NO751781L - - Google Patents

Abstract

Important information. For archival reasons, the Norwegian Patent Office has only documents available for this publicly available patent application that contain handwritten remarks, comments or deletions, or that may be stamped "Deleted" or similar. We have therefore had to use these documents for scanning to create an electronic edition. Handwritten remarks or comments have been part of the case processing, and should not be used to interpret the content of the document. indicates that newer documents have been received during the proceedings to replace the previous document. Such underlining or stamping must not be understood as meaning that the relevant part of the document does not apply. Please disregard handwritten remarks, comments or underlining, as well as any stamping with "Deleted" or the like. which has the same meaning.Procedure for the preparation of cephalosporins.

Description

The present invention relates to a method

for the production of cephalosporins.

Present/specifically concerns a new one. forward

procedure for the production of cephalosporins based on

suitably substituted thiazolinazetidinones y.

L

The transformation step from the penicillan cell to the cephalosporan cell was achieved for the first time by treatment'

of sulfoxides of penicillins with acetic anhydride

(R.R. Chauvette, "J. Org. Chem."5%; 1971, page 1259) or with acid catalysts (Belgian Patent No. 747119).' Since then, the transfer of the sulfoxide of penicillins to cephalosporins in the presence of azodicarboxylate has been described (S. Terao, "Chem. Comm.", 1304, 1972) with low yields and in mixture with other products.

The purpose of the present invention is to produce cephalosporins using a completely new method which is illustrated schematically below:

Synthesis diagram

a) Opening of the thiazoline ring with an azo derivative:

where, apart from the other substituents, V can be hydrogen or an aliphatic, aromatic, arylaliphatic or acyl residue and especially the residues: b) Cyclization of the intermediate product 23-thiohydrazoazetdinone with inorganic oxides or bases where R is chosen from hydrogen, alkyl with 1- 4 carbon atoms and among the following groups: cyano-, methyl-, thienyl-methyl-, furyl-'methyl-, naphthy1-methyl-, pheny1-methyl-, phenoxy-methyl-, phenyl-isopropyl-, phenoxy-isopropyl- . -halophenacyloxy; Z is selected from hydrogen, hydroxyl, -O-alkyl, -O-CO-alkyl and from -Br, -J, -NH2, -N^, -O-CO-CH^, -O-CO-NH2, and - S-mononuclear nitrogen heterocyclic ring. The product (I) can be obtained by heating the sulfoxide of penicillin in the presence of trialkyl phosphite (Dutch patent no. 70/08271). The method according to the present invention essentially consists of reacting the compound I in a suitable solvent at a temperature between -20 and +80°C in the presence of an organic or inorganic aqueous acid with an azo derivative of the type

where the groups R and R^ are the same or different and denote a lower alkyl, a mononuclear aryl, CN group, and a a rnono-^ nuclear heterocyclic ring or the groups -COR 4 , -COOR 4,

or can R^. and R^ also together denote the groups

where T denotes CB, N - R^, and R^ denotes a lower alkyl, a mononuclear aryl and a mononuclear heterocyclic ring or the like. The intermediate product (II) is reacted in a suitable solvent and at a temperature between -40 and +120°C with inorganic oxides as follows. such as Al^O^, Fe^O^, Cr^O^,, 5i02or with inorganic or^or" organic bases such as KOH, Na2C0^-, NH^OHj^alka^imetal alcoholatesT) aliphatic, aromatic and heterocyclic amines ,, alkylammonium bases .and basic resins In this way the cephalosporin derivative (III) is obtained which is isolated and purified in a known manner.

~©ppfinne The ice will be illustrated in more detail with the help of the following examples.

Example 1

Methyl 23-thiohydrazodicarboxymethyl-α-isopropeny1-4-oxo-3B-phenoxyacetamido-1-azetidinoacetate

A solution of 5.0 g of methyl-α-isopropenyl-3-phen-.oxymethyl-1α, 5α-4-thio-2,6-diaza-[3,2,0 ]-2-neptane-6-acetate- 7-one in 200 ml of acetone containing 5 ml of methyl azodicarboxylate, 2.5 g of p-toluenesulfonic acid monohydrate and 2.5 ml of water is left at room temperature for 6-8 hours. The whole is then cooled to 0°C, neutralized with a saturated solution of NaHCO 3 .

The sodium salt of p-toluenesulfonic acid that precipitates is filtered off and after evaporation of the acetone at room temperature, the residue is dissolved in methylene chloride and washed with salt water.

The organic layer is dried over anhydrous Na2SO4 and evaporated. The residue is chromatographed over silicon dioxide, after which one elutes with 15% benzene ethyl acetate. In this way, 6.2 g of methyl 1-2 3-thiohydrazodicarboxymethyl 1-.α-isopropeny 1-4-oxo-33-phenoxyacetamido-1-azetidine acetate are obtained, with a melting point of 133-135°C.

I.R. (CHC13): 3410 (N=H), 1775 (C = 0 3-lactam)

1735 (C = 0 ester and carbamate)

1685 cm"<1>(C = 0 amide)

N.M.R. (CDC13): 1.94 (singlet, 3H, CH"3-£=) 3.68, 3.73 and

3.81 (singlets, 9H, three COOCH^),

4.56 (singlet, 2H, 0CH2CO>, 4.90 (singlet, 1H, n-CH-COOCH-j)., 5.07 and 5.16 (extended singlets, 2H<1>, =CH2), 5 .3 - 5.7 (multiplet, 2H, CH-3-lactam) and 6.9 - 8.0 6 (multiplet, 7H, aromatic

ic H and NH).

Mass spectrum: w/ e510 (M<+>) and 363 a.m.u.

Example 2 2',2',2'-trichloroethyl-23-thiohydrazodicarboxymethyl-ct-isopropenyl-4-oxo-33-phenoxyacetamido-1-azetidine acetate

0.15 ml of water, 0.25 ml of methyl azodicarboxylate and 125 mg of p-toluenesulfonic acid monohydrate are added to a solution of 300 mg of 2 ' ,2 ' ,2 '-trichloroethyl-a-isopropeny 1-3-phenoxymethyl-1a,5ct-•4 -thia-2,6-diaza-[3.2.0]-2-heptan-6-acetate-7-one in 10 ml of acetone. The whole thing is allowed to stand for a total of 6 hours at room temperature. Neutralize with a saturated solution of NaHCO-^, add methylene chloride and shake with salt water. The organic layer is collected over anhydrous Na^SO^ and evaporated. The residue is chromatographed over silica, eluting with 85/15 volume/volume benzene ethyl acetate. In this way, 320 mg of 2',2',2'-tri-chloroethyl-2-3-thiohydrazodicarboxymethyl-a-isopropenyl-4-oxo-33-phenoxyacetamido-1-azetidine acetate are obtained as an amorphous solid.

I.R. (CHC13): 3400 (N-H), 1770 (C= 0 g-lactam),

1740 (C = 0 ester and carbamates) and 1690 cm"<1> (C = 0 amide)..

Example 3

Methyl 23-thiohydrazodicarboxyethyl-a-isopropylidene-4-oxo-33-phenoxyacetamido-1-acetidine acetate 5 ml water, 10 ml ethyl azodicarboxylate and 10 g p- toluenesulfonic acid monohydrate is added to a solution of 10 g of methyl 1~a-isopropylidene-3-phenoxy-methyl 1-lct, 5a-4-thi a- 2,6-diaza- [3.2.0]-2-heptan-6-acetate-7-one in 300 ml of acetone. The whole thing is allowed to stand at room temperature for one night, after which it is neutralized with a solution of NaHCO-^. The insoluble sodium salt of p-toluenesulfonic acid that precipitates is filtered off. Salt water and methylene chloride are then added and the whole thing is shaken. The dried organic layer is chromatographed over silica, after which the mixture is first eluted with benzene to remove the unreacted azodicarboxylate and then with benzene ethyl acetate (80:20 volume:volume). In this way, 10.8 g of a white solid is obtained which is obtained as a result of the addition of petroleum ether to a small volume solution of the product in benzene.

N.M.R. (CDCl ): 1.21 (triplet, 6H, 2CH~3, C(H2)),

2.12 and 2.28 (two s, 6H, (CH3).2C=), 3.77 (s,

3H, COOCHj), 4.13 (q, 4H, 2CH2-C(H3)), 4.56

(s, 2H, 0-CH2CO), 5.14 (dd, 1H, C(3)H), 5.86 (d, 1H, C(4)H) and 6.8 - 7.86 (m, 7H,

CgH^ and amide 2NH).

I.R. (CHCl 3 ) : 3410; (N - H)

1765 C = 0 B-lactam)

1730 (C =0 ester and k4/abamate)

1690 cm<-1>(C = .0 amide)

Example 4

2',2',2'-trichloroethyl-2 3-thiohydrazodicarboxyethyl-α-isopropylidene-4-oxo-3B-phenoxyacetamido-1-azetidine acetate

A solution of 4363 g of 2',2',2'-trichloroethyl-α-isopropylidene-3-phenoxymethyl-1α,5α-4-thio-2,6-diaza-[3,2,0]-2-heptene- 6-acetate-7-one in 200 ml of acetone containing 3 ml of ethyl azodicarboxylate, 3 ml of water and 1.91 g of p-toluenesulfonic acid monohydrate is placed at room temperature for 24 hours. Neutralize with NaHCO3, add CH2C12 and salt water and the organic matter

layer is separated. Chromatography is carried out over silicon dioxide

after which one elutes with benzene ethyl acetate (95=5 volume:volume)

and the combined fractions give 630 g of the desired product. ' N.M.R. (CDCl-j) : 1.22 and 1.27 (two t, 6H, 2CH3-C(H2)), 2.22 and 2.37 (two s, 6H, (CH3)2C=), 3.9 - 4.5 (m, 4H, 2CH2C(H3)), 4.58 (s, 2H, 0-CH2-C0), 4.79

(dd, 2H, -O-CH2-CCl3), 5.10 (s, 1H, C(3)H), 5.98 (d, 1H, C(4)H), 6.64 (s, 2H , 2NH) and 6.68 - 7.56 (m, 5H, CgHy.

I.R. '(CHC1-3.) : 3^10 (N - H)

1760 (C = 0 3-lactam)

1730 (C = 0 ester and carbamates) and 1680 cm"<1> (C = 0 amide)

Example 5

Methyl 2B-thiohydrazodicarboxymethyl-α-1'-methoxyethylidene-phenoxyacetamido-1-azetidine acetate

A solution of 0.500 g of methyl-α-1'-methoxyethylene-3-phenoxymethyl-α,5α-4-thio-2,6-diaza-[3,2,0]-2-heptane-6-acetate- 7-one in 50 ml of acetone containing 0.5 ml of methyl azodicarboxylate, 3 ml of water and 50 mg of p-toluenesulfonic acid ammonium hydrate is placed at room temperature for 12 hours. The whole is neutralized with the equivalent amount of NaHCO 3 and extracted with methylene chloride. The residue is chromatographed over silicon dioxide, after which one elutes with benzene-ethyl acetate (-85:15 volume:volume). On

in this way 320 mg of the desired product is obtained.

I.R. (CHC13) : 3420 (N - H)

1770 (C = 0 B-lactam)

1730 (C = 0 ester and carbamate)

Example 6

Methyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate

A solution of 1.0 g of methyl-2B-thiohydrazodicarboxymethyl 1-a-isopropeny l-4-oxo-33phenoxy acetamido-l-azetidine acetate in 40 ml of benzene is added to a magnetic stirrer with an excess of Al 2 O 3 at room temperature. After 60 minutes, a complete conversion to the derivative methyl-7-phenoxy-acetamido-3-methyl-3-cephem-4-carboxylate occurs.

cl^O is filtered off and the residue is crystallized from ethyl ether or chromatographed over silica, eluting with 90:10 volume:volume benzene-ethyl acetate, thereby obtaining 0.580 g of methyl 7-phenoxyacetamido-3-niethyl-3-cephem-4-carboxylate with a melting point of 140 -141°C (crystallized from ethyl ether). I.R., N.M.R. spectra in agreement with the literature values (R.B. Morin: "J.Am. Chem. Soc. 91, 1401 (1969)).

Example 7

Methyl 1-7-phenoxyacetamido3_niety 1-3-cef em-4-carboxylate

A solution of 400 mg of methyl-2B-thiohydrazodicarboxy-methyl-ra-isopropanol-4-oxo-33-phenoxyacetamido-1-azetidine acetate in 30 ml of ethyl acetate is added to a magnetic stirrer in the presence of a

f^—excess of SiO 'and the whole is heated under reflux in 48

hours. The solution is filtered from silica, evaporated and the residue is crystallized or chromatographed over silica.

In this way, 180 mg of methyl 1-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate with a melting point of 141-142°C is obtained. I.R. and N.M.R. spectra in accordance with the data specified in the literature reference under example 6.

Example 8

Methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate

\/0)8 ml of a 30% aqueous solution of KOH is added ' x uner magnetic tube mg and at room temperature to a solution of ■5^0 mg of methyl-23thiohydrazodicarboxymethyl-a-isopropenyl-4-oxo-33-phenoxyacetamido-1 -acetidine acetate in 20 ml of benzene. The whole is stirred for 30 minutes, then the organic layer is separated, washed with acidified water, then with water and dried. The residue is crystallized from ethyl ether and gives 310 mg of methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate with a melting point of 141-142°C. I.R. and N.M.R. spectra agree with the data which. is indicated in the literature source indicated under example 6.

Example 9

2',2 1,2'-trichloroethyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate

A solution of 250 mg of 2',2'}2'-trichloroethyl-2g-thiohydrazodicarb oxymethyl-a-isopropenyl-4-oxo-33-phenoxyacet-amido-1-azetidine acetate in 15 ml of benzene is stirred magnetically at room temperature in presence of an excess of A^Oy The whole is allowed to stand for 60 minutes, then filtered and chromatographed over silica, after which one elutes with 93:7 volume:volume benzene-ethyl acetate. In this way, 150 mg of 2',21,2'-trichloroethyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate with melting point 116-117°C I.R. is obtained. and N.M.R. spectra are in accordance with the data indicated in the literature (R.R. Chauvette, "J. Org. Chem." 36, no. 9, 1259 (197D ) • ' Example 10 Methyl-7-phenoxyacetamido-3-methyl-3- cefem-4-carbok sylate

In this example, the method of getting from (I) to (III) without isolation of (II) is described.

A solution of 500 mg of methyl-α-isopropenyl-3-phenoxymethyl 1-1α,5α-4-thio-2,6-diaza-[3,2,0]-2-heptane-6-acetate-7- in 25 ml of acetone with 0.5 ml of methyl azodicarboxylate, 250 mg of p-toluenesulfonic acid monohydrate and 0.25 ml of water is left at room temperature for 6 hours. The whole is cooled to 0°C, the acid is neutralized with a saturated solution of NaHCO3 and the whole is extracted

.by shaking with benzene and salt water. The organic layer is dried over anhydrous Na 2 SO 2 , A 2 O 2 is added and the whole is left for 60 minutes at room temperature under magnetic stirring.

filters, benzene is evaporated and the residue is crystallized from ethyl ether whereby 350 mg of methyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate with melting point 140-141°C is obtained.

I.R. and N.M.R. - spectra agree with what is stated in the literature source indicated in example 6. Example 11 Methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carbox- sylate

A solution of 750 mg of methy1-a-isopropeny1-3-phenoxymethyl-1a,5a-4-thio-2,6-diaza-[3,2,0]-2-hepten-6-acetate-7-one in 35 ml of acetone with 0.75 ml of methyl azodicarboxylate, 375 mg of p-toluenesulfonic acid monohydrate and 0.375 ml of water are placed at room temperature for 6 hours. After cooling to 0°C, it is neutralized with a saturated solution of NaHCO^, water is added and extraction is carried out with benzene. The organic layer is dried and 1.2 ml of a 30% solution of JtOH is added under magnetic stirring at room temperature. The whole is left for 30 minutes, the organic layer is separated, washed with deionized water, with water and then dried over anhydrous Na^SO^. After evaporation, the residue is crystallized from ethyl ether whereby 540 mg of methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate is obtained with a melting point of 141-142°C.

I.R. and N.M.R. -spectra are in accordance with the data specified in the literature source specified under example 6. Example 12

p-nitrobenzyl-7-[N-benzyloxycarbonyl-D-α-phenyl-glycinamido]~3-methyl-3-cephem-4-carboxylate

A solution of 600 mg of p-nitrobenzyl-α-isopropenyl-3-[N-benzy 1-oxycarbonyl 1-benzylamino]-1α,5α-2,6-diaza-[3,2,0]-2-heptene-6- acetate-7-one which melts at 141-143°C, in 20 ml of acetone containing 0 5 60 ml of methyl azodicarboxylate, 200 mg of p-toluenesulfonic acid monohydrate and 0.2 ml of water is placed at room temperature for 20 hours. Man' is neutralized at 0°C with NaHCO^, it is added

water and extract with benzene. One dries over anhydrous

Na 2 SO 3 and the solution is placed under magnetic stirring at room temperature with 0.2 ml of a 30% KOH solution and left to stand for 60 minutes. Finally, the organic layer is separated, washed with acidified water and then with water and dried over anhydrous Na 2 SO 3 , thereby obtaining a residue which on crystallization from ether gives 230 mg of p-nitrobenzyl-7-[N-benzyloxy-carbonyl-D-a-phenylglycinamido]-3-cephem-4-carboxylate with melting point 19.8-202°C. I.R and N.M.R. -spectra are consistent with data obtained from a sample prepared using another method.

N.M.R. (CDCl1): 1.806 (extended s, 3H, CH^-C=),

4.896 (s, 1H,'N-CH-COO-),

5.08 and 5.256 (two s, 4H,

5.106 (m, 1H = 5.356 (d, J = 6H2, 1H, CH-N(H)), 5.70 - 6.05 d (m, 3H, 2CH of 3-lactam e =

6.066 (d,J = 6H Zi,

1H, NH-C(H)), 7.2 - 7.7 and 8.1 - 8.35 (m, 14H, aromatic H).

Example 13

The following compounds are obtained in a manner analogous to that described previously: 2',2',2'-trichloroethyl ester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid with melting point 163°C;

p-Methoxybenzyl ester α<y>7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid with melting point 151-152°C,

p-chlorophenacyl ester of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid with melting point 176°C,

phenacyl ester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid with melting point 190-191°C,

p-Bromophenacyl ester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid with melting point 196-198°C, t-butyl ester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid with melting point 122° C;

p-nitrobenzyl ester of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid with melting point 191-193°C;

methyl ester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid with melting point 188-190°C, p-nitrobenzyl ester of 7-(thiophene-2-acetamido)-3-methyl-3-cephem-4-carboxylic acid with melting point 217°C;

p-Methoxy ester of 7-(thiophene-2-acetamido)-3-methyl-3-cephem-4-carboxylic acid with melting point 160°C.

Claims (1)

1. Procedure for. preparation of cephalosporins with the structural formula: where R is selected from hydrogen, alkyl with 1-4 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-, tetra-Z'Olyl-1-methyl-, and where R <1> is selected from hydroxyl, alkoxy with oJk& Å* 1" ^ carbon atoms, trichloro^t oxy -, benzyloxy-, p-methoxy benzyloxy-, p-nitrobenzyloxy-, benzhydryloxy-., triphenylmethoxy-, phenacyloxy-, p-halophenacyloxy-, Z is selected from hydrogen, hydroxyl, -O-alkyl, -O-CO-alkyl, and from the groups -Br,. -J, -N^ , -NH2 , -0-CO-CH^ , -0-CO-NH^ , and -S-mononuclear nitrogen heterocyclic ring, characterized in that a compound of the formula ;is reacted in a suitable solvent at a temperature between •-20°C and +80°C in the presence of an organic or inorganic aqueous acid with an azo derivative of the type: ;2 3 where the groups R and R are the same or different and denote lower alkyl, a mononuclear aryl, CN group and a mononuclear heterocyclic ring or the groups -COR 4 , ;-CONHR , or also Rg and R^ together can denote the groups: ;where T betegenes ii R denotes lower alkyl, a mononuclear aryl or a mononuclear heterocyclic ring for the preparation of a compound with the structural formula: ;12 3' where R, R , R. , 'R^ and Z are defined in the same way as above and j2 , intermediate product (II) is reacted in a suitable solvent by J a temperature between -40°C and +120°C with a compound which Y is chosen from among inorganic, basic or slightly acidic oxides, of ^ BÉuk ^ inorganic or organic bases, for the production of the desired ^ ede compound (III) which is isolated and purified in a known manner.;2. Process according to claim 1, characterized in that the inorganic, basic or weakly acidic oxides used to convert the intermediate product (II) into the desired compound (III) are selected from aluminium, iron, chromium or silicon oxides, either alone or in mixture with other inorganic compounds.;3. Process according to claim 1, characterized in that the inorganic bases used, for converting the intermediate product (II) into it. desired compound (III) is selected from among alkali metal 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 for conversion of the intermediate product (II) into the desired compound (III) are selected from among aliphatic, aromatic and heterocyclic amines and basic ion exchange resins.;5. Process according to claim 1, characterized in that a compound with the formula: ; in a suitable solvent is reacted at a temperature between -20 and +80 <Q> C in the presence of an organic or inorganic aqueous acid with an azo derivative of the type: ; for production of a compound with the structural formula: ;where V can denote hydrogen, or an aliphatic, aromatic, arylaliphatic or acyl group, and in particular the groups: ;12 3 - ■ where R, R-, R , R and Z are defined in the same way as above and M denotes hydrogen or an alkyl group with 1-4 carbon atoms.;6. 23-thiohydrazoazetidinone with the structural formula: where V can represent hydrogen or an aliphatic, aromatic, aryl aliphatic.or acyl group and in rare cases the groups: ;where R, R 1 , R 2 , R 3 , M and Z are indicated in the same way.as before.*