GB2141124A - Phosphorus containing semisynthetic cephalosporanic and penicillanic derivatives - Google Patents
Phosphorus containing semisynthetic cephalosporanic and penicillanic derivatives Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65613—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system (X = CH2, O, S, NH) optionally with an additional double bond and/or substituents, e.g. cephalosporins and analogs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65611—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system (X = CH2, O, S, NH) optionally with an additional double bond and/or substituents, e.g. penicillins and analogs
Abstract
Compounds of the general formula (I> <IMAGE> - wherein A represents a group of the general formula (a) or (b), R<3> and R<4> are the same or different and represent hydrogen, halogen, hydroxy, amino, sulphonic acid group, or a specified organic group or R<3> and R<4> together form oxo, hydroxyimino, O-alkylimino or substituted alkylhydroxyimino group, R<6> and R<7> are the same or different and represent hydrogen, an optionally substituted straight or branched chained C1-6 alkyl group, C3-6 cycloalkyl, phenyl or an optionally substituted phenyl group Q<1>, Q<2> and Q<3> are the same or different and typically represent oxygen or sulfur k, m and n individually represent 0 or 1, R<15> and R<16> are the same or different and represent hydrogen, C1-6 alkyl, C3-7 cycloalkyl or optionally substituted phenyl or R<15> and R<16> can form a heterocyclic ring together with the carbon atom to which they are attached, R<8> stands for hydrogen or methoxy, Q<5> stands for hydrogen, halogen, methyl, acetoxymethyl, acyloxymethyl, pyridinium-methyl, methoxy or Het-S-methyl, wherein Het stands for a 5- or 6-membered mono-, bi- or tri-cyclic heteroaryl group which can contain one or more nitrogen and/or other hetero atoms, Y stands for carboxyl, acetoxy, methoxycarbonyl, methoxy-methoxycarbonyl, pivaloyloxymethoxycarbonyl or optionally substituted tetrazol-5-yl and p stands for 0 or 1 and w stands for 0, 1 or 2, and salts thereof, have antibacterial, antiviral, antifungal and beta -lactamase inhibiting activity and can be used as active ingredient of pharmaceutical compositions.
Description
SPECIFICATION
Phosphorous containing semisynthetic cephalosporanic and penicillanic derivatives and process for the preparation thereof and pharmaceutical compositions containing same
The present invention is directed to new phosphorous containing semisynthetic cephalosporanic and penicillanic acid derivatives of the general formula (I)
process for the preparation thereof and pharmaceutical compositions containing same.
In the general formula (I)
A stands for a group of the general formula (a) or (b),
R3 and R4 are the same or different and stand for hydrogen, halogen, alkyl, optionally substituted aryl, hydroxy, amino, substituted carbonylamino, acylamino, mono- or dialkylamino, carboxyl, esterified carboxylic acid or sulphonic acid group, heteroaromatic group or R3 and R4 together form oxo, hydroxyimino, O-alkylimino or substituted alkylhydroxyimino, group,
R6 and R7 are the same or different and stand for hydrogen, straight or branched chained C, 6 alkyl optionally substituted by one or more nitro, halogen, alkoxycarbonyl or dialkylamino group, C36 cycloalkyl, phenyl or phenyl group optionally substituted by R' or R2, wherein R' and R2 are the same or different and stand for hydrogen, halogen, alkyl, hydroxy, nitro, sulphonic acid, carboxylic or NR9R'0 group, wherein
R9 and R'O are the same or different and stand for C1 6 alkyl or C37 cycloalkyl or R9 and R'O together with the nitrogen atom form a C37 heterocyclic ring which can optionally contain other heteroatoms or R6 and R7 can optionally be attached to an unsubstituted or substituted atom group forming a ring or rings, 0 and Q7 are the same or different and stand for oxygen, sulfur or selenium or = CH2 group,
Q3 stands for 0, S, Se-, -NH, = NR1l or = N-N = CR12Rl3 R11, R12 and R'3 stand for C alkyl, C37 cycloalkyl, optionally substituted phenyl, naphthyl or substituted naphthyl, a cyclic group containing one or more hetero atoms which can be substituted or unsubstituted and optionally can be heteroaromatic,
k stands for 0 or 1,
m can be O or 1 and
n can be O or 1,
R'5 and R16 are the same or different and can stand for hydrogen, C16 alkyl, C37 cycloalkyl or optionally substituted phenyl or
R'5 and R16 can form a heterocyclic ring together with the carbon atom to which they are attached,
R8 stands for hydrogen or methoxy,
Q5 stands for hydrogen, halogen, methyl, acetoxymethyl, acyloxymethyl, pyridinium-methyl, methoxy or Het-S-methyl, wherein
Het stands for a 5- or 6-membered mono-, bi- or tricyclic heteroaryl group which can contain one or more nitrogen and/or other hetero atoms,
Y stands for carboxyl, acetoxy, methoxycarbonyl, methoxy-methoxycarbonyl, pivaloyloxymethoxycarbonyl or optionally substituted tetrazol-5-yl and
p stands for 0 or 1 and
w stands for 0, 1 or 2.
The compounds of the general formula (I) can be prepared by
a) reacting a compound of the general formula (II)
wherein R3, R4, R6, R7, 01, (12, (13, m, n and k are as given above and
Q4 stands for oxygen or sulfur,
R5 stands for hydrogen, phenyl, optionally substituted phenyl such as trichlorophenyl, pentachlorophenyl, pentafluorophenyl, 1 -methyl-tetrazol-5-yI, 2-methyl-1,3,4-thiadiazol-5-yl, 1 , 3,4-thiadiazol-2-yl, 1,2,3-triazol-4-yl, 1 -substituted-tetrazol-5-yl, pyrrolidine-2, 5-dion- 1 -yl, sacharyl, 1-phenyl-3-methyl-pyrazol-4-in-5-yl, 8-quinolyl or substituted 8-quinolyl or
Q4 R5 together can optionally stand for halogen and R5 can further stand for N,N' optionally substituted amidine group in which the carbon atom of the amidine group is attached to Q4 atom and further stand for alkoxycarbonyl, aryloxycarbonyl or aralkyloxycarbonyl-with the compound of the general formula (III)
wherein R8, R15, R16, p and A are as given above or b) oxidizing a compound of the general formula (IV)
wherein R3, R4, R6, R7, R8, R1, R16, p and A are as given above--in order to prepare compounds of the general formula (I)--wherein m and k represent 0, n stands for 1, Q3 is oxygen and R3, R4, R6, R7, R8, R15, R16 and A are as given above, or c) reacting a compound of the general formula (IV)
--wherein R3, R4, R6, R7, R8, R15, R16, p and A are as given above with sulfur in order to prepare compounds of the general formula (I)wherein m and k represent 0, n stands for 1, Q3 stands for sulfur and R3, R4, R6, R7, R8, R15, R16, p and A are as given above or
d) reacting a compound of the general formula (V)
--wherein R3, R4, R6, R7, R8, R15, R16, p and A are as given abovc - with P4S,o in order to prepare compounds of the general formula (I)wherein m and k are 0, n stands for 1, Q3 is sulfur and R3, R4, R6, R7, R8, R15, R16, p and A are as given above, or e) reacting a compound of the general formula (Vl)
wherein R8 and A are as given above with the compound of the general formula (VII)
wherein R3, R4, R5, R6 R7 R15, R16, Q1, (12, (13, (14, m, n and k are as given above in order to prepare compounds of the general formula (1)-wherein p stands for 1 and R3, R4, R6,
R7, R8, Ras, R16, Q1, Q2, (13, m, n, k and A are as given above , or
f) converting a compound of the general formula (I), wherein Y stands for carboxyl to a compound of the general formula (I) containing in the place of Y an acetoxy, methoxycarbonyl, methoxy-methoxycarbonyl, pivaloyloxymethoxycarbonyl or optionally substituted tetrazol-5-yl group or
g) a compound of the general formula (I) can be set free from its salt or can be converted to the salt thereof.
The compounds of the general formula (I) show variable antibacterial, antiviral, antifungal and fi-lactamase inhibiting activity and can be thus employed as active ingredients of pharmaceutical compositions.
The reaction of process variant a) of the compounds of general formulae (II) and (III) can be preferably performed in an inert solvent which does not change under the conditions of the reaction or upon the effect of the components or in a binary, ternary or other mixture of such solvents. As a solvent preferably hydrocarbons such as benzene, toluene, hexane, chlorinated hydrocarbons such as chloroform, dichloromethane, ethers, such as diethylether, diisopropy lether, ketones, such as acetone, acetates such as ethylacetate, amides such as dimethylformamide, dimethylacetamide, tetramethyl-urea, hexamethylphosphortriamide or dioxane or tetrahydrofuran may be used.If as the starting material of the general formula (II) a free acid is used the reaction can be conducted preferably in the presence of a water withdrawing agent. As water withdrawing agents symmetric or asymmetric carbodiimides, such as dicyclohexyl-carbodiimide, diisopropyl-carbodiimide can be used.
The reaction of the compounds of the general formulae (II) and (III) can be carried out in a mixture of water and an organic solvent, preferably acetone or tetrahydrofuran as well. The reaction is preferably performed at room temperature.
If as starting material of the general formula (II) an acid halide or an active ester is employed, the reaction is preferably performed in the presence of an acid binding agent. As acid binding agent organic or inorganic bases, such as sodium or potassium carbonate or hydrocarbonate or amines can be used.
The oxydation of the compounds of the general formula (IV) can be performed by method known per se, preferably with hydrogenperoxide. (Izv. Akad. Nauk. SSSR, Ser. Him. 290-295 /1962/).
The compounds of the general formula (I) containing sulfur as Q3 can be prepared by the reaction of the corresponding phosphine derivatives of the formula (V) with sulfur (Izv. Akad.
Nauk, SSSR; Ser. Him. 290-295 /1962/) or by reacting the corresponding oxide derivatives of the general formula (V) containing oxygen as Q3 with P4S10 (J. Chem. Research/S/ 232-233; /M/ 3041-3063 /1978/).
The reaction of the compounds of the general formulae (Vl) and (VII) can be carried out under the conditions given for the process variant a).
The compounds of the general formula (I) form a salt with organic or inorganic bases and can be released from the salt thereof by method known per se.
The compounds of the general formula are active against gram-positive bacteria and at some strains they are more effective than cephalexine or cephalotine. Some representatives of the compounds of general formula (I) show similar activity against gram-negative bacteria as first generation cephalosporines. Some representatives show a surprising anti-fungal activity. The results are shown in Table (I) and II.
Table I
Gram-positive bacteria
Staphylo- Strepto- Strepto
coccus coccus coccus Bacillus
aureus faecalis agalactiae subtilis
MIC = MIC MIC MIC
Compound g/ml. g./ml. g/ml. ,ug./ml.
Cephalexine 10 150 5 2.5
Cephalotine 1 10 1 2.5
Product of example 13 10 50 - 2.5
Product of example 4 2.5 - 5 2.5
Product of example 11 10 - 25 2.5
Product of example 23 1 5 2.5 1
Product of example 22 2.5 10 2.5 1
Product of example 19 2.5 - 25
Table II
Gram-negative bacteria
Shigella Salmonella Salmonella Pasteurella
sonnei typhimurium choleraesuis multicida MIC MIC MIC MIC
Compound ,ug./ml. g./ml. g./ml. g./ml.
Cephalexine 25 150 75 2.5
Cephalotine 25 10 1 Product of example 7 - - 2.5
Product of example 14 - - 2.5
Triethylamine salt of the product of example 5 - - 2.5
Product of example 23 25 10 5 2.5
Product of example 22 50 25 10 2.5
The antifungal activity is shown in Table III.
Table 111
Penicillium Trichophyton Trichophyton
digitatum rubrum mentagroph
Compound MIC ,ug./ml. MIC yg./ml. MIC yg./ml.
Cephalexine 200 2.5 200
Cephalotine 200 200 200
Product of example 13 25 50 5
Product of example 1 5 50
Triethylamine salt of the product of example 5 25 50 25
The compounds of the general formula (I) can be used as active ingredients of pharmaceutical compositions, the compositions can be prepared by method known per se and they contain apart from the active ingredient the conventionally used carriers or diluting agents as well as other excipients.
Further details of the invention are shown in the following examples which serve merely for illustration and not for limitation.
Example 1
Preparation of diphenylphosphino-acetamido-desacetoxycephalosporanic acid
1.07 g. (5 mmole) 7-Amino-desacetoxycephalosporanic acid (referred to furtheron as 7-ADCA) and 0.42 g. sodiumhydrogencarbonate are dissolved in 40 ml. water and a solution of 2.46 g.
diphenyl-phosphino acetic acid-pentachloro-phenylester in 30 ml. tetrahydrofuran is added. The reaction mixture is stirred for 24 hours at room temperature under nitrogen atmosphere and evaporated in vacuo at 35"C. After the removal of tetrahydrofuran the residual aqueous solution is extracted with 3 X 20 ml. ethylacetate and the aqueous layer is cooled with ice, acidified wi h h 2 N hydrochloric acid to pH = 3 and extracted with ethylacetate. The ethylacetate layer is dried above magnesium sulphate and evaporated. The product is crystallized with etherpetrolether. Yield: 54%.
M.p.: 116-119"C.
R: 0.2 (benzene-ethylacetate-glacial acetic acid = 7:3:1)
IR-spectrum: 1 794 (vcO lactame) 1 622 (v amide 1.) 1 529 (v amide II.)
Analysis for the formula C22H2104N2SP = 440.45
Calculated: Found:
S % = 7.26 S % = 6.83
Example 2
Preparation of diphenylphosphino-acetamido-3-desacetoxy-cephalosporanic acid trichloroethylester
1.72 g. (5 mmole) 7-ADCA-trichloroethylester are dissolved in 30 ml. anhydrous dichloromethane and 1.22 g. (5 mmole) diphenyl-phosphino-acetic acid is added followed by the addition of the solution of 1.03 g. (5 mmole) dicyclohexyl-carbodiimide in 10 ml. of anhydrous dichloromethane.The reaction mixture is stirred at room temperature overnight preferably in nitrogen atmosphere and the precipitated urea is filtered. The filtrate is washed with a 5% sodiumhydrogencarbonate solution with water and then with 0. 1 N hydrochloric acid and dried above magnesiumsulphate and evaporated in vacuo. The obtained oily product is crystallized with absolute ether. Yield: 2.1 g. (75%).
M.p.: 138-139"C.
R,: 0.65 (benzene-ethylacetate = 1:1)
IR-spectrum: 1781 cm - 1 (vcO lactame)
(KBr) 1740 cm - 1 (vcO ester) 1630 cm (amide 1) 1550 cm (Yamide II.) Analysis for the formula C24H220 4N2CI3SP = 571, 72
Calculated: Found:
N % = 4.89 N%=5.19 S % = 5.60 S % = 6.04
Example 3
Preparation of of diphenylphosphino-acetamido-cephalosporanic acid
2.73 g. (10 mmole) 7-amino-cephalosporanic acid (referred to hereinafter as 7-ACA) and 0.84 9. sodiumhydrogen-carbonate are dissolved in 40 ml. water and 4.92 g. diphenylphosphino acetic acid and 2.06 g. dicyclohexyl-carbodiimide in 20 ml. tetrahydrofuran are added.The reaction mixture is stirred at room temperature for 20 hours preferably in nitrogen atmosphere and tetrahydrofuran is removed in vacuo whereafter the residual aqueous layer is extracted with 3 X 20 ml. ethylacetate, the aqueous layer is cooled with ice and acidified with 2N hydrochloric acid. The precipitated product is isolated with ethylacetate if it cannot be filtered. The ethylacetate layer is dried above magnesium sulphate and evaporated. The thus obtained oily product is crystallized with absolute ether, petrolether.
Yield: 65%.
M.p.: 114-116 C.
R,: 0.15 (benzene-ethylacetate-glacial acetic acid = 7:3: 1)
IR-spectrum: 1790 cm-1 (Vco lactame)
(KBr) 1735cm-1 (vcO ester) 1680 cm (Yamide I.)
1530 cm ( amide II.) Analysis for the formula C24H2306N2SP = 498.4
Calculated: Found:
S % = 6.42 S % = 6.48; 6.56.
Example 4 (Diphenyl-phosphine-sulphide)-yl-acetamido-cephalosporanic acid
1.36 g. 7-ACA and 0.42 g. sodiurnhydrogen-carbonate are dissolved in 30 ml. water and the solution of 2.62 g. (diphenyl-phosphine-sulphide)-yl-acetic acid pentachloro-phenylester in 40 ml. tetrahydrofuran is added. The reaction mixture is stirred for 24 hours at room temperature and tetrahydrofuran is distilled off in vacuo. The residual aqueous layer is extracted with 3 x 20 ml. ethylacetate. The aqueous layer is cooled with ice and acidified with 2 N hydrochloric acid to pH = 3 and extracted with ethylacetate. The acidic layer of thee last extraction is dried above magnesium sulphate and evaporated. The obtained oily layer is crystallized with a mixture of absolute ether and petrolether.
Yield: 46%.
Rf: 0.18 (benzene-ethyl acetate-glacial acetic acid:7:3:1)
M.p.: 118-120 C.
IR-spectrum: 1795 (vcO lactame)
KBr) 1740 (Vco ester)
1680 (Yamide 1.) 1530 (vamidO Il ) Analysis for the formula C24H2306N2S2P = 530.48
Calculated: Found:
N%= 5.27 N%= 5.01
S%=12.06 S%=12.39
Example 5 (Diphenyl-phosphine-oxide)-yl-acetamido-cephalosporanic acid
2.73 g. (10 mmole) 7-ACA and 0.84 g. sodiumhydrogencarbonate are dissolved in 40 ml.
water and a solution of 5.08 g. diphenylphosphineoxide-yl acetic acid-pentachlorophenyl-ester in 20 ml. tetrahydrofuran is added. The reaction mixture is stirred at room temperature for 24 hours and evaporated in vacuo at 35 C. After the removal of tetrahydrofuran the residual aqueous solution is extracted with 3 X 20 ml. ethylacetate, the aqueous layer is cooled with ice and acidified with 2 N hydrochloric acid to pH = 3 and extracted with ethylacetate. The ethyl acetate layer is dried above magnesium sulphate and evaporated. The product is crystallized from ether-petrolether.
Yield: 62%.
Example 6
Acylation directly with acid
1.3 g. (diphenyl-phosphine-oxide)-yl-acetic acid is dissolved in 10 ml. dimethyl-formamide and at 0 C 1.03 g. (5 mmole) dicyclohexyl-carbodiimide is added dropwise dissolved in 5 ml.
an hydros dichloromethane. The reaction mixture is stirred for 30 minutes at 0 C whereafter a solution prepared previously from 7-ACA-triethylamine salt in dimethylformamide is added.
(1.369. 7-ACA + 0.7 ml. triethylamine are dissolved in 10 ml. dimethylformamide). The reaction mixture is stirred overnight at 0-5"C and then poured to 200 ml. icy water, acidified with 2 N hydrochloric acid and the product is filtered. Yield: 70%.
M.p.: 123-124"C.
Rf: 0.15 (benzene-ethylacetate-glacial acetic acid = 7:3:1)
IR-spectrum: 1805 cm-' (vcO lactame)
(KBr) 1745 cm - 1 (puce ester)
1635 cm (emide 1) 1540 cm ( amide II.) Analysis for the formula C24H2307N2SP = 514.4
Calculated: Found: N%=5.44 N%=5.75 S % = 6.22 S % = 6.37, 6.46.
Example 7 7ss-[(α-diphen yl-phosphino)-acetamido@-phenylacetamido-3-dezacetoxy-cephalosporanic acid triethylammonium salt
1 mmole cephalexine and 0.3 ml. triethylamine are dissolved in 4 ml. dichloromethane and 1 mmole diphenyl-phosphino-acetic acid pentachlorophenylester is added. The reaction mixture is allowed to stand for one day at room temperature under nitrogen atmosphere and poured into 50 ml. cold petrolether and the precipitated product is filtered. When the product becomes oily it is dissolved in anhydrous dichloromethane and poured into cold absolute ether and filtered.
Yield: 70%.
M.p.: 142.5-145 C.
IR-spectrum: (KBr):
1790 cm - 1 1680 cm-' 1620 cm-l 1550 cm-'
Analysis for the formula C36H4305SP = 674.5
Calculated: Found:
N %=8.30 N %=8.19; 8.20.
Example 8 Diphen yl-phosphino-acetamido-3-f( 1 -methyl-tetrazol-5-yl)-thiometh ylcephalosporanic acid 1.64 g. (5 mmole) 7-amino-3-( 1 -methyl-tetrazol-5-yl)-thiomethyl-cephalosporanic acid and 0.7 ml. triethylamine are dissolved in 15 ml. dimethylformamide and 2.46 g. diphenyl-phosphino acetic acid pentachlorophenylester are added. The reaction mixture is stirred for 20 hours in nitrogen atmosphere at room temperature and poured into 200 ml. icy water and extracted with 3 x 20 ml. ethylacetate. The aqueous layer is acidified with 2 N hydrochloric acid to pH = 3 and the product is filtered. Yield: 34%.
IR-spectrum: 1778 cm-1 (vcO lactame)
(KBr) 1627 cm-' (vam,d I.) 1533 cm ( amide II.) Analysis for the formula C24H 2304N6S2P = 554.44
Calculated:Found: N%= 15.15 N%=15.22 15.31 S % = 11.54 S % = 11.57 11.51
Example 9
Triethylammonium salt of diphenyl-phosphino-acetamido-3-[(1-methyl-tetrazol-5-yl)-thiomethyl]- cephalosporanic acid
1 m mole 7-a mino-3-( 1 -methyl-tetrazol-5-yl)-th iomethyl-cephalosporanic acid and 0.3 ml. triethylamine are dissolved in 4 ml. dichloromethane whereafter 1 mmole diphenyl-phosphinoacetic acid pentachlorophenylester is added and the reaction mixture is allowed to stand for one day in nitrogen atmosphere. The mixture is then poured to 100 ml. cold absolute ether, the precipitated product is filtered and washed with absolute ether. Yield: 42%.
IR-spectrum: (KBr): 1780 cm-' 1675 cm-'
1605 cm-' 1530 cm - ' Analysis for the formula C30H3804N7S2P = 655.54
Calculated: Found:
N%=14.95 N%=14.76 14.77
Example 10
Triethylammonium salt of (diphenyl-phosphine-sulphide)-yl-acetamido-cephalosporanic acid
1 mmole 7-ACA and 0.3 ml. triethylamine are dissolved in 4 ml. dichloromethane and 1 mmole (diphenyl-phosphine-sulphide)-yl-acetic acid pentachloro-phenylester is added. The reaction mixture is allowed to stand for one day at room temperature whereafter it is poured into 60 ml. absolute ether and the precipitated product is filtered.
Yield: 94%.
M.p.: 114-116"C IR-spectrum: (KBr): 1775 cm-1 1735 cm-1
1680 cm-' 1610 cm-' 1530 cm-'
NMR-spectrum: (DMSO-d6) (100MMHz) (ppm): 1.28(t,9H), 2.12(s,3H), 3.14(q,6H), 3.52(AB,2H), 4.08(s, 1 H), 4.1 2(s, 1 H), 7.3-8.2(m,10H), 9.04(d,1H).
Analysis for the formula C30H3806N3S2P = 631.52
Calculated: Found: N % = 6.65 N % = 6.46, 6.34
S % = 10.15 S % = 9.92, 10.06
Example 11 Trieth ylam monium salt of (diphen yl-phosphine-oxide)-yl-acetamido-cephalosporanic acid
1 mmole 7-ACA and 0.3 ml. triethylamine are dissolved in 4 ml. dichloromethane and 1 mmole (diphenyl-phosphine-oxide)-yl-acetic acid pentachlorophenylester is added. The reaction is allowed to stand for one day at room temperature and poured into 50 ml. cold absolute ether and the precipitated product is filtered. Yield: 86%.
M.p.: 98-100"C.
NMR-spectrum: (DMSO-d6) (100 MHz)
(ppm): 1 .28(t,9H), 2.12(s,3H), 3.16(q,6H), 3.54(q.2H), 3.84(s, 1 H), 3.98(s, 1 H), 5.02(q,2H), 5.12(d,1H), 5.68(q, 1H), 7.5-8.1 (m,1 OH), 9.04(d,1 H).
IR-spectrum: (KBr) 1780 cm-' 1740 cm-' 1680 cm-1 1615 cm- 1540cm-1 Analysis for the formula C30H3607N3SO = 615.5
Calculated: Found:
N % = 6.82 N % = 6.19, 6.25
S % = 5.20 S % = 5.66, 5.69
Example 12
Triethylammonium salt of 7ss[(α-(diphenyl-phosphino)-acetamido]-phenylacet-amido-3-desacetoxy- cephalosporanic acid
One may proceed as disclosed in Example 11 by using cephalexine and diphenyl-phosphinoacetic acid pentafluoroester as starting materials.
Yield: 86%.
M.p.: 143-145"C.
Example 13
7ss[(Diphenyl-phosphine-oxide)-yl]-acetamido-3-desacetoxy-cephalosporanic acid
2.14 g. (10 mmole) 7-ADCA and 0.84 g. sodium hydrogencarbonate are dissolved in 70 ml.
water and a solution of 5.2 g. diphenyl-phosphine-oxide-yl-acetic acid pentachloro-phenylester in 60 ml. tetrahydrofuran is added. The reaction mixture is stirred at room temperature for 24 hours under nitrogen atmosphere. The reaction is further processed according to Example 1 and the title product is obtained with a yield of 60%.
IR-spectrum: 1792 (Dco lactame) 1618 (vamjde 1.) 1532 (Pamide II.) Example 14 Triethylammonium salt o f 7ss[(α-diphenyl- phosphine- of 7flUa-diphenyl-phosphine-oxide-yl)-acetamidoj-phenylacetamido-3-de- sacetoxy-cephalosporanic acid
0.7 g. cephalexine is taken up in 10 ml. anhydrous methylenedichloride and 0.8 ml.
triethylamine and 0.9 g. (diphenyl-phosphine-oxide-yl)-acetic acid pentachloro-phenylester are
added. The reaction mixture is allowed to stand at room temperature overnight and it is poured
into 200 ml. anhydrous ether. The precipitated product is filtered. Yield: 85%.
M.p.: 121 do.
IR-spectrum (KBr): 1772, 1670, 1600, 1530cm-1
'H NMR (100 MHz, DMSO-d6, 8): 1.28 (t,9H), 2.04 (s,3H),
3.16 (q, 6H), 3.8 (s,1H), 3.96 (s,1H), 5.02
(d,1H), 5.7 (d,1H), 5.74 (q,1H), 7.4-8.1 (m,
15 H, aromatic), 8.84 (d, 1 NH), 9.44 (d, 1 NH).
Example 15 Trieth yl-ammonium salt of 7,8[(a-diphenyl-phosphine--sulphide-yi)-acetamidoj-phenylacetamido-3-
desacetoxycephalosporanic acid
The title product is prepared from 0.86 g. cephalexine and 1.3 g. (diphenyl-phosphine
sulphide-yl)-acetic acid pentachlorophenyl-ester according to Example 13. Yield: 80%. M.p.:
125-125.5 C.
IR-spectrum (KBr): 1775, 1670, 1600, 1530 cm-1.
'H NMR (100 MHz, DMSO-d6,): 1.25 (t,9H), 2.04 (s,
3H), 3.12 (q, 6H), 4.02 (s, 1H), 4.20 (s,1H),
4.98 (d,1H), 5.64 (d, 1 H), 5.72 (q, 1 H),
7.4-8.2 (m, 15 H, aromatic), 8.84 (d, 1 NH),
9.40 (d, 1 NH).
Example 16
Diphenyl-phosphino-acetamido-penicillanic acid
2.16 g. (10 mmole) 6-amino-penicillanic acid and 0.84 g. sodium-hydrogencarbonate are
dissolved in 40 ml. water, the mixture is cooled to 10-15 C and a solution of 4.92 9. (10
mmole) diphenyl-phosphino acetic acid pentachlorophenylester in 20 ml. of tetrahydrofuran is
added. The reaction mixture is stirred for 20-24 hours at room temperature, preferably under
nitrogen atmosphere whereafter the tetrahydrofuran is removed at 35 C in vacuo. The residual
aqueous solution is extracted with 3 X 20 ml. ethylacetate and the aqueous layer is cooled with
ice, acidified with 2 N hydrochloric acid solution. The precipitated product is extracted with
ethylacetate if it cannot be filtered.The ethylacetate layer is dried above magnesium sulphate
and the product is crystallized after evaporation with a mixture of absolute ether and petrolether.
Yield: 72%.
M.p.: 118-121 C.
R: 0.15 (benzene-ethylacetate-glacial acetic acid = 7:3:1) IR-spectrum: (KBr): 1790 cm-l (vCO lactame)
1680 cm (ram,d I.) 1530 cm ( am,de II.) Analysis for the formula C22H2304N2SP = 442.43
Calculated: Found:
S % = 7.23 S % = 6.84; 6.92
Example 17 (Diphenyl-ph,osphine-oxide)-yl-acetamido-penicillanic acid
1.08 g. (5 mmole) 6-amino-penicillanic acid and 0.42 g. sodium-hydrogencarbonate are
dissolved in 20 ml. water, the solution is cooled to 10-15 C and a solution of 2.54 g.
diphenyl-phosphineoxide-yl-acetic acid pentachlorophenylester in 20 ml. tetrahydrofuran is
added. The reaction mixture is stirred for 20 hours at room temperature and evaporated in
vacuo at 35 C. The obtained aqueous solution is extracted with 3 X 10 ml. ethylacetate and the
aqueous layer is cooled with ice and acidified with 2 N hydrochloric acid solution to pH = 3.
The precipitated product is filtered. Yield: 78%.
M.p.: 114-117 C.
IR-spectrum: 1790 cm-1 (vCO fi-lactame) (KBr) 1680 cm-1 (Yamide 1.) 1530 cm (Vamide, II.)
Analysis for the formula C22H23OsN2SP = 458.43
Calculated: Found:
S % = 6.98 S % = 7.05, 7.07.
Example 18 (Diphenyl-phosphine-sulphide)-yl-acetamido-penicillanic acid
1.08 g. (5 mmole) 6-amino-penicillanic acid and 0.42 g. sodium-hydrogencarbonate are dissolved in 20 ml. of water, cooled to 10-15 C and 2.06 g. diphenyl-phosphine-sulphide-ylacetic acid pentachlorophenylester are added dissolved in 30 ml tetrahydrofuran. The reaction mixture is stirred for 24 hours at room temperature and evaporated at 35 C in vacuo. The residual aqueous solution is extracted with 3 X 10 ml. ethylacetate and the aqueous layer is cooled with ice and acidified with 2N hydrochloric acid solution. The precipitated product is filtered.
Yield: 82%.
M.p.: 101 -103 C.
R,: 0.1 (benzene-ethyl acetate-glacial acetic acid = 7:3:1)
IR-spectrum: 1795 cm-' (Vcoss-lactame)
(KBr) 1680 cm 1 (Yamide I.) 1515 cm-1 ( amida | Analysis for the formula C22H2304N2S2P = 474.51
Calculated: Found:
S%=13.48 S%=13.58, 13.70.
Example 19
Triethylamine salt of (diphen yl-phosphine-sulphide)-yl-acetamido-penicillanic acid
1 mmole 6-amino-penicillanic acid and 0.3 ml. triethylamine are dissolved in 4 ml.
dichloromethane and under cooling 1 mmole (diphenyl-phosphine-sulphide)-yl-acetic acid pentachlorophenylester is added. The reaction mixture is allowed to stand for one day at room temperature, it is poured into 60 ml. ether and filtered.
Yield: 70%.
M.p.: 98-100'C.
Analysis for the formula C28H3804N3S2P = 575.61
Calculated: Found: S%=11.11 S%=10.86
10.96
IR-spectrum: 1775cm-1 (Pc, lactame)
(KBr) 1680cm-1 (Pamide I.) 1530 cm (Vamide II.) NMR-spectrum: (DMSO-d6) (100 MHz)
(ppm): 1.24 (t,9H), 1.64 (s,3H), 1.75 (s,3H),
3.08 (q,6H), 4.10 (bs,2H), 4.26 (s,1H),
5.56 (bs,2H), 7.4-8.2 (m.10H), 8.8 (bs,1H).
Example 20
Triethylamine salt of (diphenyl-phosphine-oxide)-yl-acetamido-penicillanic acid
1 mmole 6-Amino-penicillanic acid and 0.3 ml. triethylamine are dissolved in 4 ml.
dichloromethane in about 30 minutes whereafter the solution is cooled to 0 C and 1 mmole (diphenyl-phosphino-oxide)-yl-acetic acid pentachlorophenylester is added. The mixture is allowed to stand for one day at room temperature whereafter it is poured into 80 ml. ether and the precipitated product is filtered.
Yield: 68%.
M.p.: 72-73 C.
IR-spectrum: 1775cm-1 (vcO lactame)
(KBr) 1675 cm-1 (vamide I.)
1605 cm-1 (Vco COO-) 1530cm-1 (Yamid, II.) NMR-spectrum: (DMSO-d6) (100 MHz)
(ppm): 1.26 (t,9H), 1.63 (s,1H9 1.73 (s,1H), 3.14 (q,6H),
3.82(s,1H), 3.96 (s,IH), 4.25 (s,1H),
5.53 (bs,2H), 7.5-8.1 (m,10H),
8.78 (bs,1H).
Analysis for the formula C28H3805N3SP = 559.53
Calculated: Found: N%=5.00 nN % = 4.60
4.73
S % = 5.71 S % = 5.64
5.67
Example 21
Triethylammonium salt of 6ss[(α-diphenyl-phosphino)-acetamido]-phenylacetamido]-penicillanic acid
10 mmole of ampicilline and 4 ml. of triethylamine are dissolved in 40 ml. dichloromethane and 10 mmole of diphenyl-phosphino acetic acid pentachloro phenylester are added. The reaction mixture is allowed to stand at room temperature under nitrogen atmosphere for 20-24 hours and the mixture is poured into 300 ml. of an hydros ether. The precipitated crystals are filtered. When the product becomes oily, it is dissolved in a minimal amount of absolute dichloromethane, poured again to absolute ether and then a white product is obtained which can be well filtered. Yield: 86%.
M.p.: 152-154 C.
IR-spectrum: (KBr) 1795 cm-t, 1680cm-1, 1530 cm-t Analysis for the formula C36H45N4O5SP = 676.79
Calculated: Found:
N % = 8.27 N%=8.06,8.17 NMR-spectrum: (DMSO-d6) (100 MHz)
(ppm): 1.30 (t,9H), 1.60 (s,3H), 1.72 (s,3H),
3.12 (q,6H), 3.42 (bs,2H), 4.24 (s,1H), 5.48 (d,1H), 5.52 (q,1H), 5.82 (d,1H),
7.2-8.1 (m,1 OH), 8.78 (d,1H),-9.24 (d,1H).
Example 22
Triethylammonium salt of 6ss[aN-[(diphenyl-phosphine-oxide)-yl-acetamido]-phenyl-acetamido]-pen- icillanic acid
10 mmole of ampicilline and 4 ml. of triethylamine are dissolved in 40 ml. dichloromethane whereafter 10 mmole of (diphenyl-phosphine-oxide)-yl-acetic acid pentachlorophenylester are added. The reaction mixture is allowed to stand at room temperature for 20-24 hours and poured into 250-300 ml. of ether. The precipitated product is filtered and washed with ether.
Yield: 92%.
M.p.: 141-144"C.
Analysis for the formula C36H45N4OeSP = 692.8
Calculated: Found:
N % = 8.09 N % = 7.80, 7.86
NMR-spectrum: (DMSO-d6) (100 MHz)
(ppm): 1.24 (t,9H), 1.60 (s,3H), 1.72 (s,3H),
3.10 (q,6H), 3.92 (d,1 H), 4.20 (s,1H), 5.45 (d,1H), 5.58 (q,1H), 5.82 (d,1H),
7.2-8.1 (m,1 OH), 8.82 (d,1H), 9.30 (d,1H).
IR-spectrum: (KBr) 1795cm-1, 1680 cm-', 1530 cm-'.
Example 23
Triethylammonium salt of 6,8-fa-[(diphen yl-phosphine-sulphide)-yl-acetamidoj-phen ylacetamidoj- penicillanic acid
10 mmole of ampicilline and 4 ml. of triethylamine are dissolved in 40 ml. dichloromethane and 10 mmole of (diphenyl-phosphine-sulphide)-yl acetic acid pentachlorophenylester are added.
The reaction mixture is allowed to stand at room temperature for one day and poured into 250-300 ml. of ether. The precipitated product is filtered and washed with ether.
Yield: 62%.
M.p.: 185.5-190 C
Analysis for the formula C36H45N4O5S2P = 708.8
Calculated: Found: N % = 7.90 N % = 7.60, 7.61
S % = 9.04 S % = 9.05, 9.14
NMR-spectrum: (DMSO-d6) (100 MHz)
(ppm): 1.30 (t,9H), 1.58 (s,3H), 1.64 (s,3H),
3.12 (q,6H), 4.16 (d,2H), 4.20 (s,1H),
5.50 (d,1H), 5.54 (q,1H), 5.80 (d,1H),
7.20-8.2 (m,10H), 8.80(d,1H), 9.20
(d, 1 H).
IR-spectrum: (KBR): 1790 cm-', 1680 cm-', 1630 cm-' 1530 cm-1
Example 24 6ss-[(Diphenyl-phosphine-sulphide)-yl-acetamido]-penicillànic acid
1 mmole diphenyl-phosphino-acetamido-penicillanic acid and 1 mmole of sulfur powder are heated under reflux in 20 ml. of absolute benzene for 2 hours and the reaction mixture is evaporated in vacuo. The product is identical with the compound obtained by direct acylation.
Yield: 98%.
Example 25
Triethylammonium salt of 6ss-(diphenyl-phosphino-acetamido)-penicillanic acid
5 mmole of 6-amino-penicillanic acid and 1.5 ml. triethylamine are dissolved in 30 ml.
dichloromethane and 5 mmole diphenyl-phosphino-acetic acid pentafluorophenylester are added at 0 C under nitrogen atmosphere. The reaction mixture is allowed to stand at room temperature for one day and poured into 200 ml. of petrolether. The precipitated product is filtered. The product is identical with a compound obtained by other route.
Example 26
Triethylamine salt of 6fl-Udiphenyl-phosphine-oxide)-yl-acetamidoj-penicillanic acid
5 mmole of 6-amino-penicillanic acid and 1.5 ml. triethylamine are dissolved in 30 ml.
dichloromethane. The mixture is cooled to 0 C and 5 mmole (diphenyl-phosphine-oxide) acetic acid pentachlorophenylester are added. The reaction mixture is allowed to stand at room temperature for one day and poured into 200 ml. petrolether and the precipitated product is filtered. The product is identical with the compound obtained by other route and identified earlier.
Example 27
Triethylamine salt of 6fi-Udiphenyl-phosph ine-sulphide)-yl-acetamidoj-penicillanic acid
5 mmole of 6-amino-penicillanic acid and 1.5 ml. triethylamine are dissolved in 30 ml.
dichloromethane. The mixture is cooled to O"C and 5 mmole (diphenyl-phosphine-sulphide)-yl acetic acid pentachlorophenylester are added. The reaction mixture is allowed to stand for one day, poured into 200 ml. petrolether and the precipitated product is filtered. The product is identical with the compound obtained by a different route and characterized earlier.
Claims (6)
1. Compounds of the general formula (I)
wherein A stands for a group of the general formula (a) or (b),
R3 and R4 are the same or different and stand for hydrogen, halogen, alkyl, optionally substituted aryl, hydroxy, amino, substituted carbonylamino, acylamino, mono- or dialkylamino, carboxyl, esterified carboxylic acid or sulphonic acid group, heteroaromatic group or R3 and R4 together form oxo, hydroxyimino, O-alkylimino or substituted alkylhydroxyimino group,
R6 and R7 are the same or different and stand for hydrogen, straight, or branched chained C16 alkyl optionally substituted by one or more nitro, halogen, alkoxycarbonyl or dialkylamino group, C36 cycloalkyl, phenyl or phenyl group optionally substituted by R' or R2, wherein R' and R2 are the same or different and stand for hydrogen, halogen, alkyl, hydroxy, nitro, sulphonic acid, carboxylic or NR9R'0 group, wherein
R9 and R'O are the same or different and stand for C16 alkyl or C37 cycloalkyl or R9 and R'O together with the nitrogen atom form a C37 heterocyclic ring which can optionally contain other hetero atoms or
R6 and R7 can optionally be attached to an unsubstituted or substituted atom group forming a ring or rings,
Q' and Q2 are the same or different and stand for oxygen, sulfur or selenium or = CH2 group,
Q stands for 0, S, Se-, -NH, NR11 or = N-N = CR'2R'3, R11, R12 and R13 stand for C16 alkyl, C37 cycloalkyl, optionally substituted phenyl, naphthyl, or substituted naphthyl, a cyclic group containing one or more hetero atoms which can be substituted or unsubstituted and optionally can be heteroaromatic,
k stands for 0 or 1,
m can be O or 1 and
n can be O or 1,
R'5 and R16 are the same or different and can stand for hydrogen, C1-6 alkyl, C3-7 cycloalkyl or optionally substituted phenyl or
R'5 and R16 can form a heterocyclic ring together with the carbon atom to which they are attached,
R8 stands for hydrogen or methoxy,
Q5 stands for hydrogen, halogen, methyl, acetoxymethyl, acyloxymethyl, pyridinium-methyl, methoxy or Het-S-methyl, wherein
Het stands for a 5- or 6-membered mono-, bi- or tri-cyclic heteroaryl group which can contain one or more nitrogen and/or other hetero atoms,
Y stands for carboxy, acetoxy, methoxycarbonyl, methoxy-methoxycarbonyl, pivaloyloxymethoxy-carbonyl or optionally substituted tetrazol-5-yl and
p stands for 0 or 1 and
w stands for 0, 1 or 2.
and salts thereof.
2. Process for the preparation of phosphorous containing cephalosporanic and penicillanic derivatives and salts thereof
wherein R3, R4, R6, R7, R8 R15, R16, (11, (12, Q3, k, m, n, p and A are as given in claim 1 which comprises
a) reacting a compound of the general formula (II)
wherein R3, R4, R6, R7, (11, (12, (13, n, m and k are as given above, Q4 represents oxygen or sulfur, stands for hydrogen, phenyl, optionally substituted phenyl, such as trichlorophenyl, pentachlorophenyl, pentafluorophenyl, 1 -methyl-tetrazol-5-yI, 2-methyl-1,3,4-thiadiazol-5-yl, 1 3,4-thiadiazol-2-yl, 1,2,3-triazol4-yl, 1 -substituted-tetrazol-5-yl, pyrrolidine-2, 5-dion- 1 -yl, sacharyl, 1-phenyl-3-methyl-pyrazol-4-in-5-yl, 8-quinolyl or substituted 8-quionolyl or Q4R5 together can optionally stand for halogen and R5 can further stand for N,N' optionally substituted amidine group in which the carbon atom of the amidine group is attached to Q4 atom and further stand for alkoxycarbonyl, aryloxycarbonyl or aralkyloxycarbonyl-with the compound of the general formula (ill)
wherein R8, R15, R16, p and A are as given above or b) oxidizing a compound of the general formula (IV)
--wherein R3, R4, R6, R7, R8, R15, R16, p and A are as given above in order to prepare compounds of the general formula (I)--wherein m and k represent 0, n stands for 1, Q is oxygen and R3, R4, R6, R7, R8, R15, R16 and A are as given above , or c) reacting a compound of the general formula (IV)
--wherein R3, R4, R6, R7, R8, R15, R16, p and A are as given above--with sulfur in order to prepare compounds of the general formula (lwherein m and k represent 0, n stands for 1, Q3 stands for sulfur and R3, R4, R6, R7, R8, R15, R16, p and A are as given above or
d) reacting a compound of the general formula (V)
--wherein R3, R4, R6, R7, R8, R15, R16, p and A are as given above with P4010 in order to prepare compounds of the general formula-(lWwherein m and k are 0, n stands for 1, Q3 is sulfur and R3, R4 R6, R7, R8, R15, R16, p and A are as given above or
e) reacting a compound of the general formula (VI)
--wherein R8 and A are as given above with the compound of the general formula (VII)
--wherein R3, R4, R5, R6, R7, R15, R16, a1, a2, (13, (14, m, n and k are as given above in order to prepare compounds of the general formula (I)--wherein p stands for 1 and R3, R4, R6,
R7, R8, R15, R16, (11, a2, a3, m, n, k and A are as given above or
f) converting a compound of the general formula (I), wherein Y stands for carboxyl to a compound of the general formula (I) containing in the place of Y an acetoxy, methoxycarbonyl, methoxy-methoxycarbonyl, pivaloyloxymethoxycarbonyl or optionally substituted tetrazol-5-yl group or
g) a compound of the general formula (I) can be set free from its salt or can be converted to the salt thereof.
3. Process according to process variant a) in claim 2, which comprises performing the reaction of the compounds of the general formulae (II) and (III) in an inert solvent or in a mixture of such solvents optionally in the presence of water withdrawing agent at room temperature.
4. A process as claimed in claim 3 which comprises using as water withdrawing agent a symmetric or asymmetric carbodiimide.
5. A process as claimed in process variant a) in claim 2 and in claim 3 which comprises using as a solvent chlorinated hydrocarbons, ethers or dipolar aprotic solvents.
6. Pharmaceutical composition which comprises as active ingredient a compound of the general formula (I) or salt thereof-wherein R3, R4, R6, R7, R8, R15, R16, a" (12, a3, m, n, k, p an A are as given in claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU171483A HU191213B (en) | 1983-05-17 | 1983-05-17 | Process for producing semisynthetic penecillin derivatives containing phosphorus and pharmaceutical compositions containing them |
| HU171383A HU191212B (en) | 1983-05-17 | 1983-05-17 | Process for production of derivattes of half-sinthetic cefem carbonic acid consisting of phosphore and preparates consisting of such compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB8412638D0 GB8412638D0 (en) | 1984-06-20 |
| GB2141124A true GB2141124A (en) | 1984-12-12 |
Family
ID=26317401
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08412638A Withdrawn GB2141124A (en) | 1983-05-17 | 1984-05-17 | Phosphorus containing semisynthetic cephalosporanic and penicillanic derivatives |
Country Status (2)
| Country | Link |
|---|---|
| FR (1) | FR2552764A1 (en) |
| GB (1) | GB2141124A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130203974A1 (en) * | 2008-11-17 | 2013-08-08 | Ronald Thaddeus Raines | Preparation of Diazo and Diazonium Compounds |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1309375A (en) * | 1970-11-04 | 1973-03-07 | Pfizer | Phosphono substituted acylpenicillins |
| GB1377307A (en) * | 1971-02-22 | 1974-12-11 | Squibb & Sons Inc | Alpha-phosphonoacetylpenicillins |
| GB1382169A (en) * | 1971-02-22 | 1975-01-29 | Squibb & Sons Inc | Alpha-phosphonoacetylcephalosporins |
| GB1388409A (en) * | 1971-11-19 | 1975-03-26 | Merck & Co Inc | 2-cephem-4-carboxylic acid esters |
| GB1428793A (en) * | 1972-11-13 | 1976-03-17 | Merck & Co Inc | Cephalosporins |
| GB1428187A (en) * | 1972-07-21 | 1976-03-17 | Politechnika Gdanska | 6-aminopenicillanic acid derivatives and process for the preparation of the same |
| GB1458410A (en) * | 1973-03-13 | 1976-12-15 | Merck & Co Inc | 1-oxadethiapenicillanic acid derivatives |
-
1984
- 1984-05-16 FR FR8407584A patent/FR2552764A1/en active Pending
- 1984-05-17 GB GB08412638A patent/GB2141124A/en not_active Withdrawn
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1309375A (en) * | 1970-11-04 | 1973-03-07 | Pfizer | Phosphono substituted acylpenicillins |
| GB1377307A (en) * | 1971-02-22 | 1974-12-11 | Squibb & Sons Inc | Alpha-phosphonoacetylpenicillins |
| GB1382169A (en) * | 1971-02-22 | 1975-01-29 | Squibb & Sons Inc | Alpha-phosphonoacetylcephalosporins |
| GB1388409A (en) * | 1971-11-19 | 1975-03-26 | Merck & Co Inc | 2-cephem-4-carboxylic acid esters |
| GB1428187A (en) * | 1972-07-21 | 1976-03-17 | Politechnika Gdanska | 6-aminopenicillanic acid derivatives and process for the preparation of the same |
| GB1428793A (en) * | 1972-11-13 | 1976-03-17 | Merck & Co Inc | Cephalosporins |
| GB1458410A (en) * | 1973-03-13 | 1976-12-15 | Merck & Co Inc | 1-oxadethiapenicillanic acid derivatives |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130203974A1 (en) * | 2008-11-17 | 2013-08-08 | Ronald Thaddeus Raines | Preparation of Diazo and Diazonium Compounds |
| US8871916B2 (en) * | 2008-11-17 | 2014-10-28 | Wisconsin Alumni Research Foundation | Diaryl phosphine compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8412638D0 (en) | 1984-06-20 |
| FR2552764A1 (en) | 1985-04-05 |
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