DE2911099A1 - PROCESS FOR MANUFACTURING BETA LACTAM ANTIBIOTICS - Google Patents

Description

Antib. 57

GLAXO GROUP LIMIIED, LOIiDOIT W1T 8DH

Process for the production of ß-Laetam antibiotics

The invention relates to a process for the preparation of ß-Laetarc antibiotics "In particular, it relates to a process for Hero division you azido derivatives of clavulanic acid.

In DE-OS 27 25 203, among other things, azido derivatives of clavulanic acid are of formula I.

^CH 2 ^N 3

(D

(in which R is a carboxyl or esterified carboxyl group and in the case that R is a carboxyl group, the salts thereof) and their preparation. The compounds of formula I are useful both as antibiotics and as β-lactamase inhibitors and they are also useful as intermediates in the preparation of compounds of formula I wherein the azido group -H ^ is converted into an amino group -KH ₂ or a triazole ring is converted.

909840/0592

The compounds in this description are below Reference to "Clavam" denotes; this designation becomes for the parent heterocycle of the formula a

(A)

used by analogy with the expression "öephata", which is used in the Designation of cephalosporin compounds in J. Amer. Chetn. So-called." 1962, £ 8, 3400 is used. Such is the connection of formula I the (3R, 5R, Z) -2- (2-azidoethylidene) clavam-3-carboxylic acid or an ester or salt thereof.

There has now been a method of making the compounds of the formula I developed, the generally improved yields of produTciTfvergTiohen tait those which when applied can be achieved by two-step processes, for example those which are obtained in the above-mentioned DE-OS. Furthermore, the process found is generally easier and more economical to carry out because it is a one-step process is. It / should be emphasized that it is often difficult to obtain good yields in reactions using clavulanic acid derivatives to obtain. A number of ejections Both one-step and two-step, for the replacement of a hydroxyl group by an azido group, have been used in general chemical literature described and apart from those which are described in the mentioned DE-OS, these have which have been investigated in relation to clavulanic acid derivatives, result in little or no of the desired product of formula I.

909840/0692

According to the invention a method for producing a Compound of formula I created, which consists in an ester of clavulanic acid of formula II

(II)

wherein R is an esterified carboxyl group having a source of aside ions, a trivalent phosphorus reagent and a Azidodicaz ^ boiiylverbindungen to implement, the trivalent Phosphorus reagent has the formula PR R R ^, where R, R and R, which can be the same or different, alkyl groups preferably having 1 to 6 carbon atoms, such as methyl, Ethyl, η-butyl and tert-butyl groups or aryl groups are preferred monocyclic aryl groups such as phenyl or tolyl groups represent and that if a compound of the formula I is desired in which R is a carboxyl group, performs a de-esterification and, if desired, forms a salt.

It should be noted that such alkyl or aryl groups can be attached to a polymer or part of a polymer bJLden. Examples of such polymers include polystyrene or polystyrene crosslinked with divinylbenzene such as von Heitz et al, Angew. Chemistry Internat. Issue yy_, 298 (1972) described in which the phenyl groups carry diarylphosphinyl groups. Such polymers are desirable used in the form of pearls or spheres or other inert forms.

A number of phosphorus reagents including trialkyl phosphites and hexaalkyl phosphorus thiamides have been investigated

9 OS 8 4 O / O ^r '

and it has been found that using particularly good yields of trivalent phosphorus reagents in which the phosphorus atom is substituted by aryl and / or alkyl groups, are obtained »

Examples of such tertiary phosphines include iriethylphosphine, Eri-n-buty! Phosphine, iriphenylphosphine, tritolylphosphine and iri ~ p ~ methoxyphenylphosphine.

Eriar3 ^r lphospines are generally preferred and sriphenylphosphine is a particularly useful phosphine reagent. In some cases, yields of 65 % and higher were obtained and this represents a considerable improvement over other reactions investigated.

The azoicarbonyl compound can, for example, ^{correspond to the formula 11 "5} COlTNCOR, where R · ³ and R, which can be the same or different from one another, denote hydrocarbyl or hydrocarbon or hydrocarbyloxy or hydrocarbonoxy groups, such as C, g ~ alkyl (e.g. methyl, Ethyl, propyl, or butyl), Cj_g-alkoxy (e.g. methoxy or ethoxy), aralkyl (e.g. benzyl), aralkoxy (e.g. benzyloxy), aryl (e.g. phenyl) or aryloxy (e.g. phenoxy) groups Azodicarbonyl compounds can either be in the cis or trans configuration or a mixture of both. Appropriate reagents are di- (C _1. ) - alkyl azodicarboxylates such as diethyl azodicarboxylate, and particularly advantageously azodiaroyls such as azodibenzoyl, ie R 1 and R are phenyl groups a preferred reagent.

The source of the azide ions is preferably hydrazoic acid with regard to their solubility in organic solvents. As the azide reagent in a nucleophilic exchange reaction occurs for the formation of the desired product, the reaction medium is preferably free of other uucleophiles. 909840/0892

In general, hydrazoic acid, that trivalent phosphorus reagent, the azodicarbonyl compound and the olavulanic acid ester in roughly the same stoichiometric proportions used »It is generally preferred to add the azodicarbonyl compound as the last component.

When the group R represents an esterified carboxyl group, so it can be represented as a group -COOR, where R ^ means an organic group which is "appropriate from an alcohol." (aliphatic! or araliphatic!), a phenol or a Stanna.no! originates. One such for the esterification of the Carboxyl group used alcohol, phenol or stannanol contains preferably no more than 24 carbon atoms.

The group R ^ can be a straight or branched unsufstituted one or substituted alkyl or alkenyl group, preferably with 1 to 8 carbon atoms, for example a methyl, Ethyl, propyl-isopropyl, butyl, sec-butyl, tert-butyl ether

Mean allyl group, where any existing with-- '
(Play mode alkoxy, for example methoxy; halogen, for example fluorine, chlorine, ■ bromine or iodine; cyano; acyloxy, for example alkanoyloxy such as acetoxy or pivaloyloxy or alkoxycarbonyloxy, for example ethoxycarbonyloxy; acyl, for example p-bromobenzoyl and alkoxycarbonyl, for example ethoxyearbonyl;

an aralkyl group with up to 20 carbon atoms, especially an arylmethyl group, for example a benzyl or substituted benzyl group, suitable substituents being halogen, for example chlorine, Hltro, for example o- or p-Nltro, cyano, alkoxy, for example p-methoxy or alkyl, for example p-methyl groups, a Diphenylmethyl or triphenylmethyl group or an i ¹ ur-2-yl-methyl, thien-2-yl-methyl or pyrid-4-yl-methyl group, where their heterocyclic groups can also be substituted, for example by a Cj -alkyl group, preferably Methyl;

an aryl groupFrols to 12 carbon atoms e.g. a phenyl or substituted phenyl group, with suitable substituents

909 8 40/069?

Halogen eg chlorine _s Mi tr ο eg o ~ or p-nitro, cyano, alkoxy eg p- ~ methoxy or alkyl eg p ~ methyl groups are a cycloalkyl group with not more than 12 carbon atoms, eg cyclopentyl, cyclohexyl and adamantyl; a heterocyclic group having not more than 12 carbon atoms, the heteroatom "being, for example, oxygen, as in the tetrahydropyranyl" or Phthaiidy group; a stannyl group with up to 24 carbon atoms, for example a stannyl group with 3 substituents, which can be identical or different, selected from alkyl · ·, alkenyl, aryl, araikyl, cycloalkyl, alkoxy, aryloxy or arallcoxy groups. Such groups include methyl, ethyl, propyl, η-butyl, phenyl and benayl groups *

The group R ^ will preferably be an arylmethyl group such as a benzyl, or an o- or p-Fitrobenaylgruppe or a methoxyraethy! group. A p-hydrobenzyl group is special suitable.

The reaction is preferably carried out in an inert organic solvent. Close suitable solvents an ether such as diethyl ether or ^ tetrahydrofuran, ester such as ethyl acetate, chlorinated hydrocarbons such as dichloromethane, amides such as dimethylformamide or mixtures thereof, tetrahydrofuran and dichloromethane are preferred solvents; tetrahydrofuran is desirably in substantially anhydrous form used. It may be useful to add the hydrazoic acid in solution, for example in a hydrocarbon solvent such as benzene.

If desired, the source of the azide ions can be produced in solution by mixing a tri-substituted silylazide with a cationic exchange resin, e.g. in the form of a column is brought into contact. The part of this method is that it is less dangerous than the release of nitrogen

909840/0692

hydrofluoric acid from its salts using mineral acids. A suitable resin is Amberlyst 15. Tri-lower alkylsilyl azides are preferred, suitably in a dry inert organic solvent of the above for the hydrocyclic exchange reaction "described syps.

The resection is advantageously "at or below ambient temperature carried out, for example, from -80 C to +20 C, wherein a iDemperatur from -60 ⁰ G bevorzugest to -30 ⁰ C. It is desirable to conduct the reaction under an inert atmosphere such as nitrogen atmosphere to carry out.

In the above reaction, the starting product is an ester, and if the corresponding acid or salt is desired, the compound can be subjected to de-esterification as described in J) E-OS mentioned above. For this purpose readily cleavable esters are beispeilsweise Arylmethylester as p ~! _F Titrobenzylester by. Reduction, for example hydrogenolysis, can be cleaved, preferably. Alternatively, a stannyl ester can be cleaved by a very mild solvolysis.

If the reductive cleavage in the deesterification reaction of a Esters of the formula I is used, the azido group may tend to be reduced to an amino group at the same time to ground to give the corresponding amine antibiotic.

However, careful use of selective methods enables the acidic acid of Formula I to be prepared

It should be mentioned that the acid of the formula I, if desired can be re-esterified to introduce an ester group different from that originally obtained in the Azido ester product was present is different.

909840/0 π?

The invention is explained in more detail below with reference to the examples, without restricting them. In the examples, all temperatures are given in centigrades.

A solution of hydrazoic acid in benzene (11.8 ml, 1.27 mol) was added to a stirred solution of 50 g of 4-nitrobenzyl- (3R, 5 [beta], Z) -2- (2-hydroethylidene) -clavam-3 ~ carboxylate and 3j 93 g of triphenylphosphine in 75 ml of dry Di chlorine than ge ™ s give the cooled atmosphere to --5O ⁰ C under nitrogen. Then 2.35 ml of diethylazodicarboxylate was added dropwise to the stirred mixture, the temperature rising to -35 ° C. The mixture was stirred for an additional 45 Hinuten at -5o ⁰ C and then partitioned between 200 ml ethyl acetate and 150 ml aqueous Uatriumbicarbonatlösung. The organic phase was separated off, washed with more aqueous sodium bicarbonate solution (100 ml), dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using ethyl acetate: petroleum ether (1: 1) as the eluent and yielded 2.54 g of product, the spectral properties of which are similar to those of Example 1 of DE-OS 27 25 203.

Example 2

Benzyl (3R <5R, 7, ) -2- (2-azidoethylidene ) clavam-3-carboxylate

A solution of hydrazoic acid in benzene (1.27 mol, 15.7 ml) was added to a solution of 5.78 g of (3R, 5R, Z) -2- (2-hydroxyethylidene) clavam-3-carboxylate and 5, 24 g triphenylphosphine in 100 ml dry dichloromethane, which was ^{cooled to -50 0} C under nitrogen atmosphere, given. Then the

9 0 9 8 40/0 6 S 2

rüLrten mixture added 3.14 ml of diethylazodicarboxylate, wherein the 'ieiapercatur rose to -37 ⁰ C. The mixture was stirred 'at -5o ⁰ C for one hour and. Then partitioned between 200 ml ethyl acetate and 100 ral saturated Natriurabicarbonatlösung The organic phase was washed with 100 ml of saturated LTA triumbicarbonatlösung washed, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using ethyl acetate; petroleum ether (1: 1) as elution agent and gave 3.1 g of the title compound,

spectroscopic properties to those in Example 8 of FIG DE-OS 27 25 203 were the same.

Example 3

A solution of 0.86 g of sriphenylphosphine and 1.10 g of 4-nitrobenesyl (3Bj5B, Z) -2 "(2-hydroxyethyl) clavara-3-carboxylate in 20 ml of dry dichloromethane was under a nitrogen atmosphere cooled to -50 C. To the stirred mixture was added a solution of hydrazoic acid in benzene (0.67 mol ₅ 5.0 ml) and then a solution of 0.78 g of azodibenzoyl in 5 ml of dichloromethane, the mixture was stirred at -4O ⁰ O under a nitrogen atmosphere while Stirred for 30 minutes. The mixture was then filtered and partitioned between 100 ml of ityl acetate and 50 ml of saturated sodium bicarbonate solution. The organic layer was separated, washed with 50 ml of aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using ethyl acetate: petroleum ether (1: 1) as the eluent and gave 0.79 g of the vanity compound whose spectroscopic properties were similar to those given in Example 1 of DE-OS 27 25 203.

909840/0592

_? Z ) _- 2- (2 ~ aziaoäthyli den ._) - clavam-jf-

A solution of hydrazoic acid in benzene (0.75 mol, 4J9 ml) was added to a stirred solution of 1 ₅ 00 g of 4- ~ Hitroben ~ cyl ~ (5R> 5R} Z) ~ 2- (2-hydroxyethylidene) -clavain ~ 3 ~ car'boxylat and, 0.94 g iPriphenylphosphin in 15 ml of dry dichloromethane and the mixture under a nitrogen atmosphere cooled to "50 ⁰ g. Then, 0.57 ml of diethylazodicarboxylate were added to the mixture and stirring at -40 ⁰ C. continued to -50 ⁰ C during v / Eiterer 45 minutes. The reaction mixture was then diluted with 15 ml dichloromethane and washed with 25 ial brine 'and twice 25 ml of saturated ITatriumbicarbonatlösung. The organic solution was concentrated dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using ethyl acetate: petroleum ether (1: 1) as the eluant to give 0.85 g of the title .
rearers, whose spectroscopic properties were similar to those in Example 1 of DE-OS 27 25 203.

Example 5

4-ΜΊtrobenzyl- (5R.5R, Z ) -2- (2-asidoethylidene) -clav am-5- carboxy-

A solution of 7.85 g of iriphenylphosphine and 10.0 g of 4-Mtrobenzyl- (3R, 5R »Z) -2- (2-hydroxyethylidene) clavam-3-carboxylate in 2.00 ml of dry dichloromethane was under a nitrogen atmosphere -50 ° C cooled. A solution of hydrazoic acid in benzene (39 ml »0.77 η Y was added to the stirred mixture and then a solution of 7.14 g azodibenzoyl in 40 ml of dichloromethane and the mixture was stirred for another 15 minutes at -40 ⁰ C. The mixture was filtered and the piltrate partitioned between 400 ml of ethyl acetate and 200 ml of saturated sodium bicarbonate solution, and the organic phase became

909840/059?

dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate: petroleum ether (1: 1) as the eluent and yielded 6.45 g Product whose spectroscopic properties were similar to those of Example 1 of DE-OS 27 25 203.

Bg isrpi ο J _% 6

4-Hi tr ob en vrg 1 - (3P _? 5R? Z ) ■ -2 ^ - (ag i fl ο äthyIi d en) -c lay arn ^ 3- car ^ b oxyla t _u

0.40 g trimethylsilyl azide was passed through a column of Amber-Iyst 15 ¹ ^ (5.0 g BDH Chemicals limited)

using i \ lu.iainiumo5: id ~ getroclnietera dichloromethane as eluant and the eluate (20 ml) to a mixture of 1.0 g

5R ₅ Z) -2- (2-h3 "drosyäthyliden) -clavam ~ 3-carbo? Cy ·

lat and 0.68 g of triphenylphosphine added. The resulting solution vairde under nitrogen to -50 ⁰ C cooled. A solution of 0.571 g of azodibensoyl in dichloroethane was added to the stirred mixture. To. The mixture was stirred for 10 minutes and the piltrate was partitioned between 100 ml of ethyl acetate and 50 ml of aqueous sodium bicarbonate solution. The aqueous phase was dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate: petroleum ether ( 1: 2) and gave 0.44 g of product, the spectroscopic properties of which were similar to those given in Example 1 of DE-OS 27 25 203. ^ Araberlyst 15 is a strongly acidic macroreticular cation exchange resin based on styrene / benzene copolymers with sulfone

acidic rut) Oen.

Ex iel; 7th

4-Ni trobenzyl (3R _< 5R, Z) -2- (2-azidoethylidene) clava with 3-carbo xylate

A solution of hydrazoic acid in benzene (2.4 ml, 1.25 mol) became a solution of 0.74 ml of tri-n-buty! Phosphine and 1.0 g of 4-nitrobenzyl (3R, 5R, Z) -2- (2-hydroxyethylidene) clavam-3-carboxylate given in 15 ml of dry dichloromethane and

9 03 8 40 / OR 92

the mixture was cooled to ~ 50 ° C under a nitrogen atmosphere. 0.47 ral Diätlrylasodicarboxylat were added to the mixture and stirring continued at -50 ⁰ G for another 15 minutes. The mixture was diluted with 50 ml of ethyl acetate and washed twice with 25 ral aqueous sodium bicarbonate solution. The organic solution was dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate petroleum ether (1: 1) as the eluent and gave a product whose spectroscopic properties were similar to those given in Example 1 of DE-OS 27 25 203.

A solution of hydrazoic acid in benzene (15 ml, 1.0 N) became a solution of 3 * 94 g triphenylphosphine and 5.0 g 4-hydrobenzyl (3R, 5R, Z) ~ 2 »(2 ~ hydroxyethylidene) ~ cla ~ VAM-3-carboxylate in 100 ml of dried over alumina [tetrahydrofuran, and the mixture under a nitrogen atmosphere to -45 ⁰ C cooled. A solution of 2.6 ml of diethyl azodicarboxylate in 10 ml of tetrahydrofuran dried over alumina was added dropwise to the stirred mixture. For 15 minutes, another aliquot of hydrazoic acid solution (5 ml of a 1.0 η solution in benzene) and then 0.5 ml of diethyl azodicarbozylate were added to the mixture at -45 ° C. and stirring continued for an additional 30 minutes. The reaction mixture was allowed to warm to room temperature and then purged with nitrogen for 15 minutes. The solution was concentrated in vacuo and the residue passed through a column of silica gel using ethyl acetate: passed as eluent to give 4> 2 ütelverbindung whose spectroscopic properties g those?: Etroläther (boiling range 40 to 60 ⁰ C) (1: 1) in Example 1 of DE-OS 27 ψ _n % X5 , indicated.

Claims (1)

Dr. F. ZLirnstein r; en. - Dr. Ξ. Ass.; Irtfctnn - Df ^r> . Koenigsbsrger Dipi.-Phys. R. Hoizbauer - i.; Ipf .- {ng. r ·. Ktingseisen - Dr. F. Zumstein yurt. PATENT LAWYERS Münchi Γι 2 ■ Br-iu '"iauii size 4 - Telephone collective no. 22 53 41 · Telegrams Zumpat - Telex 529979 Antib. 57
10 / Y / e Claims 1. / Process for the preparation of a compound of the formula I. CH ₂ N ₃ v / orin R is a carboxyl or esterified carboxyl group and the meaning of R = Palle a carboxyl group, of their SaI e ^ ^- Ii ₅ characterized in that an ester of clavulanic acid of formula II! / CH ₂ OH before R is an esterified carboxyl group, reacted with a source of azide ions, a trivalent phosphorus reagent and an azodicarbonyl compound, the trivalent phosphorus reagent having the formula PR ¹ R ² R ⁵ , wherein R ¹ , R ² and R ⁵ , which may be the same or different, each denote an alkyl or aryl group and that, if a compound of formula I is desired in which R denotes a carboxyl group, a deesterification is carried out and, if appropriate, a salt is formed. 909840/0692 2311099 2. The method according to claim 1, characterized in that R, R and R ^ are selected from alkyl groups with 1 to 6 Ko fuel atoms or monocyclic aryl groups. 3. The method according to claim 1 or 2, characterized in that 1 ? 3 that R, R "and R are selected from Vk tert-butyl, phenyl or lolyl groups. "IP that R, R and R are selected from methyl, ethyl », n ~ butyl, 4. The method according to any one of claims 1 to 3, characterized in, that the trivalent phosphorus reagent is triphenylphosphine. 5. The method any one of claims 1 to 4, characterized in that the Azodicarbonylverbindung the! R has the formula ⁵ according to COMCOR, wherein R ⁵ and R ^6, which may be identical or different, Cj_ ~ ₈ alkyl, Cj ^ g alkoxy -, aralkyl, aralkoxy, aryl or aryloxy groups. 6. The method according to claim 5, characterized in that R- ⁵ and R are C., alkoxy groups or aryl groups. 7. The method according to claim 5 or 6, characterized in that the azodicarbonyl compound is azodibenzoyl or diethyl azodicarboxylate is. 8. The method according to any one of claims 1 to 7, characterized in that that the source of the azide ions is hydrazoic acid. 9. The method according to any one of claims 1 to 8, characterized in, that if R denotes an esterified carboxyl group, this is a group -COOR ^, where R ^ is a straight-chain or branched, substituted or unsubstituted alkyl group with 1 to 8 carbon atoms, an aralkyl group with up to 20 carbon atoms, an aryl group with up to 12 carbon atoms 909840 / OB32 lenstoffatomen, a cycloalkyl group with up to 12 carbon. substance atoms, a heterocyclic group with up to 12 carbon atoms or represents a stannyl group of up to 24 carbon atoms. 10. The method according to claim 9, characterized in that R ^ represents a benzyl or o- or p-l-nitrobenzyl group. 11. The method according to claim 9fdädurch, that R ^ is a p-nitrobensyl group. 12. The method according to any one of claims 1 to 11, characterized in, that the reaction is carried out in an ether, ester, chlorinated hydrocarbon or amide solvent or a mixture is effected by it. 15. The method according to claim 12, characterized in that iteatction in essentially anhydrous tetrahydrofuran is carried out. 14. The method according to claim 12, characterized in that the reaction is carried out in dichloromethane. 15. The method according to any one of claims 1 to 14, characterized in that the reaction from -60 ⁰ C to -30 ⁰ C is carried out. 16. The method according to any one of claims 1 to 15, characterized in that that the reaction is carried out in an inert atmosphere. 17. The method according to any one of the preceding claims, characterized in that one of the alkyl or aryl groups of the trivalent -Phosphorus reagent is bound to or forms part of a polymer. 9 jj ο ρ 4 Π / ^! " ^Γ * 5? 18. The method according to claim 1, as essentially described herein. 19 «Method according to claim 1, as described here, with reference to the examples« 20. Compound of formula I prepared by a process according to any one of claims 1 to 19. 9098-0 / 0 ¹ ""?