GB2231049A - Method for producing diester compounds - Google Patents
Method for producing diester compounds Download PDFInfo
- Publication number
- GB2231049A GB2231049A GB9008395A GB9008395A GB2231049A GB 2231049 A GB2231049 A GB 2231049A GB 9008395 A GB9008395 A GB 9008395A GB 9008395 A GB9008395 A GB 9008395A GB 2231049 A GB2231049 A GB 2231049A
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- phenylacetylamino
- penicillanate
- compound
- penicillin
- reaction
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Diester compounds of the formula <IMAGE> wherein R is phenylacetylamino or phenoxyacetylamino, are produced by reacting a compound of the formula <IMAGE> wherein R<1> is hydrogen, phenylacetylamino or phenoxyacetylamino, Y<1> is sulfur or sulfonyl, and X is chlorine, bromine or iodine, with a compound of the formula <IMAGE> wherein R<2> is hydrogen, phenylacetylamino or phenoxyacetylamino, Y<2> is sulfur or sulfonyl, and M is alkali metal, in the presence of a urea group solvent or N-methyl-2-pyrrolidone. By this method, the desired compound can be obtained in high yield and high purity, and can be isolated as crystals of high purity, accompanied by no by-product. The diester compounds are useful as intermediates in the synthesis of sulbactam and sultamicillin.
Description
Method for Producing Diester Compounds
The present invention relates to an improved method for producing diester compounds which are useful as intermediates in the synthesis of penicillin group antibacterials.
Penicillanic acid 1,1-dioxide (sulbactam) has been known as a useful g-lactamase inhibitor. Further, 1,1-dioxopenicillanoyloxymethyl 6-[D-(2-amino-2-phenylacetylamino) )penicil- lanate (sultamicillin) which is a mutual prodrug wherein the sulbactam and ampicillin are ester-bonded, is an oral antibacterial developed for the purpose of increasing blood concentration and tissue concentration of ampicillin and sulbactam, and producing mutual synergistic activity on ampicillin-resistant bacteria produced by ss-lactamase in vivo.
In addition, there are known diester compounds such as 1,1 -dioxopenicillanoyloxymethyl-6-(2-phenyl or phenoxyacetylamino)penicillanate (hereinafter referred to as Compound A or B) which are important intermediates in sultamicillin synthesis.
U.S. Patent No. 4,244,951 describes a method for producing Compound A by reacting penicillin G potassium and chloromethyl penicillanate 1,1-dioxide in dimethylsulfoxide.
Additionally, U.S. Patent No. 4,530,792 describes a method for producing sultamicillin from Compound A or B. In particular a method for producing Compound A by reacting penicillin G sodium and chloromethyl penicillanate i,1-dioxide in dimethylsulfoxide is shown in Example 1, and a method for producing Compound A by reacting chloromethyl 6- (2-phenylacetylamino) -penicillanate and tetrabutylammonium penicillanate l,l-dioxide in acetone is shown in Example 2(b).
The known methods mentioned above for obtaining diester compounds are generally low in yield. For example, by the method of U.S. Patent No. 4,244,951, the yield of the diester compound is as low as about 12% on the basis of chloromethyl penicillanate l,l-dioxide; by the method of Example 1 in U.S. Patent
No. 4,530,792, the yield of the diester compound is 25.6% on the basis of chloromethyl penicillanate l,l-dioxide; and by the method of Example 2(b) of that
Patent, the yield is 45%, all of which yields are far from satisfactory from an industrial point of view.
What is worse, the diester compounds obtained by the above methods are all in the form of foamy substances, rendering difficult the separation and purification of the desired compounds.
The inventors of the present invention have experimented with the production of diester compounds in the presence of known solvents such as dimethylsulfoxide, and have found that only foamy products in low yield accompanied by considerable amounts of structurally unknown by-products were obtained, and further that such byproducts made the separation and purification of the desired compounds still more difficult.
Thus, the development of an industrial method for producing diester compounds in high yield with no by-product, which enables efficient separation and purification is desired.
The inventors of the present invention have found that by using a urea group solvent or N-methyl-2-pyrrolidone as a solvent, diester compounds represented by the formula (I)
wherein R is phenylacetylamino or phenoxyacetylamino, can be obtained in high yield with no by-product, enabling efficient separation and purification.
According to the present invention there is provided a method for producing diester compounds represented by the formula (I), which method comprises reacting a compound of the general formula (II)
whereon R1 is hydrogen, phenylacetylamino or phenoxyacetyl- amino Y1is sulfur or sulfonyl, and X is chlorine, bromine or iodine, with a compound of the formula (III)
wherein R2 is hydrogen, phenylacetylamino or phenoxyacetylamino, Y is sulfur or sulfonyl, and M is alkali metal, in the presence of a urea group solvent or N-methyl-2-pyrrolidone.
The compound of the formula (II) which is one of the starting materials can be synthesized easily by reacting penicillin G, penicillin V or penicillanic acid l,l-dioxide or a salt thereof, which are available as industrial materials at low cost, with for example, methylenechloride, chloroiodomethane or bromochloromethane, by known methods or by the method described in Japanese Patent (Unexamined) Publication (Kokai) No. 139584/1989.
The other starting material, the compound of the formula (III), needs to be water soluble and as a preferable alkali metal salt, mention can be made of, for example, the sodium salt or the potassium salt.
The reaction solvent which is the characteristic feature of the present invention is a urea group solvent or N-methyl-2-pyrrolidone and as examples of such urea group solvent, mention can be made of tetramethylurea, 1,3-dimethyl-2-imidazolidinone, 1,3-diethyl-2-imidazolidinone and 1,3-dipropyl-2- imidazolidinone, either singly or in combination.
Furthermore, the urea group solvent and
N-methyl-2-pyrrolidone of the present invention can be recovered easily and can be used repeatedly.
Addition of sodium iodide or potassium iodide during the reaction assists the reaction to proceed smoothly. The amount to be added may be about 0.1 mol to equivalent mol relative to compound (III) or in excess.
Furthermore addition of sodium thiosulfate to the reaction system has the advantages of prevention of coloring of the reaction mixture, stabilization of the reaction mixture, and prevention of by-product production. The amount to be added may be about 0.1 mol to equivalent mol relative to compound (III).
The reaction temperature may be in the range of from room temperature to 600C, preferably from 30 to 500C. The reaction time varies depending on the amount of additives, reaction temperature, etc., but normally the reaction proceeds in 1 to 24 hours. The preferable amount of the starting materials is an equivalent mol.
The diester compounds of the formula (I) thus obtained can be separated and purified by a conventional method such as precipitation, filtration, recrystallization and column chromatography, after termination of the reaction.
For example, in the case wherein the reaction solution is Compound A, addition thereof into an excess of water under cooling after reaction leads to separation of the desired compound in crystals.
The method of the present invention provides the following advantages in respect of yield, purity and reaction manipulation. Specifically, the desired compound can be obtained in high yield and high purity, (2) the product obtained can be isolated as crystals and due to high purity, they can be used in the following reaction without further purification, thus simplifying the purification procedure, and (3) no structurally unknown by-product is produced, thus rendering the reaction procedure smooth and the reaction time is shortened; and the diester compounds useful as intermediates for the synthesis of penicillin group antibacterials, specifically sultamicillin, can be advantageously produced.
The present invention is hereinafter exemplified with reference to specific working examples. However, the present invention is not limited thereto. The compounds obtained in the present invention are confirmed to be the desired compounds by IR spectrum,
NMR spectrum, HPLC, elementary analysis and so on.
Reference Example 1 : chloromethyl 6-(2-phenylacetylamino)- penicillanate
To a mixed solution of 7.45 g of potassium 6-(2-phenylacetylamino)penicillanate, 0.2 g of potassium bicarbonate and 50 g of water were added 1.3 g of 51.2% tetrabutylammonium bromide and 600 g of bromochloromethane. While vigorously stirring, the mixture was reacted at 500C for 5.5 hours. The composition of the reaction mixture after the reaction was potassium 6-(2-phenylacetylamino)penicillanate : chloromethyl 6-(2-phenylacetylamino)penicillanate : methylenebis[6 (2-phenylacetylamino)penicillanate] = 1.68 : 91.94 : 4.24 by
HPLC area ratio. The reaction mixture was cooled and the organic layer was separated and washed, followed by concentration under reduced pressure to give 7.5 g of pale brown oily substance.The composition of the obtained oily substance was chloromethyl 6-(2-phenylacetylamino)penicillanate methylenebis[6-(2-phenylacetylamino)penicillanate] = 95.43 4.22 by HPLC area ratio.
Reference Example 2 : chloromethyl 6-(2-phenylacetylamino)
penicillanate
A mixture of 300 g of bromochloromethane, 10 g of water and 1.3 g of 50.9% tetrabutylammonium bromide was kept at 450C, and thereto was added a solution of 7.45 g of potassium 6-(2-phenylacetylamino)penicillanate, 40 g of water and 0.2 g of potassium bicarbonate. While vigorously stirring, the mixture was reacted at 450C for 8 hours. The composition of the reaction mixture after the reaction was potassium 6-(2phenylacetylamino)penicillanate : chloromethyl 6-(2-phenylacetylamino)penicillanate : methylenebis[6-(2-phenylacetyl amino)penicillanate = 6.5 : 85.6 : 7.9 by HPLC area ratio.
The reaction mixture was cooled, and the organic layer was separated and washed, followed by concentration under reduced pressure to give 7.4 g of pale brown oily substance. The composition of the obtained oily substance was potassium 6 (2-phenylacetylamino)penicillanate : chloromethyl 6-(2- phenylacetylamino)penicillanate : methylenebis[6-(2-phenyl acetylamino)penicillanate3 = = 0.23 : 85.63 : 9.87 by HPLC area ratio.
Reference Example 3 : chloromethyl penicillanate 1,1-dioxide
A mixture of 300 g of bromochloromethane, 5 g of water and 0.65 g of 50.9% tetrabutylammonium bromide was kept at 50 CC, and thereto was added a solution of 2.55 g of sodium penicillanic acid 1,1-dioxide, 20 g of water and 0.67 g of potassium carbonate. While vigorously stirring, the mixture was reacted at 500C for 20 hours. The organic layer was separated and washed, and bromochloromethane was distilled off. The composition of the obtained residue was chloro methyl penicillanate 1,1 -dioxide : methylenebisl1,1-dioxo- penicillanate] = 93.18 : 6.82 by HPLC area ratio. A part of the residue was kept standing in a refrigerator to crystalize.The crystals were filtrated and washed with a small amount of a mixed solvent of ether - petroleum ether to give the desired crystals, m.p. 94 - 960C.
Example 1
The oily substance (7.6 g) obtained by the same procedure as in Reference Example 1, having the composition of chloromethyl 6-(2-phenylacetylamino)penicillanate : methylenebis[6-(2-phenylacetylamino)penicillanate] = 95.43 : 4.22 by
HPCL area ratio was dissolved in 25 g of N-methyl-2-pyrrolidone. Thereto were added 1.5 g of sodium thiosulfate, 5 g of potassium iodide and 5.1 g of sodium penicillanic acid 1,1dioxide, and the mixture was reacted at 50"C for 4.5 hours.
After the termination of the reaction was confirmed by HPLC, the reaction mixture was cooled and poured into 200 g of cool water. The precipitated crystals were ice-cooled and sufficiently matured, followed by filtration, washing and drying on phosphorus pentoxide to give 11 g of pale brown crystalline powder. The composition of the obtained crystalline powder was 1,1 -dioxopenicillanoyloxymethyl 6-(2-phenylacetylamino)penicillanate : methylenebis[6-(2-phenylacetyl- amino)penicillanate] : N-methyl-2-pyrrolidone = 93.51 : 6.00 : 0.49 by HPLC area ratio and other structurally unknown by-product was not detected at all.
Example 2
The sticky, oily substance (5.6 g) obtained by the same procedure as in Reference Example 3, having the composition of chloromethyl penicillanate 1,1-dioxide : methylenebis[1,1- dioxopenicillanate] = 96.3 : 3.7 by HPCL area ratio was dissolved in 25 g of N-methyl-2-pyrrolidone. Thereto were added 1.5 g of sodium thiosulfate, 5 g of potassium iodide and 7.4 g of potassium 6-(2-phenylacetylamino)penicillanate, and the mixture was reacted at 500C. After the termination of the reaction was confirmed by HPLC, the reaction mixture was cooled and poured into 200 g of cool water. The precipitated crystals were ice-cooled and sufficiently matured, followed by filtration, washing and drying on phosphorus pentoxide to give 11.1 g of pale brown crystalline powder.
The composition of the obtained crystalline powder was 1,1dioxopenicillanoyloxymethyl 6-(2-phenylacetylamino)penicillanate : methylenebis[1,1-dioxopenicillanate] : N-methyl-2pyrrolidone = 95.49 : 4.00 : 0.51 by HPLC area ratio and other structurally unknown by-product was not detected at all.
Example 3
The oily substance (7.6 g) obtained by the same procedure as in Reference Example 2, having the composition of chloromethyl 6-(2-phenylacetylamino)penicillanate : methy lenebis[6-(2-phenylacetylamino)penicillanate] = 97.8 : 2.2 by
HPCL area ratio was dissolved in 25 g of 1,3-dimethyl-2imidazolidinone. Thereto were added 5 g of potassium iodide, 5.1 g of sodium penicillanic acid 1,1-dioxide and 0.6 g of sodium thiosulfate, and the mixture was reacted at 400C.
After termination of the reaction was confirmed by HPLC, the reaction mixture was poured into 1 50 g of cool water.
The precipitated crystals were filtrated after maturation under ice-cooling, followed by washing and drying on phosphorus pentoxide to give 10.8 g of pale brown crystalline powder. The composition of the obtained crystalline powder was 1,1 -dioxopenicillanoyloxymethyl 6-(2-phenylacetylamino)penicillanate : methylenebis[6-(2-phenylacetylamino)penicillanate] : 1,3-dimethyl-2-imidazolidinone : water = 88.8 : 3.4 : 6.8 : 1.0 by HPLC area ratio and other structurally unknown by-product was not detected at all.
Example 4
The sticky, oily substance (5.6 g) obtained by the same procedure as in Reference Example 3, having the composition of chloromethyl penicillanate 1,1-dioxide : methylenebis[1,1dioxopenicillanate] = 96.3 : 3.7 by HPLC area ratio was dissolved in 25 g of 1,3-dimethyl-2-imidazolidinone. Thereto were added 5 g of potassium iodide, 7.4 g of potassium 6-(2 phenylacetylamino)penicillanate and 0.6 g of sodium thiosulfate, and the mixture was reacted at 400C. After termination of the reaction was confirmed by HPLC, the reaction mixture was poured into 1 50 g of cool water. The precipitated crystals were filtrated after maturation under icecooling, followed by washing and drying on phosphorus pentoxide to give 10.5 g of pale brown crystalline powder. The composition of the obtained crystalline powder was 1,1-dioxopenicillanoyloxymethyl 6-(2-phenylacetylamino)penicillanate methylenebis[1 ,1-dioxopenicillanate] : 1,3-dimethyl-2-imidazolidinone : water = 87.8 : 3.8 : 7.2 : 1.2 by HPLC area ratio and other structurally unknown by-product was not detected at all.
Example 5
The oily substance (7.6 g) obtained by the same procedure as in Reference Example 2, having the composition of chloromethyl 6-(2-phenylacetylamino)penicillanate : methylenebis[6-(2-phenylacetylamino)penicillanate] = 90.2 : 9.8 by
HPCL area ratio was dissolved in 30 g of tetramethylurea.
Thereto were added 3.3 g of potassium iodide and 5.1 g of sodium penicillanic acid 1,1-dioxide, and the mixture was stirred at 450C for 13 hours. After cooling, the reaction mixture was poured into 150 g of cool water. The precipitated crystals were filtrated after maturation under icecooling. The obtained crystals were washed and dried on phosphorus pentoxide to give 10.6 g of pale brown crystalline powder. The composition of the obtained crystalline powder was 1,1 -dioxopenicillanoyloxymethyl 6-(2-phenylacetylamino)penicillanate : methylenebis[6-(2-phenylacetylamino)penicil- lanate] : tetramethylurea : water = 83.1 : 8.2 : 7.2 : 1.5 by
HPLC area ratio and other structurally unknown by-product was not detected at all.
Example 6
The oily substance (7.6 g) obtained by the same procedure as in Reference Example 2, having the composition of chloromethyl 6-(2-phenylacetylamino)penicillanate : methylenebis[6-(2-phenylacetylamino)penicillanate] = 97.7 : 2.3 by
HPCL area ratio was dissolved in 25 g of 1,3-dimethyl-2imidazolidinone. Thereto were added 5 g of potassium iodide, 5.1 g of sodium penicillanic acid 1,1-dioxide and 1.6 g of sodium thiosulfate, and the mixture was reacted at 450C for 6 hours. The composition of the crystalline powder obtained by the same procedure as in Example 3 was 1,1-dioxopenicillanoyloxymethyl 6-(2-phenylacetylamino)penicillanate : methylenebist6-(2-phenylacetylamino)penicillanate] = 95.6 : 4.4 by
HPLC area ratio and other structurally unknown by-product was not detected at all.
The present invention has been properly and sufficiently explained in the foregoing specification including Examples, which can be changed or modified within the spirit and scope of the present invention.
Claims (12)
1. A method for producing diester compounds represented by the formula
wherein R is phenylacetylamino or phenoxyacetylamino, which method comprises reacting a compound of the formula
wherein R1 is hydrogen, phenylacetylamino or phenoxyacetylamino, y1 is sulfur or sulfonyl, and X is chlorine, bromine or iodine, with a compound of the formula
wherein R2 is hydrogen, phenylacetylamino or phenoxyacetylamino, Y2 is sulfur or sulfonyl, and M is alkali metal, in the presence of a urea group solvent or N-methyl-2-pyrrolidone.
2. A method as claimed in Claim 1 wherein the reaction is carried out in the presence of sodium iodide or potassium iodide.
3. A method as claimed in Claim 1 or Claim 2 wherein the reaction is carried out in the presence of sodium thiosulfate.
4. A method as claimed in any one of the preceding claims wherein the urea group solvent is tetramethylurea.
5. A method as claimed in any one of Claims 1 to 3 wherein the urea group solvent is 1,3-dimethyl-2imidazolidinone.
6. A method as claimed in Claim 1 substantially as hereinbefore described in any one of Examples 1 to 6.
7. The use of diester compounds when prepared by the method as claimed in any one of Claims 1 to 6 in preparing a penicillin.
8. The use of diester compounds as claimed in Claim 7 wherein the penicillin is sulbactam.
9. The use of diester compounds as claimed in Claim 7 wherein the penicillin is sultamicillin.
10. A method as claimed in any one of Claims 1 to 6 wherein the diester compound is thereafter converted to a penicillin by known procedures.
11. A method as claimed in Claim 10 wherein the penicillin is sulbactam.
12. A method as claimed in Claim 10 wherein the penicillin is sultdmicillin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1095485A JPH02273685A (en) | 1989-04-14 | 1989-04-14 | Production of diester compound |
| JP1219272A JPH0383988A (en) | 1989-08-25 | 1989-08-25 | Production of diester compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9008395D0 GB9008395D0 (en) | 1990-06-13 |
| GB2231049A true GB2231049A (en) | 1990-11-07 |
Family
ID=26436706
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9008395A Withdrawn GB2231049A (en) | 1989-04-14 | 1990-04-12 | Method for producing diester compounds |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2231049A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005051959A1 (en) * | 2003-11-28 | 2005-06-09 | Zhejiang Yongning Pharmaceutical Factory | Β-lactamase-resistant cephalosporin ester compounds and salts of thereof |
| CN112724162A (en) * | 2020-12-28 | 2021-04-30 | 华南农业大学 | Synthesis method and application of amoxicillin-sulbactam hybrid molecule |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2051057A (en) * | 1979-05-16 | 1981-01-14 | Pfizer | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
| EP0108545A1 (en) * | 1982-11-01 | 1984-05-16 | Pfizer Inc. | Process and intermediates for preparation of 1,1-dioxopenicillanoyloxymethyl 6-beta-aminopenicillanate |
-
1990
- 1990-04-12 GB GB9008395A patent/GB2231049A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2051057A (en) * | 1979-05-16 | 1981-01-14 | Pfizer | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
| EP0108545A1 (en) * | 1982-11-01 | 1984-05-16 | Pfizer Inc. | Process and intermediates for preparation of 1,1-dioxopenicillanoyloxymethyl 6-beta-aminopenicillanate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005051959A1 (en) * | 2003-11-28 | 2005-06-09 | Zhejiang Yongning Pharmaceutical Factory | Β-lactamase-resistant cephalosporin ester compounds and salts of thereof |
| CN112724162A (en) * | 2020-12-28 | 2021-04-30 | 华南农业大学 | Synthesis method and application of amoxicillin-sulbactam hybrid molecule |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9008395D0 (en) | 1990-06-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |