CH653993A5 - INTERMEDIATE PRODUCTS USED FOR THE PRODUCTION OF NEW 3-AMINO-BETA-LACTAM-1 SULPHONIC ACIDS AND THEIR SALTS. - Google Patents

Description

The invention relates to intermediates which can be used to produce a new class of β-lactam antibiotics. These ß-lactam antibiotics, which are valuable drugs with an action against gram-negative and gram-positive germs, are described in Swiss Patent No. 651 020.

β-lactams with a sulfonic acid group in the free acid form or in the salt form, including internal salts, in the 1-position and an acylamino group in the 3-position are antibiotics with action against gram-negative and gram-positive germs.

The preferred β-lactam antibiotics mentioned above have the general formula I.

§2

R, -NH-C-

1 !

H

-C-R,

-N-SO®M®

(I)

In addition to the above-described β-lactams with a sulfonic acid group in the acid form or salt form in the 1-position and an acylamino group in the 3-position, the invention also relates to β-lactams with a sulfonic acid group in the acid form or salt form (including internal salts ) in the 1-position as well as an amino or azido group in the 3-position. The preferred compounds of this type have the general formula Ia

In the general formulas I and Ia and in the description, the substituents have the following meanings:

Ri is an acyl residue

R2 represents a hydrogen atom or a C ^ alkoxy radical, 5 R3 and R4, which are the same or different, represent hydrogen atoms, alkyl or cycloalkyl radicals, phenyl or substituted phenyl groups or one of the radicals R3 and R4 represents a hydrogen atom and the other radical represents an alkoxycarbonyl -, Alkene -1- yl-, alkyne -1- yl-, 2-phenylethenyl-10 or 2-phenylethynyl group.

M® means a hydrogen atom or a cation.

Unbranched and branched radicals are suitable as alkyl and alkoxy radicals. Residues with 1 to 10 carbon atoms are preferred. Suitable cycloalkyl and cycloalkenyl radicals 15 are radicals having 3 to 7 carbon atoms. The term "alkenyl radical" means unbranched or branched radicals. Residues with 2 to 10 carbon atoms are preferred. Halogen atoms are fluorine, chlorine, chlorine, bromine and iodine atoms. The term substituted phenyl group means a phenyl group substituted by up to three halogen atoms or amino, hydroxyl, trifluoromethyl, lower alkyl or lower alkoxy groups.

The term “protected carboxyl group” means a carboxyl group that has been esterified by a common ester protecting group 25. The groups are known per se; see. e.g. U.S. Patent 4,144,333. The preferred carboxyl protecting groups are the benzyl, benzhydryl and tert-butyl groups.

The term "acyl residue" includes all residues that are derived from an organic acid, i.e. a carboxylic acid, derived by splitting off the hydroxyl group. Certain acyl groups are preferred, but this is not intended to limit the invention. Examples of acyl groups are those radicals which have hitherto been used for the acylation of β-lactam antibiotics, including 6-aminopenicillanic acid and its 35 derivatives and 7-aminocephalosporanic acid and its derivatives; see. e.g. Cephalosporins and Penicillins, edited by H. Flynn Academic Press (1972), DE-OS 2 716 677, BE-PS 867 994, US-PS 4 152 432, 3 971 778 and 4 172 199 and GB-PS 1 348 894. Reference is expressly made here to the content of these publications, insofar as it describes various acyl residues. The acyl radicals listed below serve only to further explain the expression acyl radical. Examples of acyl radicals are thus “(a) aliphatic acyl radicals of the general formula

O

II

R5 — C—

50 in which R5 denotes an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl or cyclohexadienyl radical or is an alkyl or alkenyl radical which is substituted by one or more halogen atoms, cyano, nitro, amino, mercapto , Alkylthio or cyanomethylthio groups is substituted;

ss (b) acyl groups of the general formula m2-c o ^ substituted by aromatic radicals

2 * 4

—C — R,

60

N-SO®M®

(Ia)

65

These compounds are valuable intermediates for the preparation of the corresponding 3-acylamino compounds.

R-7

O

1/

(CH2) n-C-,

653 993

* 7

iW ««

^ CII2-0-C-,

'' 0W-.

0 II

or

o II

h <mW7 ~ c "2" c "•

ry.

■ CH21

V ~ ^ CH2NH2

O

HO - / "V-ÇH-C-

O

II

R10-CH-C-,

I.

r9

O

II

15

R, o-0-CH2-C-o

II

RI0-S-CH2-C- or o o

II II Rio-C-C—,

in which n has the value 0.1, 2 or 3, the radicals R6, R7 and Rs each have hydrogen or halogen atoms, hydroxyl, nitro, amino, cyano or trifluoromethyl groups, C14-alkyl or Ci 4-alkoxy radicals or aminomethyl groups and R9 represents an amino or hydroxyl group, a carboxyl group in the salt form, a protected carboxyl group, a formyloxy group, a sulfo group (sulfonic acid group) in the salt form, a sulfoamino group in the salt form, an azido group, a halogen atom, a hydrazino, alkylhy -drazino, phenylhydrazino or [(alkylthio) thioxomethyl] thio group.

Preferred acyl radicals substituted by aromatic radicals have the formula in which n has the value 0.1, 2 or 3, R9 has the meaning given above and R10 is an unsubstituted or substituted 5-, 6- or 7-membered heterocyclic ring having a, 20 is two, three or four, preferably one or two nitrogen atoms, oxygen atoms or sulfur atoms. Specific examples of heterocyclic radicals are the thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, morpholinyl, pyrimidinyl and tetrazolyl groups. Specific examples of 25 substituents are halogen atoms, hydroxyl, nitro, amino, cyano or trifluoromethyl groups, CM-alkyl and Q 4-alkoxy radicals.

Preferred acyl groups substituted by heteroaromatic radicals are the groups of the general formula given above in which R10 is 2-amino-4-thiazolyl-, 2-amino-5-halogen-4-thiazolyl-, 4-aminopyrimidin-2-yl -, 5-Amino-l, 2,4-thiadiazolyl -5-yl, 2-thienyl or 2-furanyl group;

(d) [[(4-Substituted-2,3-dioxo-1-piperazinyl) carbonyl] -35 amino] -arylacetyl radicals of the general formula

40

O o

II II

-C-CH-NH-C-N

I.

R11

NO

r <

12

in which Rn represents an aromatic radical, including carbocyclic aromatic radicals, for example radicals of the general formula 45

wherein R9 is preferably a carboxyl group in the salt form or a sulfonic acid group in the salt form, and

50

55

^ ÇH-C-

R9

wherein R9 is preferably a carboxyl group in the salt form or a sulfonic acid group in the salt form;

(c) Acyl groups of the general formula substituted by heteroaromatic radicals

O

Rio ~ (CH2) n-C-,

and heteroaromatic radicals, and R12 is an alkyl radical or an alkyl radical which is substituted by one or more halogen atoms, cyano, nitro *, amino or mercapto groups, an arylmethylene amino group of the general formula -N = CH-R] i, in which Ri] have the above meaning has an arylcarbonylamino group of the general formula

O

II

-NH-C-R ,,

60

in which R, i has the meaning given above, or denotes an alkylcarbonylamino group.

Preferred [[(4-substituted-2,3-dioxo-1-piperazinyl) -65 carbonyl] amino] arylacetyl groups are compounds of the general formula given above, in which R12 is an ethyl, phenylmethylenamino or 2-furylmethylenamino group represents;

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(e) substituted oxyimino-arylacetyl groups of the general formula

O

II

-c-c = n-o-ri3

I.

Rn in the R! i has the above meaning and Ri3 is a hydrogen atom, an alkyl, cycloalkyl, alkylaminocarbonyl or arylaminocarbonyl radical of the general formula

O

II

-C-NH-R],

in the R! [has the above meaning, or an alkyl radical substituted by one or more halogen atoms, cyano, nitro, amino, mercapto, alkylthio or aromatic radicals, as defined by the radical Rn, a carboxyl group or a salt thereof , an amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy) phosphinyl or dialkoxyphosphinyl group.

Preferred substituted oxyiminoarylacetyl groups of the general formula given above are compounds in which Ru represents a 2-amino-4-thiazolyl group. Also preferred are compounds in which RI3 represents a methyl, ethyl, carboxymethyl or 2-carboxyisopropyl group;

5 (f) (acylamino) aryl acetyl groups of the general formula

O O

II II

10 -C-CH-NH-C-R, 4th

I.

Rn in which Rn has the meaning given above and R14 is a group of the general formula

20th

(CH2) n- ° -

or an amino, alkylamino, (cyanoalkyl) amino, Ami-25 do, alkylamido or (cyanoalkyl) amido group or the group

NH II

-CH2-NH-C

(> \

NH, 0 1 2 il -CH-CH2-C-NH-CH

S02-N (CH2-CH2-0H) 2,

rN

/ CH3

or

OH

^ —N \ -CII

\ i means.

Preferred (acylamino) aryl acetyl groups of the general formula given above are groups in which R14 represents an amino or amido group. R ,, is preferably a phenyl or 2-thienyl group;

(g) [[[3-Substituted -2- oxo -1- imidazolidinylj-carbonyl] amino] aryl acetyl groups of the general formula such as in the R]] has the above meaning, or a group of the general formula

O

-C-R

16

o o 0 r

II II / c \

-C-CH-NH-C-N

R

u

'N-Rl5 I

ch2 — ch2

in which R]] has the above meaning and R] 5 is a hydrogen atom, an alkylsulfonyl radical, an arylmethylene amino group of the general formula

-N = CH-R "

55 in which R6 is a hydrogen atom, an alkyl or haloalkyl radical, or an aromatic radical as defined by the radical R]], an alkyl or one by one or more halogen atoms, cyano, nitro, Amino or Mer-capto-substituted alkyl radical.

60 Preferred [[[3-substituted -2-oxo -1 - imidazolidinyl] carbonyl] amino] aryl acetyl groups of the general formula given above are those groups in which Rn ■ is a phenyl or 2-thienyl group. Preferably R15 is a hydrogen atom, a methylsulfonyl, phenylmeth-65 ylenamino or 2-furylmethylene amino group.

The expression “cation” here means every positively charged atom or every positively charged atom group. The rest -SOe3M® on the lactam nitrogen atom includes all

Salts of sulfonic acid. Preferred are pharmacologically acceptable salts, but other salts are also useful for purifying the compounds of the invention or as intermediates for the preparation of pharmacologically acceptable salts. The cationic part of the sulfonic acid salts can be derived from organic or inorganic bases. Examples of the cationic part are the ammonium ion, substituted ammonium ions, e.g. Alkylammonium ions, for example the tetra-n-butylammonium ion, hereinafter referred to briefly as tetrabutylammonium ion, alkali metal cations such as lithium, sodium and potassium ions, alkaline earth metal cations such as calcium and magnesium ions, the pyridinium, dicyclohexylammonium, hydrabaminium, n-methylamine and n-methylamine -D-glucaminium ion.

M® can also mean a hydrogen atom.

The above-mentioned β-lactams can be produced chemically. The non-alkoxylated, 4-unsubstituted β-lactams of the general formula I, i.e. the compounds of the general formula I in which R2, R3 and R4 denote hydrogen atoms can be prepared from 6-aminopenicillanic acid or a 6-acylaminopenicillanic acid. The β-lactams of the general formula I, in which R 2 denotes an alkoxy radical, can be prepared from the corresponding non-alk-oxylated β-lactams. Some of the compounds of the invention can be crystallized or recrystallized from aqueous solvents. In these cases, the products can be obtained as hydrates. The invention encompasses the stoichiometric hydrates and compounds which contain different amounts of water, which are obtained, for example, by freeze-drying.

Some of the β-lactams of the general formula I can also be prepared by fermentation. When a strain of Chromobacterium violaceum SC 11 378 is grown, a salt of (R) -3- (acetylamino) -3- meth-oxy -2-oxo -1- azetidinesulfonic acid is formed. The cultivation of various acetic acid bacteria, such as types of Glucono-bacter SC 11 435, provides a salt of (R) -3 [[N- (Dy-Glut-amyl) -D-alanyl] amino] -3- methoxy -2- oxo -1- azetidine sulfonic acid.

β-lactams with a sulfonic acid group in the 1-position and an amino or acylamino group in the 3-position contain at least one chiral center, namely the carbon atom in the 3-position to which the amino or acylamino group is attached. The invention relates to the β-lactams, the stereochemistry of the chiral center in the 3-position of the β-lactam ring is the same as the configuration of the carbon atom in the 6-position of the naturally occurring penicillins, such as penicillin G, and the configuration on the carbon atom in the 7-position of naturally occurring cephamycins, such as cephamycin C.

With regard to the preferred β-lactams of the general formulas I and Ia, the structural formulas were drawn in such a way that the stereochemistry at the chiral center can be seen in the 3-position. According to the current rules of the nomenclature, those compounds of the general formula I and Ia in which R2 represents a hydrogen atom have the S configuration and those compounds of the general formula I and Ia in which the radical R2 represents an alkoxy radical with the R Configuration.

ß-Lactams with a sulfonic acid residue in the 1-position of the ß-lactam ring and an amino group or an acylamino group in the 3-position of the ß-lactam ring show activity against various gram-negative and gram-positive germs. The sulfonic acid group is critical to the activity of the compounds of the invention. β-lactams of the general formulas given above, in which the radical R3 and / or R4 is a hydrogen atom

5,653,993

or an alkyl radical, in particular a methyl group, show a particularly favorable activity.

The compounds of formula (I) can be used to control bacterial infections, including infections of the 5 biliary and respiratory tract, orally or parenterally, for example intravenously or intramuscularly or in the form of suppositories.

The β-lactams of formula (I) are generally prepared by introducing a sulfonic acid group (a sulfo group 10 -SO3- onto the nitrogen atom in the 1-position of the β-lactam ring. This sulfonation can be easily achieved by treatment with a sulfur trioxide complex or with an equivalent sulfonating agent, for example a chlorosulfonate.

15 The most common sulfur trioxide complexes for sulfonation reactions are those with pyridine, lutidine, picolin and dimethylformamide. Instead of a pre-formed complex, the complex can also be formed in situ, for example by using a chlorosulfonyltri-20 methylsilyl ester and pyridine as reagents. Alternatively, the sulfonation can also be effected via an intermediate, for example by first silylating the lac-tam nitrogen atom and then subjecting the silylated compound obtained to a silyl exchange reaction with tri-25 methylsilylchlorosulfonate or a similar reagent. Examples of silylating agents are monosilyltrifluoroacetamide, trimethylsilyl chloride / triethylamine and bis-tri-methylsilyltrifluoroacetamide.

Generally, the sulfonation is carried out in the presence of an organic solvent, such as pyridine, or a mixture of organic solvents, preferably a mixture of a polar solvent, such as dimethylformamide, and a halogenated hydrocarbon, such as dichloromethane.

35 The product initially formed in the sulfonation is a salt of the sulfonated β-lactam. When using pyridine sulfur trioxide, the product initially obtained as the pyridine salt is the β-lactam -1-sulfonic acid. M® therefore means the pyridinium ion. The product has the substructure

40

&& U-SO3M

45

These salts or complexes can be converted into salts of other sulfonic acids by customary methods, for example by treatment with ion exchange resins, crystallization or ion pair extraction. These methods are also suitable for cleaning the products. The conversion of the pyridinium salt into the potassium salt using potassium phosphate or potassium ethylhexanoate, into the tetrabutylammonium salt using tetrabutylammonium hydrogen sulfate or into a zwitterion (betaine) (M® = 55 hydrogen) with formic acid is particularly suitable.

The sulfonation to introduce the sulfonic acid group onto the lactam nitrogen atom can be carried out at various stages of manufacture, including the introduction before the formation of the β-lactam ring. The procedures are explained below-60. The sulfonation reaction is preferably carried out in the presence of a solvent of the type described above and usually at room temperature. If an amino group is present in the compound used, this is preferably protected. Using a 3-amino-β-lactam of the general formula II given below, for example protected by a benzyloxycarbonyl group, the sulfonation reaction is carried out according to the following reaction scheme:

653993

6

CgH5CH2OCO-NH-

O

H2N-

>

3) sulfonation 3 cleavage • çf of the protecting group

* = 4

-R,

Â-SoftP

(II)

(III)

To protect the amino group, other protective groups can of course also be used, for example a tert-butyloxycarbonyl group, simple acyl radicals, such as the acetyl, benzoyl or phenylacetyl group. Furthermore, the amino group can be blocked by a triphenylmethyl group, finally the amino group can be in the form of an azido group which is reduced to the amino group at a later stage. After the protective group has been split off or the azido group has been converted into the amino group, the molecule can be acylated in the customary manner. The acylation of a compound of the general formula III can be carried out, for example, using a carboxylic acid (Rj-OH) or the corresponding carboxylic acid halide or carboxylic anhydride. If the radical R2 represents an alkoxy radical,

the acylation is preferably carried out with an acid chloride or acid bromide. Acylation with a carboxylic acid proceeds smoothly in the presence of a carbodiimide, 15 such as dicyclohexylcarbodiimide, and a compound that forms an active ester in situ, such as N-hydroxybenzotriazole. If the acyl radical Rj contains a reactive functional group, for example an amino or carboxyl group, it may be necessary to first protect these groups, then to carry out the acylation and finally to remove the protective groups from the product obtained. Alternatively, the sulfonation can also be carried out with the 3-acylamino-β-lactam of the general formula IV according to the following reaction scheme:

25th

R.J-NH-

O

* 2 «4

Rj-NH-

■ NH sulfonation "

O

? -R,

n-so | m®

(IV)

(V)

If the radical R2 is a lower alkoxy radical, this can be chlorinated and then the compound process obtained is also carried out in such a way that this radical is reacted with a lower alkoxide. This reaction, either after sulfonation or before sulfonation, is illustrated by the following reaction scheme: is carried out. The acylated nitrogen atom in the 3-position

40

Cl H acyl-N

(R2>

JI-S03 ^

Alkoxide

~ Àcyl-;

• NH-

5-R,

i-so ^

(VI)

The acyl radicals can also mean easily removable radicals which act as a protective group. In this way, the free 3-amino-β-lactam -1-sulfonic acids or their salts are obtained.

(VII)

The β-lactam ring can also be formed by a cyclization reaction. The sulfonation reaction can be carried out before or after the cyclization, for example according to the following reaction scheme:

acyl-NH

R_ enclisie

: T alx. acyl-NH-

<f h

«-SO®Jp

(VIII)

(IX)

In this case, too, the acyl radical can be a group which can be easily split off and serves as a protective group. After the Ab- a hydrogen atom and at least one of the radicals R3 and

Cleavage gives the 3-amino compound. R4 represents a hydrogen atom, can also be derived from amino

The ß-lactams (azetidinones) used, in which R2 acids of the general formula XII

7

653 993

nh-

ch-

oh y ^ 4

-C ^

(XII)

O'

-OH

The protective group can be removed from the 1-position of the compounds of the general formula XVI by reduction with sodium if the radical Y is an alkyl radical. An intermediate of general formula XVII

getting produced. First, the amino group is protected with a conventional protective group, for example a tert-butoxycarbonyl group (hereinafter referred to as Boc for short). Then the carboxyl group of the protected amino acid is treated with an amine salt of the general formula XIII

boc-nh-

* 4

(XVII)

-nh '

Y-0-NH ©, Cle

(XIII)

in which Y represents an alkyl or benzyl radical, in the presence of a carbodiimide to give a compound of the general formula XIV

Boc-NH-CH-

? VR <

-C ~.

* 3

-nh-o-y

(XIV)

implemented.

At least one of R3 and R4 represents a hydrogen atom. The hydroxyl group is then converted into a leaving group V by treatment with conventional reagents such as methanesulfonylchloride (methanesulfonyl is referred to as Ms below). Other leaving groups are the benzenesulfonyl or toluenesulfonyl group or the chlorine, bromine or iodine atom.

The fully protected compound of general formula XV

obtained in which at least one of the radicals R3 and R4 represents a hydrogen atom. If the radical Y represents a benzyl-15 group, the corresponding N-hydroxy compound is obtained in the catalytic hydrogenation, for example with palladium-on-carbon, which after treatment with titanium trichloride provides the intermediate of the general formula XVII, in which at least one of the Residues 20 R3 and R4 represent a hydrogen atom.

The cyclization reaction of the type described above results in an inversion of the stereochemical configuration of the radicals R3 and R4.

As already mentioned above, the β-lactam 25 (azetidinone) can also be converted into a compound of the general formula XVIII

boc-nh-

30th

R4

4 — R.

n-so30 #

(XVIII)

BOC-NH- | H- ^ c—

r3

-nh-o-y sulfonate. At least one of R3 and R4 represents a hydrogen atom.

In an alternative process for the preparation of the compounds of the general formula I in which R2 is a hydrogen atom and at least one of the radicals R3 and R4 is a hydrogen atom, an amino acid amide of the general formula XIX is used as the starting compound

(XV)

40

in which at least one of the radicals R3 and R4 represents a hydrogen atom is cyclized by treatment with a base such as potassium carbonate. This reaction is preferably carried out in an organic solvent such as acetone and under reflux. There is a compound of general formula XVI

nh2-ch-

0H

| / R4

-CL

(XIX)

45

-nh.

BOC-HH-CH ~

-R,

(XVI)

r

-N-O-Y

used, in which at least one of the radicals R3 and R4 represents a 50 hydrogen atom.

After protection of the amino group with a conventional protective group (hereinafter referred to as A), for example a benzyloxycarbonyl group, and conversion of the hydroxyl group into a leaving group V, such as Ms, a compound of the general formula XX

Obtain OMs in which at least one of the radicals R3 and R4 is a hydrogen atom.

The cyclization of the compounds of the general formula XIV can also be carried out without prior conversion of the hydroxyl group into a leaving group. The reaction of a compound of the general formula XIV with triphenylphosphine and azodicarboxylic acid diethyl ester yields a compound of the general formula XVI in which at least one of the radicals R3 and R4 denotes a hydrogen atom.

60

ANH-

T

(XX)

Cr

• NH.

obtained in which at least one of the radicals R3 and R4 is a hydrogen atom and A is a protective group.

In the sulfonation of the compounds of the general formula XX, compounds of the general formula XXI

653 993

anh ch-

OMs l ^ -R,

U & -

■ nhso a®

obtained in which at least one of the radicals R3 and R4 is a hydrogen atom.

The cyclization of the compounds of general formula XXI is carried out with a base such as potassium carbonate. The reaction is preferably carried out in a mixture of water and an organic solvent, e.g. a halogenated hydrocarbon, such as 1,2-dichloroethane, under reflux. Compounds of the general formula XXII

Cooling again to -5 ° C., 59.5 g of 1-threonine are added, and the mixture is warmed to room temperature and stirred for 16 hours. Then the reaction (XXI) mixture is evaporated and 2 hours at a pressure of

510-1 Torr evacuated. It leaves a viscous oil. The product is used immediately in the next stage.

B) Threoninamide

The crude product from stage (a) is dissolved in 2.5 liters of methanol and cooled to -5 ° C. in an ice-brine bath. The solution obtained is saturated with ammonia gas. The cooling bath is then removed, the reaction vessel is closed and left to stand for 3 days. Most of the unreacted ammonia is then removed from the water jet pump. 100 g of sodium bicarbonate and 50 ml of water are added to the residue and the mixture is evaporated. It leaves a viscous oil.

hang on

(XXII)

CP

N-SO® * ^

obtained in which at least one of the radicals R3 and R4 is a hydrogen atom.

The removal of the protective group A from the sulfonated β-lactam of the general formula XXII and the corresponding compounds in which the radical R2 is an alkoxy radical by catalytic hydrogenation gives compounds of the general formula XXIII

h2n-

(XXIII)

N-S03Qbß

in which at least one of the radicals R3 and R4 represents a hydrogen atom and R2 represents a hydrogen atom or an alkoxy radical. These compounds can in the corresponding zwitterion of the general formula XXIV

mf-

he

(XXIV)

n-s03®

are transferred in which at least one of the radicals R3 and R4 is a hydrogen atom. This can be achieved by treatment with an acid such as formic acid.

If the protective group A is a Boc group, this protective group can be eliminated from the compounds of the general formula XXII by treatment with an acid, such as formic acid. The corresponding zwitterion of the general formula XXIV is obtained.

The example explains the invention.

example

(3S-trans) -3- amino -4- methyl -2- oxo -1- azetidinsulfonic acid A) threonine methyl ester hydrochloride

500 ml of methanol are placed in a flask and cooled to -5 ° C. in an ice-common salt bath. 130 ml of thionyl chloride are introduced under nitrogen as a protective gas at such a rate that the temperature of the reaction mixture remains between 0 and 10.degree. After this

C) Benzyloxycarbonylthreoninamide

20 The crude product of stage (B), which already contains the required amount of sodium bicarbonate, is diluted to 1 liter with water. A solution of 94 g (88 ml of 90 percent pure material) of benzyloxycarbonyl chloride in 25 80 ml of tetrahydrofuran is then added to the solution with vigorous stirring within 1 hour. The reaction mixture is then stirred for a further 16 hours and then extracted first with 500 ml and then twice with 250 ml of ethyl acetate. The ethyl acetate extracts are combined, dried over magnesium sulfate and evaporated. The crystalline residue obtained is dissolved in 250 ml of hot ethyl acetate, 300 ml of hexane are added and the mixture is boiled until a clear solution is obtained. After cooling, the crystals formed are filtered off and dried. 104 g of the title compound are obtained.

35

D) Benzyloxycarbonylthreoninamide -0- mesylate

Under argon as a protective gas, 100 g of benzyloxycarbonylthreoninamide are dissolved in 400 ml of anhydrous pyridine and cooled in an ice-salt bath. The solution obtained is then mixed with 36.8 ml (54.5 g) of methanesulfonyl chloride with stirring within 15 minutes. The mixture is stirred for a further 2 hours and then 0.3 equivalents of methanesulfonyl chloride are added. The reaction mixture is stirred for 1 hour, then poured into a mixture 45 of 1.5 liters of ice and 2 liters of water. The resulting slurry is stirred for an additional 30 minutes and then filtered. The crude product is then dried in a vacuum drying cabinet at 60 ° C. for about 16 hours. 109 g of the title compound are obtained.

50

E) N-sulfonylbenzyloxycarbonylthreoninamide -0- mesylate tetrabutylammonium salt

A solution of 17.8 ml of 2-picoline in 90 ml of methylene chloride is cooled to -5 ° C. in an ice-sodium salt bath 55 and mixed with 5.97 ml of chlorosulfonic acid at such a rate that the temperature of the reaction mixture remains below 5 ° C. A suspension of 7.56 g of benzyloxycarbonylthreoninamide-0-mesylate in 120 ml of methyl 60 enchloride is then added to the solution obtained by means of an injection syringe. The heterogeneous mixture obtained is heated under reflux for about 16 hours. The resulting clear solution is poured into 500 ml of a 0.5 molar phosphate buffer solution with a pH of 4.5 and 120 ml of methylene chloride are added. The organic phase is separated off and washed once with 100 ml of the phosphate buffer solution. The aqueous phases are combined and treated with 10.2 g of tetra-n-butylammonium hydrogen sulfate and once with 300 ml and twice with 150 ml of methylene chloride ex

9

653 993

trahed. The methylene chloride extracts are combined and dried over sodium sulfate. The solution is then evaporated. 12.7 g of a foam remain.

F) (3S-trans) -3- amino -4- methyl -2- oxo -1- azetidinsulfonic acid

A mixture of 5.52 g of potassium carbonate in 20 ml of water and 160 ml of 1,2-dichloroethane is heated under reflux and with a solution of 15.5 mmol of N-sulfonylbenzyloxy-carbonylthreoninamide -0- mesylate-tetrabutylammonium salt in 20 ml of 1,2 -Dichloroethane added. Another 20 ml are used for rinsing. The mixture is then heated under reflux for 30 minutes, then placed in a separatory funnel, diluted with 50 ml of water and 100 ml of methylene chloride and left to separate the phases. The organic phase obtained is dried over sodium sulfate and evaporated. Crude (3S-trans) -3- benzyloxycarborylamine -4- methyl -2- oxo -1- azetidinesulfonic acid tetrabutylammonium salt is obtained. The crude product is dissolved in 250 ml of ethanol, mixed with 0.8 g of 5 percent palladium-on-carbon and hydrogen is passed through the solution. After 90 minutes, the catalyst is filtered off through diatomaceous earth. The filter residue is washed with 50 ml of ethanol. The filtrate and the washing solution are combined and 1.2 ml of formic acid are added. The title connection is eliminated. The mixture is stirred for a further 1 hour and then filtered. The product is dried for 1 hour at 10 "1 torr. Yield 1.1 g. A second crystal yield is obtained after evaporating the filtrate and adding further formic acid to the residue. 1.3 g of the title compound are obtained. The compound melts above is 218 ° C with decomposition. [A] D - 41.1 (c = 1 in H20). NMR (D20) 1.58 (3H, d = 7), 4.80 (2H, M).

C.

Claims (3)

653993 PATENT CLAIMS 1. Intermediates of the general formula - R.J-NH- -NH-SO in which R) is a hydrogen atom or the group Rp-NH-denotes a protected amino group, R3 and R4, which are identical or different, denote hydrogen atoms, alkyl or cycloalkyl radicals, phenyl or substituted phenyl groups or one of the radicals R3 and R4 is a hydrogen atom and the other radical is an alkoxycarbonyl, alkene-1-yl, alkyne-1-yl, 2-phenylethenyl or 2-phenylethynyl group, M® is a hydrogen atom or a cation and V is a cleavable group. 2. Intermediates according to claim 1, wherein the protected amino group is an acyl-amino group. 3. Intermediates according to one of claims 1 and 2, wherein the removable group V is a methanesulfonyl, benzenesulfonyl or toluenesulfonyl group or is a chlorine, bromine or iodine atom.