IE55402B1 - Process for the manufacture of 1-sulfo-2-oxoazetidine derivatives - Google Patents

Process for the manufacture of 1-sulfo-2-oxoazetidine derivatives

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Publication number
IE55402B1
IE55402B1 IE1305/83A IE130583A IE55402B1 IE 55402 B1 IE55402 B1 IE 55402B1 IE 1305/83 A IE1305/83 A IE 1305/83A IE 130583 A IE130583 A IE 130583A IE 55402 B1 IE55402 B1 IE 55402B1
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Ireland
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process according
het
general formula
group
amino
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IE1305/83A
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IE831305L (en
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Hoffmann La Roche
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

1. A process for the manufacture of carboxylic acids of the general formula see diagramm : EP0096297,P23,F1 in which Het signifies an optionally amino-substituted 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms and optionally also an oxygen or sulphur atom and R signifies C1-3 -alkyl, and the group =NOCH2 COOC(R)3 is present at least partially in the syn-form, characterized by cleaving off catalytically the allyl group R**5 in an ester of the general formula see diagramm : EP0096297,P23,F2 in which Het and R have the significance given above and R**5 represents allyl, and the group =NOCH2 COOC(R)3 is present at least partially in the syn-form, with the aid of a palladium compound in the presence of triphenylphosphine or a tri(lower alkyl)phosphite and in addition in the presence of an alkali metal alkanoate or an organic base. [EP0096297A2]

Description

2 b a 4 ϋ 2 The present invention is concerned with a process £or the manufacture of carboxylic acids of the general formula Het-—C—COOH J H N IVa \ OCK2-COOC(R)3 in which Het signifies an optionally amino-substituted 5 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms and optionally also an oxygen or sulphur atom and R signifies 3-alkyl, and the group =NOCH2COOC(R)3 is present at least partially in the syn-form. which comprises cleaving off catalytically the 5 . allyl group R m an ester of the general formula Het-C-COOR5 X II N ^OCHj-COOCCR) 3 in which Het and R have the significance given above and R5 represents allyl, and the group 15 =NOCH2COOC(R)3 is present at least partially in the syn-form, with the aid of a palladium compound in the presence of triphenylphosphine or a tri(lower alkyl)phosphite and in addition in the presence of an alkali metal alkanoate or 20 an organic base. 3 The present invention is also concerned with a process for the manufacture of benzthiazole thioesters of the general formula in which R and Het have the above significance and the group =NOCH2COOC(R)3 is present at least partially in the syn-form. which comprises treating a carboxylic acid of general formula IVa above, obtained in accordance with the 10 invention, with dithio-bi6-benzthiazole in the presence of a tri(lower alkyl)phosphite and a base or in the presence of triphenylphosphine.
Further, the present invention is concerned with a process for the manufacture of l-sulpho-2-oxoazetidine 15 derivatives of the general formula Het— C—CONH N wherein R1 signifies the group -CH2-COOC(R)3 or carboxymethyl and R2 signifies hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy--carbonyl. lower alkanoyloxy-lower alkyl, lower alkoxy-carbonyl-lower alkenyl, hydroxyiminomethyl, lower alkoxyiminomethyl. carbamoyl, carbamoyl-lower 20 alkenyl or carbamoyloxy-lower alkyl, and Het and E have the above significance. which comprises converting a benzthiazole thio- ester of general formula III above, obtained in accordance with the invention, into a compound, which is present in racemic form or in the form of the 3S-enantiomer, of the general formula Het-C-COHH-- II N >3CH2-COOC(RK CK \ SO3H lb 2 wherein Het, E and R have the above significance and the group =NOCH2COOC(R)3 is present at least partially in the syn-form, by reaction with a compound, which is present in racemic form or in the form of the 3S-enantiomer. of the general formula II S03li 2 wherein R has the above significance, if desired converting the group -CH2-COOC(R)3 into carboxymethyl and, if desired, converting a product obtained into a pharmaceutically compatible salt.
The heterocycle denoted by "Het" includes all 5- or 6-membered aromatic ring structures which have 1 or 2 nitrogen atoms and which are optionally substituted by an 5 amino group, e.g. pyrazolyl groups such as 2-pyrazol-3-yl, amino-pyridyl groups such as 2-amino-6-pyridyl, amino--imidazolyl groups such as 2-amino-4-imidazolyl. If desired, they can contain an oxygen atom such as e.g. in amino-oxazolyl groups, e.g. 2-amino-4-oxazolyl, or a sulphur atom such as e.g. in amino-thiadiazolyl groups such as 5-amino-3-(l,2,4-thiadiazolyl) or. especially, amino-thiazolyl groups such as 2-amino-4-thiazolyl.
The term «lower alkyl", alone or in combinations, signifies an aliphatic hydrocarbon group which can be straight-chain or branched and which contains up to 7 carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl. isopentyl, n-hexyl, n-heptyl etc. The term "lower alkoxy" has an analogous significance. The term "lower alkenyl", alone or in combinations, signifies an olefinic hydrocarbon group which can be straight-chain or branched and which contains up to 7 carbon atoms such as e.g. vinyl, allyl, isopropenyl. 2-methallyl, 2-butenyl, 3-butenyl, 2-hexenyl, 2-heptenyl etc. The term "lower alkynyl" signifies an acetylenic hydrocarbon group which can be straight-chain or branched and which contains up to 7 carbon atoms such as e.g. ethynyl, l-propynyl. 2-propynyl. 2-hexynyl, 2-heptynyl etc. The term "lower alkanoyl" or "lower alkanoyloxy" signifies an aliphatic carboxylic acid residue with up to 7 carbon atoms such as e.g. acetyl, propionyl, isobutyryl, acetoxy, propionyloxy, isobutyryloxy.
R is preferably methyl.
Preferred R1 groups are: t-butoxycarbonylmethyl and carboxymethyl; particularly carboxyraethyl.
Het is preferably 2-amino-4-thiazolyl. 2 6 Preferred R groups are methyl, ethyl, n-propyl. vinyl, allyl, ethynyl. 3-(acetoxy)-n-propyl, methoxy-carbonyl. hydroxyiminomethyl. methoxyiminomethyl, 2-(ethoxyearbonyl)-l-methylvinyl, carbamoyl, carbamoyl-vinyl and carbamoyloxymethyl; particularly carbamoyl and car bamoyloxyme thy1.
A preferred group of the formula Het—C—CO-ll is 2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino)acetyl.
The compounds of formula I can be present in various isomeric forms [e.g. cis, trans; syn (Z-form), anti (E-form): and as the 3S-enantiomer]. This also applies to the starting compounds referred to hereinafter.
The compounds of formula I can be present as free acids or as betains or also as pharmaceutically compatible salts which are obtained by salt formation with a basic salt former at the free 1-sulpho group or at a carboxy group which may be present in the substituent in the 3-position, As basic salt formers there come into consideration e.g.: inorganic cations such as sodium and potassium ions, basic amino acids such as arginine, ornithine, lysine or histidine, polyhydroxyalkylamines such as N-methylglucamine, diethanolamine, triethanolamine etc.
Carboxy groups present in a compound of formula I or salts thereof can be converted by appropriate esterification into readily hydrolyzable ester groups. Such 7 readily hydrolyzable ester groups, which are cleaved in the body into the corresponding free carboxy groups, are, for example, a-(lower alkoxy)-lower-alkoxycarbonyl groups such as methoxymethoxycarbonyl and a-methoxyethoxycarbonyl, lower alkylthiomethoxycarbonyl groups such as methylthio-methoxycarbonyl, a-(lower alkanoyl)-lower-alkoxycarbonyl groups such as acetoxymethoxycarbonyl, pivaloyloxymethoxy-carbonyl and α-pivaloyloxyethoxycarbonyl, a-(lower alkoxy-carbonyl)-lower-alkoxycarbonyl groups such as ethoxycarbonyl-oxymethoxycarbonyl, t-butoxycarbonylmethoxycarbonyl and a--ethoxycarbonyloxyethoxycarbonyl, lactonyl groups such as phthalidyl and thiophthalidyl, or the group of the formula Examples of compounds of formula X which can be 15 manufactured in accordance with the present invention are the end products described in Examples la and lb hereinafter not only in the form in which they are present in the Examples (3S-enantiomer or racemates), but also in the form of readily hydrolyzable esters and pharmaceutically 20 compatible salts of these compounds.
Especially preferred compounds of formula I are the compounds of the general formula 8 w C—CONH· I! N ,R21 la wherein E ,11 represents carboxymethyl and E' ,21 represents carbamoyl or carbamoyloxymethyl, in racemic form or in the form of the 3S-enantiomer as well as the corresponding readily hydrolyzable esters and pharmaceutically compatible salts of these compounds.
Especially preferred among these compounds is (3S.4S)--3-[(Z)-2-(2-amino-4-thiazolyl)-2 -[(carboxyraethoxy)-imino]acetamido]-4-carbamoyloxymethyl-2-oxo-l-azetidine--sulphonic acid as well as its pharmaceutically compatible salts.
The reaction of the compounds of general formulae II and III in accordance with the invention is conveniently carried out in an inert organic solvent, e.g. in a chlorinated hydrocarbon such as methylene chloride or chloroform, in an ether, e.g. tetrahydrofuran or dioxan, in an ester, e.g. ethyl acetate, in a ketone, e.g. acetone, in an aprotic solvent such as acetonitrile, dimethylformamide or dimethylacetamide or in a mixture of one of these solvents with water. The reaction temperature conveniently liee between about -40° and +60°C, advantageously between -15° and +25eC, especially 0-20°C. The reaction partners are conveniently used in about stoichiometric ratio or with a slight, excess of thioester of formula III. The reaction is advantageously carried out in 9 the presence of a base such as e.g. an organic amine such as triethylamine or N-methylmorpholine or an alkali metal bicarbonate such as sodium bicarbonate.
If desired, the group of the formula -CH2COOC(R>3 present in the reaction product of formula lb can be converted into the corresponding carboxymethyl group, namely by treatment with a strong acid such as trifluoro-acetic acid (optionally in the presence of anisole), hydrochloric acid or p-toluenesulphonic acid at a low temperature such as -10°C to room temperature.
The manufacture of the salts of the process products of formula I can be effected in a manner known per se, e.g. by reacting an acid of formula I with an equivalent amount of the desired base, optionally in the form of an ion exchanger. The reaction is conveniently carried out in a solvent such as water or in an organic solvent such as ethanol, methanol, acetone, ethyl acetate and the like.
The temperature of the salt formation is not critical, but it generally lies in the range of about 0-50°C, preferably at room temperature.
As mentioned, the thioesters of formula III are manufactured by reacting a carboxylic acid of general formula IVa above, obtained in accordance with the invention, with dithio-bis-benzthiazole in the presence of a tri-(lower-alkyl)-phosphite and a base or in the presence of triphenyl-phosphine. The reaction temperature conveniently lies between about -30° and +50°C, advantageously between about -20° and +25°C. The esterification is advantageously carried out in an organic solvent, e.g. in acetonitrile or in methylene chloride. The preferred embodiment comprises the reaction in the presence of a tri-(lower-alkyl)-phosphite and a base. Triethylphosphite is preferably used as the tri-(lower-alkyl)-phosphite and 10 an organic base, especially a tertiary organic base such as triethylamine. N-ethyl~diisopropylamine or, preferably, N-raethylmorpholine, is preferably used as the base.
An especially preferred thioester of formula III is 2-(2-amino-4-thiazolyl)-2.-[[(Z)-X-(t-butoxycarbonyl)--methoxy]-imino]-acetic acid 2-benzthiazolyl thioester.
A particular problem arises in the manufacture of the acids of formula IVa. The conventional route for the preparation of such compounds, namely reaction of the methyl or ethyl ester of the corresponding hydroxyimino compound with a halo-acetic acid C(R)3~ester and subsequent saponification, does not yield the desired acid of formula IVa, because the group -COOC{R)3 is saponified.
It is therefore necessary to adopt a different procedure.
The mentioned acids of formula IVa can. however, be obtained in good yield when in place of the mentioned methyl or ethyl ester there is used the allyl ester, i.e. by cleaving off the allyl group R5 in an ester of the general formula Het—C—COOR5 II N x \ OCH2-COOC(R)3 . . 5 in which Het, R and R have the significance given above.
"C13-Alkyl" embraces: methyl, ethyl, n-propyl and isopropyl. The preferred residue of the formula -COO-C(R)3 is that in which R represents methyl, i.e. 11 t-butoxycarbonyl.
The above cleavage is effected by the action of a palladium compound in the presence of triphenylphosphine or a tri-(lower alkyl)-phosphite, preferably triethyl-5 phosphite. As palladium compounds there come into consideration: palladium/carbon, palladium salts, especially salts with hydrohalic acids such as hydrochloric or hydrobromic acid or with lower alkanecarboxylic acids such as acetic acid or propionic acid. Palladium-organic !0 complexes with triphenylphosphine or a tri-(lower alkyl)- -phosphite such as triethylphosphite also come into consideration, whereby the cleavage can also be carried out without additional triphenylphosphine or tri-(lower alkyl)-phosphite. Palladium/carbon, palladium chloride or 15 palladium acetate is preferably used as the palladium compound. A further reaction partner is an alkali metal alkanoate, e.g. sodium acetate or, preferably, sodium 2-ethylcaproate, or, preferably, an organic base, especially triethylamine or N-raethylmorpholine. The reaction 20 temperature can vary between about 0 and 100°C, but preferably lies at room temperature (but when palladium/ carbon is used somewhat higher: about 50-80°C). The reaction is preferably carried out in an inert organic solvent, e.g. in ethyl acetate or methylene chloride.
The allyl esters of formula X can be prepared starting from diketene, chlorine gas and allyl alcohol, which are converted into allyl 4-chloroacetoacetate. The latter is nitrosated with nitrous acid and subsequently converted with thiourea into the allyl Het-2-(Z)-hydroxyimino-30 -acetate which is thereupon converted into the allyl ester of formula X with a compound of the general formula XI Hal-CH2-COO-C(R)3 12 in which R has the above significance and Hal represents chlorine, bromine or iodine, in the presence of a base such as alkali carbonate, tri-ethylamine or N-ethyl-diisopropylamine.
The starting compounds of formula II can be obtained according to various methods. For the preparation of optically uniform compounds of formula II having the 3S-cis-configuration. one can start from isopropylidene-L -glyceraldehyde in accordance with the following Formulae 10 Schemes (Schemes I-VII). The preparation of optically uniform compounds of formula II having the 3S-trans--configuration is illustrated in Schemes V and VI. 13 14 x z o o o CO Θ n X O CO Ot z o uW= ΐ NJ Λ δ * z Of O 'C* Z u wχΉ. σ> ! Nl H i QJ JZ O to CO o CM CO CM CM x z o υ o (M x υ V_./ y X T NJ % 'fl· x CQ <0 z N IS CM X z o u o CM a m O W >1 & H u I V 04 N CM CM CM X z o υ o CM X υ /1 ΐ 16 m Οw >t CLr u I Ό 0« \ OJ *—l O CN w CN ¢4 1 N 17 <Ν X ζ X ζ I η X U X Ο Ο Ο υ <Ν ΓΊ % > Η <υ ε Cm 18 Schem e V „3»θ ►CSCH Η N® H3\_>CH=CH2 \„Θ <5* \o0 27 S03 28 S03 31 32 19Λ •Ό •Ηy ο <ϋ (Μυ "*ΊΚ2S » uV -z/-4 HOC* a*. ο y η ri -U Μ ω •He Cm ^ ο s V υ υ ο 4- ο V ,/ Λ § δ X ο 0 ΰ 00 Ο cs CQ (Μ * Η £ «Ή g ζ II X Ε 0 a ο γ 1 —Ν V so 9 1 < 2 S ο γ ζ/ X =? Λ 1 ΝΙ 21 Explanations to Schemes I-VII DMB Ft Et He TSOH THF PrOH DMSO P Y Py.S03 z Trt Ac = 2,4-dimethoxybenzyl - phthalimido = ethyl = methyl = p-toluenesulphonic acid = tetrahydrofuran = n-propanol = dimethyl sulphoxide = pyridine = sulphur trioxide-pyridine complex = benzyloxycarbonyl = trityl = lower alkanoyl. e.g. acetyl Example 1 a) 71.8 g (0.3 mol) of (3S,4S)-3-amino-4-carbamoyloxy-methyl-2-oxo-l -azetidinesulphonic acid are dispersed in 1.5 1 of methylene chloride and treated while stirring with 45.6 g (0.45 mol) of triethylamine and 148.6 g (0.33 mol) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxy-carbonyl)-methoxy]-imino]-acetic acid 2-benzthiazolyl thioester. The reaction mixture is stirred at room temperature for 5 hours. 1.5 1 of water are subsequently added thereto, the aqueous phase is separated, extracted twice with 250 ml of methylene chloride and acidified by the addition of 850 ml of 37% aqueous hydrochloric acid. After stirring at room temperature for 2 hours the suspension obtained is cooled to 0°C and stirred for a further 1/2 hour. The precipitate is filtered off, washed successively with 1000 ml of cold water, 1000 ml of methanol and 1000 ml of ether and dried at 40°C/10 mm Hg for 12 hours. There are obtained ill g (79.3%) of crude (3S.4S)-3-((Z)-2-(2-amino-4-thiazolyl)-2 -[(carboxy- 22 methoxy)-imino]-acetamido]-4-carbamoyloxymethyl-2-oxo-l- -azetidinesulphonic acid of melting point 207®C. ta]D = -46.2® (c = 1 in dimethyl sulphoxide).
Elemental analysis calculated for C12N14N6C l S 2 10 2 5 C 30.90. H 3.03. N 18.02. S 13.75% Found C 28.23. H 3.81. N 16.18, S 12.26. H_0 3.61%. Corrected for anhydrous 10 substance C 29.29. H 3.53. N 16.79 S 12.72% An analytical sample gives the following data: 20 [a]D = +39° (c = 1 m water); corrected for anhydrous substance +42.5® (c = 0.9 in water) 20 5 [a]D = -43.5® (calm dimethyl sulphoxide): corrected for anhydrous substance -47.4® (c = 0.9 in water).
IR (KBr. cm-1): 3458. 3428. 3354, 3291, 1777, 1712. 1648, 1617, 1557, 1531 20 1H-NMR (DMSO. ppm): 3.9-4.4 (3H.m.CH-CH2-0), 4.79 (2H, s, 0-CH2-C00H). 5.30 (lH.dd.5 and 9 Hz. NH-CH-CH); 6.5 (6H.br.. NH3 +. NH2. COOH). 6.90 (lH.s, H-thiazole), 9.45 (lH.d, 9 Hz. CO-NH).
Elemental analysis calculated for C,_H,„N,0, s · LZ 1¾ O 1U Z C 30.90, H 3.03. N 18.02 S 13.75% Found C 28.39, H 3.43. N 16.44 S 12.47%. HzO 8.14% 23 Corrected for anhydrous substance C 30.91, H 2.74, N 17.90, S 13.58%. b) 110 g (0.235 mol) of crude (3S,4S)-3-[(Z)-2-(2-amino--4-thiazolyl)-2 -[(carboxymethoxy)-iraino]-acetamido]-4--carbamoyloxymethyl-2-oxo-l-azetidinesulphonic acid, obtained in accordance with Example 41, are dispersed in 4.7 1 of methanol and treated with 72.3 ml (0.518 mol) of triethylamine and 282.9 ml (0.566 mol) of a 2N solution of sodium 2-ethylcaproate in ethyl acetate. The solution obtained is stirred for 10 minutes, diluted with 9 1 of acetone and concentrated to 3 1. The residual suspension is diluted with 3 1 of acetone, filtered and the crystalline salt is washed with ether and dried. 108.59 g (90.5%) of (3S.4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2 -[(carboxy-methoxy)-iminoj-acetamidoj-4-carbamoyloxymethyl-2-oxo-l--azetidinesulphonic acid disodium salt are obtained. This crude salt is dissolved in 420 ml of water. 1050 ml of ethanol are added thereto and subsequently (after a few minutes) a further 210 ml of ethanol. The solution becomes turbid and is stirred for 1 hour. 1770 ml of ethanol are now added dropwise thereto within 2 hours. After stirring for a further one hour and cooling to 0°C the precipitate is filtered off and washed with ethanol. The crystals obtained are dispersed in 170 ml of ethanol and 680 ml of ether, filtered off and washed with ether. After drying under greatly reduced pressure and 40°C there are obtained 102.9 g (85.5%) of (3S.4S)-3-[(Z)-2-(2-amino-4-thiazolyl)--2 -[(carboxymethoxy)- imino]-acetamido]-4-carbamoyloxy-methyl-2-oxo-l-azetidinesulphonic acid disodium salt.
Elemental analysis calculated for Ci2Hi2N60ioS2Na2: C 28.24, H 2.37, N 16.47, S 12.56% Found C 28.18, H 2.63, N 16.34, S 12.21, H20 1,02% 24 Corrected tor anhydrous substance C 28.46, H 2.65. N 16.50, S 12.33¾ 20 [a]p = +19° (c = 1 in water) IE (KBr. cm-1): 1777, 1712, 1648, 1617. 1557, 1417 UV (H20: λ max (ε)): 295 nm (6850). 233 nm (12330) ^-NMR (D20. ppm): 4.2-4.8 (5H.m,CH-CH2-0-CO, 0-CH2-C00Na). 5.6 (lH,d.5.5 Hz. 0=C-CH), 7.05 (IH.s. H-thia-zole).
The 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxy-carbonyl)methoxy]-imino)-acetic acid 2-benzthiazolyl thioester used as the starting material can be prepared as follows: A. 84 g of diketene are dissolved in 250 ml of carbon tetrachloride and cooled to -27°C. The solution becomes turbid. 71 g of chlorine gas are introduced slowly within 5 hours while stirring, with the temperature being held at -20 to 30eC by cooling. The clear solution obtained is added slowly within 1 hour to a solution of 58 g of allyl alcohol in 250 ml of carbon tetrachloride and 80.5 ml of pyridine while stirring at 0 to -5°C. After stirring without cooling for an additional 15 minutes the precipitated pyridine hydrochloride is filtered off and washed with 100 ml of carbon tetrachloride. The carbon tetrachloride solution is washed with 2 x 300 ml of water, dried over sodium sulphate and evaporated under reduced pressure. The residue is distilled; there are obtained 136 g (77%) of allyl 4-chloro-acetoacetate as a colourless liquid of boiling point 61-69°C (0.1 mm Hg).
A solution of 35.2 g of allyl 4-chloro-acetoacetate in 25 34 ml of acetic acid is treated dropwise with a solution of 14.6 g of sodium nitrite in 21 ml of water within 45 minutes while stirring and cooling. The temperature falls gradually from 0 to -15°C during the addition. The mixture is subsequently stirred at -15°C for 2 hours. A solution, pre-warmed to 30°C, of 15.2 g of thiourea in 120 ml of water is treated with the solution obtained at such a rate that the reaction temperature remains at about 30-35°C. After stirring for an additional 7 hours the crystalline precipitate obtained is filtered off, washed successively with water, acetonitrile and ether and crystallized from acetonitrile. There are obtained 21.8 g (48%) of 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetic acid allyl ester of melting point 184-185°C.
A solution of 20.4 g of 2-(2-amino-4-thiazolyl)-2--(Z)-hydroxyimino-acetic acid allyl ester in 100 ml of dimethyl sulphoxide and 100 ml of acetone is stirred at room temperature for 5 hours together with 30 g of potassium carbonate and 19.5 ml of t-butyl bromoacetate. After removing the acetone by evaporation under reduced pressure (bath temperature 50°C) 600 ml of ethyl acetate are added thereto and the solution is washed with ice--water up to a neutral reaction, dried and evaporated under reduced pressure. There is obtained a crystalline yellowish residue which is dispersed in diisopropyl ether, filtered and dried under reduced pressure. There are obtained 20.1 g (65.5%) of 2-(2-amino-4-thiazolyl)-2--[[(Z)-(t-butoxycarbonyl) -methoxy]-imino]-acetic acid allyl ester of melting point 135-136°C. 19 g of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxy-carbonyl)-methoxy]-imino]-acetic acid allyl ester in 500 ml of ethyl acetate are treated successively while stirring with 0.09 g of palladium chloride, 0.46 ml of triethylphosphite and 30 ml of sodium 2-ethylcaproate solution (2H solution in ethyl acetate). After stirring at room temperature for four hours 500 ml of water and 100 ml of saturated aqueous sodium bicarbonate solution are added thereto. The aqueous solution is separated, washed with 100 ml of ethyl acetate and acidified to pH 2 with 2N aqueous hydrochloric acid. The crystalline precipitate is filtered off, washed successively with water, acetonitrile and ether and dried under reduced pressure. There are obtained 14.6 g (87%) of 2-(2-amino-4-thiazolyl)-2-[[(Z)--(t-butoxycarbonyl)-methoxy]-imino]-acetic acid of melting point 175-176°c (dec.).
The following are further methods for the preparation of the starting material: B. The 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxy-carbonyl)-methoxy]-imino]-acetic acid allyl ester is reacted in accordance with A above, but using 0.12 g of palladium acetate in place of palladium chloride. After identical working-up there are obtained 14.5 g (86.3%) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy] -imino]-acetic acid of melting point 171-172°C.
C. The 2-(2-amino-4-thiazolyl)-2-[f(Z)-(t-butoxy-carbonyl)-methoxy]-iminoJ-acetic acid allyl ester is reacted analogously to B above, but using 0.695 g of triphenylphosphine in place of triethylphosphite. There are obtained 3.4 g (79.7%) of 2-(2-amino-4-thiazolyl)-2--[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid of melting point 167-169eC.
D. A suspension of 1.4 g of 2-(2-araino-4-thiazolyl)-2--[[(Z)-(t-butoxycarbonyl)-methoxyJ-imino]-acetic acid allyl ester, 86 mg of palladium/carbon (5%), 0.033 ml of triethylphosphite and 2.25 ml of sodium 2-ethylcaproate solution (2N solution in ethyl acetate) in 50 ml of ethyl 27 acetate is stirred at 60°C for 12 hours. After booling to room temperature the reaction mixture is worked-up in accordance with C above. There is obtained 0.81 g (65.5%) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl) -methoxyj-iminoj-acetic acid of melting point 174-175°C.
E. 3.41 g of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxy-carbonyl) -methoxyj-iminoj-acetic acid allyl ester are dispersed in 100 ml of ethyl acetate and treated with 250 mg of triphenylphosphine and 250 mg of tetrakis-(tri-phenylphosphine)-palladium. The solution obtained is treated with 5.5 ml of sodium 2-ethylcaproate solution (2N solution in ethyl acetate). Ά thick unstirrable mass results in a short time. After standing at room temperature for 15 minutes this is shaken once with 100 ml of water and once with 300 ml of saturated aqueous sodium carbonate solution; the aqueous solutions are combined and washed once with 50 ml of ethyl acetate. The combined aqueous solutions are adjusted to pH 2 with 2N aqueous hydrochloric acid. The crystalline precipitate is filtered off and washed successively with water, acetonitrile and ether. There are obtained 2.4 g of 2-(2-amino-4-thia-zolyl)-2-[[(Z)- (t-butoxycarbonyl)-methoxy]-imino]-acetic acid of melting point 167-169°C (dec.).
F. 3.41 g of 2-(2-amino-4-thiazolyl)-2-[((Z)-(t-butoxy-carbonyl) -methoxy)-imino]-acetic acid allyl ester are dispersed in 100 ml of ethyl acetate and treated with 18 mg of palladium chloride and 0.084 ml of triethyl-phosphite. After the addition of 1.2 ml of N-methyl-morpholine the mixture is stirred at room temperature for 48 hours, whereby crystallization occurs slowly. The mixture is left to stand for 4 days, the precipitate is filtered off under suction, washed with ethyl acetate and dried in a vacuum. There are obtained 3.52 g of N-allyl-N--methylmorpholine salt of 2-(2-amino-4-thiazolyl)-2-[[(Z)- &8 -(t-butoxycarbonyl) -methoxy]-imino]-acetic acid.
The crude salt is suspended in 100 ml of dry acetonitrile. 0.49 ml of N-methylmorpholine and 3.32 g of 2,2'--dithiobenzothiazole are added successively thereto while stirring and the suspension obtained is cooled to 5°.
Within 4 hours there is now added dropwise a solution of 2.5 ml of triethylphosphite in 30 ml of dry acetonitrile. After further stirring for 30 minutes the yellow suspension obtained is cooled to -10°. The crystals are filtered off under suction and washed with cold acetonitrile and ether. There are obtained 1.9 g of 2-(2-araino--4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]-imino]--acetic acid 2-benzthiazolyl thioester of melting point 142-143°C (dec.). 54.2 g (180 mol) of 2-(2-amino-4-thiazolyl)-2-[[(Z)--(t-butoxycarbonyl)-methoxy)-imino]-acetic acid are dispersed in 1.4 1 of dry acetonitrile. 29.6 mi (270 mmol) of N-methylmorpholine are added thereto while stirring, followed by 72.1 g (216 mmol) of 2,2'-dithiobisbenzo-thiazole. The suspension obtained is cooled to 0°C. Within 4 1/2 hours there is now added thereto a solution of 53.8 ml (314 mmol) of triethylphosphite in 350 ml of dry acetonitrile. After stirring further for 30 minutes the yellow suspension obtained is cooled to -10°C. The crystals are filtered off and washed with cold acetonitrile and ether. There are obtained 59.7 g (73.6%) of 2-(2-amino-4-thiazolyl)-2-C[(Z)-(t-butoxycarbonyl)methoxy]~ -imino]-acetic acid 2-benzthiazolyl thioester.
Elemental analysis calculated for cigHy8N4°4S3 (450.561): C 47.99, H 4.03. N 12.44. S 21.35% Found C 47.88, H 4.34. N 12.34, S 21.02%. ,2 9 The (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-l--azetidinesulphonic acid sodium salt used as the starting material can be prepared as follows: a) To a solution, stirred at room temperature, of 0.9 g (5.4 mmol) of 2,4-dimethoxybenzylamine in 100 ml of methylene chloride are added 3 g of molecular sieve 4 and. after 20 minutes, 0.7 g (5.4 mmol) of isopropylidene--L-glyceraldehyde and 5 g of anhydrous magnesium sulphate. The mixture is subsequently stirred at room temperature for a further 1 hour. The organic solution of isopropyl-idene-L-glyceraldehyde (2,4-dimethoxybenzyl)imine obtained is cooled to -20°C under argon and treated while stirring with 0.88 ml (5.4 mmol) of triethylamine. A solution of 1.25 g (5.6 mmol) of phthaloylglycyl chloride in 20 ml of dry methylene chloride is then added dropwise within 1 hour .and the mixture is subsequently stirred further at room temperature overnight. The reaction mixture is washed three times with 100 ml of water each time and with 100 ml of sodium chloride solution and dried over sodium sulphate. Evaporation is carried out and the residue is chromatographed on silica gel (230-400 mesh) while eluting with hexane/ethyl acetate (1:1). There are obtained 1.77 g (70%) of N-[(3S,4S)-cis-l-(2,4-dimethoxybenzyl)-4-[(R)--2.2-dimethy1-1,3-dioxolan-4-yl]-2-oxo-3-azetidinyl]-phthalimide as a foam; [α]^ = +41° (c = 0.8 in chloroform); MS: 466 (M+). b) A solution of 149.3 g (0.32 mol) of N-[(3S,4S)-cis-l--(2,4-dimethoxybenzyl)-4-[(R)-2,2 -dimethyl-1.3-dioxolan--4-yl]-2-oxo-3-azetidinyl]phthalimide in 2.5 1 of methylene chloride is treated with 34 ml (0.64 mol) of methylhydrazine. The mixture is stirred at 28°C overnight, precipitated material is filtered off and the filtrate is evaporated under reduced pressure. The residue is taken up in 1.2 1 of ethyl acetate and the suspension obtained is filtered. The filtrate is washed three times with 500 ml of water each time and with 500 ml of sodium chloride solution and dried over sodium sulphate. After evaporation of the solvent there are obtained 104.3 g (86.8%) of crude (3S.4S)-eis-3-amino-l-(2.4-dimethoxybenzyl)-4-[ c) A stirred solution of 104 g (3.0 mol) of (3S,4S)-cis--3-amino-l-(2.4-dimethoxybenzyl)-4-[(R) -2,2-dimethyl-l.3--dioxolan-4-yl]-2-azetidinone and 104 ml (1.2 mol) of butylene oxide in 1.5 1 of methylene chloride is treated dropwise with 57.6 ml (0.4 mol) of carbobenzoxy chloride, stirred for 1 hour and subsequently evaporated under reduced pressure. The crude material obtained is treated with 2 1 of dry ether, whereby a crystalline material is obtained. There are obtained 122.6 g (84%) of benzyl (3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-[(R) -2,2-dimethyl--1,3-dioxolan-4-yl]-2-oxo-3-azetidinecarbamate of melting point 115-116°C; [a)D = +48° (c = 0.3 in methanol). d) A solution of 160 g (0.34 mol) of benzyl (3S.4S)-cis--1-(2,4-dimethoxybenzyl)-4-((R)-2,2-diraethyl-l,3-dioxolan-4--yl]-2-oxo-3-azetidinecarbamate in 1000 ml of tetrahydro-furan and 400 ml of water is stirred overnight at 60eC in the presence of 8 g of p-toluenesulphonic acid. The reaction mixture is neutralized with sat. NaHC03 and the tetrahydrofuran is evaporated. The aqueous solution is then extracted with 2 1 of ethyl acetate. After drying over Na2S04 and evaporation there are obtained 142 g (97.2%) of pure benzyl (3S.4S)-cis-4-[(R)-l,2-dihydroxy-ethyl ]-l- (2,4 -dimethoxybenzyl)-2-oxo-3-azetidine-carbamate, m.p. 177-178°C (MeOH). e) A solution of 142 g (0.33 mol) of benzyl (3S.4S)-cis--4-[(R)-1,2-dihydroxy-ethyl]-1-(2,4 -dimethoxybenzyl)-2- -oxo-3-azetidinecarbamate in 1000 ml o£ tetrahydrofuran is treated dropwise while stirring with a solution o£ 76.8 g (0.359 mol) of sodium metaperiodate in 600 ml of water.
The mixture is stirred for 1 hour, filtered and the filtrate is evaporated under reduced pressure. The residue is taken up in 400 ml of ethyl acetate and washed twice with in each case 100 ml of water and with 50 ml of sodium chloride solution. After drying and evaporation there are obtained 105 g (87.8%) of pure benzyl (3S,4S)-cis-l-(2,4--dimethoxybenzyl)-4-formyl-2-oxo-3 -azetidinecarbamate of melting point 145-147°C (from ethyl acetate/hexane); [o)D = +13.7» (C = 1. CHC13). f) 4.27 g (113 mmol) of sodium borohydride are dissolved in 1.6 1 of abs. ethanol and cooled to 0°C. This solution is treated dropwise with a solution of 90 g (226 mmol) of benzyl (3S,4S)-cis-l-(2,4-dimethoxybenzyl-4-formyl-2-oxo--3-azetidinecarbamate in 720 ml of ethanol-tetrahydrofuran (1:1). The reaction mixture is stirred at 0®C for 2 hours and subsequently treated with 350 ml of saturated aqueous sodium sulphate solution and stirred for 45 minutes. After filtration and evaporation of the solvent the residue is taken up in 1.5 1 of ethyl acetate and washed up to a neutral reaction. After drying over sodium sulphate and partial evaporation there is obtained crystalline (3S.4S)--cis-3-benzyloxycarboxamido-l-(2,4 -dimethoxybenzyl)-4--hydroxymethyl-2-azetidinone in the form of 72.2 g of colourless crystals (79.6%) of melting point 138°C, [a)D = +41.6° (c = 1 in methanol).
Elemental analysis calculated for C Η N O : 21 24 2 6 N 7.00% N 6.96% C 62.99, H 6.04, Found C 62.76, H 6.09.
IR (KBr. cm 1): 1718. 1698, 1615, 1589 33 NMR (CDC13. ppm): 2.45 (lH.dd.OH). 3.55-3.75 (3H broad. CH-CH2-). 3.79 (6H.s, 2xOCH3). 4.35 (2H.s.N-CH2), 5.08 (2H.s,0-CHz). 5.11 (lH.dd, 5 and 9Hz.H3>, 6.06 (lH.d.9HZ.NH), 6.43 (2H.rn.Ar). 7.15 (lH.m.Ar). 7.31 (5H.m. c6h5) MS: 292 (M-BzOH) g) A solution of 30 g (74.9 mmol) of (3S,4S)-cis-3--benzyloxycarboxaraido-l-(2.4 -dimethoxybenzyl)-4-hydroxy-methyl-2-azetidinone in 600 ml of methylene chloride is treated at 0-5°C with 21.22 g of chlorosulphonyl isocyanate (2 equivalents). After 15 minutes the reaction mixture is added dropwise to an aqueous solution, cooled to 5°C. of 20.9 g (2,7 equivalents) of sodium sulphite.
The reaction mixture is stirred for 2 hours, subsequently diluted with methylene chloride and the organic phase is separated, washed with aqueous sodium chloride solution and dried over sodium sulphate for 12 hours. The organic phase is subsequently treated with magnesium sulphate and stirred for a further 2 hours. After filtration and evaporation of the solvent the residue is treated with ether, the crystals obtained are filtered and washed with ether. There ate obtained 32.6 g (97%) of (3S,4S)-cis-3--benzyloxycarboxamido-4-carbamoyloxymethyl -1-(2,4--dimethoxybenzyl)-2-azetidinone of melting point 178-179°C, [a)D = +84.7° (c = 0.8 in chloroform).
Elemental analysis calculated for C22H25N3°7: C 59.59, H 5.68. N 9.48% Pound C 59.17. H 5.69, N 9.37% IR (KBr. cm-1): 1761. 1708. 1618, 1587 h) A suspension of 11.9 g (26.8 mmol) of (3S.4S)-cis-3- 33 -benzyloxycarboxamido-4-carbamoyloxymethyl -1-(2,4--dimethoxybenzyl)-2-azetidinone, 14.5 g (53.5 mmol) of potassium pecoxidisulphate, 13.98 g (80.3 mmol) of dipotassium hydrogen phosphate and 1.33 g (5.36 mmol) of copper sulphate (5H20) in 270 ml of acetonitrile and 130 ml of water is heated to 95°C in an argon atmosphere for 3 1/2 hours at a pH value between 6.5 and 7.0 (occasional addition of 10 g of dipotassium hydrogen sulphate). After cooling and filtration the aqueous phase is discarded and the organic phase is evaporated. The residue is taken up in ethyl acetate and washed with water and sodium chloride solution. After drying over sodium sulphate, filtration and evaporation of the solvent the residue is taken up in ether and filtered. The crude crystals (8.9 g) are chromatographed on Si02 (300 g, 40-63 pm, chloroform:methanol:ethyl acetate 85:10:5).
There are obtained 5.5 g (70%) of (3S,4S)-cis-3-benzyloxy-carboxamido-4-carbamoyloxymethyl -2-azetidinone as colourless crystals, [a]D = +61.2° (c = 1 in methanol).
Melting point 193-195°C.
Elemental analysis calculated for <"13Η15Ν305: IR (Kbr, cm 1): NMR (DMSO, ppm): MS (Cl with NH3): C 53.24, H 5.16, N 14.33% Found C 53.40, H 5.24, N 14.35% 3414, 3315, 1757, 1701, 1610, 1540, 1498 3.31-4.06 (3H,ra.CH-CH2-). 4.95 (lH.dd.4.5 and 9Hz,H3). 5.06 (2H. s.0-CH2). 6.53 (2H,broad, NH2), 7.35 (5H,s.C6H5), 7.95 (1H,d,9Hz,CH^-NH-CO), 8.35 (lH.s, NH-CO) 251 (M+H)+ -CONH .4 g (18.4 mmol) of (3S,4S)-cis-3-benzyloxycarbox-amido-4-carbamoyloxymethyl-2-azetidinone in 200 ml of abs. 34 dioxan are treated at room temperature with 4.3 g (1.3 equivalents) of pyridine-sulphur trioxide complex. The suspension obtained is stirred for 3 hours, subsequently treated with a further 0.99 g (0.3 equivalents) of pyridine-sulphur dioxide complex and the reaction mixture is stirred for a further hour. After the addition of a further 1.37 g (0.4 equivalents) of pyridine-sulphur trioxide complex and stirring for a further 2 hours the solvent is removed partially under reduced pressure and the residue is treated with 110 ml of saturated aqueous sodium bicarbonate solution. The brown solution obtained is left to stand in a refrigerator for 12 hours and the crystals obtained are filtered off. The mother liquor is chromatographed (MCI gel, water-ethanol 1:1 to 9:1). After lyophilization there are obtained 3.5 g (49%) of (3S,4S)--cis-3-benzyloxycarboxamido-4-carbamoyloxymethyl -2--azetidinone-l-sulphonic acid sodium salt as a colourless powder, [α]ρ = +29.6° (c = 0.5 in water).
Elemental analysis IR (KBr. cm-1): NMR (DMSO, ppm): calculated for C, H,,,Ν.,0 SNa: 13 14 3 8 C 39.50, H 3.57. N 10.63% Found C 39.41, H 3.45, N 10.36% 1798. 1758, 1739. 1693, 1584. 1547, 3.9-4.4 (3H,CH-CH2). 4.9 (dd.lH.
NH-CH), 5.1 (s,2H.0-CH2). 6.4 (2H.broad.NH2). 7.4 (5H.s.
C H ). 8.0 (lH.d.NH) b b k) 3.065 g (7.75 mmol) of (3S,4S)-cis-3-benzyloxycarbox-amido-4-carbamoyloxymethyl -2-azetidinone-l-sulphonic acid sodium salt are dissolved in 180 ml of abs. methanol and hydrogenated for 1 hour in the presence of 1.5 g of 10% palladium/carbon. The catalyst is removed by filtration and the solution obtained is evaporated. There are obtained 2.02 g (100%) of (3S,4S)-cis-3-amino-4-carbamoyl-oxymethyl-2-oxo -1-azetidine-sulphonic acid sodium salt.
IR (KBr, cm-1): 3444, 3207, 1754, 1725, 1611, 1249.

Claims (26)

1. A process for the manufacture of a carboxylic acid of the general formula Het—C—COOH iva E \ OCH2-C0OC(R)3 5 in which Het signifies an optionally amino-substituted 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms and optionally also an oxygen or sulphur atom and R signifies 3~alkyl, and the group =NOCH2COOC(R)3 is present at least partially 10 in the syn-form, which comprises cleaving off catalytically the allyl group R5 in an ester of the general formula Het—C—COOR5
2. 11 X N A XOCH2-COOC(R) 3 in which Het and R have the significance given above 15 and R represents allyl. and the group =NOCH2COOC(R)3 is present at least partially in the syn-form. with the aid of a palladium compound in the presence of triphenylphosphine or a tri(lower alkyl)phosphite and in 20 addition in the presence of an alkali metal alkanoate or an organic base.
3. 2. A process according to claim 1. wherein palladium/carbon, a palladium-organic complex with triphenylphosphine or a tri(lower alkyl)phosphite or a palladium salt with a hydrohalic acid or a lower alkane- 5 carboxylic acid is used as the palladium compound.
4. 3. A process according to claim 2. wherein palladium/carbon, palladium chloride or palladium acetate is used as the palladium compound.
5. 4. A process according to any one of claims 1-3. 10 wherein triethylphosphite is used as the tri(lower alkyl)phosphite.
6. 5. A process according to any one of claims 1-4, wherein the cleavage is carried out in the presence of an organic base. 15 6. A process according to claim 5. wherein N-methy1-morpholine or triethylamine is used as the organic base.
7. A process according to any one of claims 1-6, wherein R signifies methyl.
8. 20 B. A process according to any one of claims 1-7, wherein Het signifies 2-amino-4-thiazolyl.
9. A process according to any one of claims 1-8. wherein an obtained carboxylic acid of the general formula Het—C—COOH II N IVa 25 \ OCH2-COOC(R)3 in which Het and R have the signiCicance given in claim 1 and the gcoup »=NOCH2COOC(R)3 is present at least partially in the syn-form, is converted into a benzthiazole thioester of the general formula III in which R and Het have the significance given in claim 1 and the group -NOCH2COOC(R)3 is present at least partially in the syn-form. with dithio-bis-benzthiazole in the presence of a tridower alkyl)phosphite and a base or in the presence of triphenylphosphine.
10. A process according to claim 9. wherein the reaction with dithio-bis-benzthiazole is carried out in the presence of a tri(lower alkyl)phosphite.
11. A process according to claim 10, wherein triethylphosphite is used as the tridower alkyl)-phosphite.
12. A process according to claim 10 or 11, wherein an organic base is used as the base.
13. A process according to claim 12, wherein N-methylmorpholine is used as the organic base.
14. A process according to any one of claims 9-13, wherein an obtained benzthiazole thioester of the general formula III 38 Het— in which Het and R have the significance given in claim 1 and the group =NOCH2COOC(R)3 is present partially in the syn-form, 5 is converted by reaction with a compound, 'Which is present in racemic form or in the form of the 3S-enantiomer, of the general formula 10 15 H2Ii SO3H II 2 wherein E signifies hydrogen, lower alkyl, lower alkenyl, lower alkynyl. lower alkoxycarbonyl, lower alkanoyloxy-lower alkyl, lower alkoxycarbonyl-lower alkenyl, hydroxyiminomethyl. lower alkoxyiminomethyl, carbamoyl, carbamoyl-lower alkenyl or carbamoyloxy--lower alkyl, whereby the groups denoted by lower have up to 7 carbon atoms, into a compound, which is present in racemic form or in the form of the 3S-enantiomer. of the general formula Het-C-COtlH-- « NOa^-cooccR)^cr ^ SO3H wherein Het and R have the significance given in claim 2 20 1 and R has the above significance and the group =NOCH2COOC(R)3 is present at least partially in the syn-form. if desired converting the group -CH2COOC(R)3 into ' carboxymethyl and. if desired, converting a product obtained into a pharmaceutically compatible salt.
15. A process according to claim 14. wherein the reaction of the compounds of formulae II and III is carried out in the presence of an organic amine such as triethylamine.
16. A process according to claim 14 or 15, wherein an optically uniform 3,4-cis compound (especially a 3S.4S compound) of formula II is used.
17. A process according to any one of claims 14-16, wherein 2-(2-araino-4-thiazolyl)-2-[[(Z)-l--(t-butoxycarbonyl)methoxy]iminoJacetic acid 2-benzthia-zolyl thioester is used as the thioester of formula III and the carboxy group is liberated in the reaction product.
18. A process according to claim 17, wherein a t-butoxycarbonyl group is converted into carboxy by treatment with hydrochloric acid or trifluoroacetic acid.
19. A process according to any one of claims 14-18, wherein 2-(2-amino-4-thiazolyl)-2-[[(Z)-l--(t-butoxycarbonyl)methoxy]imino]acetic acid 2-benzthia-zolyl thioester is reacted with (3S.4S)-3-amino-4-car-bamoyloxyraethyl-2-oxo-l-azetidinesulphonic acid and the carboxy group is liberated in the reaction product by treatment with a strong organic acid.
20. A compound of the general formula X Het-C-COOR5 II N Svoch2-cooc(r)3 in which Het and R have the significance given in . 5 claim 1. R signifies allyl and the group sNOCHjCOOCiRJj is present at least partially in the syn-form.
21. A cctnpound in accordance with claim 20, wherein R signifies methyl.
22. A compound in accordance with claim 20 or 21, wherein Het signifies 2-amino-4-thiazolyl.
23. 2-(2-Amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]imino]acetic acid allyl ester.
24. A process according to claim 1 for the manufacture of a carboxylic acid of the general formula IVa given and defined therein, substantially as hereinbefore described and exemplified.
25. A carboxylic acid of the general formula IVa given and defined in claim 1, whenever manufactured by a process claimed in a preceding claim.
26. A compound of the general formula X given and defined in claim 20, substantially as hereinbefore described and exemplified. • F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.
IE1305/83A 1982-06-03 1983-06-02 Process for the manufacture of 1-sulfo-2-oxoazetidine derivatives IE55402B1 (en)

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NZ204386A (en) 1986-12-05
FI832004A0 (en) 1983-06-03
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DE3377061D1 (en) 1988-07-21
ES8504120A1 (en) 1985-04-16
AU558593B2 (en) 1987-02-05
EP0096297B1 (en) 1988-06-15
IL68817A0 (en) 1983-09-30
MC1527A1 (en) 1984-04-13
FI832004L (en) 1983-12-04
EP0096297A3 (en) 1984-04-11
EP0096297A2 (en) 1983-12-21
IE831305L (en) 1983-12-05
DK241883D0 (en) 1983-05-27
PH18877A (en) 1985-10-22
PH21897A (en) 1988-04-07
ES8601123A1 (en) 1985-11-01
NO832001L (en) 1983-12-05
GR78269B (en) 1984-09-26
AU1506883A (en) 1983-12-15
IL68817A (en) 1989-08-15
ES522886A0 (en) 1985-04-16
DK241883A (en) 1983-12-04

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