IL33889A - Preparation of 7-amino cephalosporin esters - Google Patents
Preparation of 7-amino cephalosporin estersInfo
- Publication number
- IL33889A IL33889A IL33889A IL3388970A IL33889A IL 33889 A IL33889 A IL 33889A IL 33889 A IL33889 A IL 33889A IL 3388970 A IL3388970 A IL 3388970A IL 33889 A IL33889 A IL 33889A
- Authority
- IL
- Israel
- Prior art keywords
- acid
- hydrogen
- formula
- solvent
- compound
- Prior art date
Links
- 229930186147 Cephalosporin Natural products 0.000 title claims description 9
- 229940124587 cephalosporin Drugs 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title description 2
- 239000002253 acid Substances 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- -1 nitra Chemical group 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 7
- 150000002431 hydrogen Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910052717 sulfur Chemical group 0.000 claims description 2
- 239000011593 sulfur Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- OGNVQLDIPUXYDH-ZPKKHLQPSA-N (2R,3R,4S)-3-(2-methylpropanoylamino)-4-(4-phenyltriazol-1-yl)-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid Chemical compound CC(C)C(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(O)=O)=C[C@@H]1N1N=NC(C=2C=CC=CC=2)=C1 OGNVQLDIPUXYDH-ZPKKHLQPSA-N 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 229910001868 water Inorganic materials 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- YSJGVKHCAVGBIT-AVKWCDSFSA-N (4-nitrophenyl)methyl (6r)-3-methyl-8-oxo-7-[(2-phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H]2N(C1=O)C(=C(CS2)C)C(=O)OCC=1C=CC(=CC=1)[N+]([O-])=O)NC(=O)COC1=CC=CC=C1 YSJGVKHCAVGBIT-AVKWCDSFSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229930195708 Penicillin V Natural products 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 229940056367 penicillin v Drugs 0.000 description 1
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- JFALSRSLKYAFGM-UHFFFAOYSA-N uranium(0) Chemical compound [U] JFALSRSLKYAFGM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Description
PREPARATION OF 7-AMINO CEPHALOSPORIN ESTERS The present invention provides a process for preparing 3-methyl-7-amino cephalosporin compounds from 3-methyl-7-acylamido cephalosporin compounds.
More particuJa rly, the present invention provides a process for preparing a compound having the formula C02R' which comprises treating a compound having the formula C02R' with at least one mole of a solvent having the formula R"-0H at a temperature within the range of 0* to 125°C. in the presence of at least 0.25 equivalent of an acid having a pjCa of less than 3, wherein or Q is hydrogen, to alkyl, to alkoxy, cyano, nitro h drox chloro bromo or fluoro Y is hydrogen or hydroxy; X is oxygen or sulfur; m is an integer of 0 to 2; n is an integer of 1 to 3; 2, 2, 2-trichloroethyl or p-nitrobenzyl; and R* is hydrogen or an easily removable oarboxyl pr-oteoting group, — a«d- R" is hydrogen, methyl, ethyl, or propyl.
R may be such groups as benzyl, m-chlorobenzyl, p-cyanobenzyl, a-hydroxybenzyl, a-hydroxy-o_-ethylbenzyl, phenoxymethyl, benzyloxymethyl, £-nitrobenzyloxymethyl, phenoxyethyl, thiophenoxyethyl, £-methylthiophenoxyethyl, and p-methoxybenzyloxyethyl. This process will find its greatest application with those compounds wherein R is benzyl or phenoxymethyl, since such compounds can be obtained from penicillin G and penicillin V by the Morin- 626 Jackson process described in U.S. Patent 3.» 275,636-.
The carboxyl group in the starting material for this process may be present as the free acid but is preferably ester if led by an easily removable carboxyl protect -ing group. It is well known to protect a carboxyl group by esterlfication with a group that can be easily removed by acid hydrolysis or hydrogenolysis . Examples of such groups include 2, 2, 2-trichloroethyl, bonnylj bonahydryl, p-nitrobenzyl, triroethylsllyJi, phthalimidomethyl, succln-lmidomethylj phenaoylj 2- (2-methy.L-3-butynyl) } and 2-(2 mothyl 3-butenyl). The particular carboxyl protecting group employed is unimportant and does not affect the process except that a carboxyl protecting group that can be removed by acid hydrolysis may be removed during the course of this process so that the product would contain - ceptable since the free carboxyl group will not interfere with this process.
In accordance with this process the acylated cephalosporin starting material is treated with a molar excess of water or a lower alkanol such as methanol, ethanol, or propanol. Water is preferred. It appears that a solvolysis of the amide linkage occurs with the formation of the free amine and an acid when water is the solvent or an ester when an alcohol is the solvent. It is to be understood of course that mixtures of these solvents may be used. At least one mole of the reactive solvent should be used per mole of starting cephalosporin compound. It is preferred to use an excess of the reactive solvent, and this is usually done. Any excess may be used limited only by the equipment needed to separate the products of the reaction from the excess solvent. When water is the sole reactive solvent it is preferred to use an inert organic co-solvent to aid in maintaining starting materials and products in solution. This co-solvent should be miscible with water. Suitable co-solvents include tetrahydrofuran, dioxane, acetone, dlmethylsulf-oxide, acetonitrile, dimethylformamide, and dimethyl-acetamide.
The reaction between the acylated cephalosporin and the reactive solvent is conducted in the presence of a strong acid having a pKa of less than 3. This acid may be a mineral acid or an organic acid. Examples of such acids include p-toluenesulfonic acid, methanesulfonic acid, tri-fluoroacetic acid, hydrochloric acid, sulfuric acid and phosphoric acid. The preferred acid is p-toluenesulfonic ated cephalosporin should be used and preferably one equivalent or more of acid is used. As much as a 20 to 25 fold excess of acid may be employed but such excesses are unnecessary.
The reaction may be conducted at a temperature within the range of 0° to about 125° C. The preferred temperature is 25° to 75°C. The time of the reaction is a function of the acid employed, the solvent employed, and the temperature.. The time will normally be from about 1 to about 60 hours and will usually be less than 12 hours , The process will be further illustrated by the following examples.
Example 1 A solution of 20 g. of p-nitrobenzyl 3-methyl-7-phenoxyacetamido- -cephem-4-carboxylate and 16 g. of p-toluenesulfonic acid monohydrate in 16 ml. of water and 70 ml. of tetrahydrofuran was stirred and heated under reflux for a period of 3 hours. At the end of this time 5 ml. of water was added and the mixture was stirred and chilled in an ice bath for one-half hour. The solid that precipitated was filtered, rinsed with a cold 1:1 mixture of tetrahydrofuran and water and vacuum dried. This solid was 10.5 g. of unreacted starting material. The total filtrate from above was stripped of tetrahydrofuran on a rotary evaporator. The solid that precipitated during the stripping was filtered and rinsed with cold two percent aqueous p-toluenesulfonic acid solution. This solid was pulled damp dry on the filter, washed twice with 10 ml. portions of isopropyl acetate, and air dried to - - - - - - - -carboxylate £-toluenesulfonlc acid salt monohydrate.
The procedure of Example 1 was repeated using different acids and different solvent systems. The results are summarized in Table 1.
Table 1 Acid Temp., Time Acid Cone 'n. Solvent eC. hrs.
HC1 1.2M 4 ml. ¾0 66 5 ml. THP TgOH 1.3 5 ml. H20 57 7 ml. (CH3)2C0 HpSO.. 1.8M 4 ml. H 0 5# 66 10 ml. THP MeSO_H 1.3M 5 ml. ¾0 # 66 6 -5 20 ml. THP T OH 1.3M. 3 ml. ¾0 # 65 6 ml. CH3C1 TgOH 1.3M 5 ml. H2O # 100 1 ml. DMSO TgOH = p-toluenesulf onic acid MeSO^H = methanesulf onic acid THP = tetpahydrof uran DMSO = dimethyls ulf oxide Another series of reactions was run following the procedure of Example 1 except that the starting material was 2,2,2-trlchloroethyl 3-raethyl-7-phenoxyacet-amldo- cephem-4-carbox late. The results of these runs are summarized In Table 2.
Table 2 Moles Acid Amide Temp., Time, Acid Moles Amide Solvent Conc'n.,# °C. Hrs . Yield, % HC1 20 CH30H 0.6 -^27 20 47 HC1 4 CH30H ¾7 15 52 T„OH 2.5 CH30H 5 45 22 58 TsOH 1 CH^OH 5 65 5 57 TsOH 1 C¾0H 5 65 12 52 TsOH 2.5 C9H 0H 5 78 4 38 TeOH 12.5 C¾0H 5 75 1.75 5 T OH 12.5 5 66 .5 68
Claims (5)
1. A process for preparing a compound having the formula 0=C - N ,C-CH, (I) \ c✓ 3 C02R< which comprises treating a compound having the formula C02R» with at least one mole of a solvent having the formula R"-OH at a temperature within the range of 0" to 125°C. in the presence of at least 0.25 equivalent of an acid having a PKa of- less than 3, wherein or Q is hydrogen, Cj. to alkyl, Cj. to alkoxy, cyano, nitra, hydroxy, chloro, bromo, or fluoro; Y is hydrogen or hydroxy; X is oxygen or sulfur; m is an integer of 0 to 2; n is an integer of 1 to 3; 2, 2, 2 -trichloroethyl or p-nitrobenzyl; and R* is hydrogen or an easily removable oarboxyl protect lng group j and R" is hydrogen, methyl, ethyl, or propyl.
2. The process of claim 1 wherein R is benzyl or phenoxymethyl.
3. The process of claim 2 wherein R" is hydrogen, the acid is p-toluenesul onic acid, and the temperature is within the range of 25° to 75° C.
4. The process for preparing 3 -me hyl -7 -amino cephalosporin compounds, substantially as herein described with particular reference to any one of the specific examples. of Formula I in claim 1, whenever
5. The compounds/ obtained by the process of any of claims 1 to 4. 8. HOROWITZ * CO. Agente lor Applicant*
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US80582369A | 1969-03-10 | 1969-03-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL33889A0 IL33889A0 (en) | 1970-04-20 |
| IL33889A true IL33889A (en) | 1973-04-30 |
Family
ID=25192601
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL33889A IL33889A (en) | 1969-03-10 | 1970-02-12 | Preparation of 7-amino cephalosporin esters |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS4931999B1 (en) |
| AT (1) | AT293620B (en) |
| BE (1) | BE746860A (en) |
| CA (1) | CA974516A (en) |
| CH (1) | CH529788A (en) |
| DE (1) | DE2010757A1 (en) |
| ES (1) | ES377228A1 (en) |
| FR (1) | FR2037887A5 (en) |
| GB (1) | GB1266252A (en) |
| IE (1) | IE33722B1 (en) |
| IL (1) | IL33889A (en) |
| NL (1) | NL7003048A (en) |
| SE (1) | SE374374B (en) |
-
1970
- 1970-02-06 CA CA074,173A patent/CA974516A/en not_active Expired
- 1970-02-10 IE IE176/70A patent/IE33722B1/en unknown
- 1970-02-12 IL IL33889A patent/IL33889A/en unknown
- 1970-03-03 NL NL7003048A patent/NL7003048A/xx unknown
- 1970-03-05 BE BE746860D patent/BE746860A/en unknown
- 1970-03-06 ES ES377228A patent/ES377228A1/en not_active Expired
- 1970-03-06 DE DE19702010757 patent/DE2010757A1/en active Pending
- 1970-03-09 SE SE7003123A patent/SE374374B/xx unknown
- 1970-03-10 CH CH351170A patent/CH529788A/en not_active IP Right Cessation
- 1970-03-10 JP JP45019797A patent/JPS4931999B1/ja active Pending
- 1970-03-10 GB GB1266252D patent/GB1266252A/en not_active Expired
- 1970-03-10 AT AT224670A patent/AT293620B/en not_active IP Right Cessation
- 1970-03-10 FR FR7008534A patent/FR2037887A5/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IL33889A0 (en) | 1970-04-20 |
| GB1266252A (en) | 1972-03-08 |
| IE33722L (en) | 1970-09-10 |
| CH529788A (en) | 1972-10-31 |
| BE746860A (en) | 1970-09-07 |
| NL7003048A (en) | 1970-09-14 |
| IE33722B1 (en) | 1974-10-02 |
| AT293620B (en) | 1971-10-25 |
| ES377228A1 (en) | 1972-06-01 |
| FR2037887A5 (en) | 1970-12-31 |
| CA974516A (en) | 1975-09-16 |
| JPS4931999B1 (en) | 1974-08-27 |
| SE374374B (en) | 1975-03-03 |
| DE2010757A1 (en) | 1970-09-17 |
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