GB2125807A - Preparation of penicillin and cephalosporin compounds and novel intermediates useful therein - Google Patents

Description

1

GB 2 125 807 A

1

SPECIFICATION

Preparation of penicillin and cephalosporin compounds and novel intermediates useful therein

5 This invention relates to a process for preparing penicillin and cephalosporin compounds and to novel 5

intermediates used in the process.

The importance of certain penicillicin a-sulphoxides as intermediates in the preparation of cephalosporin compounds has been described in British Patent 2 003 475 where it is shown that the a-sulphoxide derivatives are preferred to the (3-sulphoxideform in giving higher yields and involving the use of milder 10 conditions. 10

In a paper in Tetrahedron Letters (Vol. 22, No. 19, pp 1787-1790,1981), S. Djuric et al. disclose the preparation of a cyclic disilazine derivative of 6-aminopenicillanic acid, though this compound is not employed in the subsequent synthesis of further compounds.

We have now found that the silylation of certain penicillin or cephalosporin type nuclei assists in the 15 preparation of a-sulphoxides in high yield. 15

Accordingly the invention provides a process for preparing a sulphoxide of the formula

20 20

(I)

25 y 25

in which R1, R2, R3 and R4 are the same or different and are alkyl, alkoxy or aryl, X is alkylene, R5 is a 30 carboxylic acid protecting group and Y is a linking group through one or two carbon atoms forming a penam 30 orcephem nucleus, which comprises reacting a compound of formula

35 35

(II)

40 R,> R*/* ^ y 40

with an oxidising agent. Preferably the group Y is a group of the formula 45 45

: C(CH3)CH2R6

50 where R6 is hydrogen, halo, methoxy, acetoxy, formyloxy, azido, nitro, cyano or phenylamino, or a group of 50 the formula

R7

I

55 -CH2C= 55

where R7 is methyl halo, halomethyl oracetoxymethyl.

As described above, the oxidation reaction results in the production of predominantly or entirely the a-sulphoxide form and in general there is less then 10 per cent of the p-sulphoxide present in the product, 60 and the process may therefore be regarded as one for preparing the a-sulphoxide of formula (I). 60

Compounds of formula (I) are novel and are included as part of this invention. They are preferably prepared by the action of a peracid oxidising agent, in the presence of a base, since they are disilylated by the action of acid to give the corresponding free amino compound. The readiness with which this can be effected can represent a further advantage of the invention, the free amino compound being the necessary 65 starting material for subsequent acylation to give active compounds or, in the case of penicillin type 65

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GB 2 125 807 A

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derivatives, for ring expansion reactions to provide cephalosporin compounds. Antibiotic cephalosporin and penicillin compounds prepared by the process of the invention or prepared from novel intermediates of the invention are included in the invention.

Alternatively the compound of formula (I) can be reacted directly with a selective acylating agent to give 5 the desired acyiated products. The intermediates of formula (II) are readily prepared from the corresponding 5 free amino compound by reaction with a silylating agent of the formula

R1 R3

I I

10 Z-Si-X-Si-Z (III) 10

I I R2 R4

where Z is halogen, the compounds of formula (ll) with the exception of the compound in which R1, R2, R3 15 and R4 are all methyl, X is -(CH2)2-, R5 is methyl and Y is 15

^C(CH3)2

20 20

are novel and are included as a further aspect of this invention.

Thus, the invention also provides a process for producing a compound of the formula

25 ' H2N^ 25

A>

30 COCR5 - 30

in which R5 and Y have the above ascribed meanings, which comprises (a) reacting a compound of the formula

35 35

h*v n *

Joors with a silylating reagent of formula

(V)

40 Or 40

45 R1 R3 45

I I Z-Si-X-Si-Z ! I R2 R4

50 50

where R1, R2, R3, R4 and X have the meanings given above and Z is halogen, to give a compound of formula (II)

R'\,/2

-s\

^ \ y y (ii)

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GB 2 125 807 A

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(b) reacting the compound of formula (II) with an oxidising agent to give a compound of formula

10

(I)

and (c) reacting the compound of formula (I) with acid. The compound of formula (IV) can then optionally be 15 converted to its acyiated products by employing an acylating agent of for example the formula R8COZ or an anhydride derivative of R8COOH, where Z is halogen preferably chlorine, and R8, together with the associated carbonyl group, is a carboxylic acid derived acyl group. Alternatively as stated above, the compound of formula (I) can be directly converted to its acyiated product

20

?a

iooRS

(VI)

25 </

by reacting a compound of formula

30 35

(I)

40

. with an acylating agent of formula R8COZ, where Z is halogen preferably chlorine, followed by treatment ; with water or an alcohol.

Conversion of the compound of formula (II) to that of formula (I) proceeds in the presence of an oxidising agent. The oxidising agent is preferably a peracid, especially peracetic acid, m-chloroperbenzoic acid or 45 monoperphthalicacid. In view of the fact that the silyl protecting group is readily removed by acid, the reaction is performed in the presence of sufficient base to prevent loss of the side chain and is preferably conducted at a pH of from 7 to 13, more particularly in the range of 8 to 11. Convenient bases which may be employed with such acid oxidising agents are inorganic bases such as alkali metal or alkaline earth metal hydroxides, carbonates and bicarbonates and especially sodium hydroxide, sodium carbonate and sodium §q bicarbonate, or commercially available buffer solutions, or organic nitrogen bases such as for example triethylamine, dimethylaniline and pyridine. The reaction is also preferably carried out in the presence of an organic solvent forthe compound of formula (I), and is most suitably conducted at a temperature of from -10°C to 30°C, such as from 0°C to 5°C.

In the above formula (I), R1, R2, R3 and R4 can be alkyl and may be for example C1.4 alkyl such as methyl, 55 ethyl, n-propyl, isopropyl, n-butyl or f-butyl, the preferred value being methyl, or one or more of these groups may be alkoxy preferably Ci_4 alkoxy such as methoxy or ethoxy, or aryl such as for example phenyl or phenyl substituted with one or more, such as one to three, substituents selected, for example, from Cm alkyl, nitro, halo, C|„4 alkoxy. The group X is an alkylene chain preferably containing 1 to 5 carbon atoms and which can be for example -(CH2)n^ where n is an integer from 1 to 5. Preferred values of Y are

60

^C(CH3)2,bc(CH3)CH2CI,-CH2C(CH3)=, -CH2C(CI)=, -CH2C(CH2CI)= -CH2C(CH2OCOCH3)=,

10

15

20

25

30

35

40

45

50

55

60

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the compound of formula (I) being either the penam orcephem derivative:

10

5

/ xce2R6

\/CH3

or coop.5

10

5

15 The group R5 is a carboxylic acid protecting group. The term refers to the commonly used carboxylic acid 15 protecting groups employed to block or protect the carboxylic acid functionality while reactions involving other functional sites of the compound are carried out. Such carboxy protecting groups are noted for their ease of cleavage by hydrolyticorby hydrogenolytic methods to the corresponding carboxylic acid.

Examples of carboxylic acid ester protecting groups include methyl, ferf-butyl, benzyl, 4-methoxybenzyl, C2-6 20 alkanoyloxymethyl, 2-iodoethyl,p-nitrobenzyl, diphenylmethyl (benzhydryl), phenacyl, 4-halo-phenacyl, 20 dimethylallyl, 2,2,2-trichloroethyl, tri(Ci_3 alkyl)silyl, succinimidomethyi and like ester forming moieties.

Other known carboxy protecting groups such as those described in T.W. Greene in "Protective Groups in Organic Synthesis", Chapter 5, are also suitable. The nature of such ester forming groups is not critical although the use of thep-nitrobenzyl protecting group is often convenient.

25 The silylating reagent employed in the preparation of compounds of formula (II) is of the formula 25

R1 R3 I !

Z-Si-X-Si-Z

30 I I 30

R2 R4

R1, R2 R3 and R4 are the same or different and are C^ alkyl or aryl, being preferably methyl. The group X is preferably alkylene of the formula -(CH2)n where n is an integer of from 1 to 5, and is most preferably 2, but 35 can take other values as defined above. The group Z is halogen, preferably chlorine and examples of such 35 silylating reagents are:

CI(CH3)2 Si—(CH2)2—Si(CH3)2CI

40 CI(CH3)2 Si—(CH2)3—Si(CH3)2CI 40

CI(CH3)2 Si—(CH2)4—Si(CH3)2CI

CI(CH3) (Ph)Si—(CH2)2—Si(CH3) (Ph)CI 45 45

CI(CH3) (tBu)Si—(CH2)2—Si(CH3) (tBu)CI

CI(CH3) (OMe)Si—(CH2)2—Si(CH3) (OMe)CI

50 Cl(CH3) (OEt)Si—(CH2)2—Si(CH3) (OEt)CI 50

The most preferred compound is

CH3

ch3

55

55

CISi—CH2CH2—SiCI

CH3

ch3

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GB 2 125 807 A

5

One example of a preferred process according to the invention is for the preparation of a compound of the formula yCH3

0

ccx \

/\ n \

' X /CH3

io ce3 ch3 i—i x \ce 10

J \ /

coor5

where Rs is a carboxylic acid protecting group, which comprises reacting a compound of the formula 15 15

ch3V /\

20 <cs()2 X S. 20

N/N /\ .CH

/\ n vc"3

Ic ch3 ch, i 1 / x

25 ^ \ / 3 25

^00R5

with a peracid oxidising agent in the presence of a base.

30 A further example of a preferred process according to the invention is for the preparation of a compound 30 of the formula

35 /D1\ |? 35

CH., CH,

%/

(C%/\ /\

™ 1

40 CH3 CH3I I I 40

</* \ /'V

J:OOR5

45 where R5 is a carboxylic acid protecting group and R7 is methyl or chloro, which comprises reacting a 45

compound of formula

CH3>^ yCEz

50 /Si\ 50

/\

CD /s\ n i

55 CH3 CH3; 1 I 55

\/V

JQORS

60 with a peracid oxidising agent in the presence of a base. 60

In order to convert the compound of formula (I) to that of formula (IV), by removal of thesilyl group, conventional acid reagents may be employed preferably for example an acid such as hydrochloric acid or p-toluenesulphonicacid in an organic solvent for the reactants such as for example ethyl acetate or methylene chloride, the temperature employed being usually in the range of from —10 to 50°C. The 65 subsequent acylation of compounds of formula (IV) can be carried out in conventional manner employing a 65

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GB 2 125 807 A

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conventional acylating agent preferably in an organic solvent such as tetrahydrofuran, ether, acetonitrile or a chlorinated hydrocarbon such as dichloromethane, at a temperature of for example -10 to 50°C.

In the case of the direct acylation route (reaction of a compound of formula (I) with R8COZ) the intermediate formed by the first stage of the acylation process is not isolated, the initial reaction being 5 followed by reaction in situ with water or an alcohol such as for example ethanol at a temperature of from 5 -10 to 50°C to liberate the acyiated product.

The carboxylic acid derived acyl group R8CO can beany of those groups conventionally utilised in the p-lactam art, the nature of which groups will be readily apparent to those skilled in this field of chemistry.

Thus, for instance the R8 residue may be:

10 (a) hydrogen, C-|.3 alkyl, halomethyl, cyanomethyl or 3-(2-chlorophenyl)-5-methylisoxazol-4-yi; 10

(b) benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, fe/t-butoxy, or 4-methoxybenzyloxy;

(c) the groups R" wherein R" is phenyl or phenyl substituted with 1 or 2 substituents independently selected from the group consisting of halo, protected hydroxy, nitro, cyano, trifluoromethyl, C-|.3 alkyl, and C-|.4 alkoxy;

15 (d) an arylalkyl group of the formula 15

R°—(Q)m-CH2—

wherein R° is R" as defined above, 2-thienyl, 3-thienyl, or 1,4-cyclohexyldienyl, m is 0 or 1, and Q is 0 or S 20 subject to the limitation that when m is 1 R° is R"; 20

(e) a substituted arylalkyl group of the formula

R°CH —

I

25 W 25

wherein R° is as defined above and W is hydroxy, protected amino, or protected carboxy; or

(f) a heteroarylmethyl group of the formula R4CH2— wherein R4is 2-furyl, 3-furyl, 2-thiazolyl, 5-isoxazolyl, or 5-tetrazoiyl.

30 The residue R8 is preferably benzyl or phenoxymethyl (PhOCH2-). 30

The utility of compounds of formula (IV) is well documented in the literature and has already been referred to. Acylation of the 6-amino group of the penam derivative gives, for example, a 6-acylamido-2,2-dimethylpenam-3-carboxylic acid ester a-sulphoxide which on reaction with an N-chloro halogenating agent in the presence of an alkylene oxide as described for instance in British Patent 2 003 375, gives the 35 corresponding esters of a 3-methyl-2-(2-chlorosulphinyl-4-oxo-3-acylamido-1-azetidinyl)-3-butenoic acid of 35 the general formula

-9

40 I J, 40

. /-VJ&CH3

H "C00R5

45 which are useful intermediates in the preparation of 7-acylamido-3-exomethylenecepham-4-carboxylic acid 45 ester sulphoxides.

Acylation of both penam and cephem compounds of formula (IV), by well known techniques, can lead to the preparation of diacylated a-sulphoxide compounds, such as those disclosed in British Patent 1 594 271 of the formula:

50 n 50

55 J 55

which are stated to have useful antibiotic properties.

60 The invention is illustrated by the following Examples. 60

EXAMPLE 1

p-Nitrobenzy! 6-(2,2,5,5-tetramethyl- 1-aza-2,5-disilacylopent- 1-ylj penicillanate Asolution of thep-toluenesulphonic acid salt ofp-nitrobenzyl 6-aminopenicillanate (20.88 g) in methylene 65 chloride (80 ml) was washed twice with saturated aqueous sodium bicarbonate (100 ml) and then brine (100 65

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GB 2 125 807 A 7

ml), dried with magnesium sulphate and the volume reduced to 40 ml by evaporation under reduced pressure. Triethylamine (13.92 ml) and a solution of 1,2-bis-(chlorodimethylsilyl)ethane (9.48 g) in methylene chloride (80 ml) were added and the resulting mixture refluxed for 15 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and then washed with 8% aqueous sodium 5 hydrogen phosphate solution (100 ml). The organic layer was separated, concentrated under reduced 5

pressure to about 30 ml, and then diluted with isopropanol (200 ml). The remaining methylene chloride was evaporated under reduced pressure to crystallise the product. The reaction mixture was cooled to 0°C for 2 hours and then the product isolated by filtration, washed with cold isopropanol and dried overnight in vacuo at room temperature to give the title compound as white crystals, nmr (CDCI3) S 0.15 (s, 12H), 0.72 (s, 4H), 10 1.40 (s, 3H), 1.64 (s, 3H), 4.27 (s, 1H), 4.72 (d, J = 4Hz, 1H), 5.15 (d, J = 4Hz, 1H), 5.16 (s, 2H), 7.3-8.2 (m, 4H). 10

The following compound was prepared in a similar manner:

Benzhydryl 6-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)-penicillanate, a foam, nmr (CDCI3) 8 0.14 (s, 6H), 0.17 (s, 6H), 0.71 (s, 4H), 1.22 (s, 3H), 1.62 (s, 3H), 4.37 (s, 1H), 4.78 (d, J = 4Hz, 1H), 6.86 (s, 1H), 7.20 (s, 10H).

15 15

EXAMPLE 2

p-Nitrobenzy! 6-(2,2,5,5,-tetramethyl- 1-aza-2,5-disilacyclopent- 1-yl) penicillanate 1 a-oxide.

To a stirred solution of p-nitrobenzyl 6-(2,2,5,5,-tetramethyl-1-aza-2,5-disilacyclopent-1-yi) penicillanate (2.61 g) in methylene chloride (50 ml) was added 0.5 M aqueous sodium bicarbonate (15 ml) followed by 20 m-chloroperbenzoic acid (1.11 g) over 20 minutes. After 30 minutes a second amount of m-chloroperbenzoic 20 acid (0.1 g) was added, the reaction mixture was stirred for a further 20 minutes when layers were separated. The organic layer was dried over magnesium sulphate and concentrated under reduced pressure.

Di-isopropyl ether was slowly added to the residue to crystallise the product. The residual methylene chloride was evaporated under reduced pressure and then the reaction was kept overnight at 0°C to 25 complete the crystallisation. The product was filtered off, washed with di-isopropyl ether, and dried in vacuo 25 at room temperature overnight to give the title compound as creamy-white crystals, nmr (CICI3) 8 0.17 (s, 6H), 0.22 (s, 6H), 0.78 (s, 4H), 1.20 (s, 3H), 1.63 (s, 3H), 4.23 (s, 1H), 4.40 (d, J = 4 Hz, 1H), 4.85 (d, J = 4 Hz, 1H), 5.21 (s, 2H), 7.40 (d, J = 9 Hz, 2H), 8.07 (d, J = 9 Hz, 2H).

The following compound was prepared in a similar manner:

30 Benzyhydryi 6-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)penicillanate 1a-oxide as a foam, nmr 30 (CDCI3) 8 0.15 (s, 6H), 0.20 (s, 6H), 0.77 (s, 4H), 1.0 (s, 3H), 1.62 (s, 3H), 4.27 (s, 1H), 4.41 (d, J = 4Hz, 1H), 4.85 (d, J = 4Hz, 1H), 6.85 (s, 1H), 7.20 (s, 10H)

EXAMPLE 3

35 p-Nitrobenzy16-(2,2,5,5-tetramethyi- 1-aza-2,5-disilacyclopent- 1-yljpenicillanate 1 a-oxide. 35

Peracetic acid (36%, 2.65 ml) was added dropwise over 5 minutes to a rapidly stirred mixture of p-nitrobenzyl 6-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)penicillanate (6.9 g) in methylene chloride (50 ml) and 0.5M aqueous sodium bicarbonate (125 ml) atO-5°C. The reaction mixture was stirred for 45 minutes at 0-5°C. The organic layer was separated, washed with water and concentrated under reduced 40 pressure. Di-isopropyl ether (about 120 ml) was slowly added to the residue to crystallise the product. The 40 residual methylene chloride was evaporated under reduced pressure and then the reaction was kept overnight at 0°C to complete the crystallisation. The product was filtered off, washed with di-isopropyl ether, and dried in vacuo at 40°C overnight tio give the title compound as pale cream crystals.

45 EXAMPLE 4 45

p-Nitrobenzyi 6-(2,2,S,5-tetra methyl- 1-aza-2,5-disiiacyclopent- 1-yi)peniciHanate la-oxide.

A solution of monoperphthalicacid (0.51 g) in diethyl ether (12 ml) was added dropwise over 5 minutes to a rapidly stirred mixture of 5% aqueous sodium bicarbonate (30 ml) and a solution ofp-nitrobenzyl

6-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)penicillanate (1.24 g) in methylene chloride (10 ml) at

50 0-5°C. The mixture was stirred for 30 minutes at 0-5°C. The organic layer was separated, washed with brine, 50

dried with magnesium sulphate, and concentrated by evaporation under reduced pressure. Di-isopropyl ether was added and the residual methylene chloride removed by evaporation in vacuo to crystallise the product. The product was filtered off, washed with di-isopropyl ether and dried in vacuo to give the title compound as pale cream crystals.

55 55

EXAMPLE 5

p-Nitrobenzyi 6-aminopeniciiianate-1 a-oxide

To a stirred solution ofp-nitrobenzyl 6-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl) penicillanate

1a-oxide (1.35 g) in ethyl acetate (10 ml) was added p-toluenesulphonic acid monohydrate (1.9 g) in ethyl

60 acetate (20 ml). After 30 minutes the solvents were removed in vacuo to give a gum, from which the title 60 compound was obtained as its tosylate salt by trituration with ether. 'H nmr (d6 DMSO 8 values) 1.22 (s, 3H), 1.60 (s, 3H), 3.30 (s, 3H), 4.67 (s, 1H), 4.78 (d, J = 4 Hz, 1H), 5.17 (d, J = 4 Hz, 1H), 5.35 (s, 2H), 7.07 (d, J = 8 Hz, 2H), 7.53 (d, J = 8 Hz, 2H), 7.67 (d, J = 8 Hz, 2H), 8.17 (d, J = 8 Hz, 2H).

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GB 2 125 807 A

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EXAMPLE 6

p-Nitrobenzy! 6-phenoxyacetamidopenicillanate 1 a-oxide.

To a stirred solution ofp-nitrobenzyl 6-aminopenicillanate-1 a-oxide (1.85 g) in methylene chloride (50 ml) was added 0.5 M aqueous sodium bicarbonate solution (20 ml) followed by phenoxyacetyl chloride (0.83 ml), 5 and the stirring continued for 60 minutes. The organic phase was separated off, dried over magnesium sulphate and stripped of solvents in vacuo to give the title compound. 'H nmr (CDCI3) 8 1.25 (s, 3H), 1.63 (s, 3H), 4.5 (s, 3H), 4.73 (d, J = 4 Hz, 1H), 5.27 (s, 2H), 5.37 (d, J = 4 Hz and 8 Hz), 6.7-7.3 (m, 5H), 7.47 (d, J = 8 Hz, 2H), 8.13 (d, J = 8 Hz, 2H).

10 EXAMPLE 7

p-Nitrobenzy! 6-phenoxyacetamidopenicillanate 1 a-oxide

Phenoxyacetyl chloride (1.49 ml) was added dropwise to a stirred solution ofp-nitrobenzyl 6-(2,2,5,5-tetramethyl-1-aza-2,4-disilacyclopent-1-yl)penicillanate 1a-oxide (5.0 g) in tetrahydrofuran (75 ml) at room temperature. After stirring for one hour at room temperature, the reaction mixture was washed with 15 aqueous sodium hydrogen carbonate and then with water, dried with magnesium sulphate and evaporated in vacuo. The product was crystallised from isopropanol, collected by filtration, washed with isopropanol and dried in vacuo to give the title compound, nmr (CDCI3) 8 1.20 (s, 3H), 1.56 (s, 3H), 3.64 (s, 2H), 4.45 (s, 1H), 4.63 (d, J = 4Hz, 1H), 5.0-5.3 (m, 3H), 7.18 (s, 5H), 7.3-8.2 (m, 4H).

20 EXAMPLE 8

Benzhydryl 6-(phenoxyacetamido)penicillanate 1 a-oxide

A mixture ofp-toluenesulphonic acid monohydrate (1.34 g) and benzhydryl 6-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)penicillanate 1 a-oxide (3.60 g) in ethyl acetate (25 ml) was stirred for 1.5 hours at room temperature. The solvent was evaporated under reduced pressure and the residue crystallised from 25 diethyl etherto give yellow crystals of the p-toluenesulphonic acid salt of benzhydryl 6-aminopenicillanate 1a-oxide (2.03 g). A solution of this tosylate in methylene chloride (25 ml) was washed twice with saturated aqueous sodium bicarbonate (25 ml) and then brine (25 ml), and then stirred rapidly for 3 hours at room temperature with phenoxyacetyl chloride (0.46 ml) and saturated aqueous sodium bicarbonate (25 ml). The organic layer was separated, washed with saturated aqueous sodium bicarbonate, dried with magnesium 30 sulphate, and evaporated under reduced pressure to give the title compound as a foam, nmr (CDCI3) 8 1.03 (s, 3H), 1.60 (s, 3H), 4.46 (s, 1H), 4.64 (d, J = 4Hz, 1H), 5.42 (dd, J = 4 and 8Hz, 1H), 6.78 (d, J = 4 Hz, 1H), 6.84 (s, 1H),7.16 (s, 10H).

EXAMPLE 9

35 p-Nitrobenzy! 6-(2,5-dibutyl-2,5-dimethyl-1 -aza-2,4-disilacyclopent- 1-yljpenicillanate.

A solution of the p-toluenesulphonic acid salt of p-nitrobenzyl 6-aminopenicillanate (2.61 g) in CH2CI2 (50 ml) was washed twice with saturated aqueous sodium bicarbonate and then with brine, dried with sodium sulphate and evaporated in vacuo. To a solution of the residual amine in acetonitrile (50 ml) was added 1,2-bis(chiorodimethylsilyl)ethane (1.65 g) and triethylamine (1.55 ml) and the mixture was heated at reflux 40 for 3.5 hours, allowed to cool to room temperature, and then washed with aqueous 8% sodium hydrogen phosphate solution. The organic solution was evaporated and the residue chromatographed on alumina with methylene chloride-ethyl acetate 3:1 as eiuentto give the title compound as a foam, nmr (CDCI3) 8 0.10 (s, 6H), 0.22 (s, 6H), 0.6-1.5 (m, 22H), 1.73 (s, 3H), 4.33 (s, 1H), 4.83 (d, J = 4Hz, 1H), 5.22 (d, J = 4Hz, 1H), 5.24 (s,2H), 7.27-8.16 (m,4H).

45

EXAMPLE 10

p-Nitrobenzy! 6-(penoxyacetamido)penicillanate 1 a-oxide.

To a stirred solution ofp-nitrobenzyl 6-(2,5-dibutyl-2,5-dimethyl-1-aza-2,5-disilacyclopent-1-yDpenicillanate (0.5 mmol) at 0°C was added 0.5M aqueous sodium bicarbonate (1.5 ml) followed by 50 portionwise addition of m-chloroperbenzoic acid (0.11 g) over 5 minutes. The reaction mixture was stirred and allowed to warm up to room temperature over 2 hours. The organic solution was prepared and evaporated under reduced pressure. The residual 1a-suiphoxide derivative was dissolved in acetone (5 ml) and then stirred with 1N hydrochloric acid (0.55 ml) for 30 minutes. The resulting mixture was diluted with methylene chloride and then the organic layer was separated, washed with water and then saturated 55 aqueous sodium bicarbonate, dried with sodium sulphate and evaporated under reduced pressure to give p-nitrobenzyl 6-aminopenicillanate 1 a-oxide.

A solution of this amine in methylene chloride (5 ml) was stirred overnight with a saturated aqueous sodium bicarbonate solution (5 ml) and phenoxyacetyl chloride (0.07 ml). The organic layer was separated, washed with water, dried with magnesium sulphate, and evaporated under reduced pressure to give the title 60 compound.

EXAMPLE 11

p-Nitrobenzy! 7-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)-desacetoxycepha!osporanate To a stirred solution ofp-nitrobenzyl 7-aminodesacetoxycephalosporanate (3.5 g) in methylene chloride 65 (15 ml) under nitrogen was added triethylamine (3.2 ml) followed by a solution of 1,2-

5

10

15

20

25

30

35

40

45

50

55

60

65

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GB 2 125 807 A 9

i bis(chlorodimethylsilyl)ethane (2.37 g) in methylene chloride (20 ml). The resulting mixture was stirred at reflux for 16 hours, allowed to cool to room temperature and then washed once with aqueous 8% sodium hydrogen phosphate solution (30 ml). The organic solution was concentrated in vacuo to about 10 ml and isopropanol (30 ml) added. The remaining methylene chloride was removed in vacuo and the reaction 5 mixture was cooled to 0°Cfortwo hours. The product was filtered off, washed with cold isopropanol and 5 dried overnight in vacuo to give the title compound, nmr (CDCI3) 8 0.19 (s, 12H), 0.75 (s, 4H), 2.10 (s, 3H), 3.15 + 3.60 (ABq, J = 18Hz, 2H), 4.73 (d, J = 4Hz, 1H), 4.93 (d, J = 4Hz, 1H), 5.30 (s, 2H), 7.53 (d, J = 8Hz, 2H), 8.15 (d, J = 8Hz, 2H).

The following compounds were prepared in a similar manner:

10 Benzhydryl 7-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)-desacetoxycephalosporanate, a paleyel- 10 low foam, nmr (CDCI3) 8 0.16 (s, 12H), 0.73 (s, 4H), 1.69 (s) + 1.86 (s) (3H), 2.90 + 3.33 (ABq, J = 18Hz, 2H), 4.5-5.0 (m, 2H), 6.73 (s) + 6.80 (s) (1H),7.12 (s, 10H).

p-Methoxybenzyl 7-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)desacetoxycephalosporanate, a gum, nmr (CDCI3) 8 0.16 (s, 12H, 0.73 (s, 4H), 1.73 (s) + 2.0 (s) (3H), 2.98 + 3.43 (ABq, J = 18Hz, 2H), 3.36 (s, 15 3H), 4.5-5.3 (m, 4H), 6.5-7.3 (m, 4H). 15

2,2,2-Trichloroethyl 7-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)desacetoxycephalosporanate, a gum, nmr (CDCI3) 8 0.17 (s, 12H), 0.75 (s, 4H), 1.92 (s) + 2.11 (s) (3H), 3.12 + 3.55 (ABq, J = 18Hz, 2H), 4.5-5.2 (m,4H).

20 EXAMPLE 12 20

p-Nitrobenzyl 7-(2,2,5,5-tetramethyl- J-aza-2,5-disi/acyc/opent- 1-yl)desacetoxycepha/osporanate la-oxide

Peracetic acid (36%, 0.88 ml) was added dropwise over 5 minutes to a rapidly stirred mixture of p-nitrobenzyl 7-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl) desacetoxycephalosporanate (2.4 g) in methylene chloride (10 ml) and 0.5 M aqueous sodium bicarbonate (20 ml) at 0-5°C. The reaction mixture 25 was stirred for 45 minutes at 0-5°C. The organic layer was separated, washed with water, dried with 25

magnesium sulphate, and evaporated in vacuo to give the title compound as a white foam, nmr (CDCI3) 8 0.18 (s, 6H), 0.25 (s, 6H), 0.78 (s, 4H), 2.10 (s, 3H), 3.35 + 3.93 (ABq, J = 18Hz, 2H), 4.35 (d, J = 4Hz, 1H), 5.05 (d, J = 4Hz, 1H), 5.25 (s, 2H), 7.43 (d, J = 8Hz, 2H), 8.07 (d, J = 4Hz, 2H).

The following compounds were prepared in a similar manner:

30 Benzhydryl 7-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)-desacetoxycephalosporanate 1a-oxide, a 30 white solid, nmr (CDCI3) 8 0.13 (s, 6H), 0.23 (s, 6H), 0.78 (s, 4H), 1.75 (s) + 1.93 (s) (3H), 3.23 + 3.78 (ABq, J = 17Hz, 2H), 4.27-5.04 (m, 2H), 6.80 (s) + 6.83 (s) (1H), 7.17 (s, 10H).

p-Methoxybenzyl 7-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)desacetoxycephalosporanate la-oxide, a yellow foam, nmr (CDCI3) 8 0.2 (s, 12H), 0.78 (s, 4H), 1.82 (s) + 1.99 (s) (3H), 3.22 + 3.80 (ABq, J =

35 18Hz, 2H), 3.68 (s, 3H), 4.23-4.48 (m, 1H), 4.8-5.2 (m, 3H), 6.5-7.3 (m, 4H). 35

2,2,2-Trichloroethyl 7-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)desacetoxycephalosporanate la-oxide, a yellow foam, nmr (CDCI3) 8 0.18 (s, 6H), 0.26 (s, 6H), 0.81 (s, 4H), 2.02 (s) + 2.15 (s) (3H), 3.35 + 3.92 (ABq, J = 18Hz,2H), 4.3-5.2 (m,4H).

40 EXAMPLE 13 40

p-Nitrobenzyi 7-aminodesacetoxycephalosporanate 1 a-oxide p-Nitrobenzyl 7-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl) desacetoxycephalosporanate 1 a-oxide (2.0 g) in methylene chloride (15 ml) was stirred with 5% hydrochloric acid (15 ml) for 30 minutes. The resulting precipitate was filtered off and dried overnight in vacuo at 40°C to give the hydrochloride salt of the 45 title compound, nmr (d6-DMSO) 8 2.23 (s, 3H), 3.82 + 4.44 (ABq, J = 24Hz, 2H), 4.67 (d, J = 6Hz, 2H), 5.28 (d, J 45 = 6Hz, 2H), 5.33 (s, 2H), 7.53 (d, J = 12Hz, 2H), 8.03 (d, J = 12 Hz, 2H).

The following compounds were prepared in a similar manner:

Benzhydryl 7-aminodesacetoxycephalosporanate 1a-oxide, pale yellow crystals, nmr (d6-DMSO) 8 1.98 (s, 3H), 2.97 (br. s, 2H), 3.55 + 4.07 (ABq, J = 17 Hz, 2H), 4.58 (d, J = 4Hz, 1H), 4.87 (d, J = 4Hz, 1H), 6.77 (s, 1H), 50 7.22 (s, 10H). 50

p-Methoxybenzyl 7-aminodesacetoxycephalosporanate 1a-oxide, a pale yellow solid, nmr (CDCI3) 8 2.01 (s, 3H), 2.50 (br. s, 2H), 3.36 + 3.83 (ABq, J = 18Hz, 2H), 4.42 (d, J = 3Hz, 1H), 4.80 (d, J = 3Hz, 1H), 5.1 (s, 2H), 6.6-7.3 (m, 4H).

55 EXAMPLE 14 55

p-Nitrobenzyl 7-phenoxyacetamidodesacetoxycephalosporanate 1 a-oxide.

Phenoxyacetyl chloride (0.3 ml) was added dropwise to a stirred solution ofp-nitrobenzyl 7-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)desacetoxycephalosporanate 1a-oxide (1.0 g) in tetrahydrofuran (30 ml) at room temperature. After stirring for one hour at room temperature, the reaction mixture was 60 washed with aqueous sodium hydrogen carbonate and then with water, dried with magnesium sulphate and 60 evaporated in vacuo. The product was crystallised from isopropanol, collected by filtration, washed with isopropanol and dried in vacuo to give the title compound, nmr (CDCI3) 8 2.21 (s, 3H), 3.37 + 4.0 (ABq, J = 16Hz, 2H), 4.47 (s, 2H), 4.52 (d, J = 4Hz, 1H), 5.23 (s, 2H), 5.35 (dd, J = 4 and 8Hz, 1H), 6.6-8.2 (m, 10H).

10 GB 2 125 807 A

EXAMPLE 15

p-Nitrobenzyl 7-(phenoxyacetamido)desacetoxycephalosporanate 1 a-oxide

To a stirred suspension ofp-nitrobenzyl 7-aminodesacetoxycephalosporanate 1 a-oxide hydrochloride (1.0 g) in methylene chloride (25 ml) at 0°C was added a solution of sodium bicarbonate (0.462 g) in water (10 5 ml) followed by dropwise addition of phenoxyacetyl chloride (0.38 ml). After stirring the reaction mixture for one hour at 0-5°, the organic layer was separated, washed with water and then with brine, dried with magnesium sulphate and evaporated under reduced pressure to give a yellowfoam which on trituration with diethyl ether gave the title compound as white crystals.

The following compounds were prepared in a similar manner:

10 Benzhydryl 7-(phenoxyacetamido)desacetoxycephalosporanate la-oxide, white crystals, nmr(CDCI3) 8 2.13 (s, 3H), 3.17 + 3.79 (ABq, J = 16Hz, 2H), 4.3-4.5 (m, 3H), 5.28 (dd, J = 4 and 7.5 Hz, 1H), 6.6-7.4 (m, 16H), 7.69 (d,J = 7.5Hz, 1H).

p-Methoxybenzyl 7-(phenoxyacetamido)desacetoxycephalosporanate 1a-oxide, nmr (CDCI3) 8 2.0 (s, 3H), 3.17 + 3.77 (ABq, J = 17Hz, 2H), 3.58 (s, 3H, 4.32 (m, 3H), 4.97 (s, 2H), 5.24 (dd, J = 4 and 8Hz, 2H), 6.5-7.2 (m, 15 9H), 7.87 (d, J = 8Hz, 1H).

EXAMPLE 16

p-Nitrobenzy! 3-chloro-7-(2,2,5,5-tetramethyl-1-aza-2,5-disifacyclopent-1-yl)-3-cephem-4-carboxylate. A solution of 1,2-bis(chlorodimethylsilyl)ethane (3.2 g) in methylene chloride (20 ml) was added to a stirred 20 mixture ofp-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (5.0 g) and triethylamine (4.9 ml) in methylene chloride (25 ml) under a nitrogen atmosphere. The mixture was stirred at reflux for 16 hours, then allowed to cool to room temperature, and washed with 8% aqueous sodium hydrogen phosphate solution. The organic layer was separated, dried with magnesium sulphate, and evaporated under reduced pressure to give the title compound as a gum, nmr (CDCI3) 8 0.17 (s, 12H), 0.78 (s, 4H), 3.38 + 3.82 (ABq, J = 18Hz, 2H), 25 4.76 (d, J = 4Hz, 1H), 4.93 (d, J = 4Hz, 1H), 5.28 (s, 2H), 7.3-8.1 (m, 4H).

EXAMPLE 17

p-Nitrobenzyi 3-chloro-7-(2,2,5,5-tetramethyl- 1-aza-2,5-disilacyclopent- 1-yi)-3-cephem-4-carboxylate la-oxide.

30 36% Peracetic acid (2.25 ml) was added dropwise to a rapidly stirred mixture of saturated aqueous sodium bicarbonate (60 ml) and a solution ofp-nitrobenzyl 3-chloro-7-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)-3-cephem-4-carboxylate (6.57 g) in methylene chloride (30 ml) at 0-5°C. The mixture was stirred for 30 minutes at 0-5°C and then the organic layer was separated, washed with water, dried with magnesium sulphate, and evaporated to give the title compound as a yellowfoam, nmr (CDCI3) 8 0.15 (s, 6H), 0.24 (s, 6H), 35 0.80 (s, 4H), 3.56 + 4.22 (ABq, J = 18Hz, 2H), 4.43 (d, J = 4Hz, 1H), 5.10 (d, J = 4Hz, 1H), 5.30 (s, 3H), 7.3-8.1 (m, 4H).

EXAMPLE 18

p-Nitrobenzyl 3-chioro-7-(phenoxyacetamido)-3-cephem-4-carboxylate 1a-oxide.

40 Phenoxyacetyl chloride (0.81 ml) was added to a stirred solution ofp-nitrobenzyl 3-chloro-7-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)-3-cephem-4-carboxylate 1a-oxide (2.80 g) in tetrahydrofuran (85 ml) at room temperature. The mixture was stirred for one hour at room temperature, washed with saturated aqueous sodium bicarbonate and then water, dried with magnesium sulphate, and evaporated under reduced pressure to give a gum which was crystallised from isopropanol. The product was islolated by 45 filtration, washed with isopropanol and then dried in vacuo to give the title compound as white crystals, nmr (CDCI3) 8 3.75 + 4.45 (ABq, J = 18Z, 2H), 4.5 (s, 2H), 4.74 (d, J = 4Hz, 1H), 5.52 (dd, J = 4 and 8Hz, 1H), 6.6-8.2 (m, 10H).

EXAMPLE 19

50 2,2,2-Trichloroethyl 7-(phenoxyacetamido)desacetoxycephalosporanate 1 a-oxide.

A solution of phenoxyacetyl chloride (0.15 ml) and 2,2,2-trichloroethyl 7-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)desacetoxycephalosoporanate 1a-oxide (0.5 g) in tetrahydrofuran (15 ml) was stirred for one hour at room temperature, washed with saturated aqueous sodium hydrogen carbonate and then water, dried with magnesium sulphate and evaporated to give an oil which was crystallised from di-isopropyl ether 55 to give the title compound as white crystals, nmr (CDCI3) 8 2.26 (s, 3H), 3.36 + 4.01 (ABq, J = 18Hz, 2H), 4.3-4.5 (m, 3H), 4.78 (s, 2H), 5.25 (dd, J = 4 and 8Hz, 1H), 6.4-7.3 (m, 5H), 7.60 (d, J = 8Hz, 1H).

10

5

10

15

20

25

30

35

40

45

50

55

11

GB 2 125 807 A

11

Claims (1)

1. A process for preparing a sulphoxide of the formula

10

(I)

15

in which R1, R2, R3 and R4 are the same or different and are alkyl, alkoxy or aryl, X is alkylene, R5 is a carboxylic acid protecting group and Y is a linking group through one or two carbon atoms forming a penam or cephem nucleus, which comprises, reacting a compound of formula

20

25

/4 i r R4

T-^

10

15

20

25

Ay

JoOR5

(II)

30 with an oxidising agent. 30

2. A process according to claim 1 in which the oxidising agent is a peracid and the oxidation is carried out in the presence of a base.

3. An a-sulphoxide compound of the formula

35

40

45

35

40

45

in which R1, R2, R3, R4 are the same or different and are alkyl, alkoxy or aryl, X is alkylene, R5 is a carboxylic acid protecting group and Y is a linking group through one ortwo carbon atoms forming a penam or cephem nucleus.

4. A compound according to claim 3 in which the group Y is of the formula 50 v 50

j>c(ch3)ch2r6

where R6 is hydrogen, chlorine or

55 R7 55

I

-ch2c=

where R2 is ci, -ch2ci or -ch2ococh3.

60 5. A compound according to either of claims 3 and 4 in which the group X is of the formula —(ch2)2—. 60 6. A compound according to any of claims 3 to 5 in which R1, R2, R3and R4are Ci_4 alkyl.

12

GB 2 125 807 A

12

7. A compound of the formula

10

10

^ us in which R1, R2, R3, R4 are the same or different and are alkyl, alkoxy or aryl, X is alkylene, R5 is a carboxylic acid protecting group and Y is a linking group through one ortwo carbon atoms forming a penam or cephem nucleus, with the proviso that when R1, R2, R3and R4are all methyl, X is —(CH2)2— and R5is methyl, Y is not 15 yClCHslz. 15

8. A process for producing a compound of the formula

H-S

20

/SX

n \

£OCR5 •

25 in which R5 and Y have the values defined in claim 1 which comprises reacting a compound of formula

30

j_T

35

it)OR5

40

where R1, R2, R3, R4and X have the values defined in claim 1, with acid. 9. A process for producing a compound of formula

RsCONH

\ /av\

I I T

45 i00R5

in which R8, together with the associated carbonyl group is a carboxylic acid derived acyl group, and R5 and Y have the values defined in claim 1, which comprises reacting a compound of formula

50

55

;sr -

ts/ X* I '

V

Y

f boons where R1, R2, R3, R4 and X have the values defined in claim 1, with an acylating agent of formula R8COZ 60 where Z is halogen, followed by treatment with water or an alcohol.

10. An antibiotic cephalosporin or penicillin compound prepared by a process according to claim 8 or 9 or prepared from a novel intermediate according to claim 3 or 7.

11. A process according to claim 1 substantially as described in any of the Examples.

20

25

30

35

40

45

50

55

60

13

GB 2 125 807 A

13

12. A compound according to claim 3 substantially as described in any of the Examples.

13. A compound according to claim 7 substantially as described in any of the Examples.

Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon, Surrey, 1984 Published by The Patent Office, 25 Southampton Buildings, London, WC2A 1AY, from which copies may be obtained.