CN102952125A - 3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal and preparation method thereof - Google Patents
3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal and preparation method thereof Download PDFInfo
- Publication number
- CN102952125A CN102952125A CN2011102499078A CN201110249907A CN102952125A CN 102952125 A CN102952125 A CN 102952125A CN 2011102499078 A CN2011102499078 A CN 2011102499078A CN 201110249907 A CN201110249907 A CN 201110249907A CN 102952125 A CN102952125 A CN 102952125A
- Authority
- CN
- China
- Prior art keywords
- thiazoline
- azetidine hydrochloride
- sulfydryl
- solvent
- crystal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention provides a 3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal. X-ray powder diffraction detection indicates that a characteristic absorption peak exists at a diffraction angle (2 theta), as shown in Figure 1. The invention also provides a preparation method of the 3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal, which comprises the following steps: adding grease containing 3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride into one or two mixed solvents, and crystallizing at 0-40 DEG C; and filtering to obtain the crystalline 3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride. The 3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal provided by the invention has a unique crystal shape; and the crystal has the characteristics of high purity and stability and the like, and is beneficial to preservation.
Description
Technical field
The invention belongs to the organic drug synthesis technical field, relate to crystal habit azetidin compounds and preparation method thereof, 3-sulfydryl-1-(1 particularly, 3-thiazoline-2-yl)-azetidine hydrochloride crystal and preparation method thereof.
Background technology
In recent years, the quaternary azetidin compounds has been used for base group modification and the structure of modification of multi-medicament as medicine intermediate, has successfully prepared a large amount of new compounds, and wherein chemical compound lot has good pharmaceutical activity.
Crystal habit 3-sulfydryl-1-(1; 3-thiazoline-2-yl)-and azetidine hydrochloride (I) is as the important intermediate of tebipenem pivoxil, and be used for the MAP condensation, remove carboxy protective, esterification prepares carbapenems antibacterials tebipenem pivoxil.
Tebipenem pivoxil (Tebipenem Pivoxil) is the oral carbapenem antibiotic of first listing of the whole world, and as prodrug, tebipenem pivoxil is by being hydrolyzed to activeconstituents Typee training south performance anti-microbial effect.Its has a broad antifungal spectrum, to clinical separation strain such as methicillin-sensitivity gold Portugal bacterium (MSSA), methicillin-sensitivity bacterium (MSSE), methicillin-sensitivity coagulase negative staphylococcus (MS-CoNS), especially the activity to penicillin resistance pneumococcus (PRSP) is very strong.Clinical treatment for pediatric patient otorhinolaryngology and upper respiratory tract infection, persistence otitis media, bacterial pneumonia.Compare with traditional injection carbapenems medicine, tebipenem pivoxil can pass through oral administration, greatly facilitates route of administration, is one of outstanding antibacterials of an application prospect optimism.
3-sulfydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride (I) is the important intermediate of synthetic tebipenem pivoxil, its synthetic reaching is used by wide coverage.Such as JP2002003491, JP2000355592A, EP0717042, US5783703, the Journal of Antibiotics such as Isoda, 2006,59 (4): 241-247, the Chemical and Pharmaceutical Bulletin such as Isoda, 2006,54 (10): the bibliographical informations such as 1408-1411 its synthetic method and application, but all do not mention the data of relevant crystal formation.3-sulfydryl-1-(1 of the present invention, 3-thiazoline-2-yl)-azetidine hydrochloride crystal and preparation method there is no bibliographical information.
We are with reference to the synthetic 3-sulfydryl-1-(1 of currently known methods, 3-thiazoline-2-yl)-the azetidine hydrochloride, unstable chemcial property, easily moisture absorption is unfavorable for preserving.Therefore, we study successfully a kind of 3-sulfydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal and preparation method thereof, obtain the purity height, 3-sulfydryl-the 1-(1 of stable chemical nature, 3-thiazoline-2-yl)-and azetidine hydrochloride crystal, obtain crystal formation data (Fig. 1 of this crystal by X-ray powder diffraction spectrum, Fig. 2), thus finished the present invention.
Summary of the invention
One object of the present invention is to provide a kind of 3-sulfydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal, its superior in quality, favorable reproducibility, HPLC normalization method purity is more than 99.5%.
Another object of the present invention has provided 3-sulfydryl-1-(1,3-thiazoline-2-yl)-preparation method of azetidine hydrochloride crystal.
For achieving the above object, the invention provides following technical scheme:
A kind of 3-sulfydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal, it is characterized in that using Cu-K
αRadiation is to spend X-ray powder diffraction spectrum that 2 θ represent as shown in Figure 1.
3-sulfydryl-the 1-(1 of the present invention preparation, 3-thiazoline-2-yl)-the X-ray powder diffraction of azetidine hydrochloride crystal has following feature:
Instrument: Rigaku D/max2500 type X-ray diffractometer
Target: 2 θ sweep limit: 0-50 ° of Cu-Ka radiation (λ=1.5405)
Step angle: 0.04 ℃
Computing time: 0.5 second
Pipe is pressed: 40KV
Pipe stream: 100mA
Sweep velocity: 8 ℃/min
Filter disc: graphite monochromator
2θ | Spacing (d value) | I/ I 0 |
12.00 | 7.37 | 21 |
14.16 | 6.25 | 8 |
14.76 | 6.00 | 20 |
17.54 | 5.05 | 62 |
18.02 | 4.92 | 37 |
19.92 | 4.45 | 49 |
20.92 | 4.24 | 55 |
21.66 | 4.10 | 27 |
23.36 | 3.80 | 42 |
23.92 | 3.72 | 85 |
24.20 | 3.67 | 18 |
24.92 | 3.57 | 15 |
25.34 | 3.51 | 12 |
25.94 | 3.43 | 14 |
27.04 | 3.29 | 15 |
28.68 | 3.11 | 100 |
29.92 | 2.98 | 30 |
30.66 | 2.91 | 21 |
31.66 | 2.82 | 22 |
32.80 | 2.73 | 11 |
33.20 | 2.69 | 15 |
35.06 | 2.56 | 19 |
35.82 | 2.50 | 20 |
36.72 | 2.45 | 12 |
39.36 | 2.29 | 10 |
41.86 | 2.16 | 11 |
The present invention further discloses 3-sulfydryl-1-(1,3-thiazoline-2-yl)-preparation method of azetidine hydrochloride crystal, it is to contain 3-sulfydryl-1-(1,3-thiazoline-2-yl)-oily matter of azetidine hydrochloride joins in one or both mixed solvents, crystallization under 0-40 ℃ of temperature, filtration obtains the 3-sulfydryl-1-(1 of crystal habit, 3-thiazoline-2-yl)-the azetidine hydrochloride; Wherein the weightmeasurement ratio of oily matter and one or both mixed solvents is 1:3~1:10.
Solvent of the present invention is one or both mixtures that are selected from alcohols, nitrile, ketone, ethers, ester class, alkane, halo alkanes.
Wherein said alcohols refers to methyl alcohol, ethanol, ethylene glycol, 1,3-PD, n-propyl alcohol, Virahol, propyl carbinol or glycerol.
Wherein said nitrile refers to acetonitrile, propionitrile or vinyl cyanide.
Wherein said ketone refers to acetone, 2-butanone or methyl iso-butyl ketone (MIBK).
Wherein said ethers refers to ether, methyl-phenoxide, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF) or dioxane.
Wherein said ester class refers to methyl acetate, ethyl acetate, butylacetate, ethyl formate or diethyl malonate.
Described alkane refers to pentane, normal hexane, hexanaphthene, heptane or octane; Described haloalkane refers to methylene dichloride, trichloromethane, 1,2-ethylene dichloride, tetrachloromethane or glycol dibromide.
Typical 3-sulfydryl-1-(1 of the present invention, 3-thiazoline-2-yl)-and the preparation method of azetidine hydrochloride crystal is: in a 500ml there-necked flask, add 20.8g (60mmol) compound ii, 36.4g (180mmol) tributyl phosphorus, 6.5ml (360mmol) water, 42ml (500mmol) concentrated hydrochloric acid, the 200ml Virahol, 50 ℃ were stirred solvent evaporated 8 hours, obtain 48g oily matter, add 455ml acetonitrile/isopropyl ether (volume ratio 1/12), 20 ℃ of lower stirrings 1 hour are filtered, get white solid 23.8g, the X-ray powder diffraction is seen Fig. 1 and Fig. 2, yield 94%, fusing point: 119-121.5 ℃.
Another typical 3-sulfydryl-1-(1 of the present invention, 3-thiazoline-2-yl)-and the preparation method of azetidine hydrochloride crystal is: in a 250ml there-necked flask, add 8.7g (25mmol) compound ii, 17.7g (87.5mmol) tributyl phosphorus, 3.4ml (187.5mmol) water, 19ml (227.5mmol) concentrated hydrochloric acid, the 120ml Virahol, 55 ℃ were stirred solvent evaporated 7 hours, obtain about 18g oily matter, add 160ml ethanol/methylene (volume ratio 1/10), 10 ℃ of lower stirrings 1 hour are filtered, filter to get white solid 10.1g, the X-ray powder diffraction is seen Fig. 1 and Fig. 2, yield 96%, fusing point: 119.5-121.5 ℃.
3-sulfydryl-the 1-(1 of the present invention preparation, 3-thiazoline-2-yl)-azetidine hydrochloride crystal compares the positively effect that has with existing this compound solid phase and is:
(1) 3-sulfydryl-1-(1 of the present invention, 3-thiazoline-2-yl)-azetidine hydrochloride crystal, superior in quality, favorable reproducibility, HPLC normalization method purity is more than 99.5%, use 3-sulfydryl-1-(1 of the present invention, 3-thiazoline-2-yl)-tebipenem pivoxil of azetidine hydrochloride crystal preparation, yield is high, the product tebipenem pivoxil impurities is few, and HPLC area normalization method purity is more than 99.8%.So 3-sulfydryl-1-(1 of the present invention, 3-thiazoline-2-yl)-azetidine hydrochloride crystal is for improving the tebipenem pivoxil drug quality, and the reduction cost has positively effect.
(2) 3-sulfydryl-1-(1 of the present invention, 3-thiazoline-2-yl)-azetidine hydrochloride crystal, it is high to have crystallization purity, and stable chemical nature is conducive to the characteristics such as preservation.
Description of drawings
Fig. 1 is 3-sulfydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal X-ray powder diffraction;
Fig. 2 is 3-sulfydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal X-ray powder diffraction data.
Embodiment
The present invention is described further below in conjunction with embodiment, makes this area professional and technical personnel better understand the present invention.Embodiment only is indicative, means that never it limits the scope of the invention by any way.Wherein the synthetic method of compound ii is with reference to the synthetic method preparation of the report of EP0717042 or US5783703; Other raw material all has commercially available.
Embodiment 1:
Even [1-(1 to add 20.8g (60mmol) two in a 500ml there-necked flask, 3-thiazoline-2-yl) azetidine-3-yl] two sulphur things (compound ii), 36.4g (180mmol) tributyl phosphorus, 6.5ml (360mmol) water, 42ml (500mmol) concentrated hydrochloric acid, the 200ml Virahol, 50 ℃ were stirred solvent evaporated 8 hours, obtain about 48g oily matter, add 455ml acetonitrile/isopropyl ether (volume ratio 1/12), 20 ℃ of lower stirrings 1 hour are filtered, get white solid 23.8g, the X-ray powder diffraction is seen Fig. 1, yield 94%, fusing point: 119-121.5 ℃.
Embodiment 2:
In a 250ml there-necked flask, add 8.7g (25mmol) compound ii, 17.7g (87.5mmol) tributyl phosphorus, 3.4ml (187.5mmol) water, 19ml (227.5mmol) concentrated hydrochloric acid, the 120ml Virahol, 55 ℃ were stirred 7 hours, solvent evaporated obtains about 18g oily matter, adds 160ml ethanol/methylene (volume ratio 1/10), 10 ℃ of lower stirrings 1 hour, filter, filter to get white solid 10.1g, the X-ray powder diffraction is seen Fig. 1, yield 95%, fusing point: 119.5-121.5 ℃.
Embodiment 3:
In a 250ml there-necked flask, add 5.2g (15mmol) compound ii, 12.5g (62mmol) tributyl phosphorus, 2.6ml (144mmol) water, 13ml (155mmol) concentrated hydrochloric acid, the 95ml Virahol, 45 ℃ were stirred 7 hours, solvent evaporated obtains about 10g oily matter, adds 75ml methyl alcohol/methyl iso-butyl ketone (MIBK) (volume ratio 1/3), 10 ℃ of lower stirrings 1 hour, filter, filter to get white solid 5.8g, the X-ray powder diffraction is seen Fig. 1, yield 93%, fusing point: 119-121 ℃.
Embodiment 4:
In a 250ml there-necked flask, add 6.9g (20mmol) compound ii, 16.2g (80mmol) tributyl phosphorus, 3.0ml (167mmol) water, 16ml (201mmol) concentrated hydrochloric acid, the 85ml Virahol, 45 ℃ were stirred 8 hours, solvent evaporated obtains about 17g oily matter, adds 120ml tetrahydrofuran (THF)/normal hexane (volume ratio 1/1), 30 ℃ of lower stirrings 1 hour, filter, filter to get white solid 8.1g, the X-ray powder diffraction is seen Fig. 1, yield 95%, fusing point: 119.5-121 ℃.
Embodiment 5:
In a 250ml there-necked flask, add 7.6g (22mmol) compound ii, 17.1g (81.4mmol) tributyl phosphorus, 3ml (167mmol) water, 20ml (239mmol) concentrated hydrochloric acid, the 97ml Virahol, 50 ℃ were stirred 8 hours, solvent evaporated obtains about 18g oily matter, adds 100ml methanol/ether (volume ratio 1/3), 15 ℃ of lower stirrings 1 hour, filter, filter to get white solid 8.7g, the X-ray powder diffraction is seen Fig. 1, yield 94%, fusing point: 119-120.5 ℃.
Embodiment 6:
In a 250ml there-necked flask, add 9.7g (28mmol) compound ii, 18.0g (89mmol) tributyl phosphorus, 3.4ml (189mmol) water, 22ml (263mmol) concentrated hydrochloric acid, the 120ml Virahol, 55 ℃ were stirred 8 hours, solvent evaporated obtains about 24g oily matter, adds 100ml acetonitrile/ethyl acetate (volume ratio 1/2), 5 ℃ of lower stirrings 1 hour, filter, filter to get white solid 11.4g, the X-ray powder diffraction is seen Fig. 1, yield 97%, fusing point: 119-121 ℃.
Embodiment 7:
In a 500ml there-necked flask, add 11.5g (33mmol) compound ii, 26.3g (130mmol) tributyl phosphorus, 4ml (222mmol) water, 30ml (358.5mmol) concentrated hydrochloric acid, the 130ml Virahol, 55 ℃ were stirred 7 hours, solvent evaporated obtains about 29g oily matter, adds 186ml tetrahydrofuran (THF)/isopropyl ether (volume ratio 1/9), 35 ℃ of lower stirrings 1 hour, filter, filter to get white solid 13.2g, the X-ray powder diffraction is seen Fig. 1, yield 95%, fusing point: 119.5-121 ℃.
Embodiment 8:
In a 250ml there-necked flask, add 4.2g (12mmol) compound ii, 8.3g (41mmol) tributyl phosphorus, 2ml (111mmol) water, 11ml (131.5mmol) concentrated hydrochloric acid, the 50ml Virahol, 50 ℃ were stirred 7 hours, solvent evaporated obtains about 11g oily matter, adds 40ml ethanol/normal hexane (volume ratio 1/1), 25 ℃ of lower stirrings 1 hour, filter, filter to get white solid 4.9g, the X-ray powder diffraction is seen Fig. 1, yield 97%, fusing point: 119-121.5 ℃.
Embodiment 9:
In a 250ml there-necked flask, add 5.6g (16mmol) compound ii, 8.3g (53mmol) tributyl phosphorus, 2.6ml (145mmol) water, 15ml (184mmol) concentrated hydrochloric acid, the 70ml Virahol, 55 ℃ were stirred 7.5 hours, solvent evaporated obtains about 15g oily matter, adds the 50ml butylacetate, 35 ℃ of lower stirrings 1 hour, filter, filter to get white solid 6.4g, the X-ray powder diffraction is seen Fig. 1, yield 95%, fusing point: 119-121.5 ℃.
Application Example
Synthesizing of tebipenem pivoxil
Adopt the 3-sulfydryl-1-(1 of embodiment 1 preparation, 3-thiazoline-2-yl)-azetidine hydrochloride crystal, through above-mentioned route, with reference to Journal of Antibiotics such as EP0632039 or Isoda, 2006,59 (4): the synthetic method of the bibliographical informations such as 241-247, the preparation tebipenem pivoxil, the HPLC area normalization method purity of gained tebipenem pivoxil (compound V) is more than 99.8%, and related impurities meets this marketing drugs quality standard less than 0.1%.
Claims (9)
1. 3-sulfydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal, it is characterized in that using Cu-K
αRadiation is to spend X-ray powder diffraction spectrum that 2 θ represent as shown in Figure 1.
2. one kind prepares the described 3-sulfydryl-1-(1 of claim 1,3-thiazoline-2-yl)-method of azetidine hydrochloride crystal, it is characterized in that, it is to contain 3-sulfydryl-1-(1,3-thiazoline-2-yl)-oily matter of azetidine hydrochloride joins in one or both mixed crystallization solvents, crystallization under 0-40 ℃ of temperature is filtered the 3-sulfydryl-1-(1 that obtains crystal habit, 3-thiazoline-2-yl)-the azetidine hydrochloride; Wherein the weightmeasurement ratio of oily matter and one or both mixed solvents is 1:3~1:10.
3. preparation method claimed in claim 2, wherein said solvent refers to one or both mixtures of alcohols, nitrile, ketone, ethers, ester class, alkane, halo alkanes.
4. solvent claimed in claim 3, wherein alcohols is methyl alcohol, ethanol, ethylene glycol, 1,3-PD, n-propyl alcohol, Virahol, propyl carbinol or glycerol.
5. solvent claimed in claim 3, wherein nitrile is acetonitrile, propionitrile or vinyl cyanide.
6. solvent claimed in claim 3, wherein ketone is acetone, 2-butanone or methyl iso-butyl ketone (MIBK).
7. solvent claimed in claim 3, wherein ethers is ether, methyl-phenoxide, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF) or dioxane.
8. solvent claimed in claim 3, wherein the ester class is methyl acetate, ethyl acetate, butylacetate, ethyl formate or diethyl malonate.
9. solvent claimed in claim 3, wherein said alkane is pentane, normal hexane, hexanaphthene, heptane or octane; Described haloalkane is methylene dichloride, trichloromethane, 1,2-ethylene dichloride, tetrachloromethane or glycol dibromide.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110249907.8A CN102952125B (en) | 2011-08-29 | 3-sulfydryl-1-(1,3-thiazoline-2-base)-azetidine hydrochloride crystal and preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110249907.8A CN102952125B (en) | 2011-08-29 | 3-sulfydryl-1-(1,3-thiazoline-2-base)-azetidine hydrochloride crystal and preparation method thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102952125A true CN102952125A (en) | 2013-03-06 |
CN102952125B CN102952125B (en) | 2016-12-14 |
Family
ID=
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107445950A (en) * | 2017-08-25 | 2017-12-08 | 浙江海翔川南药业有限公司 | A kind of process for purification of tebipenem ester side chain |
CN108276398A (en) * | 2018-03-12 | 2018-07-13 | 山东科兴生物制品有限公司 | A kind of preparation process of L-084 |
CN108383841A (en) * | 2018-04-03 | 2018-08-10 | 山东科兴生物制品有限公司 | A kind of preparation method of L-084 intermediate and its raw material |
US11718621B2 (en) | 2017-02-06 | 2023-08-08 | Spero Therapeutics, Inc. | Tebipenem pivoxil crystalline forms, compositions including the same, methods of manufacture, and methods of use |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09278776A (en) * | 1996-04-05 | 1997-10-28 | Lederle Japan Ltd | Disulfide compound and its production |
US5783703A (en) * | 1993-07-01 | 1998-07-21 | Lederle (Japan), Ltd. | Sulfur-containing compounds method for their use and prodction |
CN1708504A (en) * | 2002-11-13 | 2005-12-14 | 株式会社钟化 | Novel intermediate for carbapenem compound for oral administration and process for producing the same |
CN102250080A (en) * | 2011-04-26 | 2011-11-23 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparation method of 1-(4, 5-dihydro-2-thiazolinyl)-3-mercaptoazetidine hydrochloride |
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5783703A (en) * | 1993-07-01 | 1998-07-21 | Lederle (Japan), Ltd. | Sulfur-containing compounds method for their use and prodction |
JPH09278776A (en) * | 1996-04-05 | 1997-10-28 | Lederle Japan Ltd | Disulfide compound and its production |
CN1708504A (en) * | 2002-11-13 | 2005-12-14 | 株式会社钟化 | Novel intermediate for carbapenem compound for oral administration and process for producing the same |
CN102250080A (en) * | 2011-04-26 | 2011-11-23 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparation method of 1-(4, 5-dihydro-2-thiazolinyl)-3-mercaptoazetidine hydrochloride |
Non-Patent Citations (1)
Title |
---|
TAKESHI ISODA,等: "Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem,L-084", 《J. ANTIBIOT.》, vol. 59, no. 4, 31 December 2006 (2006-12-31), pages 241 - 247 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11718621B2 (en) | 2017-02-06 | 2023-08-08 | Spero Therapeutics, Inc. | Tebipenem pivoxil crystalline forms, compositions including the same, methods of manufacture, and methods of use |
CN107445950A (en) * | 2017-08-25 | 2017-12-08 | 浙江海翔川南药业有限公司 | A kind of process for purification of tebipenem ester side chain |
CN107445950B (en) * | 2017-08-25 | 2020-07-21 | 浙江海翔川南药业有限公司 | Refining method of tebipenem pivoxil side chain |
CN108276398A (en) * | 2018-03-12 | 2018-07-13 | 山东科兴生物制品有限公司 | A kind of preparation process of L-084 |
CN108276398B (en) * | 2018-03-12 | 2020-12-01 | 科兴生物制药股份有限公司 | Preparation process of tebipenem pivoxil |
CN108383841A (en) * | 2018-04-03 | 2018-08-10 | 山东科兴生物制品有限公司 | A kind of preparation method of L-084 intermediate and its raw material |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8049010B2 (en) | Synthetic method and intermediates of Rosuvastatin calcium and preparation methods of intermediates | |
CN101619069A (en) | Preparation method of cefotiam hexetil hydrochloride | |
US20130281427A1 (en) | Crystalline form of ertapenem sodium and preparation method therefor | |
CN102268018A (en) | Crystallization method of cefixime | |
CN1927867A (en) | Synthesis method of biapenem | |
Xu et al. | A facile and practical preparation of P-chiral phosphine oxides | |
CN1432016A (en) | Novel crystal form of pyrrolidylthiocarbapenem derivative | |
CN103012434A (en) | Cefathiamidine compound crystal and preparation method as well as pharmaceutical composition thereof | |
CN102952125A (en) | 3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal and preparation method thereof | |
CN102516261A (en) | Preparation method of cefdinir | |
CN103992337B (en) | A kind of method preparing Aspoxicillin sodium easily | |
CN102952125B (en) | 3-sulfydryl-1-(1,3-thiazoline-2-base)-azetidine hydrochloride crystal and preparation method thereof | |
CN102336818B (en) | Peptide substance crystal B and preparation method and use thereof | |
CN100516045C (en) | Ciclopirox olamine crystal and method for preparing the same | |
CN101805359B (en) | Method for preparing biapenem with high purity | |
BR112015003520B1 (en) | method for the production of (r) -1,1,3-trimethyl-4-aminoindane | |
US9637502B2 (en) | Crystal form of Cefathiamidine compound and preparation method therefor | |
CN102617612B (en) | Biapenem B-type crystallinity | |
CN102887861B (en) | New crystal form of Ambrisentan and preparation method thereof | |
CN111559968B (en) | Preparation method of lacosamide crystal form II | |
CN102918041A (en) | Crystalline of carbapenem derivative or its hydrate, preparation methods and uses thereof | |
CN102304129B (en) | Method for adapting to industrially producing tebipenem | |
CN102584812B (en) | Preparation method of tebipenem pivoxil impurities | |
CN102432611A (en) | Dual-protection ertapenem crystal and preparation method thereof | |
CN108017658B (en) | Synthesis method of cefprozil |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |