin 4-carboxylic acid is that 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid is dissolved in the solution that obtains in the solvent to methoxybenzyl ester to the solution of methoxybenzyl ester, or synthetic 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid is to the reaction solution that obtains after the reaction that is reflected at of methoxybenzyl ester.
4, method according to claim 2 is characterized in that, described alkane solvents is normal hexane or sherwood oil; Ether solvent is ether, isopropyl ether or dibutyl ether; Alcoholic solvent is methyl alcohol, ethanol, Virahol, butanols, isopropylcarbinol, primary isoamyl alcohol or its mixture.
5, method according to claim 2 is characterized in that, described alkanes, ether solvent or its mixture and the mixed solvent of alcohols be alkanes, ether solvent or its mixture and alcoholic solvent by weight 1: 0.01-0.5 mixes and obtains.
6, method according to claim 2, it is characterized in that described 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid is 1 to the weight ratio of the mixed solvent of the solution of methoxybenzyl ester and alkanes, ether solvent or its mixture and alcohols: 1-20.
7, method according to claim 2, it is characterized in that, at-10-40 ℃, the mixed solvent that adds alkanes, ether solvent or its mixture and alcohols in the 7-phenylacetylamino-3-picolyl-solution of 3-cephalosporin-4-carboxyl acid to methoxybenzyl ester makes 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid separate out the methoxybenzyl ester crystal structure.
8, method according to claim 3 is characterized in that, described synthetic 7-phenylacetylamino-3-picolyl-3-cephalosporin-4-carboxyl acid obtains by following method the reaction solution that being reflected at of methoxybenzyl ester obtains after the reaction:
In organic solvent, 7-phenylacetylamino-3-chloromethyl-3-cephalosporin-4-carboxyl acid is 1 to methoxybenzyl ester, iodide and pyridine in molar ratio: 1-3: 1-3 reacts, the resulting reaction solution in reaction back; Or
In organic solvent, 7-phenylacetylamino-3-iodomethyl-3-cephalosporin-4-carboxyl acid is 1 to methoxybenzyl ester and pyridine in molar ratio: 1-3 reacts, the resulting reaction solution in reaction back;
Described organic solvent is ketone, ester class, halogenated hydrocarbon, nitrile solvents or its mixture; Described iodide are alkaline metal iodide, alkaline earth metal iodide or quaternary ammonium iodide.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4563523A (en) * | 1981-07-17 | 1986-01-07 | Glaxo Group Limited | Cephalosporin compounds |
| US4692518A (en) * | 1985-11-06 | 1987-09-08 | Eli Lilly And Company | Crystalline (7R)-7-amino-3-(1'-pyridiniummethyl)-3-cephem-4-carboxylate monohydrate compound |
| CN1178220A (en) * | 1996-10-02 | 1998-04-08 | 大化学株式会社 | Process for producing cefazolin |
| CN1273587A (en) * | 1998-07-01 | 2000-11-15 | 大塚化学株式会社 | Process for preparation of 3-cephem compounds |
| WO2002004464A1 (en) * | 2000-07-07 | 2002-01-17 | Lg Life Sciences Ltd | Novel cephalosporin compounds and process for preparing the same |
-
2003
- 2003-07-22 CN CNB2005101126154A patent/CN100344635C/en not_active Expired - Lifetime
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4563523A (en) * | 1981-07-17 | 1986-01-07 | Glaxo Group Limited | Cephalosporin compounds |
| US4692518A (en) * | 1985-11-06 | 1987-09-08 | Eli Lilly And Company | Crystalline (7R)-7-amino-3-(1'-pyridiniummethyl)-3-cephem-4-carboxylate monohydrate compound |
| CN1178220A (en) * | 1996-10-02 | 1998-04-08 | 大化学株式会社 | Process for producing cefazolin |
| CN1273587A (en) * | 1998-07-01 | 2000-11-15 | 大塚化学株式会社 | Process for preparation of 3-cephem compounds |
| WO2002004464A1 (en) * | 2000-07-07 | 2002-01-17 | Lg Life Sciences Ltd | Novel cephalosporin compounds and process for preparing the same |
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