CN102675351A - Crystalloid of biapenem intermediate and preparation method of crystalloid - Google Patents
Crystalloid of biapenem intermediate and preparation method of crystalloid Download PDFInfo
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- CN102675351A CN102675351A CN2012100395280A CN201210039528A CN102675351A CN 102675351 A CN102675351 A CN 102675351A CN 2012100395280 A CN2012100395280 A CN 2012100395280A CN 201210039528 A CN201210039528 A CN 201210039528A CN 102675351 A CN102675351 A CN 102675351A
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Abstract
The invention provides an improved crystalloid of a biapenem intermediate. The structure of the crystalloid is shown as in the description. The invention also provides a preparation method for the crystalloid of the biapenem intermediate. The preparation method comprises the following steps of: adding a compound II and a compound III in a mixed solvent of DMF (Dimethyl Formamide) and acetonitrile; reducing the temperature of the system to about 10DEG C and adding diisopropylethylamine; reacting at the temperature of 0-10DEG C, wherein the reaction temperature is preferably 5-10DEG C and the reaction time is preferably 2-3 hours; adding a ketone solvent in a reaction system and crystallizing by stirring; and carrying out solid-liquid separation on the reaction system to obtain the crystalloid. According to the preparation method disclosed by the invention, the ketone solvent is added when the reaction system is subjected to post treatment, so that the biapenem intermediate can be effectively crystallized and impurities can be effectively removed. The crystalloid of the biapenem intermediate, which is prepared by the preparation method provided by the invention, has the advantages of large crystalloid grains, facilitation for solid-liquid separation, favorable stability, easy drying and storing and more suitability for industrial production.
Description
Technical field
The present invention relates to xln of biapenem midbody and preparation method thereof; Relate in particular to a kind of 6-[[(4R, 5S, 6S)-2-(4-nitro carbobenzoxy-(Cbz))-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-3-yl] sulfenyl]-6; 7-dihydro-5H-pyrazolo [1; 2-α] [1,2,4] muriatic xln of triazole-4-and preparation method thereof.
Background technology
6-[[(4R; 5S, 6S)-2-(4-nitro carbobenzoxy-(Cbz))-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-3-yl] sulfenyl]-6,7-dihydro-5H-pyrazolo [1; 2-α] [1; 2,4] triazole-4-muriate is a kind of midbody of synthetic 1 Beta-methyl carbapenem antibiotic biapenem, and its structural formula is suc as formula I:
Biapenem is the exploitation of Japanese Lederle company and U.S. nitrile amine company, and gone on the market in Japan by Japanese Lederle company and Japanese Mingzhi K.K. Union in March, 2002, and its structure is suc as formula IV:
The biapenem has a broad antifungal spectrum; Has superior anti-microbial activity and biological chemistry stability; Stable to the DHP enzyme, the clinical secondary infection of treatment chronic bronchitis, pneumonia, pulmonary suppuration disease, pyelonephritis, complicacy urocystitis, peritonitis and the adnexitis of being applicable to.
People such as T.Kumagai have reported the preparation process of biapenem midbody at J.Org.Chem.1998 in 63:8145～9, be with (4R; 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (II) and 6,7-dihydro-6-sulfydryl-5H-pyrazoles [1; 2-α] muriate (III) adds in the mixed organic solvents of acetonitrile-acetone-DMF in [1,2,4] triazole; Add the alkaline reagents diisopropyl ethyl amine again, 0 ℃ was reacted crystallization 2 hours down; Filter, with the DCM washing, vacuum-drying and colourless acicular crystal.
Liu Xiangkui etc. are at Chinese Journal of Pharmaceuticals, and 2006,37; (12), 793～5, the preparation process of the biapenem midbody of report is that formula II compound and formula III compound are added in the anhydrous acetonitrile in " synthesizing of biapenem "; 0 ℃ drips the alkaline reagents diisopropyl ethyl amine down, and equality of temperature reaction 2 hours is filtered; Filter cake washs with DCM, gets faint yellow solid.
The preparation process of the biapenem midbody of report is that formula II compound and formula III compound are added in 1: 1 acetonitrile-acetone mixed solvent among the one Chinese patent application CN101121716 " a kind of compound method of biapenem "; Be cooled to 0 ℃, 0 ℃～5 ℃ drip the alkaline reagents diisopropyl ethyl amine down, drip Bi Jixu reaction 2 hours; Crystallization; Filter, drying gets faint yellow solid.
The preparation method that China applies for a patent the biapenem condensation compound of report among the CN101747352 " a kind of preparation method of biapenem condensation compound and xln thereof " adds to formula II compound and formula III compound in the acetonitrile, and adds a kind of lower alcohol, as mixed solvent; Be cooled to about 0 ℃; 0 ℃～5 ℃ drip the alkaline reagents diisopropyl ethyl amine down, in 0 ℃～5 ℃ reactions 2～5 hours, crystallization; Filter, get the biapenem condensation compound crystal.
Summary of the invention
Technical problem to be solved by this invention is: a kind of xln of improved biapenem midbody is provided, and its crystal grain is big, helps solid-liquid separation, good stability.
For this reason, the present invention adopts following technical scheme: a kind of xln of biapenem midbody, its chemical name are 6-[[(4R; 5S, 6S)-2-(4-nitro carbobenzoxy-(Cbz))-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-3-yl] sulfenyl]-6,7-dihydro-5H-pyrazolo [1; 2-α] [1; 2,4] triazole-4-muriate, its structure is suc as formula shown in the I:
Wherein, PNB is to nitrobenzyl.
Said xln powder x-ray diffraction figure is illustrated in 5.479 ± 0.2 with 2 θ angles, 7.441 ± 0.2,15.68 ± 0.2,15.981 ± 0.2; 20.22 ± 0.2,22.139 ± 0.2,24.18 ± 0.2; 28.7 ± 0.2,32.859 ± 0.2, there is the peak at 35.478 ± 0.2 places.
Said xln powder x-ray diffraction figure is illustrated in 18.019 ± 0.2 places with 2 θ angles has the peak, and peak intensity is 100%.
Use the KBr compressing tablet analyze infrared absorption spectrum that said xln obtains 3408,3118,2962,1770,1701,1670,1606,1517,1458,1386,1342,1205,1136,1045,972,844,738,650cm
-1There is absorption peak at the place.
The testing conditions of above-mentioned powder x-ray diffraction spectrogram is following:
Instrument: XRD D8ADVANCE;
Target: Cu-Ka radiation, 2 θ=5-60 °;
Step angle: 0.02 °;
Pipe is pressed: 40KV;
Pipe stream: 50mA;
Computing time: 0.3 second.
Another technical problem to be solved by this invention is: a kind of preparation method of xln of above-mentioned biapenem midbody is provided, and its crystallization is easy, more can remove the impurity in the reaction effectively, and product gas purity is high.
A) compound I I and compound III are joined in the mixed solvent of DMF and acetonitrile,
B) system is cooled to 0～10 ℃, adds diisopropylethylamine;
C) under 0 ℃～10 ℃ temperature, reacted 2～10 hours; Wherein temperature of reaction is preferred 5 ℃～10 ℃, preferred 2～3 hours of reaction times;
D) in reaction system, add ketone solvent, stirred crystallization;
E) reaction system is carried out solid-liquid separation, obtain formula I compound crystal body.
Wherein, the ketone solvent of step d) is selected from acetone, butanone, 2 pentanone, MIPK, MIBK, propione, ketopentamethylene and pimelinketone.
The solid-liquid separation of step e) can adopt any common solid-liquid separation method, like decompress filter, spinning etc.
Because adopt technical scheme of the present invention, the present invention adds the lower ketones solvent when reaction system is carried out aftertreatment, can make the crystallization of biapenem midbody effectively, can remove impurity effectively.And, xln 6-[[(4R, the 5S of the prepared biapenem midbody of the present invention; 6S)-2-(4-nitro carbobenzoxy-(Cbz))-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-3-yl] sulfenyl]-6,7-dihydro-5H-pyrazolo [1,2-α] [1; 2,4] triazole-4-muriate, its crystal grain is big; Help solid-liquid separation, good stability, be easy to drying and preservation, be more suitable for suitability for industrialized production.
Description of drawings
Fig. 1 is the powder x-ray diffraction spectrogram of xln provided by the present invention.
Fig. 2 is the infrared absorption spectrum of xln provided by the present invention.
Embodiment
Below in conjunction with embodiment the present invention is further described.
Will (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (compound I I) 60g and 6,7-dihydro-6-sulfydryl-5H-pyrazoles [1; 2-α] muriate (compound III) 22g adds in the mixed organic solvents of 1: 1 acetonitrile-DMF of 200mL in [1,2,4] triazole; Stirring is cooled to 10 ℃, drips to add the alkaline reagents diisopropyl ethyl amine, and 10 ℃ were reacted 2～3 hours down; In reaction system, add 150mL acetone, stirring and crystallizing is filtered; Washing, vacuum-drying gets crystal 4 4.8g, HPLC purity 98.8%.Xln to the biapenem midbody of gained carries out the powder x-ray diffraction analysis, and the result sees accompanying drawing 1 and table 1.
Table 1
| 2θ | The d value | The peak is strong | The peak is by force than (%) |
| 5.479 | 16.1167 | 946 | 60.3 |
| 7.441 | 11.8716 | 375 | 25.2 |
| 8.921 | 9.905 | 217 | 19.1 |
| 13.981 | 6.3294 | 277 | 15.8 |
| 15.68 | 5.6471 | 710 | 60 |
| 15.981 | 5.5414 | 354 | 54.9 |
| 16.54 | 5.3551 | 336 | 16.7 |
| 18.019 | 4.9188 | 1614 | 100 |
| 20.22 | 4.3881 | 337 | 26.4 |
| 21.18 | 4.1914 | 479 | 20.9 |
| 22.139 | 4.012 | 1061 | 69.9 |
| 22.661 | 3.9208 | 267 | 24.4 |
| 23.26 | 3.8211 | 379 | 16.9 |
| 24.18 | 3.6778 | 1123 | 75.1 |
| 25.538 | 3.4851 | 269 | 18.2 |
| 26.379 | 3.3759 | 216 | 17.3 |
| 28.7 | 3.1079 | 1194 | 72.4 |
| 32.859 | 2.7235 | 454 | 28.3 |
| 35.478 | 2.5282 | 266 | 27 |
| 45.881 | 1.9763 | 119 | 16.1 |
The testing conditions of powder x-ray diffraction spectrogram is following:
Instrument: XRD D8ADVANCE;
Target: Cu-Ka radiation, 2 θ=5-60 °;
Step angle: 0.02 °;
Pipe is pressed: 40KV;
Pipe stream: 50mA;
Computing time: 0.3 second.
To gained biapenem midbody xln use infrared absorption spectrum that the analysis of KBr compressing tablet obtains locate 3408,3118,2962,1770,1701,1670,1606,1517,1458,1386,1342,1205,1136,1045,972,844,738,650cm
-1Absorption peak is arranged, as shown in Figure 2.
Embodiment 2: the preparation method 2 of the xln of biapenem midbody.
Will (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (compound I I) 30g and 6,7-dihydro-6-sulfydryl-5H-pyrazoles [1; 2-α] muriate (compound III) 11g adds in the mixed solvent of 1: 1 acetonitrile-DMF of 150mL in [1,2,4] triazole; Stirring is cooled to 10 ℃, drips to add the alkaline reagents diisopropyl ethyl amine, and 10 ℃ were reacted 2～3 hours down; In reaction system, add the 100mL butanone, stirring and crystallizing is filtered; Washing, vacuum-drying gets crystal 2 1.2g, HPLC purity 97.7%
Embodiment 3: the preparation method 3 of the xln of biapenem midbody.
Will (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (compound I I) 30g and 6,7-dihydro-6-sulfydryl-5H-pyrazoles [1; 2-α] muriate (compound III) 11g adds in the mixed solvent of 1: 1 acetonitrile-DMF of 150mL in [1,2,4] triazole; Stirring is cooled to 10 ℃, drips to add the alkaline reagents diisopropyl ethyl amine, and 10 ℃ were reacted 2～3 hours down; In reaction system, add 2 pentanone 100mL, stirring and crystallizing is filtered; Washing, vacuum-drying gets crystal 2 0.8g, HPLC purity 98.9%.
Xln to embodiment 2 and embodiment 3 gained carries out powder x-ray diffraction analysis and the analysis of KBr compressing tablet, shows that the biapenem midbody xln crystalline form of gained is consistent with embodiment 1 gained xln crystalline form.
Being merely of above the disclosed embodiments can be realized those skilled in the art or used the present invention and specifying of making, and is not limitation of the present invention.Do not depart from modification or the improvement of being made on the basis of the present invention, all belonging to the scope of protection.
Claims (7)
1. the xln of a biapenem midbody, its structure is suc as formula shown in the I:
2. the xln of a kind of biapenem midbody as claimed in claim 1 is characterized in that the powder x-ray diffraction figure of said xln is illustrated in 5.479 ± 0.2,7.441 ± 0.2 with 2 θ angles; 15.68 ± 0.2,15.981 ± 0.2,20.22 ± 0.2; 22.139 ± 0.2,24.18 ± 0.2,28.7 ± 0.2; 32.859 there is the peak at ± 0.2,35.478 ± 0.2 places.
3. the xln of a kind of biapenem midbody as claimed in claim 1, the powder x-ray diffraction figure that it is characterized in that said xln is illustrated in 18.019 ± 0.2 places with 2 θ angles has the peak, and peak intensity is 100%.
4. the xln of a kind of biapenem midbody as claimed in claim 1; It is characterized in that, use the KBr compressing tablet analyze infrared absorption spectrum that said xln obtains 3408,3118,2962,1770,1701,1670,1606,1517,1458,1386,1342,1205,1136,1045,972,844,738,650cm
-1There is absorption peak at the place.
5. the preparation method of the xln of an a kind of biapenem midbody as claimed in claim 1 is characterized in that, it may further comprise the steps:
A) compound I I and compound III are joined in the mixed solvent of DMF and acetonitrile,
B) system is cooled to 0 ℃～10 ℃, adds diisopropylethylamine;
C) under 0 ℃～10 ℃ temperature, reacted 2～10 hours;
D) in reaction system, add ketone solvent, stirred crystallization;
E) reaction system is carried out solid-liquid separation, obtain formula I compound crystal body.
6. the preparation method of the xln of a kind of biapenem midbody as claimed in claim 5 is characterized in that, said ketone solvent is selected from acetone, butanone, 2 pentanone, MIPK, MIBK, propione, ketopentamethylene and pimelinketone.
7. the preparation method of the xln of a kind of biapenem midbody as claimed in claim 5 is characterized in that, preferred 5 ℃～10 ℃ of the temperature of reaction of said step c), preferred 2～3 hours of reaction times.
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| CN103570750A (en) * | 2013-11-15 | 2014-02-12 | 安徽悦康凯悦制药有限公司 | Preparation process of biapenem |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2004103966A1 (en) * | 2003-05-21 | 2004-12-02 | Ckd Bio Corporation | Chiral 2-azetidinone compounds, process and use thereof |
| CN101735220A (en) * | 2008-11-13 | 2010-06-16 | 石药集团中奇制药技术（石家庄）有限公司 | Crystal form of 6, 7-dihydro-6-mercapto-5H-pyrazolo[1,2-alpha][1,2,4] triazoliumchloride and preparation method thereof |
| CN101747352A (en) * | 2008-12-11 | 2010-06-23 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method for biapenem condensation compound and crystalline solid thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004103966A1 (en) * | 2003-05-21 | 2004-12-02 | Ckd Bio Corporation | Chiral 2-azetidinone compounds, process and use thereof |
| CN101735220A (en) * | 2008-11-13 | 2010-06-16 | 石药集团中奇制药技术（石家庄）有限公司 | Crystal form of 6, 7-dihydro-6-mercapto-5H-pyrazolo[1,2-alpha][1,2,4] triazoliumchloride and preparation method thereof |
| CN101747352A (en) * | 2008-12-11 | 2010-06-23 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method for biapenem condensation compound and crystalline solid thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570750A (en) * | 2013-11-15 | 2014-02-12 | 安徽悦康凯悦制药有限公司 | Preparation process of biapenem |
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