ITMI940785A1 - PROCEDURE FOR THE PREPARATION OF 3-VINYL-CEPHALOSPORANIC ESTERS - Google Patents
PROCEDURE FOR THE PREPARATION OF 3-VINYL-CEPHALOSPORANIC ESTERS Download PDFInfo
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- ITMI940785A1 ITMI940785A1 IT000785A ITMI940785A ITMI940785A1 IT MI940785 A1 ITMI940785 A1 IT MI940785A1 IT 000785 A IT000785 A IT 000785A IT MI940785 A ITMI940785 A IT MI940785A IT MI940785 A1 ITMI940785 A1 IT MI940785A1
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- 238000000034 method Methods 0.000 title claims description 15
- 150000002148 esters Chemical class 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 17
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 13
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 claims description 8
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- 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 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- -1 p-nitrobenzyl ester Chemical class 0.000 description 6
- 239000002253 acid Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AGAOMWQWVIJILM-FQNRMIAFSA-N (6r)-3-ethenyl-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound C1([C@H]2SCC(=C(N2C1=O)C(=O)O)C=C)NC(=O)CC1=CC=CC=C1 AGAOMWQWVIJILM-FQNRMIAFSA-N 0.000 description 1
- FZEVMBJWXHDLDB-ZCFIWIBFSA-N (6r)-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical class S1CC=CN2C(=O)C[C@H]21 FZEVMBJWXHDLDB-ZCFIWIBFSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- IYZOZZXIIZIBFS-SSDOTTSWSA-N [(6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl] methanesulfonate Chemical group S1CC(OS(=O)(=O)C)=CN2C(=O)C[C@H]21 IYZOZZXIIZIBFS-SSDOTTSWSA-N 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 description 1
- 229960003719 cefdinir Drugs 0.000 description 1
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 1
- 229960002129 cefixime Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000006203 ethylation Effects 0.000 description 1
- 238000006200 ethylation reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Description
Descrizione dell’invenzione industriale Description of the industrial invention
La presente invenzione concerne un procedimento per la prepararlo ne di esteri 3-vinil-cefalosporanici. The present invention relates to a process for preparing it of 3-vinyl-cephalosporan esters.
Più particolarmente, la presente invenzione si riferisce ad un pro cedimento per la preparazione di un estere dell'acido 7-fenilacetami do-3-vinil-2-cefem-4-carbossilico. Questi esteri sono intermedi utili nella preparazione di composti noti ad attività antibiotica, quali cefixima, cefdinir ed altri. More particularly, the present invention relates to a process for the preparation of an ester of 7-phenylacetamine do-3-vinyl-2-cephem-4-carboxylic acid. These esters are useful intermediates in the preparation of known compounds with antibiotic activity, such as cefixime, cefdinir and others.
E' noto che i procedimenti che si basano sull'introduzione di gruppi nucleofili nella posizione 3 del nucleo 3-cefem provocano uno slittamento del doppio legame dalla posizione 3 alla posizione 2 con formazione di miscele di 2-cefem- e 3-cefem-derivati. It is known that the procedures based on the introduction of nucleophilic groups in position 3 of the 3-cephem nucleus cause a shift of the double bond from position 3 to position 2 with the formation of mixtures of 2-cephem- and 3-cephem-derivatives .
E' noto inoltre che è possibile introdurre un gruppo vinilico nella posizione 3 del nucleo cefem a partire da 3-trifluorometansolfo nilossi-3-cefem per reazione con vinil-tributilstagno (J. Org. Chem. It is also known that it is possible to introduce a vinyl group in position 3 of the cefem nucleus starting from 3-trifluoromethanesulf nyloxy-3-cefem by reaction with vinyl-tributyltin (J. Org. Chem.
1990, 55, 5833-5847). Questa reazione avviene con una resa di circa il 70%, apparentemente senza contemporanea formazione del derivato 2-cefem. Tuttavia il trifluorometansolfonilcloruro usato come reattivo è poco maneggevole e piuttosto costoso. 1990, 55, 5833-5847). This reaction takes place with a yield of about 70%, apparently without simultaneous formation of the 2-cefem derivative. However, the trifluoromethanesulfonyl chloride used as a reagent is unwieldy and rather expensive.
E' stato ora trovato che per reazione del vinil-tributil-stagno sull'estere benzidrilico o p-nitrobenzilico dell'acido 7-fenilacetami. do-3-mesilossi-3-cefem-4-carbossilico in presenza di palladio si ottiene lo slittamento quantitativo del doppio legame in posizione 2 del nucleo e la formazione di esteri dell'acido 7-fenilacetamido-3-vinil-2-cefem-4-carbossilico. It has now been found that by reaction of the vinyl-tributyl-tin on the benzhydryl or p-nitrobenzyl ester of the 7-phenylacetamus acid. do-3-mesyloxy-3-cefem-4-carboxylic in the presence of palladium, quantitative slippage of the double bond in position 2 of the nucleus is obtained and the formation of esters of 7-phenylacetamido-3-vinyl-2-cefem- acid 4-carboxylic.
E' stato inoltre trovato che la resa in 3-vinil-2-cefem è pratica mente quantitativa, comunque sempre superiore al 90% del teorico, se la reazione viene condotta anche in presenza di ioduro di litio utilizzando 1’l-metil-2-pirrolidinone come solvente. It has also been found that the yield in 3-vinyl-2-cefem is practically quantitative, in any case always higher than 90% of the theoretical, if the reaction is carried out also in the presence of lithium iodide using 1-methyl-2 -pyrrolidinone as a solvent.
Cosi, la presente invenzione concerne un procedimento per la prepa razione di un estere di formula (I) Thus, the present invention relates to a process for the preparation of an ester of formula (I)
(I) (THE)
in cui R rappresenta un gruppo benzidrile o p-nitrobenzile, caratte rizzato dal fatto che si tratta un derivato 3-mesilossi-3-cefem di formula in which R represents a benzhydryl or p-nitrobenzyl group, characterized in that it is a 3-mesyloxy-3-cephem derivative of formula
(II) (II)
in cui R è come sopra definito, con vinil-tributil-stagno in presenza di acetato di palladio e ioduro di litio a temperatura ambiente in 1-metil-2-pirrolidinone per un periodo di almeno 24 ore. wherein R is as defined above, with vinyl-tributyl-tin in the presence of palladium acetate and lithium iodide at room temperature in 1-methyl-2-pyrrolidinone for a period of at least 24 hours.
I composti di partenza di formula (II) sono descritti in Helv. Chim. Acta 58. 2437 (1975). The starting compounds of formula (II) are described in Helv. Chim. Acta 58, 2437 (1975).
La reazione tra l'estere di formula (II) e il vinil-tributilstagno viene condotta a temperatura ambiente, in pratica tra 15°C e 30°C, preferibilmente a 20+25°C, utilizzando un leggero eccesso di stagno ed una quantità catalitica (circa 10%) di acetato di palladio. The reaction between the ester of formula (II) and the vinyl-tributyltin is carried out at room temperature, in practice between 15 ° C and 30 ° C, preferably at 20 + 25 ° C, using a slight excess of tin and a quantity catalytic (about 10%) of palladium acetate.
Lo ioduro di litio è preferibilmente usato in un eccesso di almeno il 50% rispetto al materiale di partenza (II), ma è ancora meglio se ne viene usata una quantità doppia su base molare. Lithium iodide is preferably used in an excess of at least 50% of the starting material (II), but it is even better if twice the amount is used on a molar basis.
Il tempo di reazione può variare da 24 a 96 ore, ma dipende specialmente dal tipo di substrato. Più particolarmente, se come materiale di partenza si usa un estere di formula (II) in cui R è benzidrile, occorono almeno 60 ore perchè la reazione sia completa, mentre 24+48 ore sono sufficienti se come materiale di partenza si usa un composto di formula (II), in cui R è p-nitrobenzile. The reaction time can vary from 24 to 96 hours, but it depends especially on the type of substrate. More particularly, if an ester of formula (II) is used as starting material in which R is benzhydryl, it takes at least 60 hours for the reaction to be complete, while 24 + 48 hours are sufficient if a compound of formula (II), where R is p-nitrobenzyl.
La reazione pud essere seguita per cromatografia su strato sottile (TLC) o per cromatografia liquida ad alta pressione (HPLC) e, a reazione ultimata, il prodotto viene isolato secondo i metodi convenzionali, per esempio mediante estrazione da opportuno solvente, preferibilmente da acetato d'etile, ed evaporazione del solvente. The reaction can be followed by thin layer chromatography (TLC) or by high pressure liquid chromatography (HPLC) and, once the reaction is complete, the product is isolated according to conventional methods, for example by extraction from a suitable solvent, preferably from acetate. ethyl, and evaporation of the solvent.
Il composto di formula (I) ottenuto al termine della reazione costituisce un utile intermedio per la preparazione del corrisponden te estere dell'acido 7-fenilacetamido-3-vinil-3-cefem-4-carbossilico. Quest'ultimo pud essere ottenuto con altissime rese secondo metodi noti mediante ossidazione a solfossido e successiva riduzione di detto solfossido. The compound of formula (I) obtained at the end of the reaction constitutes a useful intermediate for the preparation of the corresponding ester of 7-phenylacetamido-3-vinyl-3-cephem-4-carboxylic acid. The latter can be obtained with very high yields according to known methods by means of oxidation to sulfoxide and subsequent reduction of said sulfoxide.
Questa operazione di ossido-riduzione, che avviene con rese eleva tissime, permette l'eliminazione di tracce di stagno presenti al termine della reazione con vinil-tributil-stagno. This redox operation, which takes place with very high yields, allows the elimination of traces of tin present at the end of the reaction with vinyl-tributyl-tin.
Cosi, il procedimento della presente invenzione ha il vantaggio, rispetto ad altri procedimenti noti, per esempio a quello descritto in J. Org. Chera. 1990, 55, 5833-5847, di fornire un prodotto di elevata purezza con ottimi rendimenti. Thus, the process of the present invention has the advantage over other known processes, for example the one described in J. Org. Chera. 1990, 55, 5833-5847, to provide a high purity product with excellent yields.
I seguenti esempi illustrano l'invenzione senza, tuttavia, limitarla. Le reazioni sono state seguite mediante TLC (eluente: esa no/etile acetato = 1/1) e mediante HPLC (colonna: Brownlee Spheri 5, RP-18, 5μ, 250 x 4,6 mm; fase mobile: acetonitrile acquoso al 10%/ac qua - sistema gradiente; flusso: 1,5 ml/minuto; A = 260 nm). The following examples illustrate the invention without, however, limiting it. The reactions were followed by TLC (eluent: hexane / ethyl acetate = 1/1) and by HPLC (column: Brownlee Spheri 5, RP-18, 5μ, 250 x 4.6 mm; mobile phase: aqueous acetonitrile at 10 % / water - gradient system; flow: 1.5 ml / minute; A = 260 nm).
ESEMPIO 1 EXAMPLE 1
A temperatura ambiente ed in atmosfera di argon si trattano 0,007 3 (0,033 mmoli) di palladio acetato con 10 ml di l-metil-2-pirrolidinone anidro, 0,196 g (0,33 mmoli) di estere benzidrilico de.1 l'acido 7-fenilacetamido-3-mesilossi-3-cefem-4-carbossilico, 0,088 g (0,66 mmoli) di LiI e 0,12 ml (0,41 mmoli) di vinil tributil-stagno. si segue la reazione per TLC ed HPLC. A reazione ultimata, dopo 72 ore, si diluisce con etile acetato e si lava 3 volte con acqua. L’estratto, essiccato con Na2SO4, si concentra poi sotto vuoto. Il residuo, ripreso con etere etilico, fornisce 0,196 g (96%) di estere benzidrilico dell'acido 7-fenilacetamido-3-vinil-2-cefem-4-carbossili co. At room temperature and in an argon atmosphere, 0.007 3 (0.033 mmoles) of palladium acetate are treated with 10 ml of anhydrous 1-methyl-2-pyrrolidinone, 0.196 g (0.33 mmoles) of benzhydryl ester of 1 acid 7 -phenylacetamido-3-mesyloxy-3-cephem-4-carboxylic, 0.088 g (0.66 mmol) of LiI and 0.12 ml (0.41 mmol) of vinyl tributyl-tin. the reaction is followed by TLC and HPLC. When the reaction is complete, after 72 hours, it is diluted with ethyl acetate and washed 3 times with water. The extract, dried with Na2SO4, is then concentrated under vacuum. The residue, taken up with ethyl ether, yields 0.196 g (96%) of benzhydryl ester of 7-phenylacetamido-3-vinyl-2-cephem-4-carboxylic acid.
ESEMPIO 2 EXAMPLE 2
Operando come descritto nell'Esempio 1, a partire dall'estere p-ni trobenzilico dell'acido 7-fenilacetamido-3-meeilossi-3-cefem-4-carbos Bilico, utilizzando le stesse quantità molari di vari reattivi si ot tiene, dopo 36 ore di reazione, l'estere p-nitrobenzilico dell'acido 7-fenilacetamido-3-vinil-2-cefem-4-earbossilico con una resa del 98%. Operating as described in Example 1, starting from the p-ni-trobenzyl ester of 7-phenylacetamido-3-meeyloxy-3-cefem-4-carbos Bilico, using the same molar quantities of various reagents, it is obtained, after 36 hours of reaction, the p-nitrobenzyl ester of 7-phenylacetamido-3-vinyl-2-cefem-4-earboxylic acid with a yield of 98%.
Claims (8)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI940785A IT1269575B (en) | 1994-04-22 | 1994-04-22 | PROCEDURE FOR THE PREPARATION OF 3-VINYL-CEPHALOSPORANIC ESTERS |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI940785A IT1269575B (en) | 1994-04-22 | 1994-04-22 | PROCEDURE FOR THE PREPARATION OF 3-VINYL-CEPHALOSPORANIC ESTERS |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| ITMI940785A0 ITMI940785A0 (en) | 1994-04-22 |
| ITMI940785A1 true ITMI940785A1 (en) | 1995-10-22 |
| IT1269575B IT1269575B (en) | 1997-04-08 |
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ID=11368711
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ITMI940785A IT1269575B (en) | 1994-04-22 | 1994-04-22 | PROCEDURE FOR THE PREPARATION OF 3-VINYL-CEPHALOSPORANIC ESTERS |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | IT1269575B (en) |
-
1994
- 1994-04-22 IT ITMI940785A patent/IT1269575B/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| IT1269575B (en) | 1997-04-08 |
| ITMI940785A0 (en) | 1994-04-22 |
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