前苏联专利SU1595340A3 Method of producing dehydrated crystalline cephadroxyl

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专利摘要:
The invention relates to a substantially anhydrous crystalline cefadroxil having a water content between about 0.8% and 3.9%. Such cefadroxil is obtained slurrying a cefadroxil solvate of dimethylacetamide, or of N-methyl-2-pyrrolidone or of monomethylformamide, with isopropyl alcohol containing either from about 2% to 4% of water of from about 0.1% to 4% of water and from 0% to about 60% of methanol, at a temperature in the range of about +45 DEG C to +55 DEG C and than filtering the desired cefadroxil so obtained.
公开号:SU1595340A3
申请号:SU884355130
申请日:1988-01-25
公开日:1990-09-23
发明作者:Марсили Леонардо
申请人:Рифар С.Р.Л.(Фирма)；
IPC主号:

专利说明:

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Od
.
This invention relates to a method for producing a new crystalline form of a cephalosporin antibiotic, namely an anhydrous crystalline cefadroxil, which is used in medicine.
The purpose of the invention is the creation of a new crystalline form of cefadroxil, which has a higher resistance in time and to environmental influences.
Abbreviations used: 7-ADCA - 7-amino deacetoxycephalosporanic acid; K.F. - water content determined by Karl Fischer titration.
Nuclear magnetic resonance spectra were recorded in a deuterium dioxide (B20) solution (15 mg / mp) on a Varian XH-ZOO spectrometer.
PRI me R 1. Cefadroxyldimethyl acetamide solvate.
s
ten
7-ADCA (45 g) was added to 700 ml of methylene chloride at room temperature. 35.5 g of triethylamine are added for 15 minutes with stirring at a temperature below 25 ° C. 42.3 g of trimethylchlorosilane are then added dropwise over 30 minutes. The mixture is stirred at 90 min, then cooled to.
31 g of dimethylaniline and 63 g of D (-) - p-hydroxyphenylglycyl chloride hydrochloride hemidioxane solvate are added and the mixture is stirred at -5/0 C for about 90 minutes. Add 170 ml of water and stir the reaction 15 mixture for 30 minutes. The aqueous phase is diluted with 350 ml of dimethylacetamide and the pH is adjusted to 6.0, diethylamine is gradually added at 25 ° C. The mixture is stirred at 20 ° C for 120 minutes. The solvate of cefadroxyldimethylacetamne is collected by filtration, washed with dimethylacetamide with 2: 1 water, then with acetone; this is obtained after drying at 81.3 g of the title compound. K, F, 05.51%.
Analysis by high performance liquid chromatography (HPLC): 63.3% on a dry basis.
thirty
35
Proton Magnetic Resonance (PMR) J 6.9-7.35 {/ (multiplet, C H 4-); 5.59
c / doublet, C (7) 5.15 (singlet, CH-CO) | 4.98tf doublet, 3.02- 3.42 cP (multiplet, S-CR); 1.8 g (singlet, CH). These peaks are characteristic
for cefadroxil. The following peaks are related to the solvent: 2.83-3.01 cp (singlet, singlet, N (CH,),); 2.04 (doublet, COCH3).
C-left magnetic resonance 40 (NMR) | 21.07 (1 (d1z-C) 5 30.93 (58.78 G (CH-W); 59.51 cP (CH-S); 61.61 cP (W-CH-CO) | 124.60 (C-CHE); 126, G1 SG (C-COOH); 166.21 (0, / 3-lactam;) | 172.37 J (COOH) | 172.58 &(CO-W); 45,129 , 05, 132.7, 118 ,, 160, (aromatic carbon atoms). These peaks are characteristic of cefadrocdyl. The peaks given are for solvent: 23.15 § (CO-CHj); 37.93 s (N-CHJ; 40.85 (N-CHJ; 176.74cP.
(comp. -
PRI mme R 2. Almost anhydrous crystalline cefadroxyl.
50 g of cefadroxyldimethylacetamide. the solvate prepared according to example 1 is suspended at 48–50 ° C in 380 ml of isopropyl alcohol containing 3.8% water. After 120 minutes the mixture is cooled50
55
ten

15 20 25
53404
They give up, filtered and washed with acetone, which gives 36.5 g of practically anhydrous crystalline cephalosporin containing 2.1% of water.
The powder shows X-ray diffraction properties determined on a PW 1710 diffractometer with normal scanning radiation of radiation (wavelength 1.5405 1) obtained with a Cu / Ni x-ray tube. 40 kW, 40 mA, are given in table.1.
Example 3. Cefadroxylmonomethylformamide solvate.
30 g of 7-ADCA are added to 450 ml of methylene chloride, 28.8 g of tri- is added. methylchlorosilane and the mixture is stirred for 10 minutes Then, 23.7 g of triethylamine are dropped over a period of 30 minutes, and the temperature is allowed to reach. The mixture is stirred for 2 hours at 30 ° C, then cooled to -10 ° C.
21 g of bis-trimethylsilyl urea and 45 g of B (-) - p-hydroxyphenylgly - are added. Cyl chloride hydrochloride hemidioxane solvate and the mixture is allowed to react at -5 C for 90 minutes. After additional
thirty
35
J
40 45
50
55
Stir for 30 minutes at 0 s. Add 115 ml of water.
The reaction mixture is stirred for 30 minutes, the aqueous layer is cooled to 5 ° C, diluted for 60 minutes and the pH is adjusted to 5.7 at 20 ° C. After stirring for 2 hours, the suspension is filtered, the filter cake is washed with a mixture of monomethylformamide and water 2: 1, then with acetone, which is obtained after drying at 49 g of the indicated compound. K.F. 0.9%.
Analysis by high performance liquid chromatography (HPLC) 79.8% on a dry basis.
Proton Magnetic Resonance (PMR): along with the characteristic peaks of cefadroxil shown in Example 1, the following peaks are due to the solvent: 7.98 sG (singlet, NSO); 2.7 i cis- (NHCHj singlet).
Nuclear Magnetic Resonance (NMR): along with peaks characteristic of cefadroxyl and shown in example t, the following peaks are due to the solvent: 27.07 (f (CH.) J 167.6cf
(n-co).
PRI me R 4. Almost anhydrous crystalline cefadroxil. 30 g of cefadroxyl monomethylformamide salt, prepared as indicated in Example 3, are stirred up in a 150 MP mixture of 1: 1
five
methanol and isopropyl alcohol with water at. After 70 minutes at 52, the mixture is cooled to 10 ° C, filtered and washed with acetone, which yields 23.5 g of a practically anhydrous crystalline cefadroxil with a water content of 1.0%. K.F. 1.8%.
Analysis by high performance liquid chromatography (98.8% HPLC on a dry basis.
The powder shows the same X-ray diffraction properties as in the product obtained in Example 2.
PRI me R 5. Cefadroxydimethy acetamide solvate.
30.3 g of the potassium salt of methyl D - (-) p-hydroxyphenylglycine is added to 170 acetone and the mixture is cooled to. 11.15 g of ethyl chlorocarbamate and 0.25 MP of N-methylmorpholine are added at-AOH. The temperature is maintained at 120 minutes, then the mixture is cooled to.
21.5 g of 7-ADCA are added at 5 ° C to 50 MP of water and 90 ml of dimethyl sulfoxide and 11.3 g of triethylamine are introduced. The resulting solution is cooled to and the mixed anhydride suspension (A-55 ° C) is added to the 7-ADCA solution.
The mixture is stirred at -25 ° C for 60 minutes, the temperature is raised and 37% hydrochloric acid is added slowly, 60 minutes to a constant pH of 1.8. 175 ml of methylene chloride are added and the mixture is stirred for 15 minutes. The upper layer is diluted with 170 ml of dimethylacetamide and 70 ml of acetone, the pH is adjusted to 6.5 with triethylamine. The mixture is stirred at 2 hours.

The solvate is washed with dimethylacetamide with water 2: 1, then with acetone, which gives 40.5 g of the indicated compound after drying at. K.F. 0.63%.
Analysis conducted vysokoeffek-. good liquid chromatography (HPLC): 69.1% on a dry basis.
PRI me R 6. Cefadroxyl-1-methyl-2-pyrrolide it is a solvate.
30 g of 7-ADCA are reacted according to the procedure described in Example 1, but using 1-methyl-2-pyrrolidone instead of dimethyl acetamide. Exit 52 g. K.F. 0 ,.
ten
-

,
The analysis carried out vysokoefg1) ekg., Tive liquid chromatography (HPLC): 68.7% on a dry basis.
Proton Magnetic Resonance (PMR): along with the characteristic peaks for cefadroxyl shown in Example 1, the following peaks are due to the solvent: 3.45 J1 (triplet, CH, j (5); 2.36 sG (triplet, CH2 (3) J; 1.98 eGSquardet, CH.i (4) J; 2.84 cG (singlet, N-CH).
S-nuclear magnetic resonance (W-1R) t, along with the characteristic peaks for cefadroxil shown in Example 1, the following peaks are due to ... solvent: 19, 7 J CH (4); 32.27 cg (CCH); 33.45 L CCH.i (3) J; 52.97 eG CCHj (5) J; 180.84 f C0 (2).
PRI me R 7. Almost anhydrous- 20% crystalline cefadroxyl.
30 g of cefadroxyl-1-methyl-2-pyrrolidone solvate is stirred up in a mixture of 110 ml of isopropyl alcohol and 40 ml of methanol with 2.8% of water, kept 25 at 45-48 ° C for 110 minutes. After cooling down to 10 ° C, the mixture is filtered, the product is washed with acetone and dried at 40 ° C. Yield: 16.5 g of practically anhydrous cefadroxil with a water content of 3.6%. K.F. 1.8%.
Analysis by high performance liquid chromatography (HPLC): 97.6% on a dry basis.
Anhydrous cefadroxil according to the proposed method is obtained with a very low water content (about 0.8%), but this water content immediately increases to 3.9% depending on the environmental humidity conditions. In this case, no changes in its crystal structure does not occur. The relative humidity should be increased by more than 90% in order for the conversion of an e-5-d-water cefadroxyl to a monohydrate form, which exposes a high stability of the-dan molecule. Compared with the monohydrate form, anhydrous cefadroxil is characterized by higher stability and higher heat resistance compared to one of the monohydrate forms,
The heat resistance of the batch of monohydrate JJ cefadroxil at 40 ° C is given in Table. 2
The heat resistance of the batch of anhydrous cefadroxil at 40 ° C is given in Table. 3
thirty
35
40
As can be seen from the above data, after 5 May of storage at AO C, cefadroxyl monohydrate is characterized by a decrease in stability determined by high pressure liquid chromatography by 2.9% (from 94.8% to 91.9%), while as anhydrous cefadroxil is characterized by an increase in stability determined by liquid chromatography under high pressure by 1.5% (from 95.7% to 94.2%), under the above conditions, cefadric monohydrate is characterized by a greater increase in humidity compared to one of the present anhydrous forms ( respectively 0.3 and 0.2). In addition, at temperatures exceeding, cefadroxyl monohydrate changes its color from white to pale yellow, which causes a change in the organoleptic characteristics that require pharmacology to preserve. This does not occur with anhydrous cefadroxil.
Thus, test data proves a higher stability of new anhydrous cefadroxn in comparison with the known cefadroxyl monohydrate, which allows anhydrous cefadroxil to be stored for a longer time without changing its properties,
The formula of "invention
The method of obtaining anhydrous crystalline cefadroxil with a water content of 0.8–3.9%, having the following x-ray diffraction properties measured for a powder upon irradiation with a wavelength of 5405 A on a copper tube with a nickel filter (CuiNi) with the following interplanar distances d and relative intensities

Relative intensity, 1/1 °
10.42 8.54
21,100
0 5
0
characterized in that a solvent selected from the group consisting of dimethylacetamide, N-MeTmi-2-pyrrolidone and monomethylformamide is added to an aqueous solution of cefadroxyp, freshly prepared from 7-aminodesacidine cefadroxyp, while controlling the pH of the solution in the range of 5.5-6 , 0 to form the corresponding cefadroxyl solvate, which is precipitated, filtered and, after drying, suspended in isopropyl alcohol containing 3-4% water, or containing 25-50% methanol and 1.4% water at a temperature of 45-55 ° C the following section elimination of the target product by filtration.
Interplanar spacings, dU)

94.8 4 2
93.5
.1 05/87
Relative intensity, 1/1 °
3
4 3 06/87
92.5 4.4 07/87
92.1 4.5 08/87
91.9 .5 09/87
Table3

权利要求:
Claims (1)
[1]
Formula "invented: Oia 35
A process for preparing anhydrous crystalline cefadroxil having a water content of 0.8 - 3.9%, having the following X-ray diffraction-40 GOVERNMENTAL properties measured _on the powder when irradiated with a wavelength = 1.5405 A copper tube with a nickel filter (Cu: Ni) with the following values of interplanar distances d and relative intensities, 1/1 °:
Interplanar, distance,d, A Relative intensities, 1/1 ° 10,42 21 8.54 100
Interplanar distances4, A Relativeseverity, 1/1 ° intensive 7.06 34 6.38 fifteen 6.05 22 5.84 25 5.12 16 4.79 26 ' 4,58 21 4.35 44 4.26 21 4.18 24 . 4.02 34 3.90 eleven 3.78 12 3.52 9 3.46 17 3.27 8 3.18 14 3.12 22 2.93 fifteen 2.89 18 2.82 16 | 2.61 12 2,55 10 2,52 7 2,35 9 2,30 9 2.18 8 2.13 7 2.08 7
characterized in that a solvent selected from the group consisting of dimethylacetamide, N-methyl2-pyrrolidone and monomethylformamide is added to an aqueous solution of cefadroxil freshly prepared from 7-aminodetacetoxycephalosporanic acid, while monitoring the pH of solution 45 in the range of 5.5-6.0 to form the corresponding cefadroxyl solvate, which is precipitated, is filtered off and, after drying, suspended in isopropyl alcohol containing 3-4% 50 water, or containing 25-50% methanol and 1.4% water, at a temperature of 45 55 ° C, followed by pouring the target product by filtration.
9 1595 340 10
Table 1
---------------_Interplanar distancesd (X) Relative intensities, 1/1 ° 10,42 21 8.54 100 7.06 34 6.38 fifteen 6.05 22 5.85 25 5.12 16 4, 79 26 4,58 21 4.35 44 4.26 21 4.18 24 4.02 34 3.90 eleven 3.78 12 3.52 9 3.46 17 3.27 8 3.18 14 3.12 22 2.93 fifteen 2.89 18 2.82 16 2.61 12 2,55 10 2,52 7 2,35 9 2,30 9 2.18 8 2.13 7 2.08 7
Table 2 Indicators Values for time, months 1 2 | ³I ⁴...1 - b ...
High Pressure Liquid Chromatography Analysis Results
laziness,% 94.8 93.5 93 92.5 92, 1 91.9 K.F.,% 4.2 4.1 4.3 4.4 4,5 4,5 date 0,4 / 87 05/87 06/87 07/87 08/87 09/87
and
AZ tables
Indicators Values indicators during, month0______ L.L— .._______1 5
Liquid Chromatography Analysis Results High
pressure, X 95.7 95.4 95.1 94.8 94.7 94.2 K.F., X 0.9 04/87 0.8 0.9 1 1,1 1,1 date 05/87 06/87 07/87 08/87 09/87

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引用文献:

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DE2163514A1|1971-12-21|1973-07-05|Toyama Chemical Co Ltd|7-acylcephalosporins - prepd via a silylated inter |

BE793191A|1971-12-28|1973-06-22|Toyama Chemical Co Ltd|PROCESS FOR PRODUCING 7-ACYLAMIDO-3-CEPHEM-4- CARBOXYLIC ACIDS|

US3985741A|1972-09-15|1976-10-12|Bristol-Myers Company|Production of p-hydroxycephalexin|

GB1532682A|1976-04-27|1978-11-22|Bristol Myers Co|Process for the preparation of cephadroxil|

DE3313818A1|1983-04-16|1984-10-18|Hoechst Ag, 6230 Frankfurt|NEW CEFTAZIDIM CRYSTAL MODIFICATION|

US4904776A|1987-04-24|1990-02-27|Rifar S.R.L.|Method for producing crystalline cefadroxil hemihydrate|US4898938A|1987-08-03|1990-02-06|Rifar S.R.L.|Method for preparing crystalline cefadroxil monohydrate|

US20040077849A1|2002-10-16|2004-04-22|Orchid Chemicals & Pharmaceuticals Limited|Process for the preparation of cefadroxil|

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EP2024374A1|2006-05-19|2009-02-18|DSMIP Assets B.V.|Process for the crystallisation of cefadroxil|

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法律状态:

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申请号 | 申请日 | 专利标题

GB878714180A|GB8714180D0|1987-06-17|1987-06-17|Anhydrous crystalline cefadroxil|

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