Method of producing alfa-form crystal monohydrate of bis-hydrobromide of cephtasidime

专利摘要:
The invention relates to ceftazidime derivatives, in particular the preparation of the g-form of crystalline ceftazidium bis-hydrobromide monohydrate with a specific X-ray diffraction pattern - an intermediate in the synthesis of cefaposporin antibiotics. The goal is to create new crystalline forms for the synthesis of antibiotics with better stability and purity. Synthesis is carried out by treating a solution of ceftazidime bis-hydrobromide in aqueous HCOOH with methyl ethyl ketone or cyclohexanone, followed by separating the crystallized product. During processing, cooled with ice. 1 il. CO with CA5 ate 05; o O) 00 cm
公开号:SU1356963A3
申请号:SU853864852
申请日:1985-03-19
公开日:1987-11-30
发明作者:Чоу Та-Сен
申请人:Эли Лилли Энд Компани (Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of a novel crystalline form of a cephaloperine compound, and a p-1-substituent L-form crystalline ceftazidime bis-hydrobromide monohydrate (6R57R) -7- (Z) -2- (2-aminothiazol-4-yl) -2- {2-carboxyprop-2-oxyimino) -acetamido-3- (1-pyridinomethyl) -3-cep-4-carboxylate | used as an intermediate in the synthesis of cephalosporin antibiotics.
The purpose of the invention is the creation of new crystalline forms of intermediates for the synthesis of cephalosporin antibiotics with enhanced stability and purity.
Example. Preparation from / is a form of ceftazidime bis-Reed.bromide crystalline monohydrate.
(6R, 7R) -7-j (Z) -2- (2-tritylamino-thiazol-4-yl) -2- (2-1.-butyloxycarbonylprop-2-oziimino) acetamido 1-3- ( 1-pyridinomethyl) -3-cephem-4-carboxylate, 18.5 g (0.02 M), is added to 40 ml of 98% formic acid (53 eq.). During the addition, the temperature of the mixture is maintained below 25 ° C with ice-cooling, the cooling bath is removed, and the mixture is stirred at room temperature for 2 hours. After cooling again from 10 to 15 seconds, 1.4 ml is added to the solution dropwise. % hydrobromic acid. After the addition is complete, the solution is stirred at room temperature for 2 hours. The reaction mixture is not filtered to remove triphenylcarbinol. Instead, 150 ml of methyl lithium ketone (IEC) is slowly added to the mixture, which makes the solution clear. After 45 minutes, an additional 304 ml of MEK is added, The resulting product is an insoluble oily resin, to which 100 ml of MEK is added. After stirring for 30 minutes at room temperature, the mixture is heated to 70 to. The resin crystallizes in a hot mixture, which is then cooled to 5-10 ° C. After the mixture is stirred for 30 minutes in the cold, the crystals are filtered, washed with 50 ml of cold MEK and dried under vacuum at room temperature, 4 are obtained. 48 g L-form crystalline monohydrate of bis-hydrobromide. Also get the second fraction
N
N
five
0
6.82 g of crystalline seli (darker in color).
Elemental analysis of the first fraction after drying the sample at 40 ° C is calculated for C,., G | , 3 „2НВг Н О.
Calculated,%: C 36.38; H 3.61; 11, 57; 017.62; S 8.83; Br 22.00.
Found,%: C- 36.12; H 3.36; 11.33; O 17.76; S 8.72; Br 22.26.
Example 2. 18, O g of ceftazidime used in the previous example, having an amino-protected group and, as a t-butyl ester, the protected carboxy-group is added to 40 ml of 98% formic acid. The temperature of the mixture using a bath with ice support below. The reaction mixture is stirred for 30 minutes, and then 11.8 ml of 48% hydrochloric acid is added dropwise to the mixture with stirring. The acidic mixture is stirred for 3.5 hours and then filtered to remove insoluble triphenylmethanol. The filtrate is divided into two equal volumes and one half is added dropwise with stirring to 185 ml of methyl ethyl ketone. After addition of the filtrate, crystalline monohydrate begins to precipitate. An additional 50 ml of methyl ethyl ketone is then added and the mixture is stirred at room temperature for 1.5 hours. The crystalline monocrystalline monohydrate is filtered off, washed with 50 ml of ketone and dried under vacuum at room temperature. White crystalline J-monohydrate weighs 5.50 g.
0 ... "
Other half released
the reaction mixture (31 ml), at room temperature, 185 ml of cyclohexanol is added dropwise with stirring. Some white precipitate forms, and when half of the filtrate is added, a gum formation is observed. Then the remainder of the filtrate is added and the mixture is stirred for 2 hours to form crystals. The mixture is stirred overnight to form dense crystals. The crystals are filtered, washed with 50 ml of cyclo-P-lexanone and dried without heating under vacuum. 4.68 g of crystalline d-monohydrate are obtained melting with decomposition at a temperature of about 77 ° C.
0
five
five
0
N
N
Elemental analysis of a sample of the product after drying at 40 ° C gives the following results calculated for C H N O S 2HEr -H O.
Calculated,%: C 36.38; H 3.61; 11.57; O 17.62; S 8.83; Br 22.00.
Found,%: C 36.67; H 3.57; 11.47; O 17.52; B 8.97; Br 21.89.
Mass spectral analysis M / e 547, so pl. - begins to decompose at 175 C.
New c1-form of ceftazidime bis-hydrobromide crystalline monohydrate was characterized by IR spectrum and X-ray diffraction. I,
The diagram in the figure depicts the IR absorption spectrum of the target compound (KBr tablet).
IR absorption spectrum of c-form of ceftazidime bis-hydrobromide crystalline monohydrate
(KBG tablet) cm
1176.7 1480.5 G630.0 1725.5. 1760.2 2982.2 3034.2 3045.8 3056.4 3077.6
The X-ray diffraction pattern shown in the claims was taken using a copper target, an X-ray tube with a nickel filter and a 114.6 mm Debye-Scherrer camera ((1-inter-spacing distance; 1/1, - relative intensity).
PRI me R 3, Conversion of the CI-form of ceftazidime bis-hydrobromide crystalline monohydrate to ceftazidime pentahydrate.
To a beaker containing 36 ml of water cooled to 5-10 ° C is added 9.0 g of bis-bromo-ceftazidime monohydrate. The mixture is stirred to obtain a solution, after which the pH is adjusted with 2N. WaOH to a value of 2.2. The resulting dark solution is then filtered through a pad of acid-washed celite. The temperature of the solution is maintained in the range from 13 to 15 ° C, and
The pH was adjusted with 2N. NaOH to 3.75. The solution, which maintains a temperature of 13-15 ° C, is seeded with crystals and stirring is continued. After 2 hours, crystallisation is complete. The mixture is cooled to O - 5 ° C and stirred for 3 hours, then filtered and washed with cold water and acetone, 40 ml each. The crystals formed are air dried overnight. The product yield is 77%.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining the d-form of ceftazidime bis-hydrobromide crystalline monohydrate, having the following 2Q X-ray diffraction:
five
d
14.85 10.65 9.94 8.08 7.66 6.71
0
five
, 74 .37 16 4.77 4.37 4.22 .04 .89, 78, 56
5. 5. 5.
4, 3. 3. 3.
3.35
0
29 II
five
2.93 2.88 2.79 2.74
70 58 54
2.45
0
24 14 09
l / li .17
.50
.08
.29
.29
L5b
.38
.04
.04
.25
.83
.00
.04
.00
.17
.17
.21
.25
.25
.29
.25
.08
.17 .04 .08 .13 .13 .17 .08 .08
characterized in that. The solution of bis-giyrobromid ceftazidime in aqueous formic acid is treated with methyl ethyl ketone or cyclohex sanon, followed by separation of the distilled product.
000 3500 SOUND 2SOO 2000/750 1500 1250 foOO 750 SffO
eos / f affffe i / t / c ff
Editor A.Dolinich
Compiled by Z. Latypova Tehred L. Serdyukova
Order 5817/58 Circulation 372Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035 ,. Moscow, Zh-35, Raushsk nab., D.4 / 5
Production and printing company, Uzhgorod, Projecto st., 4
Proofreader G. Reshetnik

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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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US06/593,441|US4537959A|1984-03-26|1984-03-26|Crystalline cephalosporin antibiotic salt|

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