DE3248675A1 - METHOD FOR PRODUCING HETEROCYCLIC ACETIC ACID DERIVATIVES (II) - Google Patents

Description

DfcL-Chem. DR. PETER WAGER

Patent attorney

8 MUNICH 5, Morasaistr. 8 / Π
Telephone 223? S2

judge Qedeovx Vea ^ eezett- ^ ar R> 1. ^. 3 udo.f> e st

Process for the preparation of heterocyclic acetic acid derivatives (II)

The invention relates to a process for the preparation of heterocyclic acetic acid derivatives of the general formula (I)

HC

Y ¹ Y ² HH

CH ₂ COOX

(D

KH

Y and χ together for a removable one, the Carbony! Group protective substituents, preferably for one. Ketal group or its thio analogue, stand "and

X is a selectively removable esterifying group, preferably an arylmethyl or diarylmethyl group, means.

The compounds of the general formula (I) can be used for Production of thienamyoin and its analog psyche »

A 2666-67 PT / to

are used · Di © compounds per se and © in alternatives Process for their production are the subject of a further, on the same day as the one presented here » Patent application.

Thienamycin is an antibiotic with a broad spectrum of activity. Bs was first used microbiologically (ÜS-PS 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 uo-hydroxyethyl side chain (or a side chain that can be easily converted to this) can be built up at the beginning of the synthesis and the resulting Solus connection can then be worked up to thienamycin or s.einen fej »

It has now been found ^ that is acylated © INEI ~ \ üa-Aminogmppe protected Dialkylaminomalonates with diketene uad reacting the acylated product is obtained with a and iodine a <x-Aoetyl ™ side chain exhibiting Azetidines the general formula (VIII) ₀ this as Schlüsselintermediär suitable is _o

In the general formula (VIII), R ⁰ stands for a more _{distant "protective group g} protecting the aide group, preferably") cis = phenyl or benzyl group substituted several times by alkoxy with 1-4 carbon atoms, and Z means ") alky ! group with 1 ~ 5 carbon atoms o

The - ^^ ss® © <iä © 5? S ^ of the general formula (VIII) and production are the subject of a further Aameldmig (Hungarian © patent application Hr ₀ 2262 / 8O) _0, however, their production is also dealt with in the example part of the present application

It was further found that ^ it is convenient ⁰ "before

ft. · ■ V ■ »W f *«

. V- & -. - · '

the implementation to thienamycin or its analogue ^ »· the Keto group in the oc-C-acetyl side chain of the compound of general formula (VIII) 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 to use

"et /

Ethylene glycol or one of its thioanalogues ^ B »·, for example Mercaptoethanol, an ethylene ketal or hemithioketal protecting group to introduce. The compound of the general formula obtained in this way

Ϊ ¹

(COOZ),

(VII)

■ O

12th
where Y and Y together represent a group suitable for the temporary protection of the keto group, preferably the ethylene ketal group or its thio analogue, and the meaning of R 'and Z is the same as above, is in pyridine or a similar solvent or in aqueous dimethyl sulfoxide reacted with an alkali halide. In this way, the compounds d :: r general formula (VI) are obtained,

COOZ

(VI)

wherein the meaning of Y, Y. Z and R * the same as above is.

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

(Via)

is hydrolyzed, and thereby the trans-carboxylic acid becomes the general formula '(V) obtained.

COOH

However, it is more advantageous to hydrolyze the entire isomer mixture, because the hydrolysis is selective (only the trans-ester is hydrolyzed ) "

Then the trans-carboxylic acid of the general formula (V) is first ^{reacted with a carboxyl group activator s} ) then with diazomethane, and the compound of the general formula (IV) obtained in this way

Y ¹ Υ ² "

COCHl,

(IV)

χα presence of V / water subjected to Wolff rearrangement (diaso-ketone Uralagerung) «, The starting compounds of the present invention, namely the azetidine-acetic acids of the general formula (III)

, 2

(III)

obtained ^ In the general formulas (V) ₅ (IV) and (Hl) is

the meaning of

Y and R " the same as above _c

BATH ORIGINAL

Sin part of the compounds of general formula (VII) is in a separate earlier application (Hungarian patent application No. 2263/80). The rest of the connections of the general formula (VII) and the compounds of the general formulas (VI) - (III) are in separate applications described the same day as the present

Sw! sch en Registration have been submitted. The example part of this application also refers to the production of the ■ ■ ä received.

The compounds of the general formula (III) can be converted into the new esters of the general formula in a manner known per se (II)

GH ₂ COOX (II)

. R »

and these converted to the compounds of the general formula (I) will. The work-up of the compounds of the general formula (I) to thienamycin or its analogues is illustrated in the attached reaction scheme.

The invention is therefore a method for Preparation of compounds of general formula (I) in which the meanings of Y, Y and X are the same as above. For the process is characterized in that a compound of the general formula (III) in which the

1 2
Meaning of Y, Y and R 'is the same as above, in an

in a known manner to form an ester of the general formula (II), in which the meaning of Y, t, X and R * is the same as above, and the protective group R 'is removed from the ester, or

of an ester of the general formula (II), in which the meaning of χ, ι X and R 'is the same as above, the protective group R * removed.

According to the invention. the azetidine acetic acids of the general formula (III) are reacted with a reagent which provides the selectively removable esterifying group X. It is preferred to esterify with reagents which are suitable for the formation of a group X which can be removed by induction. Particularly preferred esterifying reagents are compounds suitable for introducing an arylmethyl or diarylmethyl group, in particular phenyldiasomethane or diphenyldiazomethane.

The obtained ester represented by the general J formula (II) may be desired can also be isolated from the reaction mixture, but it is also possible, without intermediate isolation split off the protective group R '.

Of the amide group protecting substituent R 'can be removed · on oxidative pathways is the protecting group group Dirnethoxybenzy a! So be suitably used as oxidizing agent a peroxydisulfate, preferably potassium or Hatriumperoxydisulfat (KS-Og, Ha ₂ S ₂ Og). The reaction is carried out in the presence of a buffer with a pH of about 7 and in the presence of water and an organic solvent.

If the protective group R 'is a methoxyphenyl group, then a cerium (IV) salt together with expediently as an oxidizing agent an acid used. Cer (IV) ammonium nitrate has proven to be the most suitable Proven in weakly sulfuric acid aqueous medium. In this hall too, people work in the present an organic solvent.

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

example 1

Benzhydryl-Ztrans- ^ j- (2-methyl-1,3-dioxolan- * 2-yl) -4-oxo-2-azetidinyl / acetate /

To the solution of 5 "48 g (15 mmol) / trans-l- (2" 4-dimethoxy-

- / Io .

benzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyj / - "acetic acid in 50 ml of dichloromethane are stirred at room temperature with 3.05 g (15.75 mmol After the evolution of nitrogen has ceased, the excess diphenydiazomethane is decomposed with a few drops of acetic acid. The solution is evaporated to dryness and the residue (6.77 g) is dissolved in 84 ml of acetonitrile 16.20 g (60 mmol) of potassium peroxydisulfate, 21.60 g (120 mmol) of dinatriura hydrogen phosphate monohydrate and 54 ml of water are added to the solution. The mixture is stirred vigorously for 4 hours, boiled and finally cooled. The cold mixture is filtered and the two-phase piltrate is separated into its phases. The aqueous phase is extracted with 3 × 30 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and, after filtration, evaporated. The solution of the residue prepared with benzene is worked up by column chromatography ( Adsorbent: silica gel 60, 0.050-0.200 mm, eluent: benzene and acetone in a ratio of 7: 2). 2.68 g (47 %) of the product named in the title are obtained. Melting point: 130 C (ethanol).

Elemental analysis for C ₂ 27 '2 ^H 2- NO '5 (M N 387.41) 67 calculated, % C 69 15th H" 6, 08 N 3, 55. found, % t C 69 H 6, 20th 3,

IR (KBr): 3250, 2900, 1760, 1740 cm "" ¹ .

¹ H-NIiR (CDCl J: 6 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), 6.9 s (IH) ,. 7.28 s (10H).

The starting material is obtained in the following manner: a) 109.8 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) of sodium tetrahydroborate (III) J given in small portions.

• The course of the reaction is thin-film chromatography followed (layer: I silica gel G after Stahl, developer:

-M.

Benzene and acetone in a ratio of 9: 1) "After the reaction has ended, the mixture is evaporated to a trootoe in vacuo, and 300 ml of water are added to the residue and 500 ml" of t

Ether shaken out. The aqueous phase is twice more

extracted with 200 ml of ether each «The combined essential

The phases and phases are dried over magnesium sulfate, filtered, and then 112 sal (0.66 mol) diethyl bromomalonate and 93 ml (0.66 mol) triethylamine are added to the ethereal solution. The reaction mixture is stirred for 2 to 3 days at room temperature. The precipitated triethylammonium bromide is filtered off and washed with ether. Wash liquid and piltrate are combined and evaporated

210 g of crude product recrystallized from 150 ml of ethanol are obtained which is umlsxistallisiert from 400 ml of ethanol ο 197 g (72 fs) diethyl-Zl-beasjl-IC ^^ - dimethox ^ ben ^ D-amino-malQnat / are obtained melting point § S2 < = 63 C (lth®ffiol |, _o 1750/1725 cm " ¹ , do

b) 61 ₈ 7 g (O ₉ 149 mol)
bensyl) amino-malona, t / in the presence of about 20 g Palladiuipktivkohle in 500 ml of ethanol at atmospheric pressure Pil The hydrogenated occurred after iäntfernen the crystallizer evaporated ", 47 _a lg (97%) / f bensjlamino) malonate / are obtained _o This can be converted into the hydrochloride if desired a _o Melting point of the HCl salsess 122-124% (EtOAc) ₀ ■

Elemental analysis for C ₁₆ H ₃₄ ClHOg (M = 36l _s 82) s, %% C 53.11 H 6 _D 69 Cl 9.80 N 3.87

found, %% C 52 _D 51 H 6 ₀ 77 0 110.30 H 4 _p 09 IR (film)? 325O ₉ 2900 _s 2850 _a 173O ₀ 1720 onf ^{1 1} H-EfMR (CDGl ₃ ) S Λ 1.3 (t, 6H) ₉ 3 _S 78 (s _p . 3H) _S 3.82 (s ₉

4.21 (q, 4H) ₉ 6 _s 2O (s, 2H), 6 _P 4 »6 ₉ 6 (m, 2H) 7.3» 7 _S 55 (m, IH), 7 ₀ 7 (b _O5 s _s IH) ₀

o) 39 ^ 6 g (0 ₉ 122 mol) diethyl - / (2 ₀ 4-dimetboxy-benayl ■ = amine ^ i-malonate / are mixed with 12 ₀ 3 g (11 ₉ 2 ml, 0 ₀ 146 Mol) Diketes boiled for half an hour

oily residue by trituration with 150 ml of water

Il

sated. The product is dissolved in 60 ml of ethyl acetate and recrystallized by adding petroleum ether 29.6 g (60 %) of diethyl / N- (2,4-dimetho ^ -benzyl) -3-hydro3cy-3-oethyl-5- oxo-2,2-pyrrolidine-dioarboxylate / and / or its tautomeric earth obtained. Melting point: 106-10? ⁰ G.

Elemental analysis for C 67 I TJ NO ¹ Q (M = 409 .43) calculated, % C 58 79 H 6, 65 N 3, 42 found, ^c / ° C 58 ·" H 6, 33 N 3, 34

IR (KBr) s 2950, 2850, 1730, (1740 Sch.), 1710 cm "* ^{1. 1} H-NIAR (CDCl ₃ ): 6. 1.1 (t, 3H), 1.17 (t, 3H ), 1.52 (s,

2.8 (<O, 1H), 2.65 (b., S, 2H), 3.75 (s, 6H), 3.8-4.15 (m, 4H), 6.7 (b. , s, 2H),

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

d) 20.5 g (50 mmol) of that prepared according to Example-fo)

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The product is suspended in 50 ml of anhydrous ether. to The suspension are rapidly stirred and cooled from two dropping funnels simultaneously the solution of 3.45 g (150 mmol) of metallic sodium in

Il

100 ml of anhydrous ethanol and the solution of 12.7 g (50 mmol)

Il .. -

Iodine given in 150 ml of anhydrous ether. The solution of 5 g of sodium hydrogen sulfite, prepared with 200 ml of saturated aqueous salt solution, is added to the Gemisoh while stirring. The mixture is poured into a separatory funnel and the precipitation of inorganic salts is prevented by adding 60 ml of water. The organic phase is dried over magnesium sulfate, filtered and then evaporated to a Trookne. The oily residue (18.5 g) is crystallized from 30 ml of 2-propanol. 10.9 g (54 #) Diethyl / 3-acetyl-l- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidin-dicarboxylat7 are obtained, which melts at 84-85 ⁰ C (2- Propanol).

Elemental analysis for C ₂₀ H ₂₅ NO ₈ (U = ^ 07.41) found, % z 0 58.96 H 6.19 N 3.44 found, ⁰ M C 58.99 H 6.04 N 3.57.

-JIl-

¹ H-BMR (CDCl) SJ 1.12 (t, 3H), 1.21 (t, 3H) ₉ 2.31 (a, 3H),

3 "76 (s, 6H) ₉ 3.8-3.4 (β, 4H) ₉ 4.53 (d, IH), · 4.63 (d, IH), 4.69 (s, IH), 6.3-6.4 (m, 2H), + 7.07 (d, IH).

e) To that prepared with 500 ml of anhydrous Diozan LSsuag of 179 g (0.484 mol) of diethyl / 3-aoetyl-1- (2,4-dimeth03Ey-benzyl) -4-oxo-2,2 "-azetidine dicafbosylate / (prepared according to Example 1d) and 107 ml (1.936 Hol; 120 g) ethylene glycol are carried out with intensive stirring and external ice-water cooling 179 ml (1.452 mol, 206 g) boron trifluoride diethyl etherate added dropwise. The reaction mixture is' at room temperature Let stand for a day with occasional stirring · Slowly, with stirring and external cooling 415 g (1.452 mol) of sodium carbonate decahydrate are added to the mixture.

If

· After adding one liter of ether and one liter of water, the phases are separated. The aqueous phase is extracted by shaking with 2 × 500 ml of diethyl ether. The ethereal phase is dried over magnesium sulfate, after filtering off the desiccant, it is evaporated. The residue is mixed with 33.9 g (0.58 mol) of sodium chloride * - 17.4 ml (0.968 mol) of water. and 220 ml of dimethyl sulfoxide are added, and the mixture is stirred on the oil bath at 180 C until the reaction is complete (about 15 hours! The reaction is followed by thin-layer chromatography, using a mixture of benzene and ethyl acetate as the developer _{as the adsorbent according to Stahl 9} Ratio 6s4 is used). The reaction mixture is poured into 1100 ml of saturated aqueous sodium chloride solution and then shaken out once with 1000 ml, then twice with 500 ml of diethyl ether each time. The ethereal phase is clarified with activated charcoal, dried over magnesium sulphate and, after filtering, evaporated to such an extent that about 200 ml of ether remain.

Then the solution is cooled with ice water. 59 g (35 %) it _

trans-ethyl- / 1- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3 »dioxolan-2-yl) -4-oxo-2-azetidine» oarboxylate / will get. The product melts at 95 ° C *

. f) 0.5 g Cl.2 mol) diethyl- / 3-acetyl-1- (2 "4-dimethoxy-

benzyl) -4-OXO-2,2-azetidine dicarboxylate / are boiled in 3 ml of anhydrous tetrahydrofuran together with 0.53 g (3.6 mmol) of mercaptoethanol for 4 hours. Then 10 ml of water and 10 ml of chloroform are added to the reaction mixture. The organic phase is separated off, extracted with 5% aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and filtered. The product is isolated from the piltrate by means of preparative thin layer chromatography (adsorbent: silica gel 60 P ^ oc / - * 6g »developer: toluene and acetone in a ratio of 8: 2). 0.30 g (53 %) ■ diethyl- £ 1- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-oxai; hiolan-2-yl) -4-0X0-2, 2-azetidine-dicarboxyla _i t / are obtained.

¹ H-NHR (CDCl): ς / θ, 8-1.55 (m, 6H), 1.72 + 1.77 (d, 3H),

2.9-3.4 (m, 2H), 3.75 (3, 6H), 4.0-5.0 (m, 9H), 6.4 (m, 2H) + 7.1 (d, IH).

It

g) To the suspension of 41.2 g (0.109 mol) of trans-ethyl- / r- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolane-2wyl) -4- oxo-2-azetidine-oarboxylate / (prepared according to Example Ie)

ti

in 50 ml of ethanol, the solution of 5.21 g (0.130 mol) of sodium hydroxide in 60 ml of water is added with stirring and external cooling with water. The mixture is stirred until a clear solution is obtained (about 20 minutes). The solution is mixed with 100 ml of water and then extracted 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, filtered and then evaporated. The oily residue is crystallized from a mixture of toluene and petroleum ether. Ground 35 g (92 #) trans-1- / f2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic acid obtain. Melting point: 117-118 ⁰ C (toluene).

Elemental analysis for C ₁ H ₂₁ NO ₇ (M = 351.35) calculated, %: C 58.11 H 6.03 N 3.99 found, #: C 58.17 H 6.30 N 4.24 IR (KBr ): 3500-2500, 2900, 1760, 1720 cm " ¹ .

(CDCl ₃ ) JJ 1.39 (s, 3H), 3.50 Cd, IH, J = 2.5 Hz), 3.77 Cs, 3H), 3.79 Cs, 3H), 3.86 Cd, IH, J = 2.5 Hz), 3.96 cm, 4H), 4.21 + 4.56 (d, 2H, J ^ = 15 Hz), 6.44 cm, 2H) + 7.15 Cd, IK, J = 10 Hz), 7.58 Cb., S, IH).

h) To the solution of 17.6 g (50 mmol) of trans-1- (2,4-diraethoxy-benzyl) -3- (2-methyl-1,3-dioxolan-2 ~ yl) -4-oxo- 2 ~ azetidinecarboxylic acid (prepared according to Example Ig) in 150 ml of anhydrous Tetrahydrofuran is given 7.3 ml of triethylamine.

The mixture is then added, while cooling with ice, with 5.0 ml (52.5 mmol)

¹¹ ο

Ethyl chloroformate) added, cooled to -15 C and stirred at this temperature for 20 minutes. At the same temperature, the triethylarain salt formed is filtered off under an argon atmosphere. The cold solution of 150 ralole of diazomethane in 230 ml of diethyl ether is added to the piltrate. The solution is stirred and the temperature is allowed to rise to room temperature. After two hours the mixture is evaporated to dryness. The brown, viscous mass is dissolved in 20 ml of benzene and purified by column chromatography. C -AcIs orb ens: 150 g of silica gel 60, 0.063-0.200 mm, eluent; Benzene and acetone in a ratio of 7: 2). 12.0 g (64 %) of trans-4- (diazo-aoetyl) -l-C2,4-dimethoxy-benzyl) -3-C2-methyl-1,3-dioxolan-2-yl) -2-azetidinone obtain.

Elemental ^{analysis for c} ₁₈ ^H ₂₁ ^N 3 ⁰ g CM = 375.37) calculated, %: C 57.59 H 5.64.

found, % t C'57.78 H 5.39
IR CKBr): 2900, 2110, 1760 cm " ¹ .

i) The mixture of 2.25 g (6 mmol) of trans-4- (diazo-acetyl) -l- (2,4-dimethoxy-benzyl) -3-C2-methyl-1,3-dioxolane-2- yl) -2-azetidinone, 100 ml peroxide-free tetrahydrofuran and 50 ml Water is supplied in a Pyrex device with a submersible high pressure mercury lamp (HPK 125) irradiated under argon atmosphere for about 4 hours. Then the solution is in vacuo concentrated to 50 ml and diluted to 130 ml with water. the aqueous solution, w "rd with 2.4 ml of 10>» strength aqueous sodium hydroxide solution offset. The alkaline solution is mixed with 3x20 ml dichloromethane

BAD ORIGfNAL

extracted. The aqueous phase is then acidified to pH 2 with concentrated aqueous hydrochloric acid. The acidic solution. is extracted with 3x20 ml of dichloromethane. The extract is dried over magnesium sulphate and, after filtration, evaporated to dryness. The residue is crystallized from ether. 1.82 g (83 %) / trans -1- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7-acetic acid ^ ["" Melting point: 124 ° C. (Ether} / are preserved.

Elemental analysis for C ₁₈ H ₂₃ NO ₇ (M = 365.37) calculated %: C 59.17 H 6.34 N 3.83 found, % i C 59.22 H 6.49 N 4.07. IR (KBr): 3500-2300, 2900, 1730, 1700 cm " ¹ .

Example 2

Benzhydryl- / trans- ^ 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7-acetate /

0.28 g (0.65 mmol) benzhydryl- / trans- ^ 3- (2-methyll, 3-dioxolan-2-yl) -l- (4-methoxyphenyl) -4-oxo-2-azetidinyl7- acetate/ are dissolved in 2 ml of acetone. 2 ml of 5% aqueous is added dropwise to the solution at room temperature Sulfuric acid prepared solution of 0.9 g (1 »6 mmol) cerium (IV) ammonium nitrate / Ce (KEL) (NO) g7 given. "After the addition the reaction mixture is stirred for a further 2 minutes and then carefully washed with 5% aqueous sodium hydrogen carbonate

Il

Solution neutralized. The Gemisoh is with 3x4 ml Athylaoetat extracted. The organic phase is dried over magnesium sulfate and, after filtration, evaporated in vacuo. Of the The oily residue is purified by means of preparative thin-layer chromatography (adsorbent: silica gel 60, 0.060-0.200 mm, Eluent: benzene and acetone in a ratio of 7: 2). ° »° 6 g (30%) of product are obtained, its physical Konstanten.mit match those of the product prepared according to Example 1.

The starting compound is established 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 (bromomalonate) is added Stirred at room temperature for two days. The substance obtained

(i / ηύ is triturated with 100 ml of diethyl ether; the precipitated 4-methoxy-anisidine hydrochloride 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, melting point 64-65 ° C. (ethanol).

Elemental analysis for C ₁ -H ₁ NO ₅ (M = 281.31) - calculated, %% C 59.77 H 6 "81 N 4.99 found, %% C 59 * 99 H 6.97 H 5.25 IR (KBr) s 3300, 1775, 1725 cm ** ¹

¹ H-UM (CDCl ₃ ) SJ 1.23 (t, 6H, J. 7.2 Hz) ₈ 3.67 (s, 3H),

4.2 (q ₈ 4H, J = 7 _? 2 Hz), 4.62 (s, IH), 4.1-4.5 (b., S ₀ IH) ₅ 6.55 (2H) + 6, 73 (2H), (IA ⁸ BB \ J = 9 Has) ο

b) 11.2 g (0.04 mol) of the diethyl (4-metho2 £ y-anilino) malonate prepared according to Example 2a) are dissolved in 15 ml of glacial acetic acid together with 4 g (3 ₈ 7 ml, 0.048 Mol) diketene boiled for half an hour. The solution is evaporated in vacuo. The oily residue is triturated with diethyl ether and filtered. 10.5 g (72 %) diethyl- / 1- (4-methoxyphenyl) -3-hydroxy-3-methyl-5-0x0-2,2-pyrrolidino-aicarboxylate / and / or its sautomer are obtained «Sohmela point § 13δ => 137 ° C ·

(Ethyl acetate) .-

Elemental analysis for C ₁₀ H _{00 IiO 17} (M = 365.38) calculated, %% C 59.17 H 6 ₈ 39 H 3 "83 found, %% C 58.98 H 6.90 i 4.04 IR ( ICBr) s 36ΟΟ-3ΟΟΟ, 1760, 1740, 1685 oia " ¹ .

^lw "" ^m (CDCl ₃ ) S of 1.07 (t ₈ 3H ₀ J = 7 ₅ 2 Hz) ₀ 1 ₉ 28 (t, 3H, J -

7.2 H ₂ ), 1 _D 58 (s, 3H), 2.76 (s, 2H), 3 ₀ δ 4 (s, IH) ₉ "3.76 fs, 3H), 4.1 (q ₈ 2H , J »7.2 Hz) _s 4.27 (q, 2H, J = 7 _? 2 Ha), 6 ₉ 7 (2H) + 7 ^ C ^B , J - 9 Hz).

^S. _O

c) 9 »! g (0 ₈ 025 mol) diethyl- £ L- (4-tn © tho3iy-phenyl) -3 ° ii3? drosy <=

come in 50 ml

• · · Jt TR *,

anhydrous diethyl ether can be suspended at the same time with vigorous stirring and external ice water cooling, the solution of 1.72 g of metallic sodium in 30 ml of anhydrous Ethanol and the solution of 6.35 g (0.025 mol) of iodine in 50 ml of anhydrous diethyl ether were added dropwise »The mixture is poured into 100 ml of saturated aqueous sodium chloride solution and then with 2 g of sodium hydrogen sulfite and 2 ml

\ vnd glacial acetic acid added. The ethereal phase is separated off ^ the aqueous phase is extracted by shaking with 3 × 50 ml of diethyl ether, and the combined ethereal phases are dried over magnesium sulphate. 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-dicarboxyla.t / are obtained.

ο "
Melting point: 70-71 C (ethanol).

Elemental analysis for C 50 8 ^H 2] N O ₇ (M = 363, 38) calculated, %: C 59, 04 H 5 , 82 N 3, 85 found, ⁰ As C 59, H 5 , 84 N 4, 08

IR (KBr): 1760, 1735, 1720 cm " ¹

¹ H-MIR (CDCl ₃ ): cf 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), 6.7 (2H) + 7, 31 (2H), (AA », B3 ^J , J = 9 Hs)

d) 6 g (0.0165 mol) diethyl- / I-acetyl-1- (4-methoxyphenyl) -4-oxo-2,2-azetidine dicarboxylate / _/ prepared according to Example 2c). v / ground in a mixture of 20 ml of anhydrous dioxane

Il

and dissolved 4.1 g (3.75 ml, 0.066 mol) of ethylene glycol. the The solution is stirred and cooled with ice from the outside, and 7.1 g (6.3 al, 0.05 laol) of eortrifluoride diethyl etherate are added. The reaction mixture is stirred at room temperature for a further 2 hours. The pH of the solution is adjusted with aqueous sodium carbonate solution. made alkaline, then the solution is mixed with 100 ml v / ater and extracted with 3x50 ml diethyl ether. The organic phase is dried over magnesium sulfate and evaporated after filtering. The oily residue becomes duroh

--fa-

Triturate with ether crystallized, 6 g (89 %) diethyl- / ~ 3-C2-raethyl-1,3-dioxolan-2-yl) -l ~ (4-methoxyphenyl) -4-oxo-2,2- azetidine dicarboxylate / are obtained. Melting point 82-83 C (ethanol).

Elemental analysis for C ₃₀ H ₂ UOg (M = 407 "43)

Calculated, %: C 58.96 H 6.18 If 3.44 Found, % t C 58.70 H 5.68 N 3.63 ■

IR (KBr): 1740 cm " ¹ (wide)

¹ H-MiR (CDCl ₃ ) JJ 1.17 (t, 3H, J = 7.2 .Hz), 1.26 (t, 3H),

J = 7.2 "Hz), 1.5 Cs, -3H), 3 ₉ 7 Cs, 3H), 3.9 cm, 4H), 4.2 (ra, 6H), 6.67 (2H) + 7.34 (2H), (AA ', BB', J = 9 Hz).

e) 11 g (0.0245 mol) diethyl- / 3 ~ -. (2-methyl-1,3-dioxolan-2-yl) -l- (4-methoxyphenyl) -4 - oxo-2, 2-azetidine dicarboxylate / are dissolved in 20 ml of dimethyl sulfoxide. The solution is with 1.72 g (0.0295 mol) sodium chloride and 0.9 ml (0.049 mol) Water added "and stirred at 175 C until the reaction, which is followed by thin-layer chromatography, has expired (adsorbent? silica gel G according to Stahl, developer:

ti

Benzene and ethyl acetate in a ratio of 6: 4).

After cooling, the reaction mixture is poured into 150 ml of saturated aqueous Na triumohloridlösung .. and extracted with 3x50 ml of diethyl ether. The organic phase is dried over magnesium sulfate and, after filtration, evaporated. The oily residue obtained (6 g) is dissolved in 25 ml of 96% ethanol. The solution is cooled from the outside with ice water and a solution of 0.72 g (0.018 mol) of lithium hydroxide in 10 ml of water is added. The mixture is stirred for half an hour, then diluted with 50 ml v / ater and extracted with 2x25 ml dichloromethane. The aqueous phase is acidified to pH 1 with concentrated aqueous hydrochloric acid and then extracted with 3 × 25 ml of dichloromethane. The organic phase is dried over magnesium sulfate and, after filtration, evaporated. The oily residue is crystallized from benzene. 4 g. (54 %) trans ~ 3- (2 ~ methyl-1,3-dioxolan-2-yi) ~ i ~ (4 ~ ethoxyphenyl) -4-oxQ-2-azetidine- »oarboxylic acid

obtain.

Elemental analysis for CH ₁ NOg (M = 307.32)

repaid, £: G 58.63 H 5.57 N 4.56 Found,%: 0 58.40 H 5.80 N 4.66

IR (KBr): 3400-2700, 1750 cm " ¹ (wide)

¹ H-MIR (CDCl ₃ ): cf 1.5 (s, 3H), 3.7 (d, IH, J = 2.5 Hz),

3.76 (s, 3H), 4.0 (m, 4H), 4.38 (d, IH, J * 2.5 Hz), 6.82 (2H) + 7.26 (2H), AA ', BB', J = 9.5 Hz), 9.2 (s, IH).

f) 3 g (0.01 mol) of the compound prepared according to Example 2e) are dissolved in 20 ml of anhydrous tetrahydrofuran. 1.11 g (1.56 ml, 0.011 mol) of anhydrous triethylamine are added to the solution. The solution is cooled to -15 ⁰ C and treated dropwise with constant stirring (ml 1.06, 0.011 mol) with 1.2 g of ethyl (chloroformate) was added. After 20 minutes, the precipitated salt is filtered off under a nitrogen atmosphere. 4.8 g (0.025 mol) of diazomethane, dissolved in diethyl ether, were added to the pil at room temperature. The reaction mixture is stirred for two hours, then the excess of the diazomethane is decomposed with acetic acid and the solution is evaporated in vacuo. The oily residue crystallizes. 3 g (90%) trans-4- (diazo-acetyl) -3- (2-methyl-1,3-dioxolan-2-yl) -l- (4-raethoxyphenyl) -2-azetidinone are

o μ · hold. Melting point: 95-96 C (benzal / ether).

IR (KBr): 2200, 1760, 1640 cm " ¹ .

¹ H-HMR (CDCl ): J 1.50 (s, 3H), 3.51 (d, IH, J = 2.6 Hz),

3.75 (s, 3H), 4.05 (m, 4H), 4.31 (d, IH), J = 2.6 Hz), 5.47 (s, IH), 6.85 (2H) + 7.30 (2H) (AA ', 3B', J = 9 Hz).

δ) 3.3 g (0.01 mol) trans-4- (diazo-acetyl) -3- (2-methyll, 3-dioxolan-2-yl) -l- (4-methoxyphenyl) -2- azetidinone are in a Gemisoh of 50 ml V / water and 100 ml tetrahydrofuran solved. The solution is at room temperature under a nitrogen atmosphere in a photoreactor with a high pressure mercury lamp irradiated. The course of the reaction becomes thin

Followed by layer chromatography (adsorbent? silica gel G after Stahl, developer benzene and acetone in the ratio 7 Jl). After the reaction is complete, the tetrahydrofuran is removed from the solution in vacuo. The residue will. Made alkaline with 20% aqueous sodium hydroxide solution and with 3x15 ml dichloroethane extracted »The aqueous phase is extracted with concentrated aqueous hydrochloric acid acidified to pH 1-2 and then extracted with 3x20 ml dichloromethane. The organic phase is dried over sodium sulfate and after filtration evaporated. 1.6 g (50 ^) / trans-3 ~ (2-methyl-1,3-dioxolane 2-yl) -l- (4-methoxyphenyl) -4-oxo-2-azetidiny! / - acetic acid will get.

Elemental analysis for C ₁₆ H ₁₉ NO ₆ (H = 321.35) calculated, % x C 59.80 H 5.96 H 4.36 found,%: C 59.60 H 5.76 N 4.08 IR (Ulm ): 3500-2500, 1760-1700 cm "" ¹ .

h) 1.0 g (3 »12 mmol) of the compound prepared according to Example 2g) is dissolved in 10 ml of dichloromethane. The solution of 0.53 g (3.12 mol) of diphenyldiazomethane in 10 ml of dichloromethane is added dropwise to the solution at room temperature. After the evolution of gas has ceased, the solution is evaporated in vacuo. 1.45 g (98 %) benzhydryl- ^ trans- ^ 3- (2-methyl-1,3-dioxolan-2-y1) -1- (4-methoxyphenyl) -4-oxo-2-azetidinyl / acetate / are obtained.

Elemental analysis for G ₃ H ₃ N0 _g (M = 487.55)

Calculated, %% C 71.44 H. 5.99 H 2.87 found, % C 71.13 H 6.21 N 2.93

¹ H-NMR (CEDCl): <f 1.35 (s, 3H), 2.7-3.1 (m, 2H), 3.38 (d,

IH, J = 2.5 Ha), 3.72 (s, 3H), 3.8-4.1 (m, 4H), 4.1-4.5 (m, IH), 6.85 (s, IH), 6.7-7.4 (m, 14H).

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ORIGINAL

Reacti cms scheme.

γΐ _γ 2

H ₃ C-C

Ho / Pd / C

J L

I CH ₂ COCW ₂ COOQ

Rh-SaIz

COOQ

ή. O-AcM

2. + mercaptan

/ ■

H.

■ SR '

COOQ ^J

BATH ORIGINAL

"CH ₂ COOH

'NH

k & lbeif-e's

CKo

COOQ

Claims (8)

Claims 1.) Process for the preparation of compounds of the general formula (I) I- CH ₂ COOX (D wherein Y ¹ and χ together represent a removable carbonyl protecting ,, the substituents, preferably a ketal group or its thio analog, stand and a selectively removable group verestem.de _s Ary is preferably a methyl group or Diarylmethy!, means characterized in that a compound of the general formula (III) CH ₂ COOH (III) wherein the meaning of Y ^ and χ is the same as above and R 'represents a removable protective group which protects the amide group, preferably for) phenyl or benzyl group substituted one or more times by alkoxy having 1-4 carbon atoms, in an known V / ise to an ester of the general formula (II) H
4- CH COOX (II) _R , in which "the meaning of Y, Y ^ ₈ X and R ^{9 is} the same as above ₉ reacts and splits off the 'Sij.iiu" tzgruppe R ^{D ^ from the ester} from an ester of the general formula (II), in which the meaning of L ₁ Y, R 'and X is the same as above, splits off the protective group R'. 2. The method according to claim 1, characterized in that the compound of the general formula (III) with Pheny! Diazomethane or esterified with diphenyldiazomethane. 3. The method according to claim 1, characterized in that that one of the esters of the general formula (II) is the protective group R 'with a peroxydisulfate or with in the presence of a Acid used cerium (IV) salt is split off. 4. The method according to claim 1 for the preparation of Benzhydryl- ^ trans- ^ 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl / ^r acetate /, characterized in that one / trans- (2,4-Diraethoxy-benzyl) -3- (2-raethyl ~ 1,3-dioxolan-2-yl) -4-oxo-2-azetidiny, 17-acetic acid first with diphenyldiazomethane and then with a peroxydisulfaf implements. 5. The method according to claim 1 for the preparation of benzhydryl / trans / 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl ^ -aoetajfc /, characterized in that one / trans-3- (2-methyl-1,3-dioxolan-2-yl) -l- (4-methoxyphenyl) -4-oxo-2-azetidinyl / acetic acid with diphenyldiazomethane and then in acidic medium with a Ger (IV) salt. 6. Compounds of the general formula (II) (H) X and Y together represent a removable »the carbonyl group protecting substituent, preferably a ketal group or its thio analogue, X ■ a selectively removable esterifying group, pre- an arylmethyl or diaryl methylene group, means and R 'for a removable one that protects the amide group Protecting group, preferably for by alkoxy with 1-4 carbon atoms mono- or polysubstituted phenyl or benzyl group. 7. Benzhydryl- / trans- / 3- (2-methyl-1, J »dioxolan-2-y1) -1- (4-methoxyphenyl) -4-oxo-2-azetidinyl / acetate /. 8. Benzhydryl- ^ trans - /! - (2,4-dimethoxy-benzy1) -3- (2-oethyll, 3-dioxolan-2-yl) -4-oxo-2-azetidinyl7-acetate /.