DE3248671A1 - NEW HETEROCYCLIC CARBONIC ACIDS AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Description

-fc -

DtpL-Chem- DR. PETER WAGER Patent attorney

8 MUNICH 5, Moraisstetr. 8 / Π Teteton 223752

New heterocyclic carboxylic acids and processes for their

Manufacturing

The invention relates to new heterocyclic carboxylic acids and a process for their preparation. The new Compounds correspond to the general formula (I)

(D

wherein

Y and χ together for a removable, the carbonyl group protective substituents, preferably a ketal group or its thio analogue, and

R is a removable substituent protecting the amide group, preferably one or more times

A 2663-67 PT / to

substituted by alkoxy with 1-4 carbon atoms

optionally performed benzyl group or / one or more times Alkoxy with 1-4 carbon atoms substituted phenyl group, means.

The carboxylic acids of the general formula (I) are new compounds. You are in the first line of manufacture of thienamycin and its analogues can be used as fcrc. One possibility for converting the compounds of the general formula (I) into useful end products is shown in the accompanying reaction scheme.

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

The aim of the invention was to work out a synthesis in which the azetidinone skeleton and the ύθ-Hydroxyäthy! -Seitenkette (or a side chain that can easily be set to this urasetzbarenX) can be built up at the beginning of the synthesis ^ - and the obtained key compound can then be worked up to thienamycin or its analogue ^.

It has now been found that when acylating a paj the Amino group protected dialkylaminoaalonat ^ s with diketene and reacting the acylated product with an alkali metal alcoholate and iodine having a cc-aoetyl side chain Azetidinone of the general formula (IV) is obtained, which is suitable as a Sohlüsselin termedically.

Ü
HG G 1, (COOZ).

the same meaning as above and Z stands for ") alky! group

In the general formula (IV), the protective group R has the same meaning as c
with 1-5 carbon atoms.

BATH ORIGINAL

^ Jvrst / veM.p-rociu.tf-t.
The new patomaaiäroBJ of the general formula (IV)

and their preparation are, however, subject to a further registration _t their preparation is also treated in the Examples section of the present application.

It has also been found that it is expedient, prior to the conversion to thienamycin or its analogues Keto group in the dC-C acetyl side chain of the compound of the general formula (IV) by a protective group which can be split off later, preferably a ketal group or its thio analogue, to protect. In particular, it is useful with ethylene glycol or one of its thioanalogjisj, for example Mercaptoethanol, an ethylene ketal or hemithioketal Sohutzgruppe to introduce. The compound of the general formula (III) thus obtained

Ϊ ²

(COOZ) ₂ (III)

where Y and χ together for temporary protection the keto group suitable group, preferably for the ethylene ketal group or its Ihioanalogon, and the Meaning of R and Z is the same as above, is in pyridine or a similar solvent or else in Aqueous dimethyl sulfoxide reacted with an alkali halide. A compound of the general formula (II) is obtained ,

Y ¹ Y ² HH HC ^V C '- τ - COOZ

, 1 "2

wherein the meanings of Y, Y and Z are the same as above.

The compounds of the general formula (II) are | & ef Mixtures of the cis and trans isomers. The isomers can chromatographically or based on differences in solubility

separated from each other. The separated trans isomer of the general formula (Ha)

ΥΓ _χ T- HH H ο c \ f-COOZ

(Ha)

• Ν,

O ^ -R

is hydrolyzed, and the trans form of the compound of the general formula (I) is obtained. However, it is more advantageous to hydrolyze the entire mixture of isomes, because the hydrolysis is selective (only the trans isomer is hydrolyzed).

Those of the compounds of the general formulas

K & tht (III), (II) and (Ha), in which R stands for) Dimethoxybenzy! Group "

1 2 "

Y and Y together for ethylene ketal or hemithioketal and Z ftS ^ ethyl group are the subject of their own earlier application (Hungarian patent application Mr. 2263/80). Their production is described in the example section of the present application at the appropriate point »The rest of the compounds of the general formulas (III), (II) and (Ha) are new. The compounds of the general formulas (I) - (IV) exist in the form of racemates.

The invention accordingly relates to new heterocyclic carboxylic acids of the general formula (I), in which Y and χ together for a removable, the carbonyl group protective substituents, preferably a ketal group or its thio analogue, and

R is a removable amide group protecting

Urn substituents, preferably one or more times substituted by alkoxy with 1-4 carbon atoms

possibly

ierte benzyl group or / fine or multiple through Phenyl group substituted by alkoxy with 1-4 carbon atoms.

The invention further relates to a process for the preparation of the compounds of the general formula (I).

According to the invention, these are obtained by adding compounds of the general formula (IV) in which Z is tine. Alkyl group with 1-5 carbon atoms and the meaning of R is the same as above, with a compound suitable for the temporary protection of the carbonyl group, preferably with a ketal former or its thio analogue, in the presence of a compound promoting the reaction and the compound obtained in general Formula (III), in which the meaning of ι, ι, R and Z is the same as above, in pyridine or a similar solvent or in aqueous dimethyl sulfoxide with an alkali halide and the resulting compound is present as a cis-trans mixture general formula (II), wherein the meaning of Yr ", χ, R and Z is the same as above,

a) selectively hydrolyzed or

b) separates into its components and hydrolyzes the trans isomer and that obtained according to a) or b) trans product of the general formula (I) isolated ^, or

a compound of the general formula (III), wherein the meanings of Y, Yr, R and Z are the same as above, in pyridine or a similar solvent or in aqueous dimethyl sulfoxide with an alkali halide converts and the obtained, present as a cis-trans mixture compound of the general formula (II), wherein the Meaning of Y, Y, R and Z is the same as above,

a) selectively hydrolyzed or

b) separates into its components and hydrolyzes the trans isomer of the general formula (Ha) and that isolated according to a) or b) obtained trans product.

According to the invention, the compounds of the general formula (IV) are first formed from the compounds of the general formula (IV) Formula (III) formed. A compound suitable for the temporary protection of the keto group is used as the reagent, preferably a ketal former or its thio analogue is used. It is convenient to react with a suitably chosen compound, for example with

Boron trifluoride diethyl etherate or an aryl sulfonic acid, such as p-toluenesulfonic acid, naphthalenesulfonaic acid and others support financially';

The reaction is carried out in an organic solvent, expediently in benzene, toluene, dioxane, tetrahydrofuran or the like, at one between room temperature and the temperature lying at the boiling point of the reaction mixture.

Ia second step of the process according to the invention, the compound of the general formula (III) in lyridine, quinoline, the homologues of these compounds or Mixtures of the substances mentioned or in aqueous diraethylsulfoxide with an alkali halide, preferably Sodium or lithium chloride, converted to the compound of the general formula (II).

If desired, from the compounds of the general Formula (IV) the compounds of general formula (II) even without a sil isolation the iiJ of the general formula (III) produced will.

The compounds of the general formula (II) lie

as mixtures of isomers, of which the trans component

“A

for the preparation of thienamycin or its analogue ^ used can be.

The isomer mixture of the general formula (II) can be selectively converted to the trans product by basic hydrolysis of the general formula (I) are hydrolyzed. The base is used in an equivalent amount or a reasonable amount Used excess.

If desired, the isomer mixture of the general Formula (II) can be separated into its components. As a substituent R, for example, a 2,4-dimethoxy » benzy! group, as a substituent Z an Athy! group and

containing a 1,3-dioxolanyl group as protective group Y + Y Compounds of the general formula (II) can be separated into their isomers by chromatography, with Kieaelgel 60 (0.063-0.200 mm) as the adsorbent and Elution liquid first benzene and then a benzene-acetone gradient can be used; the acetone content of the the latter increases up to a benzene-acetone ratio continuously from 9si. The separation can auoh on Reason for differences in solubility. can be made:

in ethers, especially in diethyl ether, only dissolve the cis ester.

After separating the isomers it becomes the trans isomer of the general formula (Ha) is hydrolyzed to the trans product of the general formula (I).

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

example 1

trans -1- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic acid

Il

To the suspension of 41.2 g (0.109 mol) of trans-ethyl- / r- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -

- It

4-oxo-2-azetidine-carboxylate / in 50 ml of ethanol is under Stir and cool the solution of 5.21 g (0.130 Mol) sodium hydroxide in 60 ml of water. The mixture is stirred until a clear solution is obtained (about 20 minutes). The solution is mixed with 100 ml of water

It

sets and then shaken out with 100 ml of ether. The aqueous phase is acidified to pH 1 with concentrated aqueous hydrochloric acid and then quickly extracted with 100 ml, then twice more with 50 ml of dichloromethane each time. The organic extracts are dried over magnesium sulfate and, after filtration, evaporated. The oily residue is crystallized from a mixture of toluene and petroleum ether. 35 g (92 %) trans-1- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic acid

will get. Melting point 117-118 ° C (toluene).

Elemental analysis for C ₁₇ H ₂₁ NO (M - 351.35)

Calcd, # 1 G 58.11 H 6.03 N 3.99 found, % s C 58.17 H 6.30 N 4.24

IR (KBr): 3500-2500, 2900, 1760, 1720 cm " ¹ .

¹ H-NMH (CDCl ₃ ): cf 1.39 (a, 3H), 3.50 (d, IH, J = 2.5 Hz),

3.77 (s, 3H), 3.79 (a, 3H), 3.86 (d, IH, J = 2.5 Hz), 3.96 (m, 4H), 4.21 + 4.56 (d, 2fl, J ^. 15 Hz), 6.44 (m, 2H) + 7.15 (d, IH, J = 10 Hz), 7.58 (b, s, IH) -.

The starting material of the example is prepared in the following manner.

a) 109.7 g (0.66 mol) of 2,4-dimethoxybenzaldehyde and 72 ml (0.66 mol) of benzylamine are stirred in 660 ml of methanol at room temperature for 20 minutes (from the initial Suspension becomes a clear solution). 13.2 g (0.33 mol) are added to the solution with external ice-water cooling Sodium / tetrahydroborate (III} / given in small portions.

The course of the reaction is followed by thin-layer chromatography (layer: Kieselgel G according to Stahl, developer: Benzene: acetone = 9: 1). After the reaction has ended, the mixture is evaporated to dryness in vacuo, h 300 ml of water are added to the residue and the mixture is extracted with 500 ml of ether. The aqueous phase is twice more

It

extracted with 200 ml of ether each time. The united etheric Phases are dried over magnesium sulfate ^ filtered, and then become the essential solution. 112 ml (0.66 mol) of diethyl bromomalonate and 93 ml (0.66 mol) of triethylamine given. That. The reaction mixture is stirred at room temperature for 2-3 days. The precipitated triethylammonium

bromide is filtered off and washed with ether. Washing liquid and the filtrate are combined and evaporated.

It

The residue is recrystallized from 150 ml of ethanol.

210 g of crude product are obtained, which is made from 400 ml of ethanol is recrystallized.

197 g (72%) diethyl- / N-benzyl-H- (2,4-dimethoxybenzyl) -amino-malonate / are obtained, which at 62-63 C sohmilz t (Athano1).
IR (KBr): 1750/1725 cm " ¹ , i.e.

b) 61.7 g (0.149 mol) of the diethyl- ^ N-benzyl-N- (2,4-dimethoxy-benzyl) aminomalonate obtained according to Example la) in the presence of about 20 g of palladium-activated carbon in 500 ml of ethanol at atmospheric pressure hydrogenated. The catalyst is filtered off and the filtrate is evaporated.

47.1 g (97 %) diethyl (2,4-dimethoxy-benzylamino) malonate / are obtained. If desired, this can be converted to the hydrochloride. Melting point of the HCl salt: 122-124 ⁰ C (EtOAc).

IR (film): 3250, 2900, 2850, 1730, 1720 cm " ¹ elemental analysis for C ₁₆ H ₂ ^ ClNO ₆ (M = 361.82)

calculated, %: C 53.11 H 6.69 Cl 9.80 N 3.87

found *: C 52.51 H 6.77 Cl 10.30 ff 4.09

¹ H-NMR (CDCl ₃ ): c / 1.3 (t, 6H), 3.78 (s, 3H), 3.82 (s, 3H),

4.21 (q, 4H), 6.20 (s, 2H), 6.4-6.6 (m, 2H), + 7.3-7.55 (m, IH), 7.7 (b , s, IH).

c) 39.6 g (0.122 mol) diethyl - ^^ - dimethoxy-benzylamino) malonate / (prepared according to Example Ib) are in 80 ml of glacial acetic acid with 12.3 g (11.2 ml; 0.146 mol) of diketene cooked for half an hour. The glacial acetic acid is distilled off in vacuo on a water bath and the oily residue crystallized by trituration with 150 ml of water. The product

Il

is dissolved in 60 ml of ethyl acetate and recrystallized by adding petroleum ether. 29.6 g (60 %) diethyl / N- (2,4-dimethoxy-benzyl) -3-hydroxy-3-methy1-5-0X0-2,2-pyrrolidinedicarboxylate / and / or its tautomer are obtained. Melting point: 106-107 ⁰ C.

Elemental analysis for C ₂₀ H ₂₇ NO ₃ (M = 409.43) found #: 'C 58.67 H 6.65 N 3.42 found £: C 58.79 H 6.33 N 3.34.

IR (KBr): 3400, 2950, 2850, 1730/1740 Sch./, 1710 cm " ^{1 1} H-MR CCDCl ₃ ): S 1.1 (t, 3H), 1.17 (t, 3H), 1 , 52

2.8 (<O, 1H), 2.65 (b ,, s, 2H), 3.75

(3, 6H), 3.8-4.15. (M, 4H), 6.7 (t>, s, 2H),

6.25-6.45 m + 7.0-7.25 (m, 3H).

d) 20.5 g (50 mmol) of the prepared according to Example Ic)

It

th product are suspended in 50 ml of anhydrous ether. With vigorous stirring and external cooling, two dropping funnels are added to the suspension at the same time quickly the solution of 3.45 g (150 mmol)

11th

metallic sodium in 100 ml of anhydrous ethanol and the solution of 12.7 g (50 mmol) of iodine in 150 ml of water

It

given to free ether. The solution of 5 g of sodium hydrogen sulfite, prepared with 200 ml of saturated aqueous sodium chloride solution, is added to the mixture with stirring. The mixture is poured into a separating funnel and the precipitation of inorganic salts is prevented by adding 60 ml of water. The organic phase is dried over magnesium sulfate and, after filtering, evaporated to dryness. The oil residue (18.5 g) is crystallized from 30 ml of 2-propanol. 10.9 g (54 h) of diethyl- ^ 3-acatyl-1- (2,4-dimethoxy-benzyl) -4-oxo-2,2-azetidinedicarboxylate are obtained. Melting point: 84-85 C (2-propanol).

Elemental analysis calculated for G, #: C 58.96 found, % i C 58.99

¹ H-MR (CDCl ₃ ): <£ 1.12 (t, 3H), 1.21 (t, 3H), 2.31 (s, 3H),

3.76 (s, 6H), 3.8-3.4 (m, 4H), 4.53 (d, IH), 4.63 (d, IH), 4.69 (s, la), 6.3-6.4 (a, 2H), + 7.07 (d, IH).

e) To the prepared with 500 ml of anhydrous dioxane solution of 179 g (0.484 mol) of diethyl ^: 3-acetyl-1- (2,4-diniethoxy-benzyl) -4-oxo-2,2-azetidine-dicarboxylate7 ( prepared according to Example Id) and 107 al (1.936 mol, 120 g)

BATH ORIGINAL

6, 19th (H = 407.41) η ' 6, C-; N 3.44 H N 3.57

Ethylene glycol become with vigorous stirring and external Ice water cooling 179 ml (1.4-52 mol, 206 g) boron trifluoride ethyl etherate added dropwise. The reaction mixture is stirred with occasional at Let stand room temperature for one hour. In the The mixture leaves the solution of 415 g (1.452 Hol) sodium carbonate decahydrate slowly, with stirring and external cooling with water flow in. One liter of ether and one liter of water are then added to the mixture and the mixture is separated the phases. The aqueous phase is extracted by shaking with 2 × 500 ml of diethyl ether. The essential phase is over magnesium sulfate dried and evaporated after filtering. The residue is treated with 33.9 g (0.58 mol) of sodium chloride, 17.4 ml (0.968 mol) of water and 220 ml of dimethylformamide added, and the mixture is stirred on the oil bath at 180 ° C. until the reaction has ended (about 15 booths; the reaction is followed by thin-layer chromatography, using silica gel G according to Stahl as the adsorbent as the developer

a mixture of benzene and ethyl acetate in the ratio 6: 4 is used). The reaction mixture is in 1100 ml Saturated.aqueous saline solution poured in and then once with 1000 ml, then twice with 500 ml each Diethyl ether shaken out. The ethereal phase is clarified with activated charcoal and dried over magnesium sulfate and after filtering evaporated so far that about 200 ml of ether still remain. Then the solution is covered with ice

Il _

water cooled. 59 g (35 #) trans-ethyl- _J / 1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylate / are obtained . Melting point: 95 C.

*) ° »5 g (1.2 mllol) diethyl / 3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate / (prepared according to Example Id) are in 3 ml of anhydrous tetrahydrofuran boiled together with 0.53 g (3.6 mmol) of mercaptoethanol for 4 hours. Then the reaction mixture is with 10 ml of water and 10 ml of chloroform are added. The organic phase is separated off with 5% aqueous sodium hydrogen carbonate solution shaken out, poured over magnesium sulfate

BATH

- JRr -

dries and filtered. The product is isolated from the filtrate by means of preparative thin-layer chromatography (adsorbent? Silica gel ΈΊ? ^. -Tec * developer toluene and acetone in a ratio of 8: 2). 0.30 g (53 %) diethyl- / 1- (2,4-diraethoxy-benzy1) -3- (2-methy1-1,3-oxa thiolan-2-yl) -4-oxo-2,2 azetidine dicarboxylate / are obtained.

¹ H-KMH (CDGl ₃ ): «f 0.8-1.55 (m, 6H), 1.72 + 1.77 (d, 3H) _t

2.9-3.4 (m, 2H), 3.75 (s, 6H), 4.0-5.0 (m, 9H), 6.4 (m, 2H) + 7.1 (d, IH).

Example 2

trans-l- (4-methoxyphenyl) -3- (2-methyl-l, 3-dioxolane - 2-yl) -4-oxo-2-azetidino-carboxylic acid

11 g (0.0245 mol) diethyl- / r- (4-methoxyphenyl) »3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2,2-azetidine-dicarboxylate / are dissolved in 20 ml of diethyl sulfoxide. the 1.72 g (0.0295 mol) of sodium chloride and 0.9 ml (0.040 mol) of water are added to the solution and the mixture is kept at 175.degree stirred, bi3 the reaction, the thin layer chromatography is followed (adsorbent! silica gel 3 according to Stahl, developer: Benzene and ethyl acetate in a ratio of 6: 4), expired is.

After cooling, the reaction mixture is poured into 150 ml of saturated aqueous sodium chloride solution and mixed with 3x50 ml of diethyl ether extracted. The organic phase is dried over magnesium sulfate and filtered evaporated. The oily residue obtained (6g) is in

Dissolved 25 ml of 96% ethanol. The solution comes from outside cooled with ice water and with the solution of 0.72 g (0.018 mol) of sodium hydroxide in 10 ml of water were added. That Geraisch is stirred for half an hour, intestine with 50 ml Diluted water and extracted with 2x25 ml dichloromethane. The aqueous phase is treated with aqueous concentrated hydrochloric acid acidified to pH 1 and then extracted with 3x25 ml dichloromethane. The organic phase is over magnesium sulfate dried and evaporated after filtering. The oily residue is crystallized from benzene. 4 g (54%)

of the connection named in the title. are obtained. Melting point: 131-132 ⁰ C (benzene).

Elemental analysis for G ₁₅ H _{17 IIO 6} (M = 307.32) calculated,%: C 58.63 H 5.57 N 4.56 found, % i C 58.40 DB 5.30 N 4.66 IR (KBr ): 3400-2700, 1750 cm " ¹ (broad) ¹ H-NMR (CDCl ₃ ): J 1.5 (s, 3H), 3.7 (d, IH, J = 2.5 Hz),

3.76 (s, 3H) ₁ 4.0 (m, 4H), 4.38 (d, IH, J = 2.5 Hz), 6.82 (2H) + 7.26 (2H), ΑΑ · ΒΒ ', J = 9.5 Hz), 9.2 (s, IH).

The starting substance is produced as follows.

a) A mixture of 24.6 g (0.2 mol) of 4-methoxyaniline and 23.9 g (17 ml, 0.1 mol) diethyl (br3mmalonate) is added Stirred at room temperature for 2 days. The substance obtained is triturated with "100 ml of diethyl ether enT) the excreted 4-Methoxy-anisidine-hydrobromide is filtered off and washed on the filter with a little diethyl ether. the Mother liquor is evaporated and the residue is crystallized by adding dilute acetic acid. 13.2 g (47 #) Diethyl (4-methoxy-anilino) -malonate are obtained.

0 "
Melting point: 64-65 C (ethanol).

Elemental analysis for C ₁ -H-NO (H = 281.31) calculated, % i C 59.77 H 6.81 N 4.99 found, %: C 59.99 H 6.97 N 5.25 IR (KBr ): 3300, 1775, 1725 cm " ¹

¹ H-NMR (CDCl ₃ ): J 1.23 (t, 6H, J = 7.2 Hz), 3.67 (s,

4.2 (q, 4H, J = 7.2 Hz), 4.62 (s, IH), 4.1-4.5 ( *, s, IH), 6.55 (2H) + 6.73 (2H), AA'BB », J = 9 Hz).

b) 11.2 g (0.04 mol) of the diethyl (4-methoxy-anilino) -malonate prepared according to Example 2a) are in 15 ml of glacial acetic acid and 4 g (3.7 ml; 0.048 mol) of diketene are boiled for half an hour. The solution is in vacuo evaporated. The oily residue is treated with diethyl ether

grated and filtered. 10.5 g (72 , i) diethyl, £ L- (4-methoxypheny1) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate / ~ and / or its tautoaeric obtain.

ο "
Melting point: 136-137 C (ethyl acetate).

Elementary analysis for C ₁ , 17th 8 ^H 2 " jN , 39 (M = 365 .38) calculated, #: C 59 , 98 E. 6th , 90- N 3.33 found, % i C 58 H 6th N 4.04

IR (KBr): 3600-3000, 176O, 1740, 1685 approx " ¹

¹ H-IiMR (GDCl ₃ ): ό 1.20 (t, 3H, J = 7.2 Hz), 1.22 (t, 3H,

J = 7.2 Hz), 2.33 (s, 3H), 3.7 (s, 3H),

4.17 (q, 2H, J = 7.2 Hz), 4.19 (q, 2H,

J = 7.2 Hz), 4.7 (s, IH), 0.7 (2H) + 7.31 (2H), AA.'BB 'J = 9 Hz).

0) 9.1 g (0.025 mol) diethyl _i / l- (4-methoxyphenyl) -3-hydroxy-3-methy1-5-OXO-2,2-pyrrolidine dicarboxylate / (prepared according to Example 2b) are suspended in 50 ml of anhydrous diethyl ether. At the same time, the solution of 1.72 g of metallic sodium in 30 ml of anhydrous ethanol and the solution of 6.35 S (0.025 mol) of iodine in 50 al of anhydrous dibutyl ether are added dropwise with vigorous stirring and external ice water cooling. The mixture is poured into 100 ml of saturated aqueous sodium chloride solution and then 2 g of sodium hydrogen sulfite and 2 ml of glacial acetic acid are added. The ethereal phase is separated off, the aqueous phase is shaken out with 3 × 50 ml of diethyl ether, and the combined ethereal phases are dried over magnesium sulfate. After filtering, the solution is evaporated. The oily residue is crystallized by trituration with 2-propanol. 6.2 g (68 %) diethyl- / I-acetyl-1- (4-methoxyphenyl) -4-oxo-2,2-azetidine-dicarboxylate / are obtained. Melting point 70-71 ° C (ethanol).

Elemental analysis for C ₁₈ H ₂₁ NO (M = 363.38) calculated, h \ C 59.50 H 5.82 N 3.85 found,%: C 59.04 H 5.34 N 4.08 IR (KBr) : 1760, 1735, 1720 cm " ¹ .

BATH ORIGINAL

-Ao-

¹ H-NMR (CDC1-): S 1.20 (t, 3Η, J = 7.2 Hz), 1.22 (t,

3Η, J = 7.2 Hz), 2.33 (s, 3H), 3.7 (a, 3H), 4.17 (q, 2H, J = 7.2 Hz), 4.19 (q, -2H, J = 7.2 Hz), 4.7 (s, IH), 6.7 (2H) + 7.31 (2H), AA'BB 'J = 9 Hz).

d) 6 g (0.0165 mol) diethyl / 3-acetyl-1- (4-methoxyphenyl) -4-oxo-2,2-azetidine dioarboxylate / (produced according to Example 2o) are in a device of 20 ml

ft

anhydrous dioxane and 4.1 g (3.75 ml, 0.066 mol) ethylene glycol solved. The solution is stirred, cooled externally with Sis and treated with 7.1 g (6.3 ml, 0.05 mol) of boron trifluoride diethyl etherate offset. The reaction mixture is stirred at room temperature for a further 2 hours. The pH the solution is made alkaline with aqueous sodium carbonate solution, then 100 ml barrels are added to the solution and extracted with 3x50 ml diethyl ether. The organic Phase is dried over magnesium sulfate and evaporated after filtration. The oily residue is through

Trituration with ether crystallizes. 6 g (89 %) diethyl (J) -. (2-methyl-1-1,3-dioxolan-2-yl) -1- (4-methoxy phenyl) -4-oxo-2,2-azetidine dicarboxylate / are obtained. Melting point: 82-83 ° C (ethanol).

Elementary analysis for C qH ^ NOq (M = 407.43)

Calculated,%: G 58.70 H 6.18 -N 3.44 found % i C 58.70 H 5.68 N 3.63

IR (KBr): 1740 cm " ¹ (wide)

¹ H-NMR (CDGl ₃ ): J 1.17 (t, 3H, J = 7.2 Hz), 1.26 (t, 3H,

J * 7.2 Hz), 1.5 (s, 3H), 3.7 (s, 3H), 3.9 (m, 4H), 4.2 (m, 6H), 6.67 (2H) + 7.34 (2H), AA'BB ', J = 9 Hz).

Example 3

trans -1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic acid

28.5 g (0.075 mol) of diethyl / I-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2,2-azetidine dicarboxylate / are in a mixture of 44 ml of dimethyl sulfoxide, 5.6 g

(0.1 mole) sodium chloride and 3.05 ml (0.17 mole) water Stirred at 175 C until the reaction has ended. The reaction course is based on that described in Example 2 Way followed by thin layer chromatography. The solution is dissolved in 200 ml of saturated aqueous sodium chloride solution poured in and extracted with 3x150 ml of diethyl ether. The organic phase is dried over magnesium sulfate and evaporated after filtering. The oily one

ti

The residue (16.4 g) is dissolved in 100 ml of ethanol and the Solution with ice-water cooling and constant stirring with the solution of 2.15 g (0.054 mol) sodium hydroxide in 30 ml Water added. The reaction mixture is stirred for 30 minutes, then 150 ml of water are added and 3 × 20 ml are added Diethyl ether extracted. The aqueous phase is strongly acidified with concentrated aqueous hydrochloric acid (pH = 1) and extracted with 3x50 ml dichloromethane. The organic phase is dried over magnesium sulfate and after

Filter evaporated. The oily residue crystallizes from benzene, 12 g ($ 56) of the product named in the title will get. Melting point: 165 C (benzene).

Elemental analysis for C ^ H NO (U = 277.27)

Calcd, % i C 60.64 H 5.45 N 5.05 found,% s C 60.64 H 5.72 N 4.99

IR (KBr): 3500-2700, 1770, 1730 cm " ¹

¹ H-NMR (CDCl3): cT 1.5 ( _a , 3H), 3.69 (d, IH, J = 3 Hz),

4.0 (m, 4H), 4.42 (d, IH, J = 3 Hz),

7.3 (m, 5H), 7.55 (s, IH).

The initial connection is established in the following way.

a) 38 g (0.152 mol) of diethyl (anilino-malonate) (R. Blank; Ber. 3J ₁ , 1815 ^ 1698?) are dissolved in 38 ml of glacial acetic acid with 15.3 g (13.9 ml, 0.182 mol) of Dike -ten boiled for half an hour .. The glacial acetic acid is distilled off in a vacuum on a water bath.

11th

The oily residue is crystallized by trituration with ether. 36.5 g (72 %) diethyl (N-phenyl-3-hydroxy-3-methy1-5-0x0-2,2-pyrrolidine dioarboxylate) and / or its tautomer are obtained. Melting point: 98-99 ° C

BATH ORIGINAL

(Ethyl acetate / petroleum ether).

Elemental analysis for C ₁₇ H ₂₁ NO ₆ (M = 335.35) calcd,%: C 60.88 H 6.31 N 4.18 found, % t C 60.93 H 6.15 N'4.43

IR (KBr): 3350, 2950, 1760, 1750 d, 1700 cm " ^{1 1} H-NMR (CDCl ₃ ): S 1.02 (t, -3H), 1.3 (t, 3H) ₁ 1.6 (s, 3H),

2.8 (3, 2H), 3.6 (b, s, IH), 4-4.45

(m, 4H), 7.2 (3, 5H).

b) 10.2 g (0.447 mol) of metallic sodium are in

ti

250 ml of anhydrous dissolved in ethanol. Become the solution first 50 g (0.149 mol) diethyl (H-phenyl-3-hydroxy-3-raethyl-5-oxo-2,2-pyrrolidine dicarboxylate) (prepared according to Example 3a) and then, with vigorous stirring, the solution of 37.9 g (0.149 mol) of iodine in 200 ml of anhydrous

Ether given. After the reaction has expired, be to the reaction mixture 8.5 ml (8.9 g, 0.149 mol) glacial acetic acid,

ti

Add 200 ml of water and 200 ml of ether. The organic phase

11th

is separated and the aqueous phase with 100 ml of ether shaken out. The ethereal phases are combined, dried over magnesium sulfate and filtered evaporated. The oily residue is made from 50 ml of 2-propanol recrystallized. 31 g (62 #) diethyl (3-acetyl-l-phenyl-4-oxo-2,2-azetidine dicarboxylate) will get. Melting point: 55-56 ° C (2-propanol).

Elementary analysis for C- H ^ NO, -

Calculated, %: C 61.25 H 5.75 N 4.20

Found #: C 61, 38 H 5.89 ti 4.24 IR (KBr): 1770, 1740, 1720 οα " ^χ

¹ H-NMR (CDCl ₃ ): cfl.12 (t, 6H), 2.3 (s, 3H), 4.25 (q, 4H),

4.75 (s, 1H), 7.0-7.6 (m, 5H).

0) 28.5 g (0.085 mol) diethyl (3-acety1-1-pheny1-4-oxo-2,2-azetidine dicarboxylate) are in a mixture of 90 ml of anhydrous dioxane and 21 g (18.8 ml, 0.34 mol) dissolved in anhydrous ethylene glycol. The solution is added dropwise from the outside while stirring and cooling with ice water

BATH ORIGINAL

36.5 g (31.5 ml, 0.255 mol) boron trifluoride diethyl etherate given. The solution is at room temperature for two hours stirred for a long time and then with saturated aqueous sodium carbonate solution neutralized. The neutral solution is diluted with 100 ml of water and then with 3x50 al diethyl ether extracted. The organic phase is dried over magnesium sulfate and, after filtering, evaporated in vacuo. The oily residue crystallizes on trituration with ether. 28.5 g (90%) diethyl- / T-phen; yl-3- (2-meth; yl-1,3-dioxolan-2-yl) -4-OXO-2,2-azetidine-dicarboxylate / will get. Melting point: 59-61 C (gasoline).

jSlementary analysis for CH ₂ NO

Calculated, %% C 60.47 H 6.14 N 3.71 found % t C 60.74. H 6.21 ST 3.79

IR (KBr); 177O ₅ 1740 cm " ¹

¹ H-HBiIR (CDGl) iSI ,, 18 (t, 3H, J = 7.2 Hz), 1.24 (t _f 3H ₅

J = 7.2 Ha), * l _f 51 (a, 3H) ₅ 3 ₅ 92 (a, 4H) ₅

4.3 (m, 5H), 7.2 (m, 5H) e

BATH ORIGINAL

H ₁ CC

H H

ttl QJ

UV light H ₂ O

Malonic ^{Acid 1} Half Ester Salt

• i

^ CH ₂ COCH ₂ CeOQ

Sulfonic acid azide

V 'CKtCCOX

1. Reduction

2. Esterification

Distance from
NH ₂ -Ph

^, CH ₂ COuX

_ MU

O'

NH
Reductior

J CH ₂ COOH

-4- · C

UJ

SgIz dss malonic acid semi-residual

CH ₂ COC-S ₂ COGQ

BATH ORIGINAL

-35 *

CH ₂ COCN ₂ COOQ

Rh - salt

COOQ

0-acylation mercaptan salt formation

COOQ '

Claims (14)

Claims l.JProcess for the preparation of heterocyclic carboxylic acids of the general formula (I) COOH (D wherein ι and Y together for a removable, the carbonyl group protective substituents, preferably a ketal group or its thio analogue, and R is a removable substituent protecting the amide group, preferably one or more times substituted by alkoxy with 1-4 carbon atoms optionally ierte benzyl group or / one or more times through Alkoxy substituted with 1-4 carbon atoms Phenyl group, means characterized in that compounds of the general Formula (IY) (COOZ), (IV) wherein Z represents an alkyl group having 1-5 carbon atoms and the meaning of R is the same as above, with one useful for temporarily protecting the carbonyl group Compound, preferably with a ketal former or its thio analogue, in the presence of a reaction promoting Reacts compound and the resulting compound of the general formula (III) (COOZ), (III) wherein the meaning of ζ, ι, R and Z is the same as is above, in pyridine or a similar solvent or in aqueous dimethyl sulfoxide with an alkali halide converts and the compound of the general formula (II) obtained as a cis-trans mixture COOZ (II) wherein the meaning of Y, χ, R and Z is the same as above, a) selectively hydrolyzed or b) separates into its components and the trans isomer of the general formula (Ha) (Ha) wherein the meanings of Ϊ, Y, Z and R are the same as is above, hydrolyzed and the trans product of the general formula (I) obtained according to a) or b) isolated ^ · or a compound of the general formula (III), wherein the meaning of Y, χ, R and Z is the same as above, in pyridine or a similar solvent or in aqueous dimethyl sulfoxide with an alkali metal halide converts and the obtained, present as a cis-trans mixture compound of the general formula (II), wherein the Meaning of Y, χ, R and Z is the same as above a) selectively hydrolyzed or b) separates into its components and the trans isomer of the general formula (Ha) is hydrolyzed and the trans product obtained according to a) or b) is isolated. 2. The method according to claim la) or b), characterized in that the hydrolysis is carried out in the presence of fr & n based on the compound of general formula (II) or (Ha) ^ e ^ equivalent amount of a base or in the presence of a reasonable excess of a base undertakes. 3. The method according to claim Ib), characterized in that that when separating the isomers, the trans isomer It separated by dissolving in an ether from the ether-incomplete cis-isomer * ¹ . 4. The method according to claim la) or b) for the preparation of trans-l- (2,4 ~ dimethoxy-benzyl) -3- (2-methyl-l, 3-dioxolan-2-yl) -4-oxo-2 -azetidine-carboxylic acid, characterized in that ethyl- ^ T- (2,4-dimethoxy-benzyl) -3- (2-methyll, 3 ^- dioxolan-2-yl) -4-oxo-2-azetidine carboxylate / or its trans isomer hydrolyzed. 5. The method according to claim la) for the preparation of trans-l- (4-methoxyphenyl) -3- (2-methyl-l, 3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic acid, characterized in that It - one ethyl- / 1- (4-methoxyphenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylate / hydrolyzed. 6. The method according to claim la) for the preparation of trans-l-phenyl-3- (2-methyl-l, 3-dioxolan-2-yl) -4-0X0-2-azetidine-carboxylic acid, characterized in that ethyl / l-phenyl-3- (2-methyl-l, 3-dioxolan-2-yl) -4-oxo-2-azetidine carboxylate / hydrolyzed. 7. Compounds of the general formula (I) rCOOH (I) Y and χ together for a removable, the carbonyl group protective substituents, preferably a ketal group or its thio analogue, and R is a removable substituent protecting the amide group, preferably one or more times substituted by alkoxy with 1-4 carbon atoms possibly tuted benzyl group or / one or more times Phenyl group substituted by alkoxy with 1-4 carbon atoms. 8. trans -1- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic acid. 9. trans -1- (4-methoxyphenyl) -3- (2-methy1-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic acid. 10. trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic acid. 11. The ethyl- / r- (4-methoxyphenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2- falling within the scope of the general formula (II) azetidine carboxylate /. 12. The ethyl- / I-phenyl-3- (2-.methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-oarboxylate / which falls within the scope of the general formula (II). 13 »The diethyl- / r- (4-methoxyphenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2, which falls within the scope of the general formula (III), 2-azetidine dioarboxylate /. 32Α8671 14. The in the scope of the general formula (Hl) falling diethyl ^ I-phenyl-3- (2-methyl-l, 3-dioxolan-2-yl) -4-oxo-2,2-azetidin-dicarboxylate / .