CH656123A5 - HETEROCYCLIC ACETIC ACID DERIVATIVES AND METHOD FOR THEIR PRODUCTION. - Google Patents

Description

The invention relates to heterocyclic acetic acid derivatives 35 and a process for their preparation. The new compounds correspond to the general formula (I)

chgcoox

I.

• CHgCOOX «

(I)

0 ^

«

wherein the meaning of Y1, Y2 and X is the same as above, removing the aminophenyl protecting group.

4. The method according to claim 3, characterized in that the aminophenyl protective group is removed with an oxidizing agent.

wherein Y1 and Y2 together represent a ketal group or a thioketal group and

X represents an arylmethyl or diarylmethyl group. The azetidine-acetic acid derivatives of the general formula (I) are new. They can be used as intermediates in the production of thienamycin 55 and its analogs. The compounds of the formula I can be converted into thienamycin and its analogs according to the following reaction scheme:

f CHgCOQX

H? / Pd / c

Ì * CH ^ COOH

* y iL

3rd

656 123

• Salt of the malanoic acid half-ester.

H

! ^ CH2C0CN2C00Q

SIH

Sulfonic acid azide

0 ^

/

H

! ^ H2co

CHo

I.

NH COOQ

Rh salt

H

f

// 0

- N-

• COOQ

0- acylation

+ Mercaptan

Salt formation

H

N.

COOQ

Thienamycin is an antibiotic with a broad spectrum of activity. It was first produced microbiologically (US Pat. No. 3,950,357) and later also synthetically (DE-OS No. 2,751,597).

The aim of the invention was to provide a new compound for a synthesis in which the azetidinone skeleton and the a-hydroxyethyl side chain (or a side chain which can be easily converted to this) are built up at the beginning of the synthesis and the key process obtained

60 bond to thienamycin or its analogs can then be worked up.

It has now been found that when acylating a dialkylaminomalonate protected in the amino group with di-65 ketene and reacting the acylated product with an alkali metal alcoholate and iodine, an azetidinone of the general formula (IX) having an a-acetyl side chain is obtained is suitable as a key intermediary.

656 123

4th

HjC

0

c

(cooz),

(ix)

In the general formula (IX), Z represents an alkyl group with 1-5 carbon atoms.

The new intermediaries of the general formula (IX) and their preparation are the subject of Hungarian Patent No. 181 186, but their preparation is also dealt with in the example section.

It is advantageous to protect the keto group in the a-C-acetyl side chain of the compound of the general formula (IX) by a ketal group which can be split off later or a thioketal group before the conversion to thienamycin or its analogs. In particular, it is expedient to introduce an ethylene ketal or He mithioketal protective group with ethylene glycol or one of its thio analogs, for example mercaptoethanol. The compound of the general formula (VIII) obtained in this way

V

Y1 y2

_ \ cx_

. (cooz),

wherein Y1 and Y2 together represent a ketal group or thioketal group, preferably the ethylene ketal group or their thio analogs, and the meaning of Z is the same as above, is reacted with an alkali halide in pyridine or in aqueous dimethyl sulfoxide. In this way, the compounds of the general formula (VII) are obtained

H3 °

ï1, Ï2

-V_

h cooz

where the meaning of Y1, Y2 and Z is the same as above.

The compounds of the general formula (VII) are the mixtures of the ice and trans isomers. The isomers can be separated from one another by chromatography or on the basis of differences in solubility. The separated trans isomer of the general formula (VIIa)

HC

Y1 / Ï2 - c

h h

0

cooz is hydrolyzed, and thereby the trans-carboxylic acid of the general formula (VI) is obtained.

(vi)

i5 However, it is more advantageous to hydrolyze the entire isomer mixture, since the hydrolysis is selective (only the transester is hydrolysed).

The trans-carboxylic acid of the general formula (VI) is then reacted first with a carboxyl group activator, then with diazomethane, and the compound of the general formula (V) obtained in this way

- cochil

(viii)

(v)

is subjected to the Wolff rearrangement (di-azo-ketone rearrangement) in the presence of water. The 35 compounds of the general formula (IV) are obtained

4-ch2cooh

(vii)

50

55

■ N

(Vlla)

b

(iv)

i.e. the azetidine acetic acids forming the starting substances of the present invention. In the general formulas (VI) - (IV), the meaning of Y1 and Y2 is the same as above.

The manufacture of intermediaries is discussed in the example section.

The phenyl group protecting the amide group had to be removed from the starting compounds of the general formula (IV). This problem was solved indirectly: a nitrrophenyl group was first formed by nitriding, from which an aminophenyl group was formed by reduction, and this is split off after the esterification of the acetic acid side chain. Nothing can be found in the literature about the cleavage of a phenyl protective group from β-lactam nitrogen.

The invention accordingly also relates to a process for the preparation of compounds of the general formula (I), in which Y1 and Y2 together represent a ketal group or a thioketal group and X denotes an arylmethyl or diarylmethyl group.

The compounds are prepared according to the invention by using a compound of the general formula II

ï1 ï2

*, c

H

1

H

• CHgCOOX

NH.

N. y 2

t)

wherein the meaning of Y1, Y2 and X is the same as above, removing the aminophenyl protecting group.

The compounds of the formula II can be obtained by nitriding and then reducing a compound of the general formula IV, in which the meaning of Y1 and Y2 is the same as above, and the compound of the general formula III obtained

(iii),

5 656123

(II) Effect of nitric acid on acetic anhydride formed, which dissolves in the acetic anhydride used in excess.

A compound of the general formula s (III) with A = nitro group is obtained. This is reduced. Of all the reduction methods, catalytic hydrogenation has proven to be the most suitable. The compound of the general formula (III) bearing an amino group as substituent A is either isolated from the reaction mixture or is preferably reacted immediately, in a manner known per se, to give an ester of the general formula (II).

The esters of the general formula (II) are formed with the esterifying agents which give off the esterifying group X. Phenyldiazomethane and diphenyldiazomethane have proven particularly suitable for this purpose.

The substituent protecting the amide group (the phenyl group converted to the aminophenyl group) is then removed from the esters of the general formula (II) obtained. This is done with suitably chosen oxidizing agents, 20 for example with the mixture of a cerium (IV) salt and mineral acid or preferably with chromium (VI) oxide in glacial acetic acid. The resulting product of general formula (I) is separated from the reaction mixture.

The invention is explained in more detail with reference to the following examples, but is not restricted to these examples.

wherein the meaning of Y1 and Y2 is the same as above and A after nitriding is nitro group, after reduction is amino group, in a manner known per se to give an ester of the general formula (II)

30th

35

HC

ï1 Ï2 -ci-

H !

H

"CHgCOOX

NH.

X5

wherein the meaning of Y1 and Y2 and X is the same as above, and from this cleaves the aminophenyl protecting group, or a compound of the general formula (III) in which the meaning of Y1 and Y2 is the same as above and A stands for amino group, in a manner known per se to an ester of the general formula (II), in which the meaning of X, Y1 and Y2 is the same as above, and the aminophenyl protective group is removed from the compound of the general formula (II) .

The compounds of general formulas (III), (II) and (I) are all new. They are available as racemates. Their conversion to thienamycin or its analogs is shown in the attached reaction scheme.

It is preferable to start from an azetidine acetic acid derivative protected on the amide group by a phenyl group. The raw material is nitrided first. The mixture of nitric acid and acetic anhydride at temperatures around 0 ° C., expediently at temperatures between −10 and + 5 ° C., is expediently used as the nitriding mixture. The actual nitriding agent is that in Example

Benzhydryl- [trans- / 3- (2-methyl-l, 3-dioxolan-2-yl) -

4-oxo-2-azetidinyl / acetate]

0.45 g (1 mmol) of benzhydryl- [trans- / 1- (2-aminophenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl / acetate ] are dissolved in 2 ml of glacial acetic acid. The solution is mixed at room temperature with the solution of 0.2 g (2 mmol) of chromium (VI) oxide (Cr03) in a mixture of 2 ml of glacial acetic acid and 0.2 ml of water. The solution is stirred at room temperature (II) for 30 hours, then poured into 10 ml of ethylene acetate and finally washed neutral with 5% aqueous sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulfate and, after filtering, evaporated in vacuo. The evaporation residue is purified by preparative thin layer chromatography (adsorbent: silica gel 60 PF254 + 366; developer: benzene and acetone in a ratio of 7: 3). 0.09 g (30%) of the product named in the title are obtained. Op .: 129-130 ° C (ethanol)

'H NMR (CDCIj) 8 = 1.39 s (3H), 2.63 dd (2H, J = 4.4 Hz) and 2.89 dd (2H, J = 9.1 Hz), 3.97 m (5H), 6.12 s (IH), 7.28 s (10 H).

so The starting substance of the example is produced in the following way.

a) 38 g (0.152 mol) of diethyl (anilino-malonate) (R. Blank: calc. 31.1815 / 1898 /) in 38 ml of glacial acetic acid with 15.3 g (13.9 ml, 0.182 mol) of diketene for half an hour

55 cooks. The glacial acetic acid is distilled off in vacuo on a water bath. The oily residue is crystallized by trituration with ether. 36.5 g (72%) of diethyl (N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate) and / or its tautomer are obtained. Melting point: 60 98-99 "C (ethyl acetate / petroleum ether).

Elemental analysis for CnH2iN06 (M = 335.35)

calculated,%: C 60.88 H 6.31 N4.18 found,%: C 60.83 H 6.15 N4.43.

IR (KBr.): 3350, 2950, 1760, 1750 d, 1700cm- ', es' H-NMR (CDC13): S 1.02 (t, 3H), 1.3 (t, 3H), 1.6 (s, 3H), 2.8 (s, 2H), 3.6 (b, s, 1H), 4-4.45 (m, 4H), 7.2 (s, 5H).

b) 10.2 g (0.447 mol) of metallic sodium are dissolved in 250 ml of anhydrous ethanol. Become the solution

656 123

6

first 50 g (0.149 mol) of diethyl (N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate) (prepared as described under a)) and then, with vigorous stirring, the solution of 37.9 g (0.149 mol) of iodine in 200 ml of anhydrous ether. After the reaction is over, 8.5 ml (8.9 g, 0.149 mol) of glacial acetic acid, 200 ml of water and 100 ml of ether are added to the reaction mixture. The organic phase is separated off and the aqueous phase is shaken out with 100 ml of ether. The ethereal phases are combined, dried over magnesium sulfate and evaporated after filtering. The oily residue is recrystallized from 50 ml of 2-propanol. 31 g (62%) of diethyl (3-acetyl-1-phenyl-4-oxo-2,2-azetidine dicarboxylate) are obtained. Melting point: 55-56 "C (2-propanol).

Elemental analysis calculated for Ci7H19N06,%: C 61.25 H 5.75 N4.20 found,%: C 61.38 H 5.89 N4.24.

IR (KBr): 1770.1740, 1720 cm- '.

'H NMR (CDCI3): 5 1.12 (t, 6H), 2.3 (s, 3H). 4.25 (q, 4H), 4.75 (s, 1H), 7.0-7.6 (m, 5H).

c) 28.5 g (0.085 mol) of diethyl (3-acetyl-1-phenyl-4-oxo-2,2-azetidine dicarboxylate) (prepared according to b) are mixed with 90 ml of anhydrous dioxane and 21 g (18.8 ml, 0.34 mol) of anhydrous ethylene glycol. 36.5 g (31.5 ml, 0.255 mol) of boron trifluoride diethyl etherate are added dropwise to the solution with stirring and ice-water cooling. The solution is stirred at room temperature for two hours and then neutralized with saturated aqueous sodium carbonate solution. The neutral solution is diluted with 100 ml of water and then with

3 x 50 ml of diethyl ether extracted. The organic phase is dried over magnesium sulfate and, after filtering, evaporated in vacuo. The oily residue crystallizes when triturated with ether. 28.5 g (90%) of diethyl- [l-phenyl-3- (2-methyl-l, 3-dioxolan-2-yl) -4-oxo-2,2-azetidine-dicarboxy-lat] are obtained. Melting point: 59-61 C (gasoline). Elemental analysis calculated for C19H-> 3N07,%: C 60.47 H 6.14 N3.71 found,%: C 60.74 H 6.21 N3.79.

IR (KBr): 1770.1740 cm "'

1 H-NMR (CDCI3): 5 1.18 (t, 3H, J = 7.2 Hz), 1.24 (t, 3H, J = 7.2 Hz), 1.51 (s, 3H), 3.92 (m, 4H), 4.3 (m, 5H), 7.2 (m, 5H).

d) 28.5 g (0.075 mol) of diethyl- [l-phenyl-3- (2-methyl-l, 3-dioxolan-2-yl) -4-oxo-2,2-azetidine dicarboxylate] are combined in one Mixture of 44 ml of dimethyl sulfoxide, 5.6 g (0.1 mol) of sodium chloride and 3.05 ml (0.17 mol) of water at 175 C until the reaction has ended. The course of the reaction is monitored by thin layer chromatography (adsorbent: silica gel G according to steel, developer: benzene and ethyl acetate in a ratio of 6: 4). The solution is poured into 200 ml of saturated aqueous sodium chloride solution and extracted with 3 x 150 ml of diethyl ether. The organic phase is dried over magnesium sulfate and evaporated after filtering. The oily residue (16.4 g) is in

100 ml of ethanol were dissolved and the solution of 2.15 g (0.054 mol) of sodium hydroxide in 30 ml of water was added to the solution with ice-water cooling and constant stirring. The reaction mixture is stirred for 30 minutes, then treated with 150 ml of water and extracted with 3x20 ml of diethyl ether. The aqueous phase is strongly acidified (pH = 1) with concentrated aqueous hydrochloric acid and extracted with 3 x 50 ml dichloromethane. The organic phase is dried over magnesium sulfate and evaporated after filtering. The oily residue crystallizes from benzene. 12 g (56%) of trans-l-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-azetidine-carboxylic acid are obtained. Melting point: 165 ° C (benzene).

Elementary analysis for Ci4HijN05 (M = 277.27)

calculated,%: C 60.64 H 5.45 N 5.05 found,%: C 60.64 H 5.72 N4.99.

IR (KBr): 3500-2700. 1770. 1730 cm- '

5 1 H NMR (CDC1,): 6 1.5 (s, 3H), 3.69 (d, 1H, J = 3 Hz), 4.0 (m, 4H), 4.42 (i.e. ÎH, J = 3 Hz), 7.3 (m, 5H), 7.55 (s,

1H).

e) 13.8 g (0.05 mol) of trans-l-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic acid are in

10 100 ml of anhydrous tetrahydrofuran dissolved. 5.55 g (7.7 ml, 0.055 mol) of ethyl (chloroformate) are added to the solution at -15 ° C. The mixture is stirred for 20 minutes, then the salt which has separated out is filtered off under a nitrogen atmosphere and the solution of 22.6 g (0.15 mol) of diazomethane prepared with diethyl ether is added to the filtrate with stirring. After the gas evolution has ceased, the excess of the diazomethane is decomposed by adding glacial acetic acid and the solution is evaporated. The oily residue crystallizes when triturated with ether. 20 11.5 g (77%) of trans-4- (diazo-acetyl) -l-phenyl-3- (2-methyl-l, 3-dioxolan-2-yl) -2-azetidinone are obtained. Melting point: 96-97 C (benzene / ether).

IR (KBr): 2150.1760, 1635 cm ~ '

1 H NMR (CDC1,): 5 1.50 (s, 3H), 3.5 (d, IH, J = 2.6 25 Hz), 3.50 (m, 4H), 4.34 (d , IH, J = 2.6 Hz), 5.45 (s, 1H), 7.25 (m, 5H).

f) 3.8 g (0.0126 mol) of trans-4- (diazo-acetyl) -l-phenyl-3- (2-methyl-l, 3-dioxolan-2-yl) -2-azetidinone are combined in one Mixture of 100 ml tetrahydrofuran and 50 ml water

30 solves. The solution is irradiated at room temperature under a nitrogen atmosphere in a photoreactor with a high pressure mercury lamp. The course of the reaction is monitored by thin layer chromatography (adsorbent: silica gel G according to steel; benzene and acetone in a ratio of 35 7: 1). After the reaction is over, the tetrahydrofuran is removed in vacuo. The residue is made alkaline with 20% aqueous sodium hydroxide solution and extracted with 3 x 15 ml dichloromethane. The aqueous phase is acidified to pH 1-2 an-40 with concentrated aqueous hydrochloric acid and then extracted with 3 x 20 ml dichloromethane. The organic phase is dried over magnesium sulfate and evaporated after filtering. The product crystallizes when triturated with ether. 1.8 g (50%) of [trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl] acetic acid 45 are obtained. Melting point: 128-129 CC (ethanol). Elemental analysis for C15H17NO5 (M = 291.29)

calculated,%: C 62.00 H 5.88 N4.82 found,%: C 61.75 H 5.86 N5.08.

IR (KBr): 1760.1740 cm "1 so 1 H NMR (CDCI3): 5 1.48 (s, 3H), 2.65 (dd, 1H, Jgem = 15 Hz, JV1C = 8 Hz) + 3.12 (dd, J "em = 15 Hz, Jvi (; = 8 Hz) + 3.47 (d, IH, J = 2.5 Hz), 3.98 (m, 4H), 4.4 (m, 1H ), 7.3 (m, 5H), 9.33 (b, s, 1H).

g) 0.81 ml of concentrated nitric acid (p = 1.5) are added dropwise to 3 ml of acetic anhydride with constant stirring on an ice water bath so that the temperature of the solution does not rise above + 5 ° C. The solution of 2.9 g (0.01 mol) of [trans-l-phenyl-3- (2-methyl-

60 l, 3-dioxolan-2-yl) -4-oxo-2-azetidinyl] acetic acid added dropwise in 20 ml of anhydrous dichloromethane. The mixture is stirred for one hour and then poured onto ice water. The phases are separated. The aqueous phase is extracted with 2 x 25 ml dichloromethane. The combined organic phases are dried over magnesium sulfate and, after filtering, evaporated in vacuo. The oily residue crystallizes when triturated with ether. 1.95 g (58%) [trans-3- (2-methyl-1,3-dioxolane-2-

yl) -1 - (2-nitrophenyl) -4-oxo-2-azetidinyl] acetic acid are obtained. Melting point: 175-176 C (ethanol).

Elemental analysis for C | 5Hi6N-> 07 (M = 336.33) calculated, 0 / «: C 53.57 H 4.79 N8.33 found,%: C 53.31 H 4.68 N8.21

IR (KBr): 3600-2900, 1740, 1540, 1340 cm- '.

h) 0.336 g (1 mmol) of [trans-3- (2-methyl-1,3-dioxolan-2-yl) -1 - (2-nitrophenyl) -4-oxo-2-azetidinyl] acetic acid are obtained in 15 ml of methanol dissolved and in the presence of 0.05 g of palla

7 656123

activated charcoal hydrogenated under atmospheric pressure. The catalyst is filtered off and the filtrate is evaporated. The oily residue is dissolved in 10 ml of dichloromethane, the solution is mixed with 0.17 g (1 mmol) of diphenyldiazomethane and stirred for 24 hours. Then the solution is evaporated. 0.4 g (90%) benzhydryl- [trans- / l- (2-aminophenyl) -3- (2-methyl-l, 3-dioxolan-2-yl) -4-oxo-2-azetidinyl / -acetate] are obtained.

IR (KBr): 1740, 1720 cm- '

io MS: m / z 472 (M +).

20th

25th

30th

35

40

45

50

55

60

S

Claims (7)

656123 2nd PATENT CLAIMS 1. Compounds of general formula I H3G -CH2COOX (I) 5. The method according to claim 3 or 4, characterized in that removing the aminophenyl protective group with chromium (VI) oxide in glacial acetic acid. 6. The method according to claim 3 for the preparation of benzohydyl- {trans- [3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-aceti-dinylj-acetate}, characterized that from benzhydryl- {trans - [- l- (2-aminophenyl) -3- (2-methyl-l, 3-dioxolan-2-yl) -4-oxo-2-azetidinyl] acetate; the aminophenyl protecting group removed. 7. Compounds of the general formula II wherein Y1 and Y2 together represent a ketal group or an is thioketal group and X represents an arylmethyl or di-arylmethyl group. 2. Benzhydryl- {trans- [3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl] acetate} as a compound according to claim 1. 3. Process for the preparation of heterocyclic acetic acid derivatives of the general formula I B3C Y1 Y2 H -> c 'I (II); "CHgCOOI NH, \ i2 t) H3G ' CH2COOX (I) wherein Y1 and Y2 together represent a ketal group or a 25 thioketal group and X represents an arylmethyl or di-arylmethyl group, as an intermediate for the preparation of compounds according to claim 1. 8. Benzhydryl- {trans- [1- (2-aminophenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl] acetate} as a compound according to claim 7 . / 30 wherein Y1 and Y2 together represent a ketal group or a thioketal group and X represents an arylmethyl or di-arylmethyl group, characterized in that a compound of the general formula II h3c Ï1 / H