CN1261438C - 7-amino-3-picolyl-3-cephalosporin-4-carboxylic acid dihydrochloride dihydrate crystal and its preparation method - Google Patents
7-amino-3-picolyl-3-cephalosporin-4-carboxylic acid dihydrochloride dihydrate crystal and its preparation method Download PDFInfo
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- CN1261438C CN1261438C CN 02134421 CN02134421A CN1261438C CN 1261438 C CN1261438 C CN 1261438C CN 02134421 CN02134421 CN 02134421 CN 02134421 A CN02134421 A CN 02134421A CN 1261438 C CN1261438 C CN 1261438C
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- cephalosporin
- picolyl
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Abstract
The present invention relates to a 7-amido-3-picolyl-3-cephalosporin-4-carboxylic acid dihydrochloride dihydrate crystal and a preparation method thereof. The present invention discloses an X-diffraction pattern of the crystal and a preparation method for crystallization in a concentrated hydrochloric acid solution and ketone reagents containing 7-amido-3-picolyl-3-cephalosporin-4-carboxylic acid. The crystal of the present invention can be stored for relatively a long time under an economic condition, and the stability of the crystal is good. The method for preparing the stable crystal has the advantages of easy operation, low cost and high safety.
Description
Technical field
The present invention relates to a kind of stable highly purified 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrochloride dihydrate crystal and manufacture method thereof.
Background technology
7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid is the important intermediate of synthetic ceftazime and some other cephalosporin analog antibiotic.General traditional preparation method such as Japanese Patent JP2-57073, JP2-57069, JP2-57554, JP62-5916 report method is as follows:
In these methods, thereby obtain containing the solution of 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid by disconnected 7 side chains of phosphorus pentachloride, reaction mixture added in methylene dichloride and the methanol mixed solvent form solid, then with this solid recrystallization in IN hydrochloric acid/Virahol.
The two hydrochloride dihydrate compounds of 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid, generally, in molecule, contain 2 moles hydrochloric acid, if the bonding state of 7-amino in the crystalline structure that obtains-3-picolyl-3-cephalosporin-4-carboxyl acid and hydrochloric acid is firm inadequately, long period deposits under certain condition, hydrochloric acid constantly discharges, and causes product to decompose, so product stability is poor; Particularly in recrystallization process, contain Virahol, Virahol have that hydrochloric acid discharges with unbound state in the acceleration molecular, cause the product accelerate decomposition, like this, be unfavorable for that 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrate is circulating on the market as commodity.
Summary of the invention
The object of the invention provides a kind of 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrochloride dihydrate crystal and manufacture method thereof, this crystal can be stored the long relatively time under economic condition, its good stability, and the method for making this stable crystal, and it is easy to operate, cost is low, and security is good.
The technology scheme of separating of the present invention is its crystal X-diffractogram that 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrochloride dihydrate crystal is represented by structural formula
Structural formula is
The X-diffractogram is
(copper target, diffraction angle 1.54056 dusts, graphite monochromator; Here d is an interplanar distance, I/I.Be relative intensity)
d I/I
8.9～9.2 20～24
6.3～6.8 20～24
6.0～6.3 33～39
5.1～5.6 15～19
4.8～5.0 15～19
4.6～4.8 29～34
4.4～4.6 50～60
4.1～4.4 41～49
3.8～4.1 40～48
3.7～3.8 79～89
3.6～3.7 60～72
3.5～3.6 29～34
3.3～3.5 54～66
3.25～3.3 23～29
3.2～3.25 17～21
3.15～3.2 38～46
3.0～3.15 22～26
2.9～3.0 39～47
2.85～2.9 17～21
2.75～2.85 100
2.7～2.75 26～30
2.65～2.7 18～22
2.55～2.65 24～28
2.45～2.5 25～29
2.4～2.45 22～26
2.2～2.3 19～23
2.1～2.2 15～19
1.9～2.1 46～56
1.5～1.7 20～24
The manufacture method of 7-amino of the present invention-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrochloride dihydrate crystal is crystallization in the concentrated hydrochloric acid solution that contains 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid neutralizes the solvent that contains ketone.
The above ketones solvent is a side chain ketone.
Side chain ketone of the present invention is acetone, or 2-butanone, 4-methyl-2 pentanone.
More than crystallization method of the present invention be that ketones solvent drips to this concentrated hydrochloric acid solution, in the steady district that is situated between, add crystal seed, preferably work in coordination with the crystal seed that nucleation process makes with the solvent supersonic ripple, can stir growing the grain at a slow speed at about 30 rev/mins, continue to add solvent, solution remains at the steady state that is situated between in the red-tape operati process, can obtain the crystal that size-grade distribution is even, impurity absorption is few.
Tc of the present invention is-10 ℃ to 40 ℃.
Above crystallization optimum temps of the present invention is 0 ℃ to 25 ℃.
The amount of solvent for use ketone of the present invention is 2: 1 to 100: 1 with the solution weight ratio.
Above solvent for use ketone amount of the present invention and solution optimum weight ratio are 10: 1 to 30: 1.
The 7-amino that the present invention obtains-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrochloride dihydrate crystal good stability, the purity height, the bonding state of 7-amino in the crystalline structure-3-picolyl-3-cephalosporin-4-carboxyl acid and hydrochloric acid is firm, be difficult for decomposing, simultaneously, they can not be owing to the Virahol attack, cause hydrochloric acid to discharge, thereby acceleration self degradation, even under 5-10 ℃ of condition, store still stable for a long time, so this cephalosporin crystals can be stored for a long time under economic condition, is beneficial to as circulation of commodities very much.And the 7-amino-3-picolyl-very easy decomposition of 3-cephalosporin-4-carboxyl acid dihydrochloride dihydrate of bibliographical information method preparation in the past, even under-10 ℃ of conditions, stored for 1 or 2 weeks.
Cephalosporin compound can cause required recrystallisation solvent and make crystal method inequality because of each compound structure feature difference, solvent has a significant impact the crystalline form of product, purity etc.
The 7-amino that the present invention obtains-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrate is used for synthetic widely used cephalosporin analog antibiotic, for example is used for synthetic third generation wide spectrum cephalosporin analog antibiotic-ceftazime.
Advantage of the present invention is that this crystal can be stored the long relatively time under economic condition.Its good stability, the method for making this stable crystal is easy to operate, and cost is low, and security is good.
Embodiment
Example 1
The concentrated hydrochloric acid solution 50ml (content 210mg/ml) that will contain 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid adds in the flask, be chilled to 0 ℃, under the agitation condition, slowly drip 100ml acetone in the 1h, temperature is no more than 5 ℃, add the 2mg crystal seed, stirred 8 hours, continue to add 900ml acetone under 5 ℃ of conditions then.Filter, the filter cake washing with acetone, drying under reduced pressure obtains 10.1g7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrochloride dihydrate crystal, purity 98.5% (HPLC), yield 94.7%.
This crystal X-diffractogram following (copper target, diffraction angle 1.54056 dusts, graphite monochromator; Here d is an interplanar distance, I/I.Be relative intensity):
d I/I。
9.07 22
6.55 22
6.16 36
5.31 17
4.93 17
4.75 31
4.44 55
4.33 45
3.82 44
3.75 81
3.67 66
3.58 31
3.39 60
3.27 26
3.23 19
3.18 42
3.12 24
2.94 43
2.88 19
2.82 100
2.74 28
2.67 20
2.57 26
2.45 27
2.43 24
2.28 21
2.17 17
2.00 51
1.63 22
With gained crystal of the present invention, and the 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrochloride dihydrate crystal that prepared gained by former traditional literature method, place 0～5 ℃, the stable testing data are as follows under 5～10 ℃ and 20～25 ℃ of three kinds of conditions:
| Time (moon) | Storage temperature (℃) | Purity (%) is prepared with the inventive method | It is prepared that purity (%) is pressed the document traditional method |
| 0 | 0-5 | 98.5 | 98.5 |
| 1 | 0-5 | 98.4 | 90.0 |
| 3 | 0-5 | 98.7 | 80.0 |
| 6 | 0-5 | 97.8 | 73.0 |
| 9 | 0-5 | 97.5 | 62.0 |
| 12 | 0-5 | 97.6 | 51.1 |
| 1 | 5-10 | 98.3 | 86.4 |
| 3 | 5-10 | 98.0 | 79.0 |
| 6 | 5-10 | 97.8 | 63.2 |
| 9 | 5-10 | 97.5 | 49.4 |
| 12 | 5-10 | 96.5 | 38.6 |
| 1 | 20-25 | 97.2 | 70.6 |
| 3 | 20-25 | 96.1 | 40.9 |
| 6 | 20-25 | 94.0 | 15.1 |
| 9 | 20-25 | 90.1 | 10.8 |
| 12 | 20-25 | 83.7 | 5.4 |
Example 2:
The concentrated hydrochloric acid solution 50ml (content 210mg/ml) that will contain 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid adds in the flask, be chilled to-8 ℃, under the agitation condition, slowly drip 100ml acetone in the 1h, temperature is no more than-8 ℃, add the 2mg crystal seed, stirred 6 hours, continue to add 200ml acetone then-8 under ℃ condition.Filter, the filter cake washing with acetone, drying under reduced pressure obtains 9.5g7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrate cephalosporin compound crystal, purity 99.5% (HPLC), yield 90.0%.The X-diffractogram is consistent with example 1.
Example 3:
Concentrated hydrochloric acid solution 50ml (content 2l0mg/ml) solution that will contain 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid adds in the flask, 25 ℃ of temperature adjustments, under the agitation condition, slowly drip 100ml acetone in the 1h, add the 2mg crystal seed, stirred 2 hours, and continued to add 2400ml acetone under 5 ℃ of conditions then.Filter, the filter cake washing with acetone, drying under reduced pressure obtains 10.4g7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrate cephalosporin crystals, purity 97.0% (HPLC), yield 96.1%X-diffractogram is consistent with example 1.
Example 4:
The concentrated hydrochloric acid solution 50ml (content 210mg/ml) that will contain 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid adds in the flask, be chilled to 0 ℃, under the agitation condition, slowly drip the 100ml2-butanone in the 1h, temperature is no more than 5 ℃, add the 2mg crystal seed, stirred 8 hours, continue to add the 300ml2-butanone under 5 ℃ of conditions then.Filter, filter cake washs with 2-butanone, and drying under reduced pressure obtains 10.3g7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrate cephalosporin crystals, purity 98.5% (HPLC), yield 96.6%.
Example 5;
The concentrated hydrochloric acid solution 50ml (content 210mg/ml) that will contain 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid, this solution is added in the flask, be chilled to 0 ℃, under the agitation condition, slowly drip 100ml4-methyl-2 pentanone in the 1h, temperature is no more than 5 ℃, adds the 2mg crystal seed, stirred 8 hours, and continued to add 400ml4-methyl-2 pentanone under 5 ℃ of conditions then.Filter, filter cake washs with 4-methyl-2 pentanone, and drying under reduced pressure obtains 9.8g7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrate cephalosporin crystals, purity 97.5% (HPLC), yield 91.0%.
Claims (4)
1.7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrochloride dihydrate crystal, the structural formula of this compound is as follows:
It is characterized in that described crystalline X-diffracting spectrum is as follows, this collection of illustrative plates is at the copper target, and diffraction angle is 1.54056 dusts, obtains under the condition of graphite monochromator:
d I/I。
9.07 22
6.55 22
6.16 36
5.31 17
4.93 17
4.75 31
4.44 55
4.33 45
3.82 44
3.75 81
3.67 66
3.58 31
3.39 60
3.27 26
3.23 19
3.18 42
3.12 24
2.94 43
2.88 19
2.82 100
2.74 28
2.67 20
2.57 26
2.45 27
2.43 24
2.28 21
2.17 17
2.00 51
1.63 22
Wherein d is an interplanar distance, I/I
0Be relative intensity.
2. the manufacture method of 7-amino according to claim 1-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrochloride dihydrate crystal, it is characterized in that, in the concentrated hydrochloric acid solution of 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid, drip ketones solvent, under-10～40 ℃ temperature, make whole system in the steady district that is situated between, add crystal seed, stir growing the grain at a slow speed at 30 rev/mins, continue to add ketones solvent, and this system is remained in the steady district of Jie, obtain the crystal of even particle size distribution; Wherein said ketones solvent is acetone, 2-butanone or 4-methyl-2 pentanone; The weight ratio of the concentrated hydrochloric acid solution of described ketones solvent and 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid is 2: 1 to 100: 1.
3. the manufacture method of 7-amino according to claim 2-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrochloride dihydrate crystal is characterized in that the weight ratio of the concentrated hydrochloric acid solution of described ketones solvent and 7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid is 10: 1 to 30: 1.
4. the manufacture method of 7-amino according to claim 2-3-picolyl-3-cephalosporin-4-carboxyl acid dihydrochloride dihydrochloride dihydrate crystal is characterized in that described temperature is 0 ℃～25 ℃.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02134421 CN1261438C (en) | 2002-07-22 | 2002-07-22 | 7-amino-3-picolyl-3-cephalosporin-4-carboxylic acid dihydrochloride dihydrate crystal and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 02134421 CN1261438C (en) | 2002-07-22 | 2002-07-22 | 7-amino-3-picolyl-3-cephalosporin-4-carboxylic acid dihydrochloride dihydrate crystal and its preparation method |
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| Publication Number | Publication Date |
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| CN1410427A CN1410427A (en) | 2003-04-16 |
| CN1261438C true CN1261438C (en) | 2006-06-28 |
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| CN102391289B (en) * | 2011-12-03 | 2013-09-18 | 齐鲁安替制药有限公司 | Synthetic methods of ceftazidime intermediate and ceftazidime |
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Granted publication date: 20060628 |