CN101747352A - Preparation method for biapenem condensation compound and crystalline solid thereof - Google Patents
Preparation method for biapenem condensation compound and crystalline solid thereof Download PDFInfo
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- CN101747352A CN101747352A CN200810080067A CN200810080067A CN101747352A CN 101747352 A CN101747352 A CN 101747352A CN 200810080067 A CN200810080067 A CN 200810080067A CN 200810080067 A CN200810080067 A CN 200810080067A CN 101747352 A CN101747352 A CN 101747352A
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Abstract
The invention relates to a preparation method for a biapenem condensation compound shown in a formula II and a crystalline solid thereof. Impurities in reaction raw materials can be effectively removed by adding a lower alcohol solvent in a reaction system so as to obtain the crystalline solid of the biapenem condensation compound with high purity. Because particles of the obtained crystalline solid of the biapenem condensation compound are large, the crystalline solid is beneficial to solid-liquid separation and drying, and is more suitable for industrial production.
Description
Technical field
The present invention relates to the synthetic of biapenem intermediate, be specifically related 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-a] muriatic preparation method of [1,2,4] triazole-4-and xln thereof.
Background technology
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-a] [1,2,4] triazole-4-muriate (below be called biapenem condensation compound), be an important intermediate of synthetic 1 Beta-methyl carbapenem antibiotic biapenem, its structural formula is suc as formula II:
Biapenem is by the exploitation of Japanese Lederle company and American Cyanamid Company, and gone on the market in Japan by Japanese Lederle company and Japanese Mingzhi K.K. Union in March, 2002, and its structural formula is suc as formula I.
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.
Toshio Kumagai etc. are at J.Org.Chem.1998, reported the preparation process of biapenem condensation compound in 63:8145～8149, 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 (IIi) and 6,7-dihydro-6-sulfydryl-5H-pyrazoles [1,2-α] [1,2,4] muriate (IV) adds in the mixed organic solvents of 1: 1: 0.1 acetonitrile-acetone-DMF in the triazole, adds the alkaline reagents diisopropyl ethyl amine again, 0 ℃ was reacted 2 hours down, crystallization filters, and uses washed with dichloromethane, vacuum-drying and colourless needle crystal, mp163-168 ℃ (decomposition point), IR (KBr) 1760,1695.
Liu Xiangkui etc. are at Chinese Journal of Pharmaceuticals, 2006,37 (12), 793～795, the preparation process of the biapenem condensation compound of report is that formula III compound and formula IV compound are added in the anhydrous acetonitrile in " synthesizing of biapenem ", 0 ℃ drips the alkaline reagents diisopropyl ethyl amine down, equality of temperature reaction 2h filters the filter cake washed with dichloromethane, get faint yellow solid, mp160-166 ℃.
The preparation process of the biapenem condensation compound of report is that formula III compound and formula IV compound are added in 1: 1 acetonitrile-acetone mixed solvent among the Chinese patent application CN101121716 " a kind of synthetic method of biapenem ", be cooled to 0 ℃, 0～5 ℃ drips the alkaline reagents diisopropyl ethyl amine down, drip Bi Jixu reaction 2h, crystallization filters drying, get faint yellow solid, mp163-167 ℃ (decomposition point).
The preparation method of above-mentioned patent and the described biapenem condensation compound of document, need after the purity of raw materials used formula III compound and formula IV compound reaches certain requirement (needing＞98% suc as formula the IV compound purity), just can reach expection preparation effect, this is on another aspect, preparation to raw material has also improved requirement (as needing repeatedly refining for reaching standard), and this is disadvantageous to saving cost on the industrial production.
Summary of the invention
Beat all, the inventor is in to the biapenem condensation compound synthesising process research, found a kind of improved biapenem condensation compound preparation method, adopt this method to prepare biapenem condensation compound, can effectively remove the impurity in the reaction raw materials, obtain a kind of highly purified biapenem condensation compound xln.
Therefore, an aspect of of the present present invention provides a kind of preparation method of biapenem condensation compound.
Another aspect of the present invention provides a kind of xln of biapenem condensation compound.
The preparation method of biapenem condensation compound according to an aspect of the present invention, it comprises:
A) formula III compound and formula IV compound are joined in the acetonitrile,
B) add a kind of lower alcohol solvent,
C) be cooled to about 0 ℃, drip the alkaline reagents diisopropyl ethyl amine,
D) under 0～5 ℃ of temperature, reacted 2～5 hours,
E) solid-liquid separation, the xln of biapenem condensation compound.
Wherein, lower alcohol is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol or the trimethyl carbinol.
Solid-liquid separation method is any suitable solid-liquid separation method, as decompress filter, and centrifugation etc.
The xln of biapenem condensation compound according to a further aspect of the invention is characterized in that: its powder x-ray diffraction figure is illustrated in 24.346 ± 0.2 places with 2 θ angles the peak, and the peak is by force 100% (seeing accompanying drawing 1, table 1).
The xln of biapenem condensation compound of the present invention, its further feature is: its powder x-ray diffraction figure is illustrated in 7.981 ± 0.2 with 2 θ angles, and 13.524 ± 0.2,14.674 ± 0.2,16.295 ± 0.2,18.121 ± 0.2,19.832 ± 0.2,22.513 ± 0.2,25.207 ± 0.2,28.499 there is peak (seeing accompanying drawing 1, table 1) at ± 0.2,32.086 ± 0.2 places.
The xln of biapenem condensation compound of the present invention is characterized in that: use infrared absorption spectrum that the analysis of KBr compressing tablet obtains 3415,3147,2964,1763,1695,1605,1552,1518,1442,1403,1384,1343,1322,1289,1221,1178,1137,1107,1083,1047,1000,972,934,863,848,799,766,737,691,649,607,560cm
-1There is absorption peak (seeing accompanying drawing 2) at the place.
The biapenem condensation compound xln particle of gained of the present invention is big, is beneficial to solid-liquid separation, drying, obtains the high purity sample, is more suitable in suitability for industrialized production.
Description of drawings
The testing conditions of following powder x-ray diffraction spectrum accompanying drawing is as follows:
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
Fig. 1 is the powder x-ray diffraction spectrogram of biapenem condensation compound xln of the present invention.
Fig. 2 is the infrared absorption spectra of biapenem condensation compound xln of the present invention.
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment do not constitute any restriction to the present invention.
The preparation method 1 of biapenem condensation compound xln
With 6,7-dihydro-6-sulfydryl-5H-pyrazoles [1,2-α] [1,2,4] in the triazole muriate 1kg and (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 2.5kg joins in the 12L acetonitrile, add ethanol 5L again, stir, be cooled to about 0 ℃, drip diisopropyl ethyl amine, the equality of temperature reaction is 2～5 hours again, filter washing, drying, get faint yellow biapenem condensation compound xln 1.95k g, HPLC purity 98.7%.Gained A Peinan condenses xln is carried out the powder x-ray diffraction analysis, the results are shown in accompanying drawing 1, table 1.
Table 1
| The |
2 θ values | The peak is strong | The peak is by force than (%) |
| ??2.71290 | ??32.991 | ??144 | ??17.4 |
| ??2.78735 | ??32.086 | ??344 | ??41.5 |
| ??3.12950 | ??28.499 | ??265 | ??31.9 |
| ??3.19601 | ??27.893 | ??116 | ??14.0 |
| ??3.25243 | ??27.400 | ??116 | ??13.9 |
| ??3.29528 | ??27.037 | ??125 | ??15.1 |
| ??3.53023 | ??25.207 | ??424 | ??51.1 |
| ??3.65305 | ??24.346 | ??829 | ??100.0 |
| ??3.94615 | ??22.513 | ??331 | ??39.9 |
| ??4.47314 | ??19.832 | ??428 | ??51.7 |
| ??4.62731 | ??19.165 | ??103 | ??12.5 |
| ??4.89160 | ??18.121 | ??328 | ??39.5 |
| ??5.43532 | ??16.295 | ??399 | ??48.1 |
| ??5.56942 | ??15.900 | ??196 | ??23.6 |
| ??5.76641 | ??15.354 | ??145 | ??17.5 |
| ??6.03192 | ??14.674 | ??363 | ??43.7 |
| ??6.54189 | ??13.524 | ??193 | ??23.2 |
| ??11.06946 | ??7.981 | ??210 | ??25.3 |
To gained biapenem condensation compound xln use infrared absorption spectrum that the analysis of KBr compressing tablet obtains 3415,3147,2964,1763,1695,1605,1552,1518,1442,1403,1384,1343,1322,1289,1221,1178,1137,1107,1083,1047,1000,972,934,863,848,799,766,737,691,649,607,560cm
-1There is absorption peak (seeing accompanying drawing 2) at the place.
The preparation method 2～5 of biapenem condensation compound xln
With reference to embodiment 1 preparation method, change lower alcohol solvent ethanol into methyl alcohol, n-propyl alcohol, Virahol, the trimethyl carbinol, get faint yellow biapenem condensation compound xln.Experimental result sees Table 2.
Table 2 embodiment 2～5 experimental results
| The embodiment numbering | Solvent | Product weight (kg) | HPLC purity (%) |
| ??2 | Methyl alcohol | ??1.90 | ??98.8 |
| ??3 | N-propyl alcohol | ??1.85 | ??98.6 |
| ??4 | Virahol | ??1.83 | ??98.7 |
| ??5 | The trimethyl carbinol | ??1.77 | ??98.5 |
Gained biapenem condensation compound xln is carried out the powder x-ray diffraction analysis, and KBr compressing tablet infrared analysis shows that the crystal formation of gained biapenem condensation compound xln is consistent with the crystal formation of embodiment 1 gained xln.
Embodiment 6
The preparation of biapenem
To add the 10L tetrahydrofuran (THF) by the biapenem condensation compound xln 1.8kg that the inventive method obtains, 0.3mol/L phosphate buffered saline buffer (pH5.6) 30L, stirring and dissolving adds 20% palladium carbon 0.3kg, control pressure 10kg/m
2, at 40 ℃ of reaction 30min, filtration, water adds acetone 40L with ethyl acetate 20L * 2 washings, and stirring at room 2h filters, solids washed with acetone, drying under reduced pressure gets biapenem 920g, HPLC purity 98.2%.
Claims (5)
1. the preparation method of a formula II compound,
It comprises:
A) formula III compound and formula IV compound are joined in the acetonitrile,
B) add a kind of lower alcohol solvent,
C) be cooled to about 0 ℃, drip the alkaline reagents diisopropyl ethyl amine,
D) under 0～5 ℃ of temperature, reacted 2～5 hours,
E) solid-liquid separation, the xln of formula II compound.
2. the preparation method of formula II compound as claimed in claim 1 is characterized in that: lower alcohol solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol or the trimethyl carbinol.
3. xln as the defined formula II compound of claim 1, it is characterized in that: its powder x-ray diffraction figure is illustrated in 24.346 ± 0.2 places with 2 θ angles the peak, and the peak is by force 100%.
4. the xln of formula II compound as claimed in claim 3, its further feature is: its powder x-ray diffraction figure is illustrated in 7.981 ± 0.2 with 2 θ angles, 13.524 ± 0.2,14.674 ± 0.2,16.295 ± 0.2,18.121 ± 0.2,19.832 ± 0.2,22.513 ± 0.2,25.207 ± 0.2,28.499 there is the peak at ± 0.2,32.086 ± 0.2 places.
5. the xln of formula II compound as claimed in claim 3 is characterized in that: use infrared absorption spectrum that the analysis of KBr compressing tablet obtains 3415,3147,2964,1763,1695,1605,1552,1518,1442,1403,1384,1343,1322,1289,1221,1178,1137,1107,1083,1047,1000,972,934,863,848,799,766,737,691,649,607,560cm
-1There is absorption peak at the place.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102675351A (en) * | 2012-02-21 | 2012-09-19 | 景德镇市富祥药业有限公司 | Crystalloid of biapenem intermediate and preparation method of crystalloid |
| CN104072523A (en) * | 2014-07-14 | 2014-10-01 | 上海新亚药业有限公司 | Preparation method of biapenem |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100497349C (en) * | 2006-01-26 | 2009-06-10 | 江苏先声药物研究有限公司 | Improved Biapenem preparation method |
| CN101121716A (en) * | 2007-09-28 | 2008-02-13 | 严洁 | Synthesis method for biapenem |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102675351A (en) * | 2012-02-21 | 2012-09-19 | 景德镇市富祥药业有限公司 | Crystalloid of biapenem intermediate and preparation method of crystalloid |
| CN102675351B (en) * | 2012-02-21 | 2015-05-13 | 江西富祥药业股份有限公司 | Crystalloid of biapenem intermediate and preparation method of crystalloid |
| CN104072523A (en) * | 2014-07-14 | 2014-10-01 | 上海新亚药业有限公司 | Preparation method of biapenem |
| CN104072523B (en) * | 2014-07-14 | 2017-10-24 | 上海上药新亚药业有限公司 | The preparation method of Biapenem |
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Effective date of registration: 20140620 Address after: 050035 the Yellow River Road, Shijiazhuang high tech Zone, Hebei, No. 226 Patentee after: Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. of CSPC Group Patentee after: Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd., Shiyao Group Address before: 050035 the Yellow River Road, Hebei, Shijiazhuang, No. 226 Patentee before: Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. of CSPC Group |