CN1035435C - Condensation process for semi-synthetic penicillin - Google Patents
Condensation process for semi-synthetic penicillin Download PDFInfo
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- CN1035435C CN1035435C CN93110174A CN93110174A CN1035435C CN 1035435 C CN1035435 C CN 1035435C CN 93110174 A CN93110174 A CN 93110174A CN 93110174 A CN93110174 A CN 93110174A CN 1035435 C CN1035435 C CN 1035435C
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- 238000000034 method Methods 0.000 title claims abstract description 36
- 229930182555 Penicillin Natural products 0.000 title claims abstract description 9
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 title claims abstract description 9
- 229940049954 penicillin Drugs 0.000 title claims abstract description 9
- 238000009833 condensation Methods 0.000 title claims abstract description 8
- 230000005494 condensation Effects 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 239000002243 precursor Substances 0.000 claims abstract description 12
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000006482 condensation reaction Methods 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical class [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 claims description 11
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 8
- 229910052700 potassium Inorganic materials 0.000 claims description 8
- 238000012546 transfer Methods 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 150000008065 acid anhydrides Chemical class 0.000 claims description 6
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000013078 crystal Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 150000002960 penicillins Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 abstract description 6
- 230000003213 activating effect Effects 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 230000004888 barrier function Effects 0.000 abstract description 2
- 150000003839 salts Chemical class 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000007796 conventional method Methods 0.000 abstract 1
- 150000003512 tertiary amines Chemical class 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 8
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000006884 silylation reaction Methods 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- -1 phenylglycine acyl chloride Chemical class 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- KLOHDWPABZXLGI-YWUHCJSESA-M ampicillin sodium Chemical compound [Na+].C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 KLOHDWPABZXLGI-YWUHCJSESA-M 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 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 group 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 150000003952 β-lactams Chemical group 0.000 description 1
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- Cephalosporin Compounds (AREA)
Abstract
The present invention introduces a new condensation process of semi-synthetic penicillin. In the process of forming mixed anhydride with precursor acid salt, tertiary amine type compound is used as catalyst, isobutyl chloroformate which has large steric barrier and stronger electron-pushing capability group is used as activating reagent, so that selective reaction is facilitated, and the required compound is prepared by treating the isobutyl chloroformate with a conventional method after condensation reaction. The method has the advantages of stable process, simple operation, good reproducibility, easily obtained raw materials, high product yield and good quality.
Description
The present invention relates to a kind of condensation process for semi-synthetic penicillin.
Still very active to preparation method's research of semisynthetic penicillin product both at home and abroad at present.Can be divided into mixed anhydride method, chloride method, enzyme condensation method, one-step synthesis about semisynthetic penicillin condensation process method.The more introduction of document is a chloride method; be that 6-amino-penicillanic acid (being called for short 6-APA) carries out silylation in CH2Cl2; or it improvedly uses a kind of N; O-pair-silylation acid amides generates single silyl derivatives as the silylation medium; and then carry out acylation reaction with the phenylglycine acyl chloride hydrochloride and (see CN85102130A for details, US4625021).The preparation of acyl chloride hydrochloride, storing all acquires a certain degree of difficulty, and manufacturing condition requires harsh, and suitability for industrialized production has inconvenience.By test contrast, still mixed anhydride method less expensive, safety, the three wastes are handled easily and are solved, suitable suitability for industrialized production.The operating process of mixed anhydride method is by phenylglycine or D-pHPG and methyl aceto acetate (or methyl esters) formed N-(2-ethoxy carbonyl-1-methyl ethylene)-D-(-)-alpha-amino group-benzene (or para hydroxybenzene) potassium acetate (or sodium) in the presence of alkali; promptly be commonly referred to as the precursor hydrochlorate and form mixed acid anhydride with Vinyl chloroformate (or methyl esters) again; low temperature descends and 6-APA carries out condensation reaction; remove the alpha-amino group protecting group through acidolysis; transfer PH to iso-electric point again, the finished product are separated out.Above-mentioned mixed anhydride method production technique level is not high, and (" Chinese Pharmaceutical Journal " 1992,5,262-265), and other products may also will hang down at 70-80% as penbritin three water acid yield.The producer that had in the last few years adopts pivaloyl chloride to become mixed anhydride method, and the lab scale yield is higher, but technology is loaded down with trivial details, and industrialized condition is strict, and need be-60 ℃ of reactions, solvent reclaims difficulty, and the three wastes are handled difficult, and agents useful for same is many, reaction time is long, and the energy consumption height is so production cost is still very high.Therefore further simplify semisynthetic penicillin technology,, improve technology level, reduce production costs, become important research project.
The purpose of this invention is to provide a kind of condensation process for semi-synthetic penicillin, this process stabilizing, simple to operate, the reaction conditions gentleness helps suitability for industrialized production, and raw materials used being easy to get obviously improved product yield and purity, reduces production costs.
The object of the present invention is achieved like this: adopt high precursor hydrochlorate and the isobutyl chlorocarbonate of purity, in acetone, be catalyzer with the tertiary amine-type compound, form mixed acid anhydride, again 6-amino-penicillanic acid salt is added in the mixed acid anhydride, carry out condensation reaction under low temperature-15～-40 ℃, reaction finishes and adopts ordinary method to add hydrochloric acid to transfer PH to be no more than 2.0 to be hydrolyzed, to extract acetone, water transfers to iso-electric point with ammoniacal liquor, and the crystal oven dry gets product; Raw materials used weight ratio is: 6-amino-penicillanic acid: precursor hydrochlorate: isobutyl chlorocarbonate: acetone: tertiary amine-type compound: ammoniacal liquor: hydrochloric acid: toluene=1: 1.46-1.63: 0.71: 14.04: 0.0069: 1.13: 1.25: 45.25.
Above-mentioned precursor hydrochlorate is N-(2-ethoxy carbonyl-1-methyl ethylene)-D-(-)-alpha-amino group-toluylic acid potassium (or sodium), or is N-(2-ethoxy carbonyl-1-methyl ethylene)-D-(-)-alpha-amino group-p-hydroxyphenylaceticacid potassium (or sodium).The tertiary amine-type compound is N-methylmorpholine or N, the N-dimethyl benzylamine.
Because the present invention adopts isobutyl chlorocarbonate (the iso Butylchlorocarbonace with strong electron repulsive ability group, be called for short CFT) prepare the activating reagent of mixed acid anhydride as the precursor hydrochlorate, with the tertiary amine-type compound is catalyzer, after carrying out condensation reaction with the salt of 6-APA, get product through the routine processing, thus raw materials used being easy to get, process stabilizing, simple to operate, the reaction conditions gentleness.Compared with prior art, the used activating reagent CFT of the present invention has stronger electron repulsive ability than Vinyl chloroformate (or methyl esters), and steric barrier is big, more help selectivity and carry out condensation reaction, CFT has character soluble in water and very easily removes, so react completely favorable reproducibility.The present invention is because of adopting higher degree precursor hydrochlorate in addition; the alpha-amino group of phenylglycine or D-pHPG really is protected; the alpha-amino group that does not add protection can not be sneaked in the precursor hydrochlorate, so can protect the beta-lactam skeleton not bad by glass effectively, obviously improves product yield.Product yield can improve 10-12% than existing Technology, and its product purity also obviously improves, and quality is good.Therefore, production cost of the present invention is low, and the three wastes are handled easily, more help suitability for industrialized production.
The general formula of the used precursor hydrochlorate of the present invention is:
Wherein R be H or-OH, M is K or Na, R1 for-CH3 or-general formula of the penicillin derivative that C2H5 makes is:
Wherein R represents that a phenyl or its contraposition are replaced by hydroxyl, also can be the 1 base.
The invention will be further described below in conjunction with embodiment.
Embodiment 1:6-(D-(-)-alpha-amino group-phenylacetamide) penicillanic acid
12.4 gram N-(2-ethoxy carbonyl-1-methyl ethylene)-D-(-)-alpha-amino group-toluylic acid potassium and 86 milliliters of acetone are made into emulsion, it are stirred the cooling back add 0.55 milliliter of N, N-dimethyl benzylamine, 5.45 milliliters of isobutyl chlorocarbonates.The continuation stirring is cooled to-35 ℃ and makes solution A.In addition 8 gram 6-APA are made into suspension with 56 milliliters of acetone and 30 ml waters, stir down that 0-5 ℃ of dropping ammonia of control transfers to PH7.8 for about 8 milliliters, promptly molten entirely till, be cooled to below-15 ℃ and make solution B.Solution B joined stir in the solution A that is cooled to-35 ℃ down, carry out condensation reaction half an hour, reaction finishes to add hydrochloric acid and be warming up to 0 ℃ and transfers about PH1.5, hydrolysis reaction half an hour.Hydrolysis finishes, divide extraction acetone three times with toluene 420ml, isolate water, under 0-5 ℃, solution is transferred to PH2.8, the very fast crystallization of product with ammoniacal liquor, stirred 10 minutes, slowly add ammoniacal liquor then, PH is transferred to iso-electric point, place down for 3-5 ℃ and spend the night, filter next day and washing, drain the back only with 10 milliliters of washing with acetones, filter.Place 50 ℃ baking oven to dry product, promptly get title compound.
Yield 90% (theoretical value)
Content 97% (spectrophotometry)
Embodiment 2:6-(D-(-)-alpha-amino group-phenylacetamide) penicillanic acid
11.7 gram N-(2-ethoxy carbonyl-1-methyl ethylene)-D-(-)-alpha-amino group-sodium phenylacetates and 70 milliliters of acetone and 12 ml waters are made into emulsion, it is stirred the cooling back add 0.55 milliliter of N, the N-dimethyl benzylamine is to-35 ℃, add 5.45 milliliters of isobutyl chlorocarbonates again, stirring reaction is cooled to-35 ℃ and makes solution A.In addition 8 gram 6-APA are added in 30 milliliters of acetone and 30 ml waters, add ammoniacal liquor and make ammonium salt and get solution B, be cooled to-15 ℃, add solution A again and carry out condensation reaction half an hour.Handle as method identical as described in the example 1 and to obtain this title compound.
Yield 85% (theoretical value)
Content 97%
Embodiment 3:6-(D-(-)-alpha-amino group-phenylacetamide) penicillanic acid
Example 2 described identical methods make solution A and B, then B are joined among the A by the method for example 1, obtain title compound through the same procedure processing.
Yield 87% (theoretical value)
Content 97%
Embodiment 4:6-(D-(-)-alpha-amino group-phenylacetamide) penicillanic acid
11.7 gram N-(2-ethoxy carbonyl-1-methyl ethylene)-D-(-)-alpha-amino group-sodium phenylacetates and 86 milliliters of acetone are made into emulsion, it is stirred the cooling back add 0.55 milliliter of N, the N-dimethyl benzylamine is to-35 ℃, add 5.45 milliliters of isobutyl chlorocarbonates again, the continuation stirring is cooled to-35 ℃ and gets solution A.Method by example 1 makes solution B in addition, then B is joined among the A, obtains title compound through the same procedure processing.
Yield 89% (theoretical value)
Content 97%
Embodiment 5; 6-(D-(-)-alpha-amino group-phenylacetamide) penicillanic acid
12.4 gram N-(2-ethoxy carbonyl-1-methyl ethylene)-D-(-)-alpha-amino group-toluylic acid potassium and 70 milliliters of acetone and 12 ml waters are made into emulsion, below make solution A and B by example 1, post-reaction treatment and title compound.
Yield 88% (theoretical value)
Content 97%
Embodiment 6:6-(D-(-)-alpha-amino group-phenylacetamide) penicillanic acid
13.01 gram N-(2-ethoxy carbonyl-1-methyl ethylene)-D-(-)-alpha-amino group-p-hydroxyphenylaceticacid potassium and 86 milliliters of acetone are made into emulsion, it is stirred cooling add 0.55 milliliter of N, to-35 ℃, add 5.45 milliliters of isobutyl chlorocarbonates behind the N-dimethyl benzylamine.The continuation stirring is cooled to-35 ℃ and makes solution A.In addition 8 gram 6-APA are made into suspension with 56 milliliters of acetone and 40 ml waters, stir down that 0-5 ℃ of dropping ammonia of control transfers to PH7.8 for about 8 milliliters, promptly molten entirely till, be cooled to below-15 ℃ and make solution B.Solution B joined stir in the solution A that is cooled to-35 ℃ down, carry out condensation reaction half an hour.As identical method as described in the example 1, use hydrochloric acid hydrolysis, ammoniacal liquor is transferred PH5.1, and separating treatment obtains the compound under this title.
Yield 85% (theoretical value)
Content 97% (spectrophotometry).
Claims (5)
1, a kind of condensation process for semi-synthetic penicillin, it is characterized in that the precursor hydrochlorate and the isobutyl chlorocarbonate that adopt purity high, in acetone, be catalyzer with the tertiary amine-type compound, form mixed acid anhydride, again 6-amino-penicillanic acid salt is added in the mixed acid anhydride, carry out condensation reaction in low temperature-15 under to-40 ℃, reaction finishes and adopts ordinary method to add hydrochloric acid to transfer PH to be no more than 2.0 to be hydrolyzed, extract acetone, water transfers to iso-electric point with ammoniacal liquor, the crystal oven dry gets product, and raw materials used weight ratio is: 6-amino-penicillanic acid: precursor hydrochlorate: isobutyl chlorocarbonate: acetone: tertiary amine-type compound: ammoniacal liquor: hydrochloric acid: toluene=1: 1.46-1.63: 0.71: 14.04: 0.0069: 1.13: 1.25: 45.25.
2, novel process according to claim 1, it is characterized in that the precursor hydrochlorate is N-(2-ethoxy carbonyl-1-methyl ethylene)-D-(-)-alpha-amino group-toluylic acid potassium, or be N-(2-ethoxy carbonyl-1-methyl ethylene)-D-(-)-alpha-amino group-p-hydroxyphenylaceticacid potassium.
3, novel process according to claim 1 is characterized in that the tertiary amine-type compound is N, the N-dimethyl benzylamine.
4, novel process according to claim 1 is characterized in that carrying out setting-up point and selects-35 ℃ for use.
5, novel process according to claim 1 is characterized in that the general formula of making penicillin derivative is;
Wherein R represents that a phenyl or its contraposition are replaced by hydroxyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93110174A CN1035435C (en) | 1993-03-16 | 1993-03-16 | Condensation process for semi-synthetic penicillin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93110174A CN1035435C (en) | 1993-03-16 | 1993-03-16 | Condensation process for semi-synthetic penicillin |
Publications (2)
| Publication Number | Publication Date |
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| CN1076698A CN1076698A (en) | 1993-09-29 |
| CN1035435C true CN1035435C (en) | 1997-07-16 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN93110174A Expired - Fee Related CN1035435C (en) | 1993-03-16 | 1993-03-16 | Condensation process for semi-synthetic penicillin |
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| CN104644629A (en) * | 2015-01-27 | 2015-05-27 | 华北制药股份有限公司 | Ampicillin sodium sulbactam sodium preparation for injection and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4310460A (en) * | 1979-11-02 | 1982-01-12 | Dobfar S.P.A. | Process for the production of 6-D-α-amino-p-hydroxyphenylacetamido penicillanic acid |
| EP0439096A2 (en) * | 1990-01-22 | 1991-07-31 | Biochemie Gesellschaft M.B.H. | Improvements in or relating to beta lactam production |
-
1993
- 1993-03-16 CN CN93110174A patent/CN1035435C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4310460A (en) * | 1979-11-02 | 1982-01-12 | Dobfar S.P.A. | Process for the production of 6-D-α-amino-p-hydroxyphenylacetamido penicillanic acid |
| EP0439096A2 (en) * | 1990-01-22 | 1991-07-31 | Biochemie Gesellschaft M.B.H. | Improvements in or relating to beta lactam production |
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| CN1076698A (en) | 1993-09-29 |
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Address after: Room 1202, block D, Shenyang scientist garden, No. 100 Binhe Road, Shenhe District, Liaoning, Shenyang, China Patentee after: Xue Shouli Address before: No. 60, Changqing street, Dongling District, Liaoning, Shenyang Patentee before: Shenyang Inst. of Pharmaceutical Industry |
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| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |