IE42481B1 - Thiazoline ring cleavage - Google Patents

Description

This invention relates to cleavage of azetidinothiazoline compounds. More specifically, it relates to a process for hydrolytic cleavage of certain thiazoline ring compounds to give 4-mercapto-3-acylamino-2-oxoazetidine derivatives.

The process of the present invention operates according to the following reaction scheme: R‘ R'CONH SH \_/ AHr S acid water N-R , wherein R' is a residue of an acyl group of the formula 10 R'CO--, and R is hydrogen, an optionally substituted hydrocarbyl group (e.g. alkyl (including aralkyl), alkenyl or aryl) or an optionally substituted monovalent amino protecting group (other than optionally substituted hydrocarbyl), preferably containing up to 20 carbon atoms, e.g. acyl deriyed-'from' an organic or an inorganic acid, silyl - or-sulfenyl.

The.products of the present process may be used for preparing useful cephem compounds by cyclization (see later) The optional substituent(s) referred to in the above scheme may be, for example, chosen from halogen (e.g. fluorine, chlorine or bromine), nitrogen functions (e.g. amino, hydrazino, azido, alkylamino, arylamino, acylamino, alkylideneamino, acylimino, imino or nitro), oxygen functions (e.g. hydroxy, alkoxy, aralkoxy, aryloxy, acyloxy or oxo), sulfur functions (e.g. mercapto, alkylthio, aralkylthio, arylthio, acylthio, thioxo, sulfo, sulfonyl, sulfinyl, alkoxysulfonyl or aryloxysulfinyl), carbon functions (e.g. alkyl, alkenyl, aralkyl, aryl, carboxy, carbalkoxy, carbamoyl, alkanoyl, aroyl, aminoalkyl, aralkanoyl or cyano), or phosphorus functions (e.g. phospho (PO^H^) or phosphoroyl (-PO(OH)-)).

Acyl groups which may be represented by R'CO- in the products of the present process include inorganic acyl, (i.e. a group derived from an inorganic oxyacid by removal of a hydroxy group) such as carbonic acyl (e.g. alkoxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl), sulfuric acyl and phosphoric acyl (e.g. dialkoxyphosphinyl, alkoxy PS or alkoxyaminophosphoroyl, in which phosphoroyl means -PO(OH)-)? and organic acyl such as alkanoyl, cycloalkanoyl, aralkanoyl, aroyl, alkylsulfonyl, arylsulfonyl or alkylphosphonyl. These groups can, where possible, be interrupted by a hetero atom in their skeleton or can be unsaturated or substituted by, for example, halogens (e.g. fluorine, chlorine or bromine), nitrogen functions (e.g. amino, hydrazino, azido, alkylamino, arylamino, acylamino, alkylidineamino, acylimino, imino or nitro), oxygen functions (e.g. hydroxy, alkoxy, aralkoxy, aryloxy, acyloxy or oxo), sulfur functions (e.g. mercapto, alkylthio, aralkylthio, arylthio, acylthio, thioxo, sulfo, sulfonyl, sulfinyl, alkoxy-sulfonyl - 4 or aryloxy-sulfinyl), carbon functions (e.g. alkyl, alkenyl, aralkyl, aryl, carboxy, carbalkoxy, carbamoyl, alkanoyl, aroyl, aminoalkyl, aralkanoyl or cyano), or phosphorus functions (e.g. phospho (PO3H2) or phosphoroyl). By the term function is meant a group linking to the rest of the molecule through the atom in question, i.e. a carbon function links with the rest of the molecule by a carbon atom and an oxygen function contains an oxygen atom and links to the rest of the molecule by this oxygen atom.

IO More preferably, the said acyl group can be chosen from those found in penicillin side chains (e.g. phenylacetyl, phenoxyacetyl or heptanoyl), or those groups which are desirable having regard to the antibacterial activity of the desired cephem end products (see later) (e.g. hydrogen, N-tertiary butoxyearbonyl-2-phenylglycinamido, α-(I-carbomethoxy-1-isopropen-2-yl)-amino, α-phenylglycyl, 4-phenyl-2,2-dimethyl-5-oxo-l,3-imidazolidin-l-yl or adiphenylmethoxycarbonyl-a-phenylacetamido).

Representative acyl groups R'CO- include:2o 1) alkanoyl containing from 1 to 5 carbon atoms; 2) haloalkanoyl containing from 2 to 5 carbon atoms; 3) azidoacetyl; 4) qyanoacetyl; ) a group of the formula: Ar-CQQ'-coin which Q and Q' are each hydrogen or methyl; and Ar is phenyl, cyclohexadienyl or a monocyclic heterocyclic aromatic group containing from 1 to 4 nitrogen atoms or an oxygen or sulfur atom and optionally from 1 to 3 nitrogen atoms, and Ar may be optionally substituted by an alkyl or alkoxy group containing from 1 to 3 carbon atoms, chlorine. - 5 bromine, iodine, fluorine, trifluoromethyl, hydroxy, cyano, aminomethyl, amino or nitro; 6) a group of the formula: Ar-G-CQQ'-coin which G is oxygen or sulfur; and Ar, Q, and Q' are as defined in 5) above; 7) a group of the formula: Ar-CHT-COin which Ar is as defined above? and T is i) amino, ammonium, amino substituted by an amino-protecting group substituted from benzyloxycarbonyl, alkoxycarbonyl containing from 1 to 4 carbon atoms, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzhydryloxycarbonyl, cyclopropylmethoxyoarbonyl, methanesulfonylethoxycarbonyl, triphenylmethyl , 2,2,2-trichloroethoxycarbonyl, guanidylcarbamoyl, optionally substituted ureido-carbonyl including 3-methanesulfonyl-2-oxo-imidazolidin-l-yl-carbonyl, alkanoyl containing from 1 to 5 carbon atoms, oxopyrancarbonyl, thioxopyranearbonyl, oxodihydropyridine-carbonyl, homo- or heterocyclicmonocyclic aromatic acyl (optionally substituted by hydroxy, alkanoyloxy containing from 1 to 3 carbon atoms, halogen, trifluoromethyl or alkyl containing from 1 to 3 carbon atoms), or by aminoalkyl containing from 1 to 3 carbon atoms or hydroxyalkyl containing from 1 to 3 carbon atoms, or amino protected in a form of phthalimido or enamino derived from acetoacetates, acetylacetone, acetoacetamide or acetacetonitrile, ii) hydroxy, acyloxy containing from 1 to 7 carbon atoms, carbamoyloxy or aralkyloxy containing from 7 to 12 carbon atoms, iii) carboxy, alkoxycarbonyl containing from 2 to 7 carbon atoms, indanyloxycarbonyl, phenoxycarbonyl, or iv) azido, cyano, carbamoyl, sulfo, or alkoxysulfonyl; 43481 - 6 8) 2-(3-syndone)-alkanoyl containing from 3 to 5 carbon atoms; 9) (2- or 4-pyridon-l-yl)acetyl; ) 5-aminoadipoyl, 5-aminoadipoyl protected at the amino group by aroyl or alkanoyl containing up to 10 carbon atoms, ehloroalkanoyl containing from 1 to 5 carbon atoms or alkoxy carbonyl containing from 2 to 10 carbon atoms; or 5-aminoadipoyl protected at the carboxy group by benzhydryl, 2,2,2trichloroethyl, trialkylsilyl, alkyl containing from 1 to 6 carbon atoms, nitrobenzyl or methoxybenzyl; and 11) a group of the formula: L-O-CO25 in which L is an optionally substituted hydrocarbon group containing from 1 to 8 carbon atoms or isobornyl.

Specific examples of preferred groups R* are benzyl and phenoxymethyl (c.f. natural penicillin side chains).

The preferred group R is a group of the formula given below, and the compounds which are the products of the present process wherein R is as given below may be subjected to cyclization to give 3-oxygenated 3-cephem-4carboxylic acids: CH Hal / R = —C=C , \ COX Y wherein Hal is halogen; COX is carboxy or protected carboxy, preferably containing up to 20 carbon atoms; and Y is hydroxy, protected hydroxy or substituted amino, preferably containing up to 20 carbon atoms. 43481 - 7 The carboxy protecting group which can be represented by X as part of a protected carboxy group COX can, for example, contain up to 20 carbon atoms and can be an oxygen function such as, for example, alkoxy containing from 1 to 8 carbon atoms (e.g. methoxy, ethoxy or tertiary butoxyl), aralkoxy containing from 7 to 20 carbon atoms (e.g. methoxybenzyloxy, nitrobenzyloxy - both substituted aralkoxy, of course - benzyloxy, diphenylmethoxy or trityloxy), mono- or bi-cyclic aryloxy (e.g. phenoxy or naphthyloxy), or organo metaloxy (e.g. trimethylstannyl oxy or trimethylsilyloxy), organic or inorganic acyloxy containing up to 8 carbon atoms, or metal oxy of groups I, II or III in the periodical table (e.g. sodioxy, potassiooxy or magnesiodioxy); or X may be selected from sulfur functions such as those forming thiol esters or thioearboxyr nitrogen functions such as those forming amides, hydrazides or azides; or X may, of course, be some other carboxy-protecting group.

These groups can, where possible, be interrupted by a hetero atom, can be unsaturated or can be substituted by a substituent such as those referred to above (e.g. halogen or the nitrogen, oxygen, sulfur, carbon or phosphorus functions referred to above). Among preferred carboxy protecting groups X are those forming haloalkyl esters containing from 1 to 5 carbon atoms, acylalkyl esters containing from 2 to 10 carbon atoms, alkoxyalkyl- or aminoalkyl esters containing from 2 to 8 carbon atoms, arylester or aralkyl esters containing from 7 to 20 carbon atoms, esters with an oxime containing from 2 to 10 carbon atoms, N-alkoxyamides containing from 1 to 5 carbon atoms, an imide with saccharin, an imide with phthalimide, an N,N‘diisobutylhydrazide, a metal salt or an alkylamine salt containing from 1 to 6 carbon atoms. (In the above, the specified numbers of carbon atoms are for group X), 43481 - 8 Antibacterially preferred carboxyl-protecting groups X include those which form acyloxymethyl esters, phenacyl esters, the benzaldoxime ester, the N,N-dimethylaminomethyl ester, alkali metal salts and alkaline earth metal salts.

Preferred carboxy protecting groups X include tert butoxy, benzyloxy, benzhydryloxy, p-nitrobenzyloxy, p-methoxybenzyloxy, 2,2,2-trichloroethoxy and alkali metal-oxy.

As indicated earlier, Y may be a substituted amino group (e.g. containing from 2 to 20 carbon atoms). Preferred groups Y include dialkylamino, alkylaralkylamino, alkylalkenylamino, alkyleneamino, diaralkylamino and dialkenylamino, all of which are optionally substituted, Group Y is (see later) removed from the molecule during cyclization to form a cephem compound and it can, therefore, be varied considerably, so long as the cephem end product is not disturbed by the variation. Most preferred groups Y are morpholino, alkyleneamino containing 4 to 8 carbon atoms, dialkylamino containing 2 to 6 carbon atoms and diaralkylamino containing 14 to 20 carbon atoms, optionally substit20 uted by C^_3 alkyl or halogen.

Examples of group Y when it is protected hydroxy include cyclopropylmethoxycarbonyloxy and benzyloxycarbonyloxy.

The present cleavage process can be carried out by treating the starting thiazolinoacetidine compounds with acid and water. An equivalent of water is necessary for hydrolyzing the thiazoline ring to give 4-mercapto and 3acylamino groups on the acetidine ring in the resulting product. Preferred acids include mineral acids (e,g. hydrogen halides, sulfuric acid, nitric acid, phosphoric acid, perchloric acid or chloric acid), sulfonic acids (e.g. alkanesulfonic acids, arylsulfonic acids, aralkyl- 9 424S1 sulfonic acids or, especially, α-haloalkanesulfonic acids), α-halocarboxylic acids and polycarboxylic acids. It is further preferred that the acid have a dissociation constant of at least 0.01. A list of specific acids which can be used is:- perchloric acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, trifluoromethanesulfonic acid, trichloromethanesulfonic acid, hydrogen tetrafluoroborate, hydrochloric acid, hydrofluoric acid, hydrobromic acid, nitric acid, phosphoric acid, benzenesulfonic acid, toluenesulfonic acid, bromobenzenesulfonic acid, methanesulfonic acid and ethanesulfonic acid.

The reaction can, if desired, be carried out in a solvent, and preferred solvents are polar solvents capable of dissolving water and the acid used (e.g. ethers, ketones, alcohols, amides, sulfoxides or aqueous solvents), solvents capable of dissolving the starting material (e.g. halohydrocarbons, esters, ethers or ketones), and mixtures thereof.

When a strong acid is used side reactions, e.g. the decomposition of the azetidinone ring, can take place.

The yield can be improved by carefully selecting the reaction conditions, e.g. concentration, temperature and reaction time. Generally, the reaction proceeds rapidly even at room temperature, sometimes within from 10 minutes to 1 hour, to give the desired compound in high yield.

The products of the present process are unstable to alkali and oxygen. The reaction and subsequent work-up should, therefore, be effected without exposure to such conditions (which conditions lead to side reactions).

The products of the process of this invention are useful as intermediates for producing azetidinones, especially cephalosporins. One means of forming cephalosporins from the products of the present process is 43481 -ΙΟΙ I illustrated by the following reaction scheme: Patent Specification No. from whioh the present application Is divided, relates to intermediates which can be used in making cephem compounds, which intermediates are compounds of one of the following formulae: *N B/ Ν SR Y I SR NC=CCH2Hal , COX NCHCOCH_Hal , I 2 cox .NC=CCH Hal I COX -,-NCHCOCH-Hal X I cox wherein A and B are each hydrogen or an amino substituent; R is a hydrogen or a thiol substituent; Hal is halogen; X is a hydroxy or a carboxy-protecting group; Y is hydroxy (when Y is hydroxy it can be in the oxo form), protected hydroxy or substituted amino; and R‘ is a residue of an acyl group of the formula R'CO-. - 11 42481 Patent Specification No. If-XH-flo also relates to the following two cyclization processes which utilize said intermediates as starting materials:A), a process for preparing a compound of the formula: COX COX wherein A, B and X are each as defined immediately above, which process comprises cyclizing a compound of the formula: A 'S'N SH f NC=CCH_Hal I ' 2 j OH COX by treating said compound with an acid, a base or a solvent, 10 if required, in the presence of a catalyst? and B). a process for preparing a compound of the formula: BZ y- OH COX or wherein A, B and X are each as defined immediately above, which process comprises treating an intermediate as defined above wherein Y is disubstituted amino containing from 2 to 20 carbon atoms, with an aqueous acid.

It will be appreciated that, in that the definition of A and B given above means that the group includes within its scope groups R'CONH- as defined above (in terms of the R'CO- moiety thereof) and R in the products (and starting materials) of the process of the present invention may be —C=C COX wherein X, Hal and Y have the same meaning as given above with respect to the intermediates of Patent Specification No. 4-2-4-74 , cyclization process (A) includes the use of the products of the present process as starting materials (wherein Y is hydroxy). Furthermore, process (B) using as a starting material an intermediate wherein Y is disubstituted amino as defined above also includes within its scope (when said intermediate has an azetidinothiazoline ring system) a process which has two aspects, i.e. cleavage of the thiazoline ring within the scope of the present process and cyclization (and conversion of Y to hydroxy). The reader is referred to Patent Specification No. 4-2-4-74 for details of such cyclization.

The following Examples 1-4 are given to further illustrate and describe the invention.

It should be noted that Example 5 describes an overall process leading to a cephem compound without intermediate isolation of any product which is a 4-mercapto-3-acylamino4 2 4 81 - 13 2-oxoazetidine product of the process of this invention. Nonetheless, thiazoline ring cleavage is effected in accordance with this invention using an acid in one stage of the Example cyclization and thiazoline ring cleavage are effected together.

EXAMPLE 1.

To a solution of 3-phenoxymethyl-7-oxo-4-thia-2,6diazabicyclo[3,2,0]hept-2-ene (200 mg) in a mixture of dichloromethane (8 ml) and acetone (8 ml) is added a 30% aqueous solution of perchloric acid (1.0 ml), and the mixture is stirred for 40 minutes at room temperature.

After diluting with excess water, the reaction mixture is extracted with dichloromethane. The extracted solution is washed with water, dried over sodium sulfate, and evaporated. The white crystalline residue is 40-mercapto-3pphenoxyacetamido-2-oxoazetidine, m.p. 137-138°C. [a] 23 + 38.0 + 3.0° [c = 0.261, CHCl + C H 0H(4:l)] .

XR: v NU301 ( Trade Mark) 3290, 3200, 2562, max 1757, 1658, 1549, cm1.

NHR: 5d6_DMSO 3.17brslH, 4.58s2H, S.OObrslH, 5.32dd(9?5Hz)lH, 6.80-7.43m6H.

EXAMPLE 2. 3 In this Example, the designations R , R , R , 1 and 2 refer to Tables I and II given below. Various individual reactions were effected as follows:To a solution of an a-[3-substituted (R1)-7-oxo-4thia-2,6-diazabicyclo[3,2,o]hept-2-en-6-yl]-ra-substituted 2 3 (R )-acetic acid ester (R ) (1) in a solvent is added an acid, and the mixture is stirred at the specified temperature (see Table I) for a specified time (Table I). The reaction mixture is diluted with water, and extracted with - 14 dichloromethane. The extracted solution is washed with water, dried over sodium sulfate, and evaporated to give the desired a-[4-mercapto-3-substituted amino (R1CONH-)-22 oxoazetidin-1-yl]-α-substituted (R )-acetic acid ester (R3) (2).

Table I shows the reaction conditions, and Table II shows the physical constants of various products (2).

In Table I, the crude yield means the weight of the products. They are almost pure when analysed by thin-layer chromatog1O raphy and their NMR spectrum.

Some of them can be purified to give crystalline pure products.

In reactions Nos. 3 and 6, the desired compounds were obtained in low yield, accompanied by a large amount of the starting materials and by-products.

EXAMPLE 3.

To a solution of p-nitrobenzyl a-[3-phenoxymethyl-7oxo-4-thia-2,6-diazabieyclo[3,2,0]hept-2-en-6-yl]-aisopropenylacetate (200 mg) in tetrahydrofuran (5 ml) are added oxalic acid (200 mg) and water (0.5 ml), and the mixture is stirred at room temperature for 3 hours. The chromatogram of the reaction mixture shows the presence of p-nitrobenzyl a-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-l-yl] -α-isopropenylacetate and the starting material.

EXAMPLE 4.

By a procedure similar to that of Example 2, the following compounds may be prepared: (1) 4-mercapto-3-thienylacetamido-2-oxo-1-acetylazetidine from 6-acetyl-3-thienylmethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2, o] hept-2-ene; - 15 434S1 (2) 4-mercapto-3-benzamido-2-oxo-1-trifluoroacetylazetidine from 6-trifluoroacetyl-3-phenyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,o] hept-2-ene; (3) 4-mercapto-3-aeetamido-2-oxo-l-methylazetidine from 3,6dimethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-3-ene; (4) 4-mercapto-3-( a-phenyl-a-chloroacetamido)-2-oxo-1carbethoxycarbonylazetidine from 6-carbethoxycarbonyl-3-(aphenyl-a-chloromethyl)-7-oxo-4-thia-2,6-diazabicyclo[3,2,0] hept-2-ene; (5) a-[4-mereapto-3-formamido-2-oxoazetidin-l-yl] -aisopropylideneacetic acid from a-[7-oxo-4-thia-2,6-diazabicyclo [3,2,0]hept-2-en-6-yl]-α-isopropylideneacetic acid; and (6) 4-mercapto-3-benzylthiocarbonylamino-2-oxo-l-p-toluenesulfonylazetidine from 3-benzylthio-6-p-toluenesulfonyl-7oxo-4-thia-2,6-diazabicyclo[3,2,o]hept-2-ene.

EXAMPLE 5.

Diphenylmethyl a-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3,2,0]hept-2-3n-6-yl] -a-(1-hydroxyethylidene)acetate (4.84 g) is dissolved in tetrahydrofuran (60 ml), the solution is cooled to -20°C and triethylamine (2.84 ml) is added with stirring followed by a dropwise addition of methanesulfonyl chloride (0.82 ml). After 30 minutes morpholine (0.96 ml) is added to the solution of the thusproduced diphenylmethyl a-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3,2,0]hept-2-en-6-yl]-a-(1-methanesulfonyloxyethylidene)acetate at -40°C, the mixture stirred for 3.5 hours and pyridine (0.77 ml) added to the resulting solution of diphenylmethyl a-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-a-(l-morpholinoethylidene)acetate.

The solution is then cooled to -40°C, bromine (0.49 ml) added and the mixture stirred for 30 minutes to give a 43481 -absolution of diphenylmethyl a-[3-benzyl-7-oxo-4-thia-2,6diazabicyclo[3,2,01hept-2-en-6-yl]-< t- (2-bromo-1-roorpho1 i no etbylidcnc)acetate. 5% Hydrochloric acid (72 ml.) and methanol (60 ml) are added dropwise to the stirred solution and the solution is kept at room temperature for 3 hours and then in a refrigerator overnight. The reaction mixture is evaporated and purified to give diphenylmethyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (3.51 g) by recrystallization from n-hexane. m.p. 93-96°C. o o CM OJ OJ TABLE 0-0%s fi •H · fi 0 0 S3 nJ a> PS H to O bS o — o o oj o o oi oi a a o o=o I oi a a o o=o I a o o s Ό fi fi · 0 fi o< a I u ft U — CP QJ β Ό '-x β U β β ·Η q ε •Η <4J Ο Φ rt β Φ ·Η Οί Β< ί ΕΗ Η CM η Ο CM 4J Μ Ο* ΧΡ & η § φ ιη %· $ β ο •rl •Ρ □ φ φ « 43481 Μ* Ο «—I tf ο «Η Ο U CM CM Η Ό CO cm ra ra ο o Ο ϋ CM CM ι—Ι --Ο η cm ra ra ο o 'Ο fi · 0 Ρ ara β ο □ ο ο CM ο ο CM ο ο CM §* Μ α — σι ω S Ό Μ □ m m ω Ο r-l ο ra Ό ω fi *rl Ρ fi Ο Ο Hi £ fi ο •Η · Ρ Ο ο ra Φ φ tf ra ο ra V CM Ο ra ϊςΓ** φ υ CM ra □ I ra CM ra CM ra u ra u ra o a o = u a == = u CM CM CM ra ra ra a ϋ o o O o X XI Xi ra ra ra fi ·Η •S5 Ρ U Φ fi S Φ ·Η tf Η Ο rn coo o ra · r-l • o r-J o ra cn CM ro tf fi fi 0 0 »rt •rl P P 0 0 (tf (tf Φ Φ tf tf % CF COOH rt 240 125 fi Ή Ρ ϋ (tf Φ tf ω υ ffl co O fn ffiNS u —· o o CM CM r-M U J0 CM ffi ffi O U -. *u c ? · O Q ft ffl I TABLE I (Continued) Q fl CN O 01 CN CN CN CN CN O ffl ffl fl ffl rd iX> Φ ϋ U υ u CN cn CN ffl ffl ffl V υ a I S' P □ ~ tP Φ S Ό S P O «5 •SS +1 U 0 S4 ft Em O rd o fl O CN CN in fl H fl O fl ffi § U —o J n ffi ffi o u — u I υ -P Ο P h* •P P xi ft ffi ft CN ffl -« §°. *-» «ςρ m o r-i rd α oo ο o § fl a Ή •P υ ri S ffl £ o •H P O ri ffl tf tf o o CM CM rM □ 2° CM ffi ffi· P p tf β β · 0 £ υ H CM CM r* CM CM o o CM g* M U cn Φ g tf — β M O rH Φ CM rH cn cm CM CM CM rH CM TABLE I (Continued) o O to szr tf cn tf ffi «τ··. a φ cn φ p ffi o CM p CM ffi ffi p U p o to ffi o ι β β ·Η ο ε •Η '·“-* -Ρ Φ ti β Φ ·Η tt ιη Η Ο cn β Ή · •P £ o to ti Φ tt CM ffi ffi U o— a ι CM CM CM 1 ffi ffi ffi JN P P P ffi O O o u XJ XJ XJ Xi ft ft ft ft rH CM H μ Μ «Ρ Μ •μ μ tf •«Η ϋ tf Ο Τ-ί □ ιη ffi · Χ° & cn ϋ ο υ ω ο ιη * ®2 8 j Λ τ-ί Ο Ο ο § cn σ» rH rH rH β β β β ο 0 0 0 •Η •Η Ή •Η ψΙ •μ «μ +J □ ϋ υ ϋ ti ti ti ti Φ Φ φ Φ tt tt tt tt Ph is for phenyl; THP is for tetrahydrofuran; rt is for room temperature; and TsOH is for p-toluenesulfonic acid. 3 W N tt ra Φ 43481 U3 Μ· ra •μ Q) β ra •P MJ β β Φ rd M MJ rtf ra ft ΰ 0 fi V •rl cn ra β TABLE II κ rt V tt tt CM rH e ra m r*· • co in Mp rtf □ • X tt ·. co CM tt rH ra CM O r* ra tt in tt U » CM • X m rH * tt * CM rH tt « rH o in ra • μ II 00 Λ η* τι rH » CM » tt rH in O 0 * rH CM CM s £ t tt tn Mp x rH CM 1> tt ra • 1 CO μ co ra rQ I co co co rt DO tt O 00 rrn • • β rH in V0 t—4 <μ as 3=8 I rt a a o I rf 0) a J3 tt <*) H U X tt Φ u e > CO in tt in vo CM rH tt H in oo rH Mp Mp hco h Ό C 3 Ο Ο ft Ζ Ε Ο *0 β β Ο QiH ε ο ο tompound 3425, 2568, 1776, 2.13d(9)lH, 2.2OsH, 4.55s2H, 5.3OS2H, , 1692, 1522. ca. 5.30m2H, 6.78-8.2OmlOH, 12.6OslH 424S1 - 22 0 ft Ti Φ G G •ri P G ϋ H H w a < H u u cv ffl u I ffl offl o -u ffl u ffl o -u ffl o o XJ Di o XJ ft Ό G G · O P Pi S £ ri* eses show in Hz tj χί ra •P fi G G ra rt P -P •ri rt « tri P< G 0 0 IQ G 0 Ή •ri W &» ra ti ti Ή ro ω η !§· ffl 0 co r-1 «—s. o co Q ffl u □ □ I Ϊ ffl 1 CM ffl U O (5 . XJ ft H in ffl CM CQ ft ffl o ·» rd CM CM SJ • CM CO CM in S. H r· m ffl tri • tPH ffl ffl ra CM f< CM ra ft Ti in cn o Λ TJ in • in CO m « • in m ri* ri* • » 4- • co in n 1* «, ffl + σι ffl ffl o GO *. • VD VD o ft ri* g ra g • rd ft σ o ri* rd ri* ra o -- co rd CO CO r- ϋ ω ffl ·*. ra l 1 H ft TJ VD co CM n * ft CM Γ- O ri* 00 • • in • •ri —· » CM vd CM VD *-* Ti r~ • Ti Tt * CM () ft ·. ffl ffl ffl O tri ft CM CM • • ft fi ffl g CM ft ts in in ι—1 <5 ft • ϋ O K ft cn Ch ffl ffl • >w· in *»-· m cn CM Γ- *n 1 Tt 1 ra ra 1 (J CM CM in in cn o H in tri co ri* ri* r- CM ft CM m tri ri* vo «» • <» • σ» ft CM ft co r- r- CM γ- H n· r- ft γ- ft rd rd rd η H • ft cn ri* ft o ri* VD rri vD cn in cn ft ft ft VD tn VD CM rd CM rd CM H <> ft ri* ft VP ft o CM cn CM CM H ri* ri* VO ri* Γ- ri* Γ- co rd co Η ft Η Ό tj τί G G G G G G 0 0 0 ft ft ftri* ft ft g g g 0 0 0 □ a □ - 23 TABLE IX (Continued) s ta rrt 1 Φ Is* in Μ cn • 0 • • a XJ ιη st· CN ffl N 1 6 a Ο * M· Φ CN a • φ β • irt in ω ·η ιη Φ φ r- «* Χί φ « r* a 44 44 a • o β β CN rrt Φ Φ Φ E Ρ 44 CO * CN Φ Φ tn a rrt ft β » • CN • 0 it Φ CO β U rrt 00 1 g g •Η Φ m o ro ro &» £ irt • rrt 0 0 ω β CN cn » g ft ft Ρ ·Η *—» CN > Φ η CN irt Λ ft a * Ε β u ·. rrt a β 0 tn a CN a υ CN σι CO Φ • ε *—' CN CN Μ· 13 CN o o CN in • £ & cn K CO O in •d* «Φ irt a • m £ £ υ irt 1 CN * ca ID ID δ «—» M* a o 0 υ O 00 ·» rrt CM CN *ο irt a « £ Q £ s_ ID cn P υ 13 Φ £ Y 1 «· in « Is* O βί CN ta 00 rrt 2 • T • • £ CN B rrt m έί c*) cn Ol a a ft W o it u • * • u — o o == □ CN rrt irt Y Y σ» Γ* CN ID w irt irt irt cn . ·» irt o tn o 00 ο χ 00 O m p* it Π) Is· to m ID 1 α β rrt r-l CN rrt CM I W y CN » * * *. rrt £ δ o 00 p* 05 0 u «« o irt rrt X! Xj 05 ID Xf r· ft ft Η cn trt cn trt U 13 13 β β β β · β β , • Β. • 10 ο · ft P- 5 B e 0 0 0 U U u

Claims (19)

1. - 24 CLAIMS:1. A process for preparing a compound of the formula R'CONH SH . N-R wherein R' is a residue of an acyl group of the formula 5 R'CO-, and R is hydrogen, optionally substituted hydrocarbyl or an optionally substituted monovalent amino protecting group '(othqr than optionally substituted hydrocarbyl); which process comprises reacting a compound of the formula: R' S \_/ I with an aqueous acid so as to cleave the thiazoline ring of the starting compound.

2. A process as claimed in claim 1, wherein the acid is a mineral acid, a sulfonic acid, an a-halocarboxylic 15 acid or a polycarboxylic acid.

3. A process as claimed in claim 1, wherein the acid has a dissociation constant of at least 0.01.

4. A process as claimed in claim 1, wherein the acid is perchloric acid, trifluoroacetic acid, trichloroacetic 20 acid, dichloroacetic acid, trifluoromethanesulfonic acid, trichloromethanesulfonic acid, hydrogen tetrafluoroborate, hydrochloric acid, hydrobromic acid, hydrofluoric acid. 4 2481 nitric acid, phosphoric acid, benzenesulfonic acid, toluenesulfonic acid, bromobenzenesulfonic acid, methanesulfonic acid or ethanesulfonic acid.

5. A process as claimed in any one of claims 1 to 4, wherein R' is derived from an acyl group R'CO- which is a group referred to hereinbefore in general or specific exemplification of such acyl groups.

6. A process as claimed in any one of claims 1 to 4, wherein R' is benzyl or phenoxymethyl.

7. A process as claimed in any one of claims 1 to 6, wherein R is hydrogen, hydrocarbyl, acyl derived from an organic or an inorganic acid, silyl or sulfenyl; provided that R may be substituted.

8. A process as claimed in claim 7, wherein R is optionally substituted alkyl (including aralkyl), alkenyl or aryl.

9. A process as claimed in any one of claims 1 to 8 wherein the substituent(s) in group R is/are selected from those referred to hereinbefore.

10. A process as claimed in any one of claims 1 to 6, wherein R rt is a group of the formulas COX Y wherein Hal is halogen, COX is carboxy or protected carboxy, and Y is hydroxy, protected hydroxy or substituted amino.

11. A process as claimed in claim 10, wherein COX and/or Y contain(s) up to 20 carbon atoms.

12. A process as claimed in claim 10, wherein X and/or Y is a group referred to hereinbefore in general or specific exemplification of groups X and/or Y. 4«481

13. A process as claimed in. any one of claims 1 to 12, wherein the reaction is effected in a solvent.

14. A process as claimed in claim 13, wherein the solvent is a solvent referred to hereinbefore in general 5 or specific exemplification thereof.

15. A process as claimed in any one of claims I to 14, wherein during the reaction and a subsequent work-up exposure to alkali and oxygen is avoided.

16. A process as claimed in any one of claims 1 to 10 15, wherein R is a group containing up to 20 carbon atoms.

17. A process as claimed in claim 1 and substantially as hereinbefore described.

18. A process as claimed in claim 1 and substantially as hereinbefore described in Example 1 or Example 3 or in 15 any one of the individual runs of Example 2 or Example 4.

19. A 4-mercapto-3-acylamino-2-oxoazetidine derivative as defined in Claim 1 which has been prepared by a process as claimed in any one of claims 1 to 18.