NO753954L - - Google Patents

Description

Procedure for the production of derivatives

of (7-ACA) and 7-ADCA.

The present invention relates to a new process for the production of derivatives of 7-amino-cephalosporaniric acid (7-ACA) and 7-aminodesacetoxy-cephalosporaninic acid (7-ADCA).

Norwegian patent application no. 751-781 submitted by the present applicant describes, among other things, 3_acylamino-23-thiohydrazoazetidinones with the following formula:

where V can be hydrogen or an a]phatic, aromatic, aryl-aliphatic or acyl residue, then in particular one of the following

-v

residues:

where R. is selected from the group consisting of hydrogen, alkyl with from 1 to 4 carbon atoms and from the following groups: cyano-methyl, thienyl-methyl, furyl-methyl, naphthy-1-methyl, phenyl-methyl, phenoxy-

methyl, phenyl-isopropyl, phenoxy-isopropyl, pyridyl-4-tki0-

methyl, tetrazolyl-1-raethyl

and where R"<*>" is selected from the group consisting of: hydroxyl, alkoxy with from 1 to 4 carbon atoms, trichloroethoxy, benzyloxy, p-methoxybenzyloxy, p-nitrobenzyloxy, benzhydryloxy, triphenylmethoxy, phenacyloxy, p-halophenacyloxy.

Z is selected from the group consisting of hydrogen, hydroxyl, -0-

alkyl, -O-CO-alkyl or from residues -Br, -I, -N^, -NHg,

-O-CO-CH^, 0-C0-NH2 and an S-mononuclear nitrogen heterocyclic ring.<;:>"<->-V.:<;>R<2>and r3 are the same or may be different and- ^};-^v.;.-;" represents a lower alkyl, a mononuclear aryl, CN group, a mononuclear heterocyclic ring or the radicals -COR^, -P-tOR^),,, -CONHR^ or R2 and R^ can together form one of the b following residues:

where UT represents ^.CHg, - R^ and where R^" is a lower alkyl group, a mononuclear aryl and a mononuclear heterocyclic ring or the like. It has now been surprisingly found, and this findings constitute a basis for the present invention, that said 3-?Cylamino-2P-thiohydrazoa3etidinones can be desacylated to the corresponding 3-?S 2p-thiohydrazoazetidinones with the formula IV by a successive treatment with a halogenating agent, a lower aliphatic alcohol and a hydrolysis agent using the equation:

where R, R<2>, R^ and V have the same meaning as stated above" It has also surprisingly been found: ate if the aforementioned 3-amino-2p-thiohydrazoazetidinones where the substituent V represents the residue

are reacted with inorganic oxides or bases in accordance with the conditions described in the aforementioned Norwegian patent application no. 751,781, then they will be cyclized to derivatives of 7-ÅCA .'v: or 7-ACDA as indicated by means of the equation:

l 9 q where R , R , R-<*>and Z have the same meaning as stated above. This process, which will be described in more detail in the following.

following, represents a new and surprising method for the preparation of derivatives of 7-amino-cephalosporanic acid (7-ACA)

and 7-amino-desacetoxy-cephalosporanic acid (7-ADCA), which are important intermediates for the production of a variety of cephalosporins.

It is a further purpose of the present invention to prepare cephalosporins of formula III starting from the aforementioned compounds of formula IV, and where these last-mentioned are reacted with an R-CO-X compound, and where in the first step one obtains .3-acylamino-2P-thiohydrazo-azetidinones of formula II*, - which are then reacted with inorganic oxides or bases as indicated in the aforementioned Norwegian patent application no. J51* J& 19 whereby ;■; you get cephalosporins with formula III. This is shown by the following equation:

where R, R 1 , R 2 , F ^ and Z have the same meaning as stated above, and X* represents chlorine, bromine, a hydroxyl, gt acyl radical with from 1 to 4 carbon atoms or the residue JI _ q In the first step, 3 -acylamino-2p-thiohydrazoaaetidinones converted to an imino halide by reacting with a phosphorus halide, e.g. as phosphorus pentachloride in a suitable solvent

agent at temperatures between -10°C and +100°C in the presence of a tertiary amine such as pyridine. After evaporation of the solvent

distilled under vacuum, the residue was dissolved at 0°C in a lower aliphatic alcohol, preferably methanol, and then left for a couple of hours at room temperature. In this way, a corresponding iminoether is formed. The solvent is eliminated by evaporation to dryness, and the residue is redissolved in an aqueous solvent such as tetrahydrofuran/water to hydrolyze the iminoether to the amine of formula IV.

The reaction product was left at room temperature, and the solvent was evaporated under vacuum, after which water, sodium chloride and a solvent immiscible with water were added, and the whole mixture was shaken..,..

The desired product of formula IV will convert into

the aqueous layer from which it can be extracted by weak alkalization and extraction with a solvent immiscible with water. 'I

The cyclization of the intermediates of formula IV' to derivatives of 7-ACA or 7-ADCA (V) constitutes, as mentioned above,

for a new and surprising method for a practical preparation of 7-amino-cephalosporanic acid and 7-amino-desacetoxy cephalosporanic acid.

The intermediate product with IV is reacted in a suitable solvent at temperatures between -100°C and + 120°C with inorganic oxides such as AlgO^, FegOq, Cr2°3» SiO2 or inorganic i';, or organic bases such as KOH, NagCO^, NH^OH, alkali metal alcoholates, aliphatic, aromatic and heterocyclic amines, alkylammonium bases and basic resins.

In this way, the derivative with for- . flour V, which can then be isolated and purified in a conventional manner. ;v The invention also relates to a modification of the method for producing cephalosporins with formula III,

which is described in the aforementioned Norwegian patent application no. 751»78l submitted by the present applicant:

where one starts from a 3-amino-20-thiohydrazoazetidinone with for-

flour IV<*>as described above. This compound is acylated with the amino group in position 3 by reacting it with a compound

R-CO-X<*>, whereby 3-acylamino-2P-thiohydrazoazetidinones of formula II<*> are obtained. These intermediates which are described in the fore- ,\ \ . ;in the said patent application are then cyclized by the same method by treating them with inorganic oxides or bases and finally cephalosporins with the aforementioned formula III are obtained, where R, R and Z have the same meaning as stated above, and X<*>represents chlorine . bromine. a hvdroksvl an acvloxvradical with from 1 to 4. car-

bonatoms, or the residue

v

The following examples illustrate the invention.

EXAMPLE 1

Methyl^ g- thiohydrazodicarpheoxyethyl- tt- isopropenyl- Æ- oxo-^ B-amlno- l- azetidine- acetate

1.05 g of PCl^ was added to a solution of 2.2 g of methyl-2£-thiohydrazodicarboxyethyl-α-isopropenyl-4-oxo-38-phenoxy-acetamido-1-azetidine-acetate in 100 ml of anhydrous benzene containing 1.5 ml of anhydrous pyridine, and the mixture was kept at 5°C for 60 minutes. The solvent was evaporated, and the residue was cooled to 0°C and redissolved in cold methanol and left at room temperature for two hours. The solvent was evaporated, and the residue redissolved under cooling, using tetrahydrofuran and water (1:1, volume/volume) and then left for 30 minutes at room temperature. The tetrahydrofuran was evaporated under vacuum and salt, water and ethyl acetate were added with stirring. The desired product will completely pass into the aqueous phase from which it can be extracted by alkalizing with NaHCO^ and extracting several times with ethyl acetate. In this way, 1.1 g of the desired product was obtained.

I.R. (CH2C12): 34OO caT1 (NH and NHg)

I76O cm"<1>(C=0 0 lactam)

1735 cm" (00 ester and carbonates)

EXAMPLE 2

Methyl- 2B- thiohvdrazodicarboxethyl- a- isopropylidine- 4-- oxo- 3S-amino- l- azetidine- acetate

2.3 g of phosphorus pentachloride was added to a solution of 5.0 g of methyl-2P-thiohydrazodicarboxyethyl-α-isopropylidene-4-oxo-39-phenoxyacetamido-1-azetidine-acetate in 250 ml of anhydrous benzene containing 3 ml of anhydrous pyridine, and the mixture was kept at 50°C for 90 minutes. The benzene was evaporated, and anhydrous methanol

was added at 0°C after which the blank was left at room temperature for 90 minutes. The methanol was evaporated, and tetrahydrofuran/water (1:1, volume/volume) was added with continuous stirring. The mixture was allowed to stand for 40 minutes at room temperature, after which the tetrahydrofuran was evaporated under vacuum,

and salt water and ethyl acetate were added. The product passed into the aqueous phase which was then alkalized with NaHCO 3 and repeatedly extracted with ethyl acetate. In this way, 3*0 g of the product was obtained.

I.R. (CH2C12): 3400 cm"1 (HH)

1755 cm"<1>(00 p-lactam)

1725 cm (00 ester and carbonates)

EXAMPLE 3

2 * 12\, 21- trichloroethyl- 2 p- thiohyd razodicarboxyethyl- a- isopropenyl-4- oxo- 3P- araino- l- azetlidine- acetate

3 ml of anhydrous pyridine and 2.5 g of PCI were added to a solution of 6.55 g of 2*,2T,2*-trichloroethyl-20-thiohyo>azodicar-

boxylethyl-α-isopropenyl-4-oxo-3P-phenoxyacetamido-1-azetidine acetate in 200 ml of anhydrous benzene, and the mixture was kept at 50°C for 90 minutes. The benzene was evaporated, and anhydrous methanol was added while cooling, after which the mixture was left at room temperature for one hour. The solvent was again evaporated, and the residue, after cooling, was dissolved in a mixture of tetra- . hydrofuran and water (1:1, volume/volume)» The mixture was left for 30 minutes at room temperature, after which the tetrahydrofuran was

evaporated and brine and ethyl acetate were added* The aqueous phase was separated and alkalized with NaHCO^ and extracted several times with ethyl acetate, which gave 3*7£ of the desired product, " " ■

I, R. (C<H>2C12): 34OO cm"<*1>(NH and NHg)

I76O cm<-1>(C«0 6-lactam)

1735 cm"<1>(0*0 ester and carbonates)

EXAMPLE A

Methyl ester of 7~ amino-desacetoxycephalosporanic acid

A 30 # solution of KOH in water was added under magnetic stirring to a solution of 2 g of methyl-2p-thiohydrazodi-

carboxy tyl-a-isopropenvl-4-pxp^ - i

100 ml of benzene, and the mixture was left at room temperature for one hour. The organic layer was separated and washed several times with water. The product was chromatographed over silica with , benzene-ethyl ether. 0.800 g of the product was produced in this way. Melting point 123-124°C (ethyl-fcer). /This product had chemical and physical characteristics (i.e. melting point, I.R., N.M.R., and mass spectrum) similar to those found for a product produced in a different way,3/

EXAMPLE

<2>*.2<*>, 2'-trichloroethyl ester of 7- amlnodesacetoxycephalo3Poranoic acid'

A 30# solution of KOH in water was added to a solution of 2.1 g of 2<*>,2<*>,2'-trichloroethyl-28-thiohydrazodicarboxyethyl-α-isopropenyl-4-oxo-3P-amino- 1-azetidine acetate in 100 ml of benzene, and the mixture was stirred for one hour. The organic layer was separated and stirred with acidified water, so that the product passed into the water as a salt. The organic layer was eliminated and the aqueous layer was made alkaline with NaHCO 3 and extracted with ethyl acetate. In this way, 1.3 g of the desired product was obtained. The product has the characteristics stated in the literature (J. Org. Chem. 1971, 36, 1259). When this product was treated by known methods, it gave 7-amino-desacetoxycephalosporanic acid (7-ADCA).

EXAMPLE 6 •• v Methyl- 2P- thiohydrazodicarboxyethyl- a- isopropylidene- 4- oxo- 3B- - phenylacetamido- l- azetidine- acetate

A solution of 2.0 g of methyl-2P-thiohydrazodicar-.; boxylethyl-α-isopropylidene-4-oxo-3B-an&no-1-azetidine-acel^ 80 ml of benzene was added with stirring to 40 nil of a saturated solution of NaHCO^, and to the mixture was added 1.5 ml of the chloride of phenylacetic acid at 0°C. The mixture was stirred at room temperature for one hour, after which the organic layer was separated, dried over Na 2 SO 4 and evaporated. The residue was chromatographed over silicon dioxide, eluted with benzene-ethyl acetate (70:30, v/v). In this way, 2.1 g of the desired product was obtained. IR (CHCl^): 3420 cm"<1>(N-H)

1765cm"1 (00 8-lactam)

1725 cm"<1>(O»0 ester and carbamates) 1670 cm"<1>(C-0 amide)

NMR (CDCl 2 ): 1.14 and 1.17 (two t, 6H, 2 CRy£(H 2 )-), 2.02 and

2.19 (two s, 6H, 2 CH^-C»), 3.57 (s, 2H, C6(H5)--CH2-C0-), 3.67 (s, 3H, C00CH3), 4, 08 (q, 4H, 2 CH2-C(H3) ), 4.88 (dd, 1H, C(3)H), 5.70 (d, 1H, C(4)H ) and 6.5-7 .4 d(m, 7H, 2 CONH and CgH^).

EXAMPLE 7

Methyl- 28- thiohydrazodicarboxyethyl- a- isopropenyl- 4- oxo- 3P-phenyl- acetamido- I- azetidine- acetate

This product was prepared as indicated in example 6. The prepared product was treated with bases in a known manner, and then gave the corresponding desacetoxycephalosporin with characteristics, which correspond to what is found in a sample prepared in another way, and in accordance with the data which is indicated in the literature. (J. Chem. Soc. 1971, 3540).

EXAMPLE 8

2.* f2f ^'-t richloroethyl^ B- thiohydrazodicarboxyethyl- tt- isopropenyl-4- oxo- 38-/ N-( ter- butoxycarbonyl)- D- a- phenylglycinamidoJr~ i- azetl- K din- acetate .. " >'

A solution of 1.1 g of carboterbutoxyphenylglycine

and 0.62 ml of triethylaraine in 10 ml of methylene chloride was added at -15°C with stirring to 0.4 ml of ethyl chloroformate dissolved in 10 ml of anhydrous methylene chloride. The mixture was left for 30 minutes under the mentioned conditions. A solution of 1.7 g of 2<*>,2<*>-2 1-trichloroethyl-28-thiohydrazodicarboxyethyl-α-i3opropenyl-4-oxo-3P-amino-1-azetidine acetate in 30 ml of CHgClg was then added while slowly adding and stirring. The mixture was left for 3 hours at -10°C, after which water and CHgClg were added. The organic layer was separated, the aqueous layer was again extracted with CHgClg, and the aqueous layers were dried and evaporated to give a residue which was chromatographed over silicon dioxide with benzene-ethyl acetate (80:20, v/v). In this way, 2.1 g of the resulting

in

desired product.

NME (CDC1«):'1.14 and 1.1? (two h, 6 H, 2 CHq -C(H2) ), 1.40

(s, 9 H, -C(CH3)3), 1.94 (s, 3 H, CH3-C«), 4.08

(q, 4 H, 2 CH2-C(H3) ), 4.90 fs, 1 H, JuCH-C00~)/

• •<•' c=

4.88 and 5.00 (2 d, 2 H, -COO-CHg-CCl^) 5.07 and 0 5.16 (broad s, 2 H, -CHg), 5.28 (s, 1 H, C6(H5)-CH-C-),

N-

i 5.3-5.7 (m, 2 H, H of p-lactam) and 6.5-8.Oa (m, 8 H, aromatic H and 3 NH).

EXAMPLE 9

2*, 2*. 2T- trichloroethyl- 7-/N-(ter- butoxycarbonyl)- D- a- phenylglucinamido7»3- methyl- 3- cephem- 4- carboxylate

A solution of 0.4 g of 2*,2•^'-trichloroethyl^B-thiohydrazodicarboxyethyl-a-isopropenyl-4-oxo-3P-/l3-(tert-butoxy-carbonyl)-D-a-phenylglycinamido/-l-azetidine -acetate in 100 ml of benzene was stirred in the presence of an excess of AlgO 2 . The mixture was allowed to stand for 2 hours, then filtered off from said AlgO^ whereupon the residue was chromatographed over silica gel, eluting the product with benzene-ethyl acetate (90:10, volume/volume), whereby 200 mg of the cephalosporanin product was obtained. This product had the same characteristics as stated in the literature. (J. Org. Chem. 1971, 36, 1259) When the product was treated by known methods, it gave 7-(I«-&niino-a-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid, with the same characteristics as stated in the literature (J. Org. Chem. 1971, 36, 1259).

Claims (1)

1. Process for the production of derivatives of 7-amino-cephalosporanic acid and 7-amino-desacetoxycephalosporanic acid with the formula: -,;• <>> :• (v) where R 1 is selected from the group consisting of hydroxyl, alkoxy. with; .from 1 to 4 carbon atoms, trichloroethoxy, benzyloxy, p-methoxy-benzyloxy, p-nitrobenzyloxy, benzhydryloxy, triphenylmethoxy, phenacyloxy, p-halophenacyloxyy Z is selected from the group consisting of hydrogen, hydroxyl, -O-alkyl, -O-CO-alkyl,. or from residues -Br, -I, - Hy -NHg, -0-CO-CH^ , O-CO-NHg and an S-mononuclear heterocyclic ring, starting from a 3-acylamino-28-thiohydrazoazetidinone such as this is stated in Norwegian patent application no. 751-781, with the following formula: where R is selected from the group consisting of hydrogen, alkyl with from 1 to 4 carbon atoms and from the following groups: cyano-methyl, thienyl-methyl, furyl-methyl, naphthyl-methyl, phenyl-methyl, phenoxy-methyl, phenyl-isopropyl, phenoxy-isopropyl, pyridyl-4-thiomethyl, tetrazolyl-1-methyl and where the groups R and RJ may be the same or different and represent, a lower alkyl group, a mononuclear aryl group, a CN group and a mononuclear heterocyclic group or the radicals or where Rg and Rq can represent the following residues: and where T represents <r>^ CHg, > N-R^ and R^" is a lower alkyl group, a mononuclear aryl group or a mononuclear heterocyclic group or the like, characterized in that compounds of formula IIT are reacted with a phosphorus halide such as phosphorus pentachloride or phosphorus oxychloride in the presence of a tertiary amine such as pyridine, and the corresponding irainochloride is reacted with a lower aliphatic alcohol, after which the formed iminoether is hydrolysed with water in an acidic medium, whereby a 3-aminc,-23-thiohydrazoazetidinone with the following formula is produced: 1 2 3' where R , R , RJ and Z have the same meaning as stated above, after which this compound in a suitable solvent and at a temperature between -100°C and +120°C is reacted with a compound selected from the group consisting of inorganic basic or weakly acidic oxides, or inorganic and organic bases, whereby the desired compound of formula V is obtained, which is then isolated and purified in a known manner. 2.. Method according to claim 1, characterized in that the inorganic basic or weakly acidic oxides used to convert intermediates with formula IV into the desired compound with 7 are selected from the group consisting of aluminum, iron, chromium or silicon oxides, either alone or in a mixture with other inorganic compounds. 3" Method according to claim 1, character i" s F t in that the inorganic bases used to convert the intermediate product of formula IV into the desired compound of formula V are selected from the group consisting of alkali metals and alkaline earth metal hydroxides, ammonium hydroxide, alkali carbonates and alkali metal alcoholates. 4»' ' Process according to claim 1, characterized in that the organic bases used to convert the intermediates of formula IV into the desired compounds of formula V are selected from the group consisting of aliphatic, aromatic and heterocyclic amines and basic ion exchange resins.