Process for preparation of crystalline half-hydrade of cefadroxyl

专利摘要:
The invention relates to a novel crystalline cefadroxyl hemihydrate having a K.F. between about 3.5 and 2.0% : such compound is more stable than other cefadroxyl molecules. The novel cefadroxyl is obtained preparing and isolating a novel cefadroxil solvate of dimethylacetamide, or of N-methyl-2--pyrrolidone or of monomethylformamide, slurrying said solvate with a mixture methanol/isopropyl alcohol 30:70 to 70:30 by volume in the presence of from 5% to 12% of water a temperature of about +45 DEG C to + 55 DEG C and then filtering the so obtained compound.
公开号:SU1630613A3
申请号:SU884355195
申请日:1988-02-15
公开日:1991-02-23
发明作者:Марсили Леонардо
申请人:Рифар С.Р.Л. (Фирма)；
IPC主号:

专利说明:


ABOUT
This invention relates to a process for the preparation of a new crystalline form of a cephalosporin antibiotic, namely crystalline cefadroxil hemihydrate, which is used in medicine.
The purpose of the invention is the creation of a new crystalline form cefadroxyl, possessing a higher resistance in time and to environmental influences.
Abbreviations used: 7-ADSA 7-amino deacetoxycephalosporanic acid; K.F, - water content9 determined by Karl Fischer titration.
The NMR spectra were recorded in a solution of Df) 0 (15 mg / ml) on a Brian XL-300 spectrometer,
Example 1. Cefadroxy solvate with dimethylacetamide.
7-ADSA (45 g) was added to methylene chloride (700 ml) at room temperature. Triethylamine (35.5 g) is added over 15 minutes while stirring at a temperature below 25 ° C. Trimethylchlorosilane (43.2 g) is then added dropwise over a 30 minute period. The mixture was stirred at 30 ° C for 90 minutes and then cooled to -10 ° C.
Dimethylaniline (31 g) and 1 (-) - p-hydroxyphenylglycyl chloride semi-dioxane solvate of the hydrochloride (63 g) are added and the mixture is stirred at (-5) Q ° C for about 90 minutes. Water (170 ml) was added and the reaction mixture was stirred for 30 minutes. The aqueous phase is diluted with dimethylacetamide (350 ml) and the pH is adjusted to 6.0 with the slow addition of diethylamine at 25 ° C. The mixture is stirred for 20 minutes. The dimetylacetamide solvate of cefadroxyl is collected by filtration, washed with a mixture of pimethylacetamide and water 2: 1, then with acetone. After drying at 40 ° C., 81.3 g of the expected compound are obtained.
K.F .: 0.51%.
Analysis by high pressure or high resolution liquid chromatography (HPLC): 69.3% on a dry basis. IMP: 6 / 9-7.35 f (multiplet, C6H4); 5.59 s (doublet, C (7) -H), 5.15 J1 (synglet, CH-CO), 4.93 s (doublet, CK-S), 3.02-3.42 a (multiplet, S-CH), G, $ 8 (singlet, SKU, characteristic of the cefadroxyl molecule; the following peaks relate to the solvent: 2.83-3.01 in (snnglet, singlet, K (CH3) 4), 2.04 ( duolet, With OSI b).
0
five
0
five
0
five
0
HAC-NQR: 21.07 R (CHa-C); 30.93 (CHft-S); 58.78 J (CH-NHa), 59.51 (CH-S), 61.160 (NH-CH-CO), 124.600
(about 3
(C-CK3), 126.11 O (C-COOH), 166,210
(Cp7p-lactam), 172.37 C (COOH), 172.58 U (CO-in), 129.050, 132.7 (J, 118.99 o, 160.45 a (aromatic carbon atoms) characteristic of cefadroxyl molecules; the following peaks relate to the solvent: 23.15 ° (CO-CH3), 37.93 ° (N-CH5), 40.85 51 (K-CH3), 176.74 O (CO). Example 2. Cefadroxyl Crystal Hemihydrate,
The dimethylacetamide solvate of cefadroxyl (50 g), obtained according to example 1, is suspended in a mixture of isopropyl alcohol (250 ml) and methanol (320 ml) in the presence of 24 ml of water at 48–50 ° C,
After 120 minutes, the mixture was cooled to 10 ° C, filtered and washed with acetone to obtain 34.5 g of crystalline cefadroxyl hemihydrate.
K.F .: 2.8%.
Methanol: 0.009%.
Isopropyl alcohol: 0.17%.
HPLC analysis: 99.1% on a dry basis.
The powder exhibits the following x-ray diffraction properties measured for a powder under irradiation with a wavelength of 54051 A using a copper tube with nickel filtrate (Cu / Ni) with interplanar values: distances d and relative intensities 1/1 given in Table 1.
Table 1
The continuation of the table.1.
Example 3. Cevadroxyl solvate with monomethylformamide.
7-ADSA (30 g) was added to methylene chloride (450 ml), trimethylchlorosilane (28.8 g) was added, and the mixture was stirred for 10 minutes. Triethylamine is then added dropwise over a 30 minute period (23.7 g at this temperature, it is possible to reach 30 ° C. The mixture is stirred for 2 hours at 30 ° C and then cooled to.
Bis-trimethylsilyl urea (21 g) was added to the semi-dioxane solvate of D (-) - p-hydroxyphenylglycyl chloride hydrochloride (45 g), and the mixture was allowed to react at -5 ° C for 90 minutes. After an additional 30 minutes of stirring at 0 ° C, water (115 ml) was added. .
The reaction mixture is stirred for 30 minutes, the aqueous layer is cooled to 5 ° C and diluted with monomethylformamide (240 ml). Triethylamine was added slowly over 60 minutes and the pH was 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, and then with acetone, to obtain, after drying at 40 ° C, 49 g of the desired compound:
K.F .: 0.9%.
HPLC analysis: 79.8% dry.
five
0
five
0
PNR: in addition to the peaks characteristic of the cefadroxyl molecule shown in Example 1, the following peaks are observed as a result of the solvent 7.98 8 (singlet, HCO), 2.71 $ cis (singlet, NHCKj)
 3C-NMR: in addition to the peaks characteristic of the cefadroxyl molecule shown in Example 1, the following peaks relate to the solvent: 27.07 o (CH3), 167.6 (H-CO).
Example 4. Crystalline cefadroxyl hemihydrate.
Monomethylformamide solvate of cefadroxil 30 g, obtained according to example 3, is suspended in 150 ml of a mixture of 1: 1 methanol and isopropyl alcohol in the presence of 16 ml of water at 52 ° C. After 70 minutes at 50 ° C, the mixture is cooled to 50 ° C, filtered and washed with acetone to obtain 23.2 g of cefadroxyl crystalline hydrate.
K.F .: 2.9%.
HPLC analysis: 99.6% on a dry basis.
Methanol: 0.008%.
Isopropyl alcohol: 0.15%.
The powder exhibits the same X-ray diffraction properties as the product obtained in Example 2.
Example 5. MES cefadroxil with dimethylacetamides.
A potassium salt of methyl P (-) - p-hydroxyphenylglycine (30.3 g) is added to acetone (170 ml) and the mixture is cooled to -AO ° C.
Sodium chlorocarbonate (11.15 g) and N-methylmorpholine (0.25 ml) are added at -40 ° C. The temperature is maintained at -35 ° C for 120 minutes, then the mixture is cooled to -55 ° 0.
7-ADSA (21.5 g) was loaded at 5 ° C into water (50 ml) and dimethyl sulfoxide (90 ml) and triethylamine (11.3 g) were added. The resulting solution is cooled to 0 ° C and a suspension of the mixed anhydride is added to the 7-ADSA solution (at -55 ° C).
The mixture was stirred for 60 minutes. The temperature was raised to 0CC and 5 was slowly added to it over 60 minutes. 37% HC1 to a constant pH of 1.8. Methylene chloride (175 ml) is added and the mixture is stirred for 15 minutes. The upper layer is diluted with dimethylacetamide (170 ml)
five
0
five
0
and acetone (70 ml), the pH was adjusted to 6.5 at 0 ° C with triethylamine.
The mixture was stirred at 0 ° C for 2 hours. The solvate was washed with a mixture of dimethylacetamide / water 2: 1 and then with acetone to obtain} 40.5 g of the title compound after drying at 40 ° C.
KR: 0.63%.
HPLC analysis: 69.1% on a dry basis. Methanol: 0.008%.
Example 6. Cefadroalkyl solvate with 1-methyl-2-pyrrolidone.
7-ADSA (30 g) is reacted according to the procedure described in Example 1 using. 1-methyl-2-pyrrolidone instead of dimethyl acetamide. Output: 52 g.
K.F. 0.85%.
HPLC analysis: 68.7% on a sudda-20 basis for 90 minutes while cooling, it is allowed to reach 10 ° C, filtered and washed
PMR: in addition to the peaks characteristic of the cefadroxyl molecule shown in Example 1, the following are observed
tanol (200 ml) and water (30 ml) at 18-50 ° C.
After 120 minutes, the mixture was cooled to before, filtered and washed with acetone to obtain 26.8 g of cefadroxyl crystalline hemihydrate.
K.F .: 3.1%.
HPLC analysis: 98.7% on a dry basis.
Isopropyl alcohol: 0.02%.
Example 9. Crystalline cefadroxyl hemihydrate.
The monomethylformamide solvate of cefadroxyl (30 g) is suspended in a mixture of methanol (100 ml), isopropyl alcohol (47 ml) and water (13 ml) at 50 ° C. After keeping the mixture
acetone to give 22.9 g of cefadroxyl crystalline hemihydrate. i K.F. 3.0%.
Peaks resulting from solution 25 HPLC analysis: 99.1% on a dry basis of 3.45 a (triplet), is. 2.36 (Y (triplet, SC (W)), 1.98 U Methanol: 0.008%.
(quartet, CH (4)), 2.84 (Ј (singlet, Isopropyl alcohol: 0.010%. N-CKj,). Example 10. Crystalline
S-NQR: in addition to the peaks characteristic of 30 cefadroxyl hemihydrate. for the cefadroxyl molecule, shown as 1-Methyl-2-pyrrolidone solvate in Example 1, the following peaks of cefadroxyl (30 ml) are suspended to the solvent: 19.71 ° C in a mixture of methanol (80 ml), isopropanol ( 4) X 32.27 8 (N, CE-5), 33.45 8 lilac alcohol (60 ml) and water (10 ml), 52.97 JHCH2 (5), 180.84 35 CENTURIES For 90 minutes After oh
 CO (2) 1.
Example 7. Crystalline. Cefadroxyl hemihydrate.
Cefadroxyl 1-methyl-2-pyrrolidone solvate (30 ml) was suspended in a mixture of 100 ml of isopropyl alcohol and 50 ml of methanol, left to stand at 45-48 ° C in the presence of 19 ml of water for 100 minutes. After cooling to 10 ° C the mixture is filtered, the product is washed with acetone and dried at 40 ° C.
The output of the hemihydrate: 19.5 g
K.F .: 2.5%.
After drying up to 10 ° C, the mixture is filtered, the product is washed with acetone and dried at 40 ° C to obtain 19.1 g of cefadroxyl crystalline hemihydrate.
K U. about 4VF, G. . Ј, U / o.
KPLC analysis: 98.9% on a dry basis.
Methanol: 0.009%.
Isopropyl alcohol: 0.16%. 45 Cefadroxyl crystal hemihydrate compared with the known cefadroxyl monohydrate is more stable against heat. After
ten,
HPLC analysis: 98.2% for a dry basis — 50–5 months at a temperature of 40 ° C. Cefadroxyl monohydrate shows a decrease.
Methanol: 0, 009%.
Isopropyl alcohol: 0.18%. 4 EXAMPLE 8. Cefadroxyl Crystal Hemihydrate.
Cefadroxyl dimethylacetamide solvate (40 g) is suspended in a mixture of isopropyl alcohol (100 ml), me55
The concentration of the main substance in the analysis of high-performance liquid chromatography by 2.9% (from 94.8 to 91.9%), while cefadroxyl hemihydrate in the same conditions shows a decrease in the content of the basic substance by 2.3% ( from 95.5% to 93.2%). Under the above conditions, monohydanol (200 ml) and water (30 ml) at 18-50 ° C.
After 120 minutes, the mixture was cooled to, filtered, and washed with acetone to obtain 26.8 g of cefadroxyl crystalline hemihydrate.
K.F .: 3.1%.
HPLC analysis: 98.7% on a dry basis.
within 90 min when it is cooled to 10 ° C, filtered and washed
Isopropyl alcohol: 0.02%.
Example 9. Crystalline cefadroxyl hemihydrate.
Monomethylformamide solvate of cefadroxyl (30 g) is suspended in a mixture of methanol (100 ml), isopropyl alcohol (47 ml) and water (13 ml) at 50 ° C. After keeping the mixture
 cefadroxyl hemihydrate. Cefadroxyl 1-methyl-2-pyrrolidone solvate (30 ml) is suspended in a mixture of methanol (80 ml), isopropyl alcohol (60 ml) and water (10 ml) for 90 min. After
After drying up to 10 ° C, the mixture is filtered, the product is washed with acetone and dried at 40 ° C to obtain 19.1 g of cefadroxyl crystalline hemihydrate.
K U. about, g. . Ј, U / o.
KPLC analysis: 98.9% on a dry basis.
Methanol: 0.009%.
Isopropyl alcohol: 0.16%. Cefadroxyl crystal hemihydrate compared with the known cefadroxyl monohydrate is more stable against heat. After
ten,
5 months at a temperature of 40 ° C cefadroxyl monohydrate shows a decrease
The concentration of the main substance in the analysis of high-performance liquid chromatography by 2.9% (from 94.8 to 91.9%), while cefadroxyl hemihydrate in the same conditions shows a decrease in the content of the basic substance by 2.3% ( from 95.5% to 93.2%). Under the above conditions, cefadroxyl monohydrate exhibits an increase in moisture content (0.3), while the hemihydrate form does not show a change in this parameter. The test results are summarized in Tables 2 and 3, where data on the heat resistance of a portion of cefadroxyl monohydrate and hemihydrate at 40 ° C, respectively, are given.
Thus, the above data clearly proves a higher stability of the new crystalline cefadroxyl hemihydrate compared to the known monohydrate form, and this stability provides a safer and longer storage of the product.
table 2
ten
characterized in that to the aqueous solution of cefadroxyl obtained by acylation of 7-amino-desacetate-hydroxycephalosporanic acid with a corresponding acylating agent, followed by dilution of the reaction mixture with water, is added to a solvent selected from the group comprising methyl methylacetamide, methyl 2-pyrrolidone and monomethylformamide, with the support of 20
When the pK value of the solution is 5.5-6, the corresponding solvate of cefadroxyl is formed as a precipitate is filtered off, dried and suspended in methanol, with isopropyl alcohol in a volume ratio of 30:70 - 70:30, containing 5-12% by volume of water, at a temperature of 45-55 ° C and the desired product is isolated from the reaction mass.
Priority signs: 24.04.87. Take a mixture of methanol with isopropyl alcohol in a volume ratio of 30:70 -50: 50, containing water.
08/04/87. Take a mixture of methanol with isopropyl alcohol in a volume ratio of 30: 70-70: 30, containing 5-12% by volume of water.

权利要求:
Claims (1)
[1]
In this case, the corresponding solvate of cefadroxyl is formed as a precipitate of the solution pK 5.5-6, filtered, dried and suspended in a mixture of methanol and isopropyl alcohol in a volume ratio of 30:70 70:30 containing 5-12% by volume of water at a temperature of 45 -55 ° C and from the reaction mass click the target product.
Priority featured:
04.24.87. Take a mixture of methanol with isopropyl alcohol in a volume ratio of 30:70 -50: 50, containing water.
08/04/87. Take a mixture of methanol with isopropyl alcohol in a volume ratio of 30: 70-70: 30, containing
5-12% by volume of water.

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引用文献:

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

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US4504697A|1982-04-28|1985-03-12|Littelfuse, Inc.|Sealed electrical devices|GB8714180D0|1987-06-17|1987-07-22|Rifar Srl|Anhydrous crystalline cefadroxil|

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AT112780T|1989-07-10|1994-10-15|Biochemie Sa|STABLE FORM OF CEPHRADIN, METHOD FOR THE PRODUCTION THEREOF AND INTERMEDIATE PRODUCTS USED IN IT.|

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IN190389B|1999-07-14|2003-07-26|Ranbaxy Lab Ltd|

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AU5418300A|1999-07-14|2001-01-30|Ranbaxy Laboratories Limited|Process for preparing crystalline cefadroxil hemihydrate from cefadroxil dimethylformamide solvate|

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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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CN102134250B|2011-01-19|2013-03-13|天津大学|Crystallization method of cefadroxil monohydrate and crystals|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB878709804A|GB8709804D0|1987-04-24|1987-04-24|Crystalline cefadroxil|

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GB878718394A|GB8718394D0|1987-08-04|1987-08-04|Crystalline cefadroxil hemihydrate|

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US07/089,168|US4904776A|1987-04-24|1987-08-25|Method for producing crystalline cefadroxil hemihydrate|

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