HU185081B - Process for preparing azetidinone-acetic acid derivatives - Google Patents

Process for preparing azetidinone-acetic acid derivatives Download PDF

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HU185081B
HU185081B HU814014A HU401481A HU185081B HU 185081 B HU185081 B HU 185081B HU 814014 A HU814014 A HU 814014A HU 401481 A HU401481 A HU 401481A HU 185081 B HU185081 B HU 185081B
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solution
mol
protecting
formula
diethyl
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HU814014A
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Karoly Lempert
Gabor Doleschal
Gyula Hornyak
Jozsef Fetter
Jozsef Nyitrai
Gyula Simig
Karoly Zauer
Tibor Gizur
Kalman Harsanyi
Gyoergy Fekete
Laszlo Szporny
Gyoergy Hajos
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Richter Gedeon Vegyeszet
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D205/00Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24Oxygen or sulfur atoms
    • C07D207/262-Pyrrolidones
    • C07D207/2732-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/282-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D411/00Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/04Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Heterocyclic acetic acid derivatives of the general formula (I), <IMAGE> wherein Y<1> and Y<2> form together a removable carbonyl protecting group, and X is a selectively removable esterifying group, are prepared by esterifying a compound of the general formula (III), <IMAGE> wherein Y<1> and Y<2> are as defined above and R' is a removable amido protecting group other than phenyl group, and removing the protecting group R' of the resulting novel compound of the general formula (II), <IMAGE> wherein X, R', Y<1> and Y<2> are as defined above. The compounds of the general formula (I) are valuable intermediates of the synthesis of thienamycin and thienamycin analogues.

Description

The present invention relates to novel azetidinone acetic acid derivatives of the formula (I):

Y 1 and Y 2 may be taken together to remove the carbonyl protecting group by an ethylene ketal group or a thio analogue thereof;

X is an esterification group which may be C 1-5 alkyl or benzhydryl.

The compounds of formula (I) are intermediates useful in the preparation of thienamycin and its derivatives, which are protected in our separate application filed on the same day as the present application.

Thienamycin is a broad-spectrum antibiotic, first produced microbiologically (U.S. Patent No. 3,950,357) and then synthetically (German Patent Publication No. 2,751,597).

It is an object of the present invention to provide a synthetic pathway which, at the beginning of the synthesis, combines the azetidinone backbone with the α-hydroxyethyl side chain (or an easily convertable side chain) and the resulting key compound is thienamycin or to a related compound.

In our experiments, it has been found that acylation of a dialkyl [(protected amino) malonate] with diketene and reaction of the acylated product with alkali phenol alcohol and iodine yields an azetidinone having the a-acetyl side chain of the general formula (VIII). which is suitable for the key media role.

In the formula (VIII), R 'is a removable amide protecting group substituted by one or more C 1-4 -alkoxy or phenyl or benzyl, and Z is C 1-5 -alkyl.

The intermediates of formula (VIII) and their preparation are protected by separate application (T / 23230), but their preparation is described in the corresponding examples in the present application.

It has further been found that it is expedient to form the keto group in the C-acetyl side chain of the compound of Formula VIII before converting it to thienamycin or a related compound with a protecting group which can be subsequently cleaved, preferably ethylene ketal or thioanalogon, e.g. -chalate or hernitoketal protecting group. The resulting compound of general formula (VII), wherein Y 1 and Y 2 together represent an ethylene ketal group or a thioanalogon, and R 'and Z are as defined above for the temporary protection of a keto group, in pyridine or the like or in aqueous dimethylsulfoxide with reacted. There is thus obtained a compound of general formula (VI) wherein R ', Y 1 and Y 2 and Z are as defined above.

The compound of formula (VI) is a mixture of cis and trans isomers. The isomers may be separated by chromatography or by differences in solubility, and the separated trans isomer of formula (VIa) is hydrolyzed to yield the resulting trans-carboxylic acid of formula (V). However, it is even better to hydrolyze the isomer mixture because the hydrolysis is selective (only the trans ester hydrolyses).

Hereinafter, the trans-carboxylic acid of formula (V) is first reacted with a carboxyl group activator and then with diazomethane, and the compound of formula (IV) thus obtained is subjected to a Wolff diazoketone rearrangement in the presence of water. The resulting azetidinone acetic acids of formula (III) are converted to the esters of formula (II). However, it is also possible to subject the compounds of formula (IV) to a diazo ketone rearrangement in the presence of an alcohol to give compounds of formula (H). In the formulas (V), (IV), (III) and (II), Y 1 and Y 2 and R 'have the meanings given above. The compound of formula (II) is then deprotected.

Some of the novel compounds of formula (VII) have been described in our previous application [T / 22925], the other compounds of formula (VII) and the new compounds of formula (VI) to (H) have been disclosed in separate applications filed on the same day but the formulation of the preparation is also given in the examples of the application.

The present invention therefore relates to a process for the preparation of compounds of the formula I in which Y 1 and Y 2 are a removable carbonyl protecting group substituted by ethylene ketal or thioanalogon and

X ester group having 1 to 5 carbons atoms, or benzhydryl can be such that a compound of formula (II) wherein Y 1 cs Y 2 and X are as defined above and R 'is a removable amido group protective substituent which phenyl or benzyl substituted with one or more C 1 -C 4 alkoxy groups, the protecting group R 'is removed by oxidation.

According to the invention, an ester of formula (II) is started from which the amide protecting group is cleaved by oxidation.

The oxidizing agent used to remove the dimethoxybenzyl protecting group is eschenium peroxydisulfate type compound, preferably potassium or sodium peroxydisulfate (K 2 SO 2 , Na 2 SO 2 0g). The reaction is carried out for about one hour. PH 7 buffer, water and organic solvent.

In the removal of the methoxyphenyl protecting group, a cerium (IV) salt and an acid are preferably used as the oxidizing agent. Most preferred was cerium (IV) ammonium nitrate in dilute aqueous sulfuric acid. The oxidations are carried out in the presence of an organic solvent.

The invention is further illustrated by the following non-limiting examples.

Example 1

Benzhydryl (trans- [3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl] acelate>

5.48 g (15 mmol) of [trans-1- (2,4-dimethoxybenz; l) -3- (2-methyl-1,3-dioxolan-2-yl) 4-oxo-2-azetidinyl] - To a solution of acetic acid in 50 ml of dichloromethane was added 3.05 g (15.75 mmol) of diphenyl diazomethane with stirring at room temperature. After the evolution of nitrogen has ceased, the remaining diphenyl diazomethane is reacted with a few drops of acetic acid. The solution was evaporated to dryness and the residue (6.77 g) was dissolved in acetonitrile (84 mL). To the solution was added 16.20 g (60 mmol) of potassium peroxydisulphate (K 2 SO 4), 21.60 g (120 mmol) of disodium hydrogen phosphate monohydrate (Na 2 HPO 4 .H 2 O) and 54 ml of water, then that

The 185,081 mixture was stirred vigorously for 4 hours, refluxed and finally cooled. The cold reaction mixture was filtered and the biphasic filtrate separated. The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated. The remaining benzene solution was worked up by column chromatography. (Adsorbent: Kieselgel 60,? 0.050-0.200 mm; eluent: benzene-acetone = 7: 2). Yield: 2.68 g (47%) of the title compound.

130 ° C (ethanol)

Elemental analysis for cAljjNOj (387.41): calculated% ·. C 69.27: H 6.08; N, 3.67. Found: C, 69.15; H, 6.20; N, 3.55.

IR (KBr): 3250, 2900, 1760, 1740 cin - '.

1 H-NMR (CDCl 3): 51.39 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 (111), 6.9 s (JH), 7.28 s (10H).

The starting material of this example was prepared as follows:

a) 109 S g (0.66 mole) of 2,4-dimethoxybenzaldebehyde and 72 ml (0.66 mole) of benzylamine in 660 ml of methanol are stirred for 20 minutes at room temperature (initially as a suspension) and then with external ice-water. while cooling, 13.2 g (0.33 mol) of sodium [tetrahydroborate (HI)] is added in small portions.

After completion of the reaction, which was monitored by TLC (layer: Kieselgel G; Stahl; developing mixture: benzohacetone = 9: 1), the mixture was evaporated to dryness in vacuo, water (300 mL) was added and the residue was extracted with 500 mL ether. The aqueous phase was extracted with 2 x 200 mL ether. The combined ethereal phase was dried over magnesium sulfate, filtered, and then treated with diethyl bromomalonate (112 mL, 0.66 mol) and triethylamine (93 mL, 0.66 mol). The reaction mixture was stirred for 2-3 days at room temperature. The precipitated triethylammonium bromide was filtered off and washed with ether. The mother liquor was evaporated and the residue was crystallized from ISO nd ethanol. 210 g of crude product are obtained, which is recrystallized from 400 ml of ethanol.

Yield: 197 g (72%) of diethyl [N-benzyl-N- (2,4-dimethoxy-benzyl] -uraminomalonate).

Mp 62-63 ° C (ethanol)

IR (KBr): 1750/1725 cm -1 , d.

b) 61.7 g (0.149 mol) of diethyl [N-benzyl-N- (2,4-dimethoxybenzyl) amino-malonate] prepared in Example 1a) in the presence of about 20 g of palladium on charcoal, 500 g. hydrogenated in atmospheric pressure.

The catalyst was filtered off and the filtrate was evaporated.

Yield: 47.1 g (97%) of diethyl [(2,4-dimethoxybenzylamino) -inalonate]; optionally converting it to the acid addition salt with hydrochloric acid.

HCl salt: mp 122-124 ° C (EtOAc).

Analysis for C 6 H 6 m C1NO (361.82) Calcd: Calculated%: C, 53.11: H, 6.69; Cl, 9.80; N, 3.87. Found: C, 52.51; H, 6.77; Cl, 10.30; N, 4.09.

IR (film): 3250, 2900, 2850, 1730, 1720 cm -1 .

1 H-NMR (CDCl 3): 51.3 (t, 6H); 3.78 (s, 3H); 3.82 (s, 3H); 4.2! (q, 4H); 6.20 (s. 2H); 6.4-6.6 (m, 2H) + + 7.3-7.55 (m, 1H); 7.7 (s, s, 1H).

c) 39.6 g (0.122 mol) of diethyl [(2,4-dimethoxybenzylamino) malonate] prepared in Example 1b) in 80 ml of glacial acetic acid were treated with 12.3 g (11.2 ml, 0.146 mol). moles) with diketene and boiling at half price. The glacial acetic acid was distilled off from a water bath in vacuo, the residual oil was crystallized by trituration with 150 ml of water, then dissolved in 60 ml of ethyl acetate and recrystallized by addition of petroleum ether.

Yield: 29.6 g (60%) of diethyl [N- (2,4-dimethoxybenzyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidinedicarboxylate] and / or tautomer.

Mp 106-107 a C.

Elemental analysis for C 10 H 11 NO 4 (409.43): Calculated: 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 (1740v), 1710 cin '.

1 H-NMR (CDCl 3): 51.1 (t, 311); 1.17 (t, 311); 1.52 (s 3H); 2.8 (<0.1H); 2.65 (s, s, 2H); 3.75 (s, 6H); 3.8 4.15 (m, 4H); 6.7 (s, 2H); 6.25-6.45 m + 7.0-7.75 (m, 3H).

1) 20.5 g (50 mmol) of the intermediates prepared in Example le) are suspended in 50 ml of anhydrous ether and subjected to force; while stirring and cooling in external ice-water, two drops of funnel were simultaneously added rapidly with a solution of 3.45 g (150 mmol) of sodium metal in 100 mL of anhydrous ethanol and a solution of 12.7 g (5C mmol) of iodine in 150 mL of anhydrous ether. To the mixture was added 5 g of sodium bisulfite dissolved in 200 ml of saturated brine. The mixture was transferred to a separatory funnel, and the inorganic salts were removed by addition of water (60 mL). The taste phase was separated and shaken with 2X 100 mL ether. The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated. The residual oil (18.5 g) was crystallized from 30 ml of 2-propanol.

Yield: 10.9 g (54%) of diethyl [3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate.

□ p .: 84-85 ° C (2-propanol).

Elemental analysis for C 10 H 25 NO 4 O (407.41): Calculated: C, 58.96; H, 6.19; N, 3.44; % Tah: C, 58.99; H, 6.04; N, 3.57.

IR (KBr): 2900; 1780, 1740, 1710 cin ' 1 .

1 H-NMR (CDCl 3): 51.12 (t, 3H); 1.21 (t, 3H): 2.31 (s, 3H); 3.76 (s, 6H); 3.8-3.4 (m, 4H); 4.53 (d, 1H); 4.63 (d, 1H); 4.69 (s, 1H); 6.3-6.4 (m, 2H) + 7.07 (d, 1H).

e) 179 g (0.484 mol) of diethyl [3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidicarboxylate] prepared in Example 1d and 107 ml (1.936 mol); g) To a solution of ethylene glycol in 500 ml of anhydrous dioxane was added dropwise 179 ml (1.452 mol; 206 g) of boron trifluoride diethyl etherate under vigorous stirring and cooling in ice-water and allowed to stand at room temperature for 1 day with stirring. Sodium carbonate water (1/10) (415 g, 1.452 mol) was added slowly with stirring and cooling in external ice-water and stirred for 15 minutes. Then 1 liter of ether and 1 liter of water are added and the phases are separated. The aqueous phase was extracted twice with 500 ml of diethyl ether. The ethereal phase is dried over magnesium sulfate, filtered and the filtrate is evaporated. To the residue were added 33.9 g (0.58 mol) of sodium chloride, 17.4 ml (0.968 mol) of water and 220 ml of dimethylsulfoxide, and the mixture was stirred in a 180 ° C oil bath until the reaction was complete (ca. 15 hours, TLC (adsorbent: Kieselgel G; Stahl; developing mixture: benzene-ethyl acetate 6: 4). The reaction mixture was 1100 m! is poured into a saturated aqueous solution of sodium chloride and once 1000, then twice

-3185 081

Shake with 500 ml of diethyl ether. The food phase was clarified with charcoal, dried over magnesium sulfate, and the color was evaporated to about ca. Leave 200 ml cter. The solution was then cooled with ice-water.

Yield: 59 g (35%) of tris-ethyl [1- (2,4-dineloxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) 4-oxo-2-azelidine. carboxylate].

Mp: 95 c C

f) Diethyl [3-acetyl-1- (2,4-dimethoxybenzyl) 4-oxo-2,2-azetidine dicarboxylate (0.5 g, 1.2 mmol) obtained in Example 1d. A solution of mercaptoethanol (0.53 g, 3.6 mmol) in anhydrous tetrahydrofuran (mL) was heated at reflux for 4 hours, then water (10 mL) and chloroform (10 mL) were added. The organic layer was separated, partitioned between 5% aqueous sodium bicarbonate solution and the organic layer was dried over magnesium sulfate, filtered and the filtrate was subjected to preparative thin layer chromatography (adsorbent: Kieselgel 60; 2) recovering the product.

Yield: 0.30 g (53%) of diethyl [1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-oxathiolan-2-yl) 4-oxo-2,2 azelidine dicarboxylate] 1 H-NMR (CDCl 3): 60.8-1.55 (m, 6H); 1.72 + 1.77 (d, SH). 2.9-3.4 (m, 2H), 3.75 (s, 6H), 4.0-5.0 (m, 9H), 6.4 (m, 2H) + 7.1 (d, IH).

g) 41.2 g (0.109 mol) of the trans-ethyl [1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) prepared according to example le). To a suspension of 4-oxo-2-azetidinecarboxylate] in ethanol (50 ml) was added 5.21 g (0.130 mole) of sodium hydroxide in 60 ml of water while stirring and cooling with external ice-water, and the mixture was stirred until a clear solution was obtained. about 20 minutes). Water (100 mL) was added and the mixture was extracted with ether (100 mL). The aqueous phase was acidified to pH = 1 with concentrated aqueous hydrochloric acid and then rapidly extracted with dichloromethane (100 mL, then 50 mL x 2). The dichloromethane solution was dried over magnesium sulfate, filtered and the filtrate was evaporated. The residual oil was recrystallized from toluene / petroleum ether.

Yield: 35 g (92%) of trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) 4-oxo-2-azelidine carboxylic acid.

Mp 117-118 ° C (toluene).

Anal calcd for C] 7 H 21 NO 7 (351.35): Calculated% \ C, 58.11; H, 6.03; N, 3.99; Found: C, 58.17; II, 6.30; N, 4.24.

IR (KBr): 3500-2500, 2900, 1760, 1720 cm-first

1 H-NMR (CDCl 3 ): 61.39 (s, 3H), 3.50 (d. III, J = 2.5 Hz), 3.77 (s, 3H), 3.79 (s, 3H), 3.86 (d, 111, J = 2.5 Hz), 3.96 (m, 4H), 4.21 + 4.56 (d, 211. J AC = 15 Hz), 6 , 44 (m, 211) + 7.15 (d, 1H, J = 10 Hz), 7.58 (s, s, 111).

h) 17.6 g (50 min) of tert-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) prepared according to Example 1g) - To a solution of 4-oxo-2-azetidinecarboxylic acid in 150 ml of anhydrous tetrahydrofuran was added 7.3 ml (52.5 mmol) of trictylamine, followed by 5.0 ml (52.5 mmol) of ethyl chloroformate under ice-cooling. is added. The mixture was cooled to -15 ° C and stirred at this temperature for 20 minutes, and then at this temperature, under an argon atmosphere, the formed trielylamine salt was filtered off. A solution of diazomethane (150 mmol) in cold diethyl ether (230 mL) was added to the filtrate. The solution was stirred and allowed to warm to room temperature and after 2 hours the mixture was evaporated to dryness. The brown, thick mass was dissolved in 20 mL of benzene and subjected to column chromatography (adsorbent: 150 g of 5 Kieselgel 60, -0 0.063-0.200 mm, eluent: benzene-acetone 7: 2).

Yield: 12.0 g (64%) of trans 4 - (diazoacetyl) -1 (2,4-dimethoxybenzyl) -3- (2-methylethyl-1,3-dioxolan-2-yl) -2-azetidinyl .

Analysis calculated for C 18 H 2 N 3 O 6 (375.37): C, 57.59; H, 5.64; Found: C, 57.78; II, 5.39.

IR (Circle): 2900, 2110, 1760 cm @ -1 . .

i) 2.25 g (6 mmol) of trans 4 - (diazoacetyl) -1- (2,44-methoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) prepared according to Example 111). 2-azetidinone, 100 mL of peroxide-free tetralydrofuran and 50 mL of water was added to ca. irradiated for four hours in a submerged pyrex apparatus with a high pressure mercury vapor lamp (HPK 125) under argon. The solution is then reduced to 50 ml in vacuo and diluted with water to 130 ml. To the aqueous side was added 2.4 ml of 10% aqueous sodium hydroxide solution. The alkaline solution is extracted with dichloromethane (3 x 20 mL) and the aqueous phase is acidified to pH 2 with concentrated aqueous hydrochloric acid. The acidic solution was extracted with dichloromethane (3 x 20 mL). The extract was dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The residue was crystallized from ether and filtered.

Yield: 1.82 g (83%) [trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) 4-oxo-2-azetidinyl] acetic acid.

124 ° C (ether).

Analysis calculated for C 18 H 23 NO 7 (365.37):% C, 59.17; H, 6.34; N, 3.83; found %; C, 59.22; II, 6.49; N, 4.07.

IR (KBr): 3500-2300, 2900, 1730, 1700 cm -1 ,

Example 2

Benzhydryl (trans- [3- (2-methyl-l, 3-dioxolan-2-yl) -4-oxo-2-azetidinyl] -acetate>.

0.28 g (0.65 mmol) of benzhydryl-trans- [3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) 4-oxo-2-azetidinyl 1-acetate) was dissolved in 2 ml of acetone. A solution of 0.9 g (1.6 mmol) of cerium (IV) ammonium nitrate [Cc (NH 4 ) 2 (NO 3 ) 6 ] in 2 ml of 5% aqueous sulfuric acid is added dropwise with stirring at room temperature. After the addition, the reaction mixture was stirred for another two minutes and then carefully neutralized with 5% aqueous sodium bicarbonate. It was extracted with ethyl acetate (3 x 4 mL) and the organic phase was dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residual oil was purified by preparative thin layer chromatography as in Example 1. mining; 0.06 g (30%) of the title compound having the same physical constants as in Example 1.

i [«The starting material of the example was prepared as follows; ·

a) 24.6 g (0.2 mol) of 4-methoxyaniline and 23.9 g (17 ml, 0.1 mol) of diethyl bromo malonate are stirred for 2 days at room temperature. The resulting material was taken up in 100 ml of diethyl ether 4

After trituration with 185,081, the precipitated 4-methoxyanisidine hydrobromide was filtered off and washed on the filter with a little diethyl ether. The mother liquor was evaporated and the residue crystallized by the addition of acetic acid.

Yield: 13.2 g (47%) of diethyl (4-methoxyanilino) malonate.

64-65 ° C (ethanol).

Elemental Analysis for: C 28 H 34 NO 5 (281.31): Calculated: C, 59.77; II, 6.81; N, 4.99; Found: C, 59.99; 11, 6.97; N, 5.25.

IR (KBr): 3300, 1775, 1725 cm @ -1.

1 H-NMR (CDCl 3 ): 51.23 (t, 611, J = 7.2 Hz), 3.67 (s, 3H), 4.2 (q, 4H, J = 7.2 Hz), 4.62 (s, 1H), 4.1 A5 (s, s, 1H), 6.55 (2H) + 6.73 (2H), (AA'BB ', J = 9 Hz).

b) Diethyl (4-methoxyanilino) nialonate (11.2 g, 0.04 mol) prepared in Example 2a) was heated in glacial acetic acid (15 ml) with diceline (4 g, 3.7 ml, 0.048 mol). The solution was evaporated in vacuo and the oily residue was triturated with diethyl ether and filtered.

Yield: 10.5 g (72%) of diethyl [1- (4-methoxyphenyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate] and / or its tautomer.

136-137 ° C (ethyl acetate).

Elemental Analysis for: C 18 H 3 NO 7 (365.38): Calculated: C 59.17; H, 6.39; N, 3.83; Found: C, 58.98; H, 6.90; N, 4.04.

IR (KBr): 3600-3000, 1760, 1740, 1685 cm-first

1 H-NMR (CDCl 3): 51.07 (t, 3H, J = 7.2 Hz), 1.28 (t, 3H, J = 7.2 Hz), 1.58 (s, 3H) , 2.76 (s, 2H), 3.64 (s, 1H), 3.76 (s, 3H), 4.1 (q, 2H, J = 7.2 Hz), 4.27 (q, 2H, J = 7.2Hz), 6.7 (2H) +7.0 (2H), (AA ', BB', J = 9Hz).

c) 9.1 g (0.025 tnol) of the diethyl [1- (4-methoxyphenyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate obtained in Example 2b). It is suspended in 50 ml of anhydrous diethyl ether and a solution of 1.72 g of metal sodium in 30 ml of anhydrous ethanol and 6.35 g (0.025 mol) of iodine in 50 ml of anhydrous diethyl ether are added dropwise with vigorous stirring and external ice-cooling. The mixture was poured into 100 ml of saturated aqueous sodium chloride solution and 2 g of sodium bisulfite and 2 ml of glacial acetic acid were added. The ether layer was separated and the aqueous layer was extracted with 3 x 50 mL of diethyl ether. The combined ethereal phases were dried over magnesium sulfate, filtered and the filtrate was evaporated. Trituration of the oily residue with 2-propanol crystallizes.

Yield: 6.2 g (68%) of diethyl [3-acetyl-1- (4-methoxyphenyl) 4-oxo-2,2-azetidine dicarboxylate].

M.p. 70-71 ° C (ethanol).

Analysis calculated for C 18 H 2 NO 7 (363.38):% C, 59.50; H, 5.82; N, 3.85; Found: C, 59.04; H, 5.84; N, 4.08.

IR (KBr): 1760, 1735, 1720 cm-first

1 H-NMR (CDCl 3 ): 51.20 (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, 1H), 6, 7 (2H) +7.31 (2H), (AA ', BB', J = 9 Hz).

d) 6 g (0.0165 mol) of diethyl [3-acetyl-1- (4-methoxyphenyl) -4-oxo-2,2-azetidinedicarboxylate] prepared in Example 2c) in 20 ml of anhydrous dioxane and 4 ml. Dissolve 1 g (3.75 mL, 0.066 mol) in ethylene glycol. To the solution. 7.1 g (6.3 ml, 0.05 mol) of boron trifluoride-diethyl etherate complex were added dropwise with external ice-cooling and stirring was continued for 2 hours at room temperature. The solution was basified with saturated aqueous sodium carbonate solution and 100 ml of vial was added and the mixture was extracted with diethyl ether (3 x 50 ml). The organic phase is dehydrated with magnesium sulfate, filtered and the filtrate is evaporated. The oily residue is crystallized by trituration with ether.

Yield: 6 g (89%) of diethyl [3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) 4-oxo-2,2-azetidine dicarboxylate. ].

M.p. 82-83 ° C (ethanol).

Elemental Analysis for C; 0 H 25 NO 8 (407.43) Found:% C, 58.96; H, 6.18: N, 3.44; t%. C, 58.70; H, 5.68; N, 3.63.

IR (KBr): 1740 cm -1 (wide).

1 H-NMR (CDCl 3 ): 51.17 (t, 3H, J = 7.2 Hz), 1.25 (t, 311, J = 7.2 Hz), 1.5 (s, 3H), 3.7 (s, 3H) .3.9 (m, 4H), 4.2 (m, 5H), 6.67 (2H) +7.34 (2H), (AA'BB ', J = 9 Hz).

e) 11 g (0.0245 mol) of diethyl [3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) 4-oxo-2,2-azetidine- dicarboxylate was dissolved in 20 mL of dimethyl sulfoxide and the solution was added with 1.72 g (0.0295 mole) of sodium chloride and 0.9 mL (0.049 mole) of water at 175 ° C until the reaction followed by thin layer chromatography. (Adsorbent: Kieselgel G, Stahl-like; developing mixture: benzene-ethyl acetate = 6: 4.)

After cooling, the reaction mixture was poured into 150 ml of a saturated aqueous sodium chloride solution and extracted three times with 50 ml of diethyl ether each time. The organic phase is dried over magnesium sulfate, filtered and the filtrate is evaporated. The oily residue (6 g) was dissolved in 96 ml of ethyl alcohol (25 ml), and a solution of sodium hydroxide (0.72 g, 0.018 mol) in water (10 ml) was added to the solution under external ice-water cooling and diluted with 50 ml of water. and extracted with dichloromethane (2 x 25 mL). The aqueous layer was acidified with concentrated aqueous hydrochloric acid, and after reaching the value pE = l x 25 ml of dichloromethane is extracted. The organic layer was demineralized with magnesium sulfate, filtered and the filtrate was evaporated. Marathi wax oil crystallizes from benzene.

Yield: 4 g (54%) of trans-3- (2-methyl-1,3-dioxolan-2-1) -1- (4-methoxyphenyl) 4-oxo-2-azetidine carboxylic acid.

Calcd for CISH 17 NO 6 (307.32) Calcd: Calculated%. C, 58.63; H, 5.57; N, 4.56; talilt%; C, 58.40; H, 5.80; N, 4.66.

IR (KBr): 3400-2700, 1750 cm -1 (br) 1 H-NMR (CDCl 3 ): 51.5 (s, 3H), 3.7 (d, 1H, J = 2.5 Hz), 3, 76 (s, 3H), 4.0 (m, 4H), 4.38 (d, 1H, J = 2.5 Hz), 6.82 (211) +7.26 (2H), (AA'BB ', J = 9.5 Hz), 9.2 (s, 1H).

f) 3 g (0.01 mol) of the compound prepared in Example 2e) are dissolved in 20 ml of anhydrous tetrahydrofuran and 1.11 g (1.56 ml, 0.011 mol) of anhydrous triethylamine are added. The solution was cooled to -15 ° C and 1.2 g (1.06 mL, 0.011 mol) of ethyl chloroformate was added dropwise with constant stirring. After 20 minutes, the precipitated salt was filtered off under a nitrogen atmosphere and a solution of 4.8 g (0.025 mol) of diazomethane in diethyl ether was added to the filtrate at room temperature. After stirring for 2 hours, the excess diazomethane was decomposed with acetic acid and the solution concentrated in vacuo. The product crystallizes from an oily residue.

Yield: 3 g (90%) of trans 4 - (diazoacetyl) -3- (2-methyl-, 3-dixolan-2-yl) -1- (4-methoxyphenyl) -2-azetinone.

3p .: 95-96 ° C (benzene ether)

-5IR (KBr): 2200, 1760, 1640 cm-first

1 H-NMR (CDCl 3 ): 51.50 s (3H), 3.51 d (1H, J = 2.6 Hz), 3.75 s (3H), 4.05 m (4H), 4, 31d (1H, J = 2.6 Hz), 5.47 s (1H), 6.85 (2H) + 7.30 (2H) (AA'BB ', J = 9 Hz)

g) 3.3 g (0.01 mol) of trans-4- (diazoacetyl) -3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -2-azetidinone 50m! water and 100 ml of tetrahydrofuran. The solution is irradiated at room temperature with a high pressure mercury vapor lamp under nitrogen atmosphere in a photoreactor. The progress of the reaction was monitored by thin layer chromatography. (Adsorbent: Kieselgel G, Stahl; developing mixture benzene-acetone = 7: 1). After completion of the reaction, tetrahydrofuran was distilled off in vacuo, and the residue was made basic with 20% aqueous sodium hydroxide and three times with 15 ml of dichloromethane. extraction with methane. The aqueous phase was acidified with concentrated aqueous hydrochloric acid (pH 1-2) and extracted three times with 20 ml of dichloromethane. The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated.

Yield: 1.6 g (50%) of [trans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidine] acetic acid.

Analysis calculated for C 16 H 19 NO 6 (321.33):% C, 59.80; H, 5.96; N, 4.36; Found: C, 59.60; H, 5.76; N, 4.08

IR (film): 3500-2500, 1760-1700 cm -1 .

h) 1.0 g (3.12 mmol) of the compound prepared in Example 2g) is dissolved in 10 ml of dichloromethane and a solution of 0.53 g (3.12 mmol) of diphenyl diazomethane in 10 ml of dichloromethane is added dropwise with stirring at room temperature. After gas evolution ceased, the solution was concentrated in vacuo.

Yield: 1.45 g (98%) of benzhydryl (trans- [3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-) azetidinyl acetate>.

Anal calcd for C 29 H29N0c (487.55): Calculated% C, 71.44; H, 5.99; N, 2.87; Found: C, 71.13; H, 6.21; N, 2.93.

1 H-NMR (CDCl 3 ): 51.35 (s, 3H), 2.7-3.1 (m, 2H), 3.38 (d, 1H, J = 2.5 Hz), 3.72 (s) , 3H), 3.8-4.1 (m, 4H), 4.1-4.5 (m, 1H), 6.85 (s, 1H), 6.7-7.4 (ni, 14 H).

185 081

Example 3

Ethyl <Trans-3 - [(2-methyl-l, 3-dioxo-2al n) 4-oxo-2-azetidinyl] -acetate>.

g Trans-4- (diazoacetyl) -1- (2,4-dimethoxybenzyl) -3- {2-methyl-3-dioxolan-2- (0.38 g, 1 mmol) prepared in Example 1h. il) -2-Azetidinone is dissolved in 100 ml of anhydrous ethanol. The solution was irradiated in a submerged pyrex apparatus with a high pressure mercury vapor lamp (HPK 125) under argon. After the reaction was complete, the solution was evaporated and the residue was purified by chromatography (adsorbent: Kieselgel 7: 3). There was obtained 0.27 g (70%) of ethyl trans-1 - [(2,4-dimethylbenzyl) -3- (2-methyl-1,315-dioxolan-2-yl) -2-azetidinyl]. Acetate), the dimethoxybenzyl protecting group is then removed with potassium peroxydisulfate as described in Example 1.

Claims (2)

  1. A process for the preparation of azetidinone acetic acid (25) derivatives of the formula I
    Y * and Y 2 may be taken together to remove the carbonyl protecting group by an ethylene ketal group or a thioanalogon, and
    An esterification group X which may be C 1 -C 5 alkyl or benzhydryl group, wherein a compound of formula II wherein Y 1 and Y 2 and X are as defined above and R 'is a removable amide protecting group which may be phenyl or benzyl substituted with one or more C 1 -C 4 alkoxy groups, the R 'protecting group is removed by oxidation.
  2. 2. The process of claim 1 wherein the removal of the protecting group R 'is carried out with a peroxydisulfate compound or, in the presence of an acid, a cerium (IV) salt.
HU814014A 1981-12-30 1981-12-30 Process for preparing azetidinone-acetic acid derivatives HU185081B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
HU814014A HU185081B (en) 1981-12-30 1981-12-30 Process for preparing azetidinone-acetic acid derivatives

Applications Claiming Priority (19)

Application Number Priority Date Filing Date Title
HU814014A HU185081B (en) 1981-12-30 1981-12-30 Process for preparing azetidinone-acetic acid derivatives
AT0453382A AT379148B (en) 1981-12-30 1982-12-14 Method for producing heterocyclic acetic acid derivatives
JP57234851A JPS58118563A (en) 1981-12-30 1982-12-27 Manufacture of heterocyclic acetic acid derivative
BE1/10677A BE895490A (en) 1981-12-30 1982-12-28 Process for the preparation of heterocyclic derivatives of acetic acid
FR8221973A FR2518995B1 (en) 1981-12-30 1982-12-29 Process for the preparation of heterocyclic derivatives of acetic acid and derivatives thus obtained
SE8207477A SE453085B (en) 1981-12-30 1982-12-29 Process for the production tell up of azetidinone ettiksyraderivat
LU84567A LU84567A1 (en) 1981-12-30 1982-12-29 Process for the preparation of heterocyclic derivatives of acetic acid
CH7604/82A CH660186A5 (en) 1981-12-30 1982-12-29 Method for producing heterocyclic acetic acid derivatives.
DE19823248675 DE3248675A1 (en) 1981-12-30 1982-12-30 Method for producing heterocyclic acetic acid derivatives (ii)
FI824517A FI824517L (en) 1981-12-30 1982-12-30 Foerfarande foer framstaellning av heterocycliska aettikssyraderivat
AU91970/82A AU557596B2 (en) 1981-12-30 1982-12-30 Azethidine acetic acid derivatives
ES518722A ES518722A0 (en)