IE46154B1 - Azetidinone derivatives - Google Patents

Description

This invention relates to azetidinone derivatives and processes for their preparation.

Our Patent Specification No. 46153 discloses and claims certain azabicyclo[4.2.0]octane-2-carboxylic acid derivatives which . have antibacterial activity. The azetidinones of this invention are useful as intermediates in the preparation of these azabicyclo[4.2.0]octane-2-caboxylic acid derivatives.

Accordingly the present invention provides compounds of formula (I) :R A \ _CH„CET 2 \ A (I) where R is a protected primary amino group as dofinnd herein, is hydrogen or a secondary amine protecting group and both groups A together represent an oxygen atom or the residue of an acetal moiety.

The term protected amino group used herein includes derivatives of the primary amino group in which the amine is protected with a conventional protecting group or a chemical precursor of the amino group, that is to say a group which is not a derivative of the amino group but which can be converted chemically into a primary amine.

A comprehensive review of amino protecting groups is given in Protective Groups in Organic Chemistry J.F.W.

McOmie Plenum Press 1973.

Examples of derivatives for R in which the amine is protected 25 are benzyloxy carbonylamino, phthalimido, succinimido, maleimido and 4,5-diphenyl-2-oxo-4-oxazolin-3-yl. 615 4 When R is a derivative of the primary amino group in which the amine is protected by a protecting group preferably it is phthalimido.

An example of a chemical precursor for R is azido.

Examples of secondary amine protecting groups are 4-methoxybenzyl, 2,4-dimethoxyben2yl, trityl, benzhydryl and methoxy substituted benzhydryl.

When R1 is a secondary amine protecting group preferably it is 2,4-dimethoxybenzyl.

By way of example both groups A are the same and each represents an alkoxy group containing up to four carbon atoms optionally substituted with phenyl or halogen, allyloxy, methallyloxy, or taken together represent ethane-1,2-dioxy or propane-1,3-dioxy.

Preferably both groups A each represent methoxy.

Compounds of formula (I) can be prepared by reducing an acid chloride of formula (IX) :- /7 (IX) where R and R1 are as defined with reference to formula (I) provided that R1 is not hydrogen with a reducing agent which selectively reduces acid chlorides to aldehydes, optionally converting the aldehyde into an acetal and optionally converting R1 into hydrogen.

One reducing agent which can be used in this process is i lithium aluminium tri-t-butoxyhydride.

The reaction is generally carried out at reduced temperature e.g. down to -78°C in an inert atmosphere e.g. dry argon.

Acid chlorides of formula (II) can be prepared by reacting the corresponding acid with,an acid chloride-forming reagent for example oxalyl chloride and pyridine.

Compounds of formula (I) can also be prepared by reacting ' an alkali metal salt of a nitroethane of formula (III) :\_ xCn2CH2NO2 (III) where R and R^ are as defined with reference to formula (I) provided that R is not hydrogen with concentrated sulfuric acid in a lower alkanol to obtain the compound of formula (I) where both groups A are lower alkoxy optionally converting the group R1 into hydrogen, and optionally converting the groups A into oxygen or into a different acetal.

Preferably the alkanol is methanol.

Preferably the alkali metal salt is the sodium salt which is prepared from the alkoxide (e.g. sodium methoxide).

The process is generally carried out at moderate to low temperatures e.g. -10°C and under an inert atmosphere for example under nitrogen.

The following Examples illustrate the invention. All temperatures are Centigrade.

EXAMPLE 1 Methyl eis-l-(2,4-Dimethoxybenzyl)-3-azido-4-oxoazetidine-2-carboxylate Method A: To a solution of 15.1 g (0.149 mole) of azidoacetic acid in 130 ml of anhydrous methylene chloride at 0° (ice bath) was added dropwise 21.0 ml (0.15 mole) of trifluoroacetic anhydride. This mixture was stirred at 0° for 15 minutes and then 20.8 ml (0.15 mole) of triethylamine was added dropwise. Stirring was continued for an additional 45 minutes and then the entire reaction mixture was transferred under argon into an addition funnel which was cooled externally by dry ice. The addition funnel was attached to a flask containing methyl N-(2,4-dimethoxybenzylJiminoacetate (prepared from 16.82 g of 2,4-dimethoxybenzylamine and 10.05 g of methyl glyoxalate), anhydrous methylene chloride (200 ml), and triethylamine (20.8 ml, 0.15 mole). The solution of the mixed anhydride was added dropwise from the addition funnel to the solution of imine at 0°. Stirring was continued at 0° for 1 hour and then the dark reaction mixture was transferred to a separatory funnel and washed with H20, aqueous NaHCOg and brine and then dried over anhydrous magnesium sulfate. The solvents were removed in vacuo and the residue chromatographed on 300 g of silica gel (70-230 mesh) affording an off-white solid which was further purified by trituration with ether to give 14.45 g (45£) of the title product as a white solid; tic: benzene: ethyl acetate (1:1), silica gel GF, Rf = 0.64. Recrystallization from ethyl acetate-hexane afforded an analytical sample, mp 82-84°.

Method B: A solution of 1.6 g (9.55 mmol) dimethoxybenzylamine in 5 ml of CH^Cl,, was rapidly added at 0° to a solution of 1.06 g (10 mmol) freshly distilled methyl glyoxylate in 15 ml CH2C12. A slight exotherm occurred and water droplets appeared. Magnesium sulfate (5 g) was added and the mixture stirred at 0° for 2 hours. Fresh magnesium sulfate (1.0 g) was added, the magnesium sulfate removed by filtration under argon and washed with a minimum of ch2ci2. *ϊ I To a solution of 3.8 g (36 mmol) of azidoacetic acid (pumped in high vacuum 3 hr) in 125 ml of CHgClg was added 10.6 ml (/6 mmol) of triethylamine with cooling. Magnesium sulfate (3 gm) was added, the mixture stirred 10 minutes at room temperature, filtered under argon and washed with a 25 ml CHgClg.

The azidoacetic acid solution was added at 0° to the imine, sufficient methylene chloride was added to bring the total volume to 200 ml, the solution cooled to 0° under argon and 5.3 ml (38 mmol) trifluoroacetic anhydride added slowly over £ hour with vigorous stirring and cooling. The mixture was stirred for 1 hour at 0°, allowed to warm to room temperature, transferred to a separatory funnel, washed with water, 555 NaHCOg, 2% phosphoric acid and 5% HaHCOg, dried over magnesium sulfate-charcoal, filtered and the filtrate was retreated twice with charcoal and evaporated to dryness. The residue was dissolved in a minimum of ether and stored at -20° to allow crystallization. The crystalline mass was isolated and washed with cold ether to give 1.9 gm (64%) product, mp 79°-80.5°.

Method C: A solution of 1.6 g of 2,4-dimethoxybenzylamine in 15 ml of methylene chloride was shaken with an excess of magnesium sulfate then reacted with 1.05 g of methyl glyoxylate in 2 ml of methylene chloride at 25° (room temperature) overnight. The mixture was filtered, stripped and degassed with argon.

A solution of 1.5 g of azidoacetic acid in 25 ml of methylene chloride was cooled to 0° then reacted with 1.3 ml of oxalyl chloride with 1.2 ml of pyridine in 3 ml of methylene chloride at 0°. Argon was passed through the mixture which was stirred for one hour.

The imine from above was taken into 20 ml of methylene chloride with 4.15 ml of triethylamine. The solution of azidoacetyl chloride was added dropwise at 0°. After one hour at 0° the mixture was washed with water, sodium bicarbonate solution, salt solution, dried and stripped. After passing over a silica gel column with methylene chloride the yield was 1.31 g of the desired compound.

Substitution of ethyl glyoxylate, n-butyl, tert, butyl, benzyl or methoxybenzyl glyoxylate for methyl glyoxalate gives the corresponding ester congeners of the title compound.

EXAMPLE 2 Ci s-1 -(2,4-dimethoxybenzyl)-2-diazacetyl-3-azi do-4-azeti di none To a suspension of 10.1 g (33 mmole) of cis-1-(2,4-dimethoxy10 benzyl)-3-azido-4-oxo-azetidine-2-carboxylic acid (prepared by reacting the product of Example 1 with potassium carbonate in aqueous tetrahydrofuran) in 100 ml of dry benzene at 5° was added 2.54 ml (29.5 mmole) of oxalyl chloride under argon. With vigorous stirring, 2.37 ml (29.5 mmole) of dry pyridine was added dropwise during which time con15 siderable gas evolution occurred. After stirring for 1 hour, the suspension was filtered, the solid washed with cold dry benzene and the combined filtrates concentrated to one-half its volume in vacuum. The acid chloride solution was diluted to its original volume with dry benzene and added dropwise to an ethereal diazomethane solution (0.12 mole, 1.1 L) at 0° with vigorous stirring. A slow stream of argon was passed through the suspension while stirring was continued for 18 hours. 200 ml of water was added to the reaction mixture, the organic phase separated, dried (MgSO^), filtered with suction, and the solvent removed by distillation at reduced pressure.

The product was then triturated with 50% diethyl ether in hexane, collected by suction filtration, and chromatographed (silica gel: benzene with an ethyl acetate gradient up to 30%) yielding 8.5 g (78.0%) of the title compound as light yellow crystals, mp 83-84.5°. fhe corresponding α-chloroketone (2.6 gr, 22.2%) was isolated as a white crystalline solid (mp. 69-71°).

Ethereal diazomethane was afforeded by the slow addition of 30 g of N-methyl-N'-nitro-N-nitrosoiminourea, 97% (MNNG) to a vigorously stirred solution of 51 g of potassium hydroxide in 85 ml of water layered with 810 ml of diethyl ether at -10°. After vigorous stirring for an additional one-half hour, the ether solution was carefully decanted, the aqueous phase was washed with fresh ether (3 x 150 ml), and the combined organic phases were dried over fresh potassium hydroxide pellets.

EXAMPLE 3 Cis-l-(2,4-dimethoxybenzyl)-3-azido-4-oxo-azetidj.nyl acetic acid A solution of 6.0 g (18.2 nmol) of cisyl-(2,4-dimethoxybenzyl)2-diazacetyl-3-azido-4-azetidinone in 3.0 L of aqueous dioxane (50%) was degassed with argon, photolyzed using a Pyrex* filter, (Pyrex is a Registered Trade Mark) and the organic solvent was removed by distillation at reduced pressure. The aqueous phase (pH = 7) v;as then extracted with ethyl acetate (4 x 300 ml), adjusted to a pH of 2.5, and extracted again with ethyl acetate (4 x 300 ml).

The last four organic extracts were combined, dried (MgSO^), treated with charcoal, filtered with suction, and solvent distilled at reduced pressure to yield 2.21 g (38%) of an off-white crystalline solid (mp. 151°d).

The neutral pH washings were combined and treated in the same fashion to yield after chromatography 2.9 g of recovered starting material and 2.6 g· α-chloroketone (42/).

EXAMPLE 4 «-Ci s-1-(2,4-dimethoxybenzyl)-3-azi do-4-oxo-azeti dinyl-acetaldehyde To a solution of oxalyl chloride (1.37 ml, 16.2 mmol) and 5 g (15.5 mmol) of cis-l-(2,4-dimethoxybenzyl)-3-azido-4-oxo-2azetidinyl acetic acid in 70 ml of dry glyme (freshly distilled from lithium aluminum hydride) was added dropwise over a period of 30 minutes, 1.27 ml of pyridine under argon at 0°. The solution was allowed to stir at room temperature for 40 minutes after complete addition of the pyridine. The bright yellow solution was then concentrated under vacuum to half volume and quickly filtered with suction. A solution of 4.37 g (1.1 equivalents) of lithium aluminum tri-t-butoxyhydride in 100 ml of dry glyme was stirred for 30 minutes then quickly filtered through a Celite* pad (Celite is a Registered Trade Mark) and placed in an addition funnel. The hydride solution was added dropwise under argon over a period of 2.5 hrs to the vigorously stirred acid chloride solution at -78°. After complete addition, the reaction mixture was allowed to stir for an additional 1.5 hours. Then the dry-ice/isopropanol bath was removed and brine was added slowly, followed by addition of 3N HCl. After dilution of the reaction mixture with ethyl acetate, the layers were separated, and the aqueous phase was extracted with ethyl acetate several times. The combined organic portions were washed with 5% sodium bicarbonate and brine, dried over magnesium sulphate and evaporated to give 4.8 g. Tic (ethyl acetate:benzene 1:1) showed one spot corresponding to aldehyde and origin material. The crude aldehyde gives satisfactory results in the next step.

EXAMPLE 5 Cis-l-(2,4-dimethoxybenzyl)-2-(21,2’-dimethoxyethyl)-3-azido-4-azetidi none To a solution of 1.4 g (4.6 nmole) of cis-l-(2,4-dimethoxybenzyl)3-azido-4-oxo-azetidinyl-aceta1dehyde in dry benzene (10 ml) was added 4,0 ml (35.6 mmole) of freshly distilled trimethyl orthoformate and 50 mg of £-toluenesulfonic acid. The mixture was stirred at 50° under an argon stream for 18 hours, diluted with 100 ml of benzene and extracted with 52 aqueous sodium bicarbonate. After drying over magnesium sulfate, the solvents were removed in vacuo and the residue chromatographed over silica gel with benzene-ethyl acetate to give 1.25 g (77%) of the title compound as a light yellow oil.

EXAMPLE 6 Cis-2-(2',2'-dimethoxyethyl)-3-azido-4-azetidinone To a stirred solution of 1.15 g (3.28 mmole) of cis-1-(2,4dimethoxybenzyi)-2-(21,2'-dimethoxyethyl)-3-azido-4-azetidinone in 120 ml of degassed acetonitrile was added at 80°, a solution of 11,8 g (43.7 mmole) of potassium persulfate and 4.05 g (23.3 mmole) of potassium monohydrogenphosphate in 135 ml of degassed water in 6 portions over a 1 hour period. The pH of the mixture was adjusted to 6.5 - 7.0 with potassium monohydrogenphosphate after each addition. ,, 46154 After one hour, the mixture was cooled to room temperature, the acetonitrile removed in vacuo and the pH adjusted to 8.0.

Extraction with ethyl acetate (4 x 75 ml) afforded a mixture of product and 2,4-dimethoxybenzaldehyde which was chromatographed over silica gel with benzene-ethyl acetate to give 0.51 g (77%) of the title compound as a light yellow oil.

EXAMPLE 7 Ci s-1-(2,4-dimethoxybenzyl)-3-azido-4-oxo-2-azetidinyl formaldehyde To a stirred solution of 16.0 g (52.3 mmol) of cis-l-(2,4dimethoxybenzyl)-3-azido-4-oxoazetidinyl-2-carboxylic acid and 4.48 ml (52.3 mmol) of oxalyl chloride in 250 ml of glyme freshly distilled from lithium aluminum hydride was added dropwise over a period of 1 hour at 0°, 4.24 ml of pyridine under argon. After stirring at room temperature for an additional one hour, the reaction mixture was concentrated at reduced pressure to half volume and quickly filtered. A solution of 14.84 g of lithium tri-t-butoxy-aluminum hydride (1.1 equivalents) in 250 ml dry glyme (prepared by stirring at room temperature overnight and filtering through Celite. Celite is a Registered Trade Mark) was added dropwise under argon over 6 hours to the acid chloride solution at -78° with vigorous stirring. The reaction vessel was kept overnight at -78° then allowed to warm to room temperature after dilution with brine and 3N hydrochloric acid. The aqueous solution was extracted several times with ethyl acetate and the combined organic extracts were extracted with 5% sodium bicarbonate several times and washed with brine. Acidification and extraction of the basic extracts with ethyl acetate gave 6.15 g of recovered starting material as a white crystalline solid. The ethyl acetate solution was dried over magnesium.sulfate, filtered and concentrated to give quantitatively 9.5 g of cis-l-(2,4-dimethoxybenzyl)-3-azido-4oxoazetidinyl-2-formaldehyde as a colorless oil. The crude aldehyde gives satisfactory yields in subsequent reactions, however, chromatography on silica gel results in a large loss of material. 1 EXAMPLE 8 1-[Ci s-1-(2,4-dimethoxybenzy1)-3-azido-4-oxo-azeti di nyl]-2-ni tro-1-ethanol A solution of 39 g (0.134 mol) of crude cis-l-(2,4-dimethoxybenzyl)-3-azido-4-oxoazetidinyl formaldehyde, 24.5 ml (0.16 mol) of triethylamine, and 240 ml of nitromethane in 240 ml of dimethylsulfoxide was stirred at room temperature for 18 hours. The reaction mixture was diluted with water, stirred, and extracted four times with ethyl acetate. Each ethyl acetate extract was backwashed separately with water, 3N hydrochloric acid and brine. The combined extracts were dried over magnesium sulfate, treated with charcoal and filtered. Concentration of the ethyl acetate at reduced pressure gave an oil which afforded, after chromatography on silica gel (1:1 ethylacetate/ hexane), 22.93 g (49%) of l-(cis-l-(2,4-dimethoxybenzyl)-3-azido-4oxo-2-azetidinylj-2-nitro-l-ethanol as a pale yellow oil.

EXAMPLE 9 1 - ]Ci s-1 - (2,4-dimethoxybenzyl)-3-azi do-4~oxo-2-azeti dinyl]-2-ni troethylene A solution of 22.93 g (65.5 mmol) of l-l£is-l-(2,4-dimethoxybenzyl)3-azido-4-oxoazetidtnyl]-2-nitroethan-l-o1 and 36.4 ml of acetic anhydride in 460 ml of pyridine was stirred at room temperature for 3 hours. The pyridine was removed under high vacuum and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed four times with water, two times with 3N hydrochloric acid, twice with 5% sodium bicarbonate solution and once with brine. After drying over magnesium sulfate and charcoal the solution was filtered and concentrated at reduced pressure to give 20.8 g (95%) of l-[cis-l(2,4-dimethoxybenzyl)-3-azido-4-oxo-2-azetidinylj-2-nitroethylene as a red oil.

EXAMPLE 10 1-Cis-1-(2,4-dimethoxybenzyl)-3-azido-4-oxo-2-azetidi nyl-2-nitroethane At -10°, 3.6 g (95 mmol) of sodium borohydride was added to 100 ml of methanol, swirled and then added immediately to a vigorously stirred solution of 20.8 g (62.5 mmol) of l-ci£-l-(2,4-dimethoxybenzyl)3-azido-4-oxo-2-azetidinyl-2-nitroethylene in 500 ml of methanol a,lso at -10°. The reaction mixture was stirred for 20 minutes followed by a second treatment of 3.6 g sodium borohydride in the same manner. After dilution of the reaction mixture with water and acidification with 3N hydrochloric acid, the mixture was concentrated under reduced pressure to remove the methanol. The aqueous solution was extracted with ethyl acetate. The organic extracts were washed with 5% bicarbonate and brine, dried and concentrated. The yellow oil was chromatographed on silica gel by elution with 1:1 ethyl acetate/hexane giving 9 g (43%) of 1-cis-1-(2,4-dimethoxybenzyl)-3-azido-4-oxo-2-azetidinyl -2-nitroethane as a yellow oil.

EXAMPLE 11 Ci s-1-(2,4-dimethoxybenzyl)-2-(21,2‘-dimethoxyethy1)-3-azi do-4-oxoazeti di ne A solution of 9.0 g (0.027 mole) of cis-l-(2,4-dimethoxybenzyl)3-azido-4-oxo-2-azetidiny1-2-nitroethane in 250 ml of a 0.12 molar sodium methoxide solution (700 mg sodium in 250 ml of freshly distilled methanol) was added at -10° under argon to a mixture of 98 ml of cone, sulfuric acid in 260 ml of methanol at a rate of 1 drop per second.

The mixture was stirred for 5 minutes, diluted with 2 L of methylene chloride and washed with a sodium phosphate solution until the wash was alkaline. The methylene chloride extract was dried over magnesium sulfate and evaporated to dryness in vacuo to give 9.4 g (100%) of the acetal as a viscous golden oil.

EXAMPLE 12 Use of the 3-Phthalimido Blocking Group 2,4-Oimethoxybenzylamine (5.01 g, 0.03 mol) and benzyl glyoxalate (0.036 mol) were condensed as in Example 1 at 0-5° for 2 hours. The resulting imine was dissolved in methylene chloride (800 ml) and cooled in an ice bath. Triethylamil e (5.4 ml) was added, followed by the dropwise addition of a solution of N-phthalimidoacetic acid chloride (7.54 g, 0.0338 mol) [J. Amer. Chem. Soc., 71_, 1856 (1949)] in methylene chloride (80 ml). After the reaction was stirred 2 hours, the solution was concentrated and then washed with water, dilute hydrochloric acid, and dilute bicarbonate. The dried organic phase was evaporated to give benzyl cis-l-(2,4-dimethoxybenzyl)-3-phthalimido4-oxoazetidine-2-carboxylate which can be optionally purified over silica gel in 10% ethyl acetate/chloroform.

The benzyl ester in methanol was hydrogenated at 5 p.s.i. using % palladium on charcoal. After reaction, the catalyst was removed and the desired free acid isolated by evaporation in vacuo, m.p. 198-199.5°.

The acid is converted in to cis-l-(2,4-dimethoxybenzyl)-2-(21,2'15 dimethoxyethyl)-3-phthalimido-4-oxoacetidine via the nitro route of Examples 7 to 11 with variations of reaction conditions which would be obvious to the skilled synthetic organic chemist. The acetal is debenzylated as in Example 6 to give cis-2-(2',2'-dimethoxyethyl)-3phthali mi do-4-oxoazeti di ne.

Claims (12)

1. A compound of formula (I) :r* rrr 0 V m where both groups A together represent an oxygen atom or the residue of an acetal moiety,R is a protected primary amino

2. A compound as claimed in claim 1 where R is azido. 15

3. A compound as claimed in claim 1 where R is phthalimido.

4. A compound as claimed in anyone of claims 1 to 3 where R 3- is 2,4-dimethoxybenzyl, 4-methoxybenzyl, trityl, benzhydryl, or methoxy substituted benzhydryl.

5. A compound as claimed in anyone of claims 1 to 3 where R 3- is 2,4-dimethoxybenzyl.

6. A compound as claimed in anyone of claims 1 to 3 where R 3, 25 is hydrogen.

7. A compound as claimed in anyone of claims 1 to 6 where the groups A are the same and each represents an alkoxy group containing up to four carbon atoms optionally substituted with 30 phenyl or halogen, allyloxy or methallyloxy or taken together represents ethane-1,2-dioxy or propane-1,3-dioxy.

8. A compound as claimed in anyone of claims 1 to 6 where the groups A are methoxy.

9. A process for preparing a compound as claimed in - 14 46154 claim 1 which comprises reducing an acid chloride of formula (II) :CH-CQCl s ί (II) where R and R are as defined with reference to formula (I) 10 provided that R is not hydrogen with a reducing agent which selectively reduces acid chlorides to aldehydes, optionally converting the aldehyde to an acetal and optionally converting R 1 into hydrogen.

10. A process for preparing a compound as claimed claim 1 which comprises reacting an alkali metal salt of nitroethane of formula (III) :in a ,ch 2 ch 2 no 2 (III) where R and R^ are as defined with reference to formula (I) provided that R^ is not hydrogen with concentrated sulfuric acid in a lower alkanol to obtain the compound of formula (I) where both groups A are lower alkoxy, 'optionally converting 3G the group R^ into hydrogen, and optionally converting the groups A into oxygen or into a different acetal moiety. 10 group as defined herein and R 1 is hydrogen or a secondary amine protecting group.

11. A process as claimed in claim 9 substantially described in Example 4.

12. A process as claimed in claim 10 substantially as described in Example 11.