NZ209684A

NZ209684A - Preparation of optically uniform azetidinones

Info

Publication number: NZ209684A
Application number: NZ209684A
Authority: NZ
Inventors: G Schmid
Original assignee: Hoffmann La Roche
Priority date: 1983-10-03
Filing date: 1984-09-26
Publication date: 1987-08-31
Also published as: IL73089A; DK411384D0; JPS6092263A; CN85100624A; PH19418A; ATE33830T1; CA1251455A; EP0138113A1; IL73089A0; AU572194B2; DK411384A; EP0138113B1; KR850003392A; AU3370584A; DE3470736D1; ZA847585B

Abstract

1. A process for the manufacture of optically uniform azetidinones of the general formula see diagramm : EP0138113,P5,F1 wherein R signifies benzyl, beta-(trimethylsilyl)-lower alkyl or beta-halo-lower alkyl, R**1 signifies a readily cleavable protecting group from the group consisting of benzyl, 2,4- or 3,4-di(lower alkoxy)benzyl, di[4-(lower alkoxy)phenyl]methyl, 4-(lower alkoxy)phenyl, lower 2-alkenyl and the group of the formula -CH2 -CH(OR**5)2 (a) or see diagramm : EP0138113,P5,F2 in which R**5 signifies lower alkyl and n signifies the number 0 or 1, R**2 signifies lower alkyl, phenyl-lower alkyl or lower alkoxyalkyl and R**3 signifies lower alkyl or phenyl-lower alkyl or R**2 and R**3 together with the centre of chirality and the oxygen atom signify a 5 or 6-membered 0-heterocycle which optionally contains a further oxygen atom not directly linked with the centre of chirality and which is optionally substituted by lower alkyl, lower alkoxy, oxo or spirocyclo-lower alkyl, and the residues denoted by lower have up to eight carbon atoms, characterized by reacting an alkali metal salt of a carboxylic acid of the general formula ROCONHCH2 COOH wherein R has the above significance, with an optically uniform compound of the general formula see diagramm : EP0138113,P6,F3 wherein R**1, R**2 and R**3 have the above significance, in the presence of a base and a sulphonic acid chloride of the general formula R**4-SO2 -Cl wherein R**4 signifies phenyl, lower alkylphenyl, halophenyl, lower alkyl or halo-lower alkyl, whereby the reaction is carried out in an anhydrous inert organic solvent at a temperature in the range of about -30 degrees C to about 50 degrees C.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £09684 f , \ / No.: Date: NfLDRAttfoski 2?09684 ..V'iPto Sncc.r.cition Filed: c;, .C0.10^05|08.v ^10^00(01 Publication Da::: ?. 1 »**) NEW ZEALAND PATENTS ACT. 1953 COMPLETE SPECIFICATION PROCESS FOR THE MANUFACTURE OF OPTICALLY UNIFORM AZETIDINONES ¥/We. F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT, 124-184 Grenzacherstrasse, Basle, Switzerland, a Swiss company, hereby declare the invention for which we pray that a patent may be granted to oaatVus, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by la) 2096#4, - la - RAN 4410/17-0- 5 The known 3, 4-cis-3-acylamino-azetidinones are valuable intermediates for the production of antimicro-bially active 3-lactam antibiotics. Their manufacture is usually carried out by the cycloaddition of phthaliraido-or azidoacetyl chloride with a corresponding N-protected imine (e.g. benzaldehyde (2.4-dimethoxybenzyl)imine) in the presence of a base, whereafter the phthalimide or azide group in the 1-protected N-(2-oxo-3-azetidinyl)-15 phthalinide or -azide obtained is converted into the amino group (the phthalimide group by reaction with hydrazine, methylhydrazine or dimethylaminopropanamine. the azide group by reduction with ammonium sulphide or with elementary hydrogen and a catalyst such as palladium/carbon). 20 and the liberated amino group is protected by reaction with an acyl chloride, e.g. carbobenzoxy chloride, for reasons of the further processing. The direct cycloaddition of N-carbobenzoxyglycine 25 chloride with a N-protected imine gives, however, only low yields of the desired azetidinone; see J. Chem. Soc.. 1880 (1975). N-Carbobenzoxyglycine chloride itself is an unstable compound which decomposes to unusable byproducts even at low temperatures. This direct cycloaddition has 30 thus been regarded as being impracticable; see Tetrahedron 37. 2321 (1980). It has now surprisingly been found that a direct cycloaddition with good yields is achieved when a N-carbo-35 benzoxyglycine alkali metal salt is used in place of N-car- ■Nt/l7.7-»G4 - 2 - boben2oxyglycine chloride and the cycloaddition with the N-protected imine undertaken in the presence oC a base is carried out under the additional influence of a specific 5 sulphonic acid chloride, especially of p-chlorobenzenesul-phonyl chloride. By choosing a N-protected imine with suitable substitution (see formula III hereinafter) two new optical 10 centres are induced in the cycloaddition product (azetidinone). whereby the substituents in the 3- and 4-position are in cis-relationship and. further; only one of the two possible diastereomeric products is formed with high diastereoselectivity. The present novel synthesis therefore 15 leads to optically uniform process products, as will be evident from the following. The present invention is concerned, in particular, with a process for the manufacture of optically uniform azeti-20 dinones of the general formula 30 35 wherein R signifies ben2yl. fl-(trimethyl-silyl)-lower alkyl or fl-halo-lower alkyl, R1 signifies a readily cleavable protecting group. R signifies a lower, optionally oxygen-containing. hydrocarbon group linked via 3 a carbon atom and R signifies a lower hydrocarbon group linked via a carbon atom. or 2 3 R ana R together with the carbon aton and the oxygen aton to which they are attached represent a 5- or 6-menbered O-hetero-cycle which optionally contains a further oxygen, atom not directly linked with the centre of chirality and which can be optionally substituted by lcwer alkyl, lower alkcxv, cxo or spirccyclo-lower alkyl, - 3 - 2 096 84 -is 5 10 30 which process comprises reacting an alkali metal salt of a carboxylic acid of the general formula roconhch2cooh 11 wherein R has the above significance. with an optically uniform compound of the general formula III 15 12 3 wherein R . R and R have the above significance. 20 in the presence of a base and a sulphonic acid chloride of the general formula R4-S02-C1 IV 25 wherein R4 signifies phenyl, lower alkyl- phenyl. halophenyl. lower alkyl or halo-lower alkyl. In the above process products of formula I the following come into consideration, for example, as readily cleavable protecting groups R1: benzyl. 2.4- or 3,4-di- (lower alkoxy)benzyl, especially 2,4- or 3,4-dimethoxy-benzyl, di[4-(lower alkoxy)phenyl]raethyl, especially di-(4-methoxyphenyl)methyl, or 4-(lower alkoxy)phenyl, espec-ially 4-methoxyphenyl; further, lower 2-alkenyl or a group of the formula ~ ^ • "v-v-v.;. \ ... 2"? i34 - 4 - -CH2-CH(OR5)2 (a) or 10 7rO fol_ CH2CH2 a -J (b) ,5 15 20 wherein S signifies lower alkyl and n signifies the number O or 1. The tern "readily cleavable protecting group" is to be interpreted in the widest sense, and thus also includes groups which are not directly cleavable per se. but which can be converted into a directly cleavable protecting group by a simple chemical transformation. Thus. e.g. the following groups R*" are converted prior to the cleavage into the cleavable groups given afterwards: lower 2-alkenyl lower 1-alkenyl -CH2-CH(OR5)2 ►-CH2-CHO-»-CO-CH(OH) 2 —CH2CH2—s -o- —CH2CH2—S—^ -CH*CH2 -> —CHO The transformation and cleavage of these groups are illustrated in more detail in New Zealand Patent Specification "No. 205 246. 25 35 The term "lower hydrocarbon" denotes a hydrocarbon group which can be straight-chain or branched, and which contains up to 8, especially up to 4, carbon a tans. The term "lower 2-alXenyl" denotes an oleEinic hydro-carbon group which can be straight-chain or branched, which has a double bond in the 2-position and which J* if- ifcjUNWtf t 2<»r i 1,1 - 5 - contains up to 8. especially- up to 4, carbon atoms such as e.g. 2-pcopenyl (allyl), 2-methallyl. 2-5 butenyl. 2-hexenyl, 2-heptenyl, 2-octenyl etc. The term "lower alKyl" denotes a saturated hydrocarbon group which can be straight-chain or branched and which contains up to 8, especially up to 4. carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl. iso-10 butyl, sec-butyl, t-butyl. n-pentyl. isopentyl. n-hexyl, n-heptyl, n-octyl etc. The term "lower alkoxy" denotes a lower alkyl group linked via an oxygen atom. Preferred groups R1 are: 2-propenyl (allyl). 2,2-di-15 methoxyethyl. 2.2-diethoxyethyl. 2-phenylthioethyl, 2-phenylsulphinylethyl. 2,4- or 3,4-dimethoxybenzyl and benzyl. Allyl. benzyl and 2.4-dimethoxybenzyl are the most preferred groups denoted by Bl. R3° 2 20 Preferred groups \ , H ? are those in which R y- R signifies lower alkyl. phenyl-lower alkyl. lower alkoxy-alkyl. e.g. lower alkoxymethyl. and R3 signifies lower r3o 25 alkyl or phenyl-lower alkyl. The groups v H V— R2 can also represent a 5- or 6-membered O-heterocycle which optionally contains a further oxygen atom not directly linked with the centre of chirality and which can be 30 optionally substituted by lower alkyl, lower alkoxy. oxo or spirocyclo-lower alkyl. Examples of such groups, which are likewise preferred, are: 209684 - 6 - 10 20 25 30 35 rv >—CH2-O H X-J is especially preferred. The group 9 [(R)-2.2-dimethyl-l,3-dioxolan-4-yl] 15 In the process products of formula I R is preferably benzyl. However, as already mentioned, B can also signify 8-(trimethylsilyl)-lower alkyl. e.g. B-(trimethylsilyl)-ethyl, or B-halo-lower alkyl, e.g. 8-trichloroethyl, B-di-chloroetbyl, B-chloroethyl or fl-trichloroisopropyl. As alkali metal salts of a carboxylic acid of formula II there come into consideration the potassium, sodium and also the lithium salts. The potassium salts are preferred . As the sulphonic acid chloride of formula IV there is preferably used p-chlorobenzenesulphonyl chloride. For the purpose of the present invention there are, however, also suitable p-toluenesulphonyl chloride and methanesul-phonyl chloride. The reaction of the compounds of formulae II, III and IV is carried out in the presence of a base, for example a tertiary amine such as triethylamine. and preferably in an inert organic solvent, especially in anhydrous form, whereby ethers such as tetrahydrofuran. diethyl ether. 2H9.JS4 W 10 - 7 - t-butyl methyl ethec. dioxan. ethylene glycol dimethyl ether or the like, halogenated hydrocarbons such as methylene chloride, chloroform. l.2-dichloroethane or the like, acetonitrile. dimethylforraamide or the like preferably come into consideration. The temperature of the reaction preferably lies in the range of about -30* to about 50°C. The conversion of a compound o£ formula I into an antimicrobially valuable B-lactam antibiotic is described e.g. in New Zealand Patent Specification No 201 660 and in New Zealand Patent Specification No 205 246. The cleavage of is R1 in the significance "benzyl" which is necessary is carried out in the same manner as when R is "2,4- or 3.4-di(lower alkoxyJbenzyl". i.e. oxidatively with the aid of a buffered peroxodisulphate such as potassium peroxodi-sulphate/dipotassium hydrogen sulphate. The benzyl group 20 can. however, also be cleaved off reductively by the action of an alkali metal, e.g. of sodium or lithium, in liquid ammonia. Example 1 25 30 g of anhydrous magnesium sulphate and 17.7 g (71.6 mmol) of N-carbobenzoxyglycine potassium salt are dispersed in 400 ml of methylene chloride. After the addition of 20 ml (143 mmol) of triethylamine the suspension 3° obtained is stirred vigorously at room temperature for 1 1/2 hours and subsequently cooled to 5°C. This suspension is treated vith 10.0 g (35.8 mmol) of isopropylidene-D-glyceraldehyde (2,4-dimethoxybenzyl)imine (prepared from 2,4-diraethoxybenzylamine and isopropylidene-L-glyceralde-35 hyde in 20 ml of methylene chloride). 15.1 g (71.6 mmol) of p-chlorobenzenesulphonyl chloride in 50 ml of methylene </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 209684 - a - chloride are subsequently added dropwise at 5°C within 45 minutes. The suspension is stirred at room temperature 5 for 3 hours and filtered. The filtrate is evaporated, the yellow-brown oil obtained is dissolved in 300 ml of ethyl acetate and washed successively twice with 100 ml of IN aqueous hydrochloric acid, twice with 100 ml of 5% aqueous sodium bicarbonate solution and once with 100 ml of 10 aqueous sodium chloride solution. The organic phase is evaporated and the oily yellow residue is crystallized at 0*C by the addition of 300 ml of ether. There are obtained 10.5 g (62%) of benzyl (3S.4S)-cis-l-(2.4-dimethoxybenzyl )-4-[(R)- 2,2-dimethy1-1,3-dioxolan-4-yl)-2-15 oxo-3-azecidinecarbamate of melting point 113-114°C.;Example 2;When allylamine is used in Examp'le 1 in place of 20 2.4-dimethoxybenzylamine there are obtained in the same manner, after chromatography on silica gel (0.040 to 0.063 mm). 7.05 g (67%) of benzyl (3S,4S)-cis-l-allyl-4-[(E)-2.2-dimethy1-1.3-dioxolan-4-yl)-2-oxo-3-azetidinecarbamate of melting point 94-96*C. 30 35 2"°>34 - 9 - •V'l.-"" fr'Y; is •

1. A process Cor the manufacture of optically uniform azetidinones of the general formula ROCONH wherein R signifies benzyl. 8-(trimethyl-silyl)-lower alkyl or B-halo-lower alkyl. 1 2 R signifies a readily cleavable protecting group, R signifies a lower, optionally oxygen-containing, hydrocarbon group linked via 3 a carbon atcnt and R signifies a lcwer hydrocarbon group linked via 2 3 a carbon atom, or R and R together with the carbon atom and the oxygen atcra to which they are attached represent a 5- or 6-manbered O-hete-rocycle which optionally contains a further oxygen a tan not directly linked with the centre of chirality and which can be optionally substituted by lcwer alkyl, lower alkoxy, oxo or spirocyclo-lower alkyl, the terms lcwer hydrocarbon, lower alkyl and lcwer alkoxy being as hereinbefore defined, which process comprises reacting an alkali metal salt of a carboxylic acid of the general formula ROCONHCH2COOH II wherein R has the above significance. with an optically uniform compound of the general formula 2 09684 - 10 - 12 3 wherein R . R and R have the above significance, in the presence of a base and a sulphonic acid chloride of the general formula r4-so2-ci IV a wherein R signifies phenyl, lower alkyl-phenyl. halo-phenyl, lower alkyl or halo-lower alkyl.

2. A process according to claim 1, wherein an alkali metal salt of a carboxylic acid of formula II in which R signifies benzyl is used.

3. A process according to claim 1 or 2, wherein a potassium salt of a carboxylic acid of formula II is used.

4. A process according to any one of claims 1-3. wherein a compound of formula III in which the group >3° X signifies the group is used. V I-,'

5. A process according any one of claims 1-4, wherein a compound of formula III in which R1 signifies allyl. benzyl or 2.4-dimethoxybenzyl is used.

6. A process according to any one of claims 1-5. A wherein a compound of formula IV in which R signifies p-chlorophenyl is used.

7. A process according to any one of claims 1-6. wherein triethylamine is used as the base. 209684 - ii -

8. A process according to any one of claims 1-7, wherein the reaction is carried out in an anhydrous inert organic solvent.

9. A process according to claim 8 wherein the reaction is carried out in anhydrous methylene chloride.

10. A process for the manufacture of optically uniform azetidirtones of the general formula I, as defined in claim 1, substantially as hereinbefore described with particular reference to either of the foregoing Exanples 1 and 2.

11. An optically uniform azetidinone of the general formula I, as defined in claim 1, whenever prepared according to the process claimed in any one of claims 1 to 10. </div>