CN1545514A - Production method for beta type crystal anhydrous ammonia leaven - Google Patents
Production method for beta type crystal anhydrous ammonia leaven Download PDFInfo
- Publication number
- CN1545514A CN1545514A CNA028163427A CN02816342A CN1545514A CN 1545514 A CN1545514 A CN 1545514A CN A028163427 A CNA028163427 A CN A028163427A CN 02816342 A CN02816342 A CN 02816342A CN 1545514 A CN1545514 A CN 1545514A
- Authority
- CN
- China
- Prior art keywords
- aztreonam
- type
- production method
- leaven
- solution
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title description 8
- 239000013078 crystal Substances 0.000 title description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 title 1
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 claims abstract description 37
- 229960003644 aztreonam Drugs 0.000 claims abstract description 37
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 11
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 7
- 238000011146 sterile filtration Methods 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims 2
- -1 2-amino-4-thiazolyl Chemical group 0.000 abstract description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 2
- 229960002727 cefotaxime sodium Drugs 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- OIXLLKLZKCBCPS-RZVRUWJTSA-N (2s)-2-azanyl-5-[bis(azanyl)methylideneamino]pentanoic acid Chemical compound OC(=O)[C@@H](N)CCCNC(N)=N.OC(=O)[C@@H](N)CCCNC(N)=N OIXLLKLZKCBCPS-RZVRUWJTSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000003311 flocculating effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 125000001181 organosilyl group Chemical class [SiH3]* 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
A process is described for producing anhydrous beta -form of ((Z)-2-[[[(2-amino-4-thiazolyl)[[trans-(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2-methylpropionic acid (also known as Aztreonam).
Description
Technical field
The present invention relates to a kind of crystal anhydrous beta type (Z)-2-[[[(2-amino-4-thiazole) [[suitable-(2S, 3S)-2-methyl-4-oxo-1-sulfo--3-azetidinyl]-carbamyl] methylene radical] amino] oxo]-2 Methylpropionic acid " (Z)-2-[[[(2-amino-4-thiazolyl) [[trans-(2S, 3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]-carbamoyl] methylene] amino] oxy]-2-methylpropionic acid " production method of (being also referred to as aztreonam).
Background technology
Aztreonam shown in the molecular formula I (Aztreonam) is a kind of monocycle beta-lactam antibiotics preparation (synthetic monocyclic beta-lactam antimicrobialagent) of synthetic, and (gram-negative organism) has anti-microbial activity to gram-negative micro-organism.
Molecular formula I
Some reference have disclosed the technology of preparing of aztreonam, for example: american documentation literature 4,775,670 and 5,194,604.Present known aztreonam has polymorphism (polymorphism), and american documentation literature 4,826,973 reported four kinds of different aztreonam crystalline structure forms, i.e. a-, and β-, γ-, δ-type.The a-type is hydrated crystal (hydrated crystals), comprises the moisture of 7-14% usually, and storage stability is poor.Therefore, should convert it into β-type, the latter possesses anhydrous (anhydrous), moistureproof (substantially non-hygroscopic) and have good flowability (possesses good flowability), less surface-area (low surface area), stronger solid-state stability features such as (enhanced solid state stability), be more suitable for as medicinal preparations.
American documentation literature the 4th, 946, the preparation flow of describing β-type aztreonam No. 838 promptly makes a-type crystallization (crystallization) by raw spirit (anhydrous alcohol).Wherein, the a-type can be dissolved in methyl alcohol and ethanol under 55-60 ℃.Under these conditions, the a-type can temporary transient dissolving, recrystallize (recrystallises), formation β-type aztreonam naturally afterwards.Above-mentioned flow process is not suitable for carrying out sterile production (sterile preparation), because aztreonam does not have (in solution) maintenance sufficiently long time in raw spirit, to carry out sterile filtration (asepticfiltration).
American documentation literature the 4th, 946 has been introduced the method for the another kind of β of preparation-type aztreonam No. 838.Wherein, the a-type is dissolved in dehydrated alcohol (anhydrous ethanol) with triethylamine salt form (triethylamine salt), just can obtain β-type aztreonam to wherein adding anhydrous chlorides of rase hydrogen solution (anhydroushydrogen chloride solution) afterwards.Though this method is suitable for carrying out sterile filtration, target product is polluted by triethylamine hydrochloride (triethylaminehydrochloride).
At american documentation literature the 4th, 946, in another production sequence that No. 838 are introduced, at dipolar aprotic solvent (aprotic solvent), for example in the acetonitrile (acetonitrile), add binding agent (silylating agent) the a-type is handled, to obtain the solution of aztreonam bonding derivative (Aztreonam as silyl derivative).Add ethanol in above-mentioned solution, β-type is precipitated comes out.The output of this method is very low, in bonding process (silylationstep), the a-type must be dissolved simultaneously.Purpose of the present invention described below will address these problems exactly.
Summary of the invention
The present invention relates to a kind of brand-new Production Flow Chart, with preparation high purity, aseptic crystal-anhydrous beta-type aztreonam.Utilize the present invention, just no longer need to add triethylamine or binding agent when in dehydrated alcohol (absolute ethanol), preparing a-type aztreonam solution, and the solution of preparation like this can carry out sterile filtration to generate aseptic β-type aztreonam crystal.
It is worth noting that the present invention can make the a-type be dissolved in dehydrated alcohol at low temperatures.A-type aztreonam can be dissolved in dehydrated alcohol between-10-+15 ℃, when temperature is increased to 50-55 ℃, form β-N-type waferN by recrystallize.If temperature rests on-10-+15 ℃, aztreonam will can recrystallize in this solution.This uncommon solvability of a-type aztreonam (solubility characteristic) is not report in the literature so far.But, american documentation literature 4,912, in No. 211 6 pairs of another kind of microbiotic of example (antibiotic)---the similar solvability of cefotaxime sodium (cefotaxime sodium) is described.Above-mentioned a-type aztreonam solution can be sloughed color after by carbon treatment, and sterilizing filter that also can be by 0.2 micron is to carry out sterile preparation (aseptic preparation).
A-type aztreonam is dissolved in raw spirit, especially dehydrated alcohol.Temperature range is-10-+15 ℃, and optimum temps is 5-10 ℃.Keep the said temperature level, application of active carbon (activated carbon) is handled respectively, purifies filter (clarification filter) and sterile filters (sterile filter) and filters a-type aztreonam solution to obtain sterile solution.Afterwards, the temperature of aseptic filtrate (sterile filtrate) is risen to 50-55 ℃, will form anhydrous beta-type aztreonam crystallization.At last, above-mentioned product also need pass through vacuum filtration and drying.β-type aztreonam by these program preparations is suitable for as medicinal preparations (pharmaceutical agent), with basic substance, after for example L-arginine (L-arginine) mixes, can be by intravenous injection and muscle injection mode medication (intravenous and intramuscular administration).
Compared with former technology, main beneficial effect of the present invention is to simplify production process.The Production Flow Chart of prior art needs extra step, promptly must add triethylamine or binding agent and make the dissolving of a-type aztreonam, thereby carry out sterile filtration.And in flow process of the present invention, a-type aztreonam can directly be dissolved in ethanol at low temperatures to obtain a solution, and this solution is fit to be used for preparing aseptic β-type aztreonam.
By the flow process that describes below, can finish by a-type aztreonam preparation β-type aztreonam.
Description of drawings
Embodiment
Under 8-10 ℃,, stir 30 minutes to obtain limpid liquid with in the dehydrated alcohol of a-type aztreonam (40g) adding precooling (2400ml).Still under 8-10 ℃, handled above-mentioned solution 15 minutes with activated carbon (1g).Suspension (suspension) is filtered by flocculating aids (celite), and surplus materials washs with ethanol (50ml).Afterwards, filtrate (filtrate) slowly was heated to 50-55 ℃ in 2 hours, and recrystallize forms β-type aztreonam.The suspension of heating is cooled to 15-20 ℃, stirs 1 hour and filters once more.Above-mentioned crystalline product carries out drying in a vacuum, and finally forms the 33g end product.Utilize IR spectrum (IR spectrum), powder x ray diffraction pattern (powder X-ray diffraction pattern) and dsc (differential scanning calorimetry) to confirm that this end product is exactly β-type aztreonam.
Claims (1)
1, preparation anhydrous beta type (Z)-2-[[[(2-amino-4 thiazole) [[suitable-(2S, 3S)-2-methyl-4-oxo-1-sulfo--3-azetidinyl] carbamyl] methylene radical] amino] oxo]-method of 2 Methylpropionic acid (aztreonam), it includes:
Under-10-+15 ℃ temperature, a-type aztreonam is dissolved in dehydrated alcohol, through after the sterile filtration, solution is heated to 50-55 ℃ again, to form anhydrous beta-type aztreonam crystallization.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN700CH2001 | 2001-08-27 | ||
| IN700/MAS/2001 | 2001-08-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1545514A true CN1545514A (en) | 2004-11-10 |
Family
ID=11097009
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA028163427A Pending CN1545514A (en) | 2001-08-27 | 2002-08-21 | Production method for beta type crystal anhydrous ammonia leaven |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1545514A (en) |
| WO (1) | WO2003018578A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101412715B (en) * | 2008-12-16 | 2010-04-14 | 海南百那医药发展有限公司 | Aztreonam compound and preparation thereof |
| CN101579336B (en) * | 2009-07-07 | 2010-06-23 | 重庆市庆余堂制药有限公司 | Aztreonam for injection and production method thereof |
| CN101830895A (en) * | 2010-04-16 | 2010-09-15 | 海南新中正制药有限公司 | Aztreonam anhydrous crystal compound and preparation method thereof |
| CN102351855A (en) * | 2011-08-12 | 2012-02-15 | 山西仟源制药股份有限公司 | Production method of beta-crystal form aztreonam aseptic raw drug |
| CN103232449A (en) * | 2013-05-08 | 2013-08-07 | 四川省惠达药业有限公司 | Aztreonam compound, as well as preparation method and pharmaceutical composition thereof |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003265373A1 (en) | 2002-08-05 | 2004-02-23 | Teva Gyogyszergyar Reszvenytarsasag | Preparation of aztreonam |
| US7452991B2 (en) | 2003-05-15 | 2008-11-18 | Teva Gyógyszergyár Zártkörüen Müködö Részvénytársaság | Aztreonam β polymorph with very low residual solvent content |
| MY150088A (en) | 2003-05-19 | 2013-11-29 | Irm Llc | Immunosuppressant compounds and compositions |
| ES2304078B2 (en) | 2003-07-02 | 2009-09-16 | Gilead Sciences Inc. | AZTREONAM-L-LISINA SALT AND METHODS FOR THE PREPARATION OF THE SAME. |
| ES2321336T3 (en) | 2005-05-09 | 2009-06-04 | Sicor Inc. | PROCEDURE FOR THE MANUFACTURE OF AZTREONAM. |
| CN113876722B (en) * | 2021-11-04 | 2022-12-02 | 海南皇隆制药股份有限公司 | Aztreonam for injection and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1181075A (en) * | 1981-07-13 | 1985-01-15 | David M. Floyd | CRYSTALLINE ANHYDROUS FORM OF [3-S-[3.alpha.(Z),4 .beta.]]-3-[[(2-AMINO-4-THIAZOLYL) [(1-CARBOXY-1-METHYLETHOXY)IMINO]ACETYL] AMINO]-4-METHYL-2-OXO-1-AZETIDINESULFONIC ACID |
| US4946838A (en) * | 1981-07-13 | 1990-08-07 | E. R. Squibb & Sons, Inc. | Crystalline anhydrous aztreonam |
| US4826973A (en) * | 1984-07-20 | 1989-05-02 | E. R. Squibb & Sons, Inc. | Delta form of aztreonam and preparation thereof |
-
2002
- 2002-08-21 CN CNA028163427A patent/CN1545514A/en active Pending
- 2002-08-21 WO PCT/IN2002/000169 patent/WO2003018578A1/en not_active Application Discontinuation
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101412715B (en) * | 2008-12-16 | 2010-04-14 | 海南百那医药发展有限公司 | Aztreonam compound and preparation thereof |
| CN101579336B (en) * | 2009-07-07 | 2010-06-23 | 重庆市庆余堂制药有限公司 | Aztreonam for injection and production method thereof |
| CN101830895A (en) * | 2010-04-16 | 2010-09-15 | 海南新中正制药有限公司 | Aztreonam anhydrous crystal compound and preparation method thereof |
| CN102351855A (en) * | 2011-08-12 | 2012-02-15 | 山西仟源制药股份有限公司 | Production method of beta-crystal form aztreonam aseptic raw drug |
| CN103232449A (en) * | 2013-05-08 | 2013-08-07 | 四川省惠达药业有限公司 | Aztreonam compound, as well as preparation method and pharmaceutical composition thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003018578A1 (en) | 2003-03-06 |
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