FI70717C - 2-AZETIDINONDERIVAT FOER ANVAENDNING SOM MELLANPRODUKTER VID FRAMSTAELLNING AV THERAPEUTISKT ANVAENDBARA PENEMDERIVAT - Google Patents

Description

1 70717 2-Azetidinone derivatives used as intermediates in the preparation of therapeutically useful penem derivatives

Separated from patent application 793903 5

The invention relates to novel 2-azetidinone derivatives of the formula

O

Xy. SC- (Alk) -A- (Alk ') - N3 10 lf Λ-n P (Q) 11 o γ 3 CO2R "15 wherein Alk is C2-alkylene, A is O, S or SO, Alk' is C2- 4-alkylene, Y is hydrogen or lower alkyl which may be substituted by hydroxy, R "is an easily cleavable ester-forming group and Q is phenyl or lower alkyl. The compounds of formula II can be used as intermediates in the preparation of antibacterial penem derivatives of formula

Yv- <V

I Λ— (Alk) -A- (Alk ') - NHp 25 J- O Λ co2h wherein Y, Alk, A and Alk' have the same meaning as above. Penem derivatives according to Kaa-30 van I and their antibacterial properties are described in FI patent application 793903.

The term "readily cleavable ester-forming group" refers to groups known from β-lactam and peptide chemistry which are used to protect the carboxyl group in chemical reactions and which can be subsequently removed by standard methods to give the free 2,70717 carboxylic acid. Such known protecting groups include 2,2,2-trichloroethyl, tertiary alkyl of 4 to 6 carbon atoms, tertiary alkenyl of 5 to 7 carbon atoms, tertiary alkynyl of 5 to 7 carbon atoms, alkoxy-5-methyl, 2 to 7 carbon atoms. alkanoylmethyl, N-phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, benzhydryl, trityl, trimethylsilyl, triethylsilyl, β-trimethylsilylethyl, etc.

The choice of ester protecting group depends on the reaction conditions used in subsequent reactions. The expert is well able to select the appropriate group. The most preferred ester is p-nitrobenzyl ester, which is easily removed by catalytic hydrogenation.

Particularly preferred intermediates of the invention are those wherein Q is phenyl, R "is p-nitrobenzyl, Y is hydrogen or d-hydroxyethyl, Alk is CH2, A is O and Alk 'is ch2ch2.

Compounds of formula II can be prepared as described in the following reaction schemes. In the reaction schemes, X is a group (Alk) -A- (Alk ') - N 1, wherein Alk, A and Alk' have the same meaning as above.

3 "70717

Method I (Variation 1) Y ®

_ ^. 0 Ac II

Y-CH = CH-OAc CSI \ XC-SNa 5 * N PH 7 .5 "

0 ^ H

0 0 v V H

__SC-X ^ S C - X _ ^ 10 - ^ ^ CHO | SOCl2

N \ CO.R "_r0H

O H 2 o co2r "15 O 0 y ii γ-s Ί Y \ -rSC-X Y ^ -.-. Sc-x I ——> J— N - ^^ C1 baseS 0> —Ν-γ ^ Ρ03

20 I

co2R "co2r" o

II

25 Ac = CH, C- 0 * c6h5-

Method I (Variation 2) 4 70717 v 0

1 ^ OAc N

] -CH, C-SNa Y-CH = CH-OAc C5I ^ __

5 * J_ N pH 7.5 X

O ^ H

Y "W. ^ SAc \ Y-u, _ ^ .SAc _ ^ 10 -r - ^ --7 cho I SOCl- O ^ H <= 02R" 0 ^ "Ννγ" ° Η CO2R "15 Y, Y-w

| -p - SAC P0 -r '' SAO

—-> J— • me · 0 <^ - N \ ^ P03 20 1 co2r "co2r"

O

Y-v O 11

^ ς, Μ II Y "^ .SC-X

- rt x-c—> rt co2r "co2R" 30 _ o tr X-C- 0 = acylating agent MA = heavy metal salt

Method I (Variation 3) 5 7071 7 \ - ^ - OAc 0 CSNa Y-CH = CH-OAc CSI ^ I __i_ ^ 5 * N pH 7.5

O "'H

10 Y "^ - r ^ SC03 _Υ> η-r'SC ^ 3 - CHO I soci2

(Γ ΝχΗ ^ R "o ^ -N ^ ° H

CO2R "15

\ - ^ SC03 P0 -r SC03 MA

i— N \ ~ / -cl base -N \ ^ P03

20 O O

co2r "co2r ··

O

Y_ o v II

SM II _ Y ~ ^ sc-x 25 | X-C- Θ] - [3 * o0-h ^ p03 CO2R "CO2R" 30

In Method I, a vinyl ester containing the desired Y substituent is converted to 4-acetoxy-2-azidinone by cycloaddition of chlorosulfonyl isocyanate (CSI) and then reduction with an organic reducing agent such as sodium sulfine. Most conveniently, the CSI reaction is carried out in an inert organic solvent such as diethyl ether at a temperature of 6707170 ° C or less. The reduction step can be performed in an aqueous or aqueous-organic reaction mixture at a temperature of 0 ° C or below at a slightly basic pH.

Following the formation of 4-acetoxy-2-azetidinone, Method I can be continued in three different ways. Transformation 1

O

According to tf, azetidinone is reacted with thiolic acid X-C-SH, or a salt thereof, in a suitable solvent (e.g., water or an aqueous organic solvent). The displacement reaction is preferably performed at or below room temperature at a slightly basic pH (about 7.5). When Y is not H, the cis and trans isomers of the azetidinone formed are preferably separated at this stage of the process (e.g. by chromatography). In variants 2 and 3 described above, 4-acetoxy-2-azetidinone is converted to its 4-acetylthio-2-azetidinone and 4-tritythio-2-azetidinone products, respectively, by nucleophilic substitution with thioacetic acid or triphenylmethyl mercaptan (or a salt thereof) such as sodium, respectively.

Next, 4-thioazetidinone is reacted with gly-0

II

with the oxylate ester HC-CO 2 R ", where R" is an easily removable ester protecting group such as p-nitrobenzyl or trimethylsilylethyl or a reactive oxo derivative thereof such as a hydrate in an inert organic solvent (e.g. benzene, toluene, xylene, etc.) and preferably at elevated temperature (e.g. at 50 ° C and preferably at reflux temperature). When using ester hydrate, the water formed can be removed azeotropically or by molecular sieves. The hydroxy ester product is formed as an epimer mixture, which can optionally be purified by chromatography or used directly in the next step.

Conversion of the hydroxy ester to the corresponding chloro ester is accomplished by reacting with a chlorinating reagent 35 (e.g., SO 2, POCl 4, PCl 2, etc.) in an inert organic solvent (e.g., tetrahydrofuran, diethyl ether, preferably methylene chloride, dioxane, etc.). , in the presence of a tertiary amine (e.g. triethylamine) or a heterocyclic, tertiary amine (e.g. pyridine or collidine). Reaction 5 is preferably carried out at a temperature between about -10 ° C and room temperature. The chloroester product is obtained as an epimer mixture which, if desired, can be purified in the next step before use.

The phosphorane intermediate can be obtained by reacting the chloro-10 ester with the appropriate phosphine in an inert organic solvent such as dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane, dioxane or aliphatic, cycloaliphatic or aromatic hydrocarbon (e.g. hexane), hexane, hexane. ) in the presence of a base, preferably an organic tertiary amine such as triethylamine, pyridine or 2,6-lutidine. The reaction is preferably carried out at a temperature between room temperature and the reflux temperature of the solvent system.

In variants 2 and 3, the phosphorane is converted to a heavy metal limercaptide of the formula:. S-- 25 r ~ f

M III

* -N ^ P (Q). 111 o 3 co2R "_ x 30 or

SHgCOOCH

35 r ~ T ^ | Ula co2r "7071 7 β where χ is 1 or 2 and M is Cu (II), Pb (II) or Hg (II) f when x is 2 or Ag (I) when x is 1. The mercaptide is formed by reacting phosphorane Hg (II), Pb (II), Cu (II) or Ag (I) salt or (methoxycarbonyl) mercury (II) acetate 5 in a methanolic solvent and an organic or inorganic base such as aniline, pyridine, collidine , 2,6-lutidine or alkali metal carbonate The preferred base is pyridine The reaction may be carried out at room temperature or, if desired, with moderate cooling or heating The anion (A) of the heavy metal salt may be any anion which gives a soluble salt in the chosen solvent , e.g. NO 2, CH 2 COO, BF 2,

F, ClO 2, NC> 2, CNO, etc. The mercaptide intermediate is then reacted with an acylating agent capable of conjugating.

Il II

to this part X-C-. The acylating agent (X-C- ©) may be acid 0

M

X-C— © or a reactive functional derivative thereof such as an acid halide (preferably acid chloride), acid azide, acid anhydride, mixed acid anhydride, active ester, active thioester, etc. The acylation is performed in an inert solvent such as a halogenated hydrocarbon such as a halogenated hydrocarbon such as in dioxane, tetrahydrofuran or diethyl ether) and using an acid derivative in the presence of an acid acceptor such as tri-lower alkylamine (e.g. triethylamine) or a tertiary organic base such as pyridine, collidine or 2,6-lutidine. When free acid is used, the acylation is carried out in the presence of a suitable condensing agent, e.g. a carbodiimide such as N, N'-dicyclohexylcarbodiimide. The acylation of mercaptide can be carried out over a wide temperature range, but preferably at a temperature of -20 to + 25 ° C. The phosphorane formed after acylation is cyclized as described above to give the desired panester.

35 It has been found that the production of phosphorane via the mercaptide intermediate (variants 2 and 3) results in a much 9,70717 purer product than using the more conventional route of variant 1.

Method II

5 _ SC03 _ ^ SC03 J— tl ^ _.J—!

0 SH 0 'B

1 0 V>

base Ä-N

O B

1 5 MA / base YN -_ ^ sc03 Y \ - ^ -N J-N \ o nh 0 nb 25 and ίΗ0 n ^ CO R "x-c © i 2 ψ 30

O

-, ^ SC03 Yv ^ | _pSC-X

A-N, _OH} -N \ 35 co2r "SOC1-. Deprotection v 2 Ψ 7071 7 10 o

Υ γ II

Ή. , -SO 3 V- ^ SC-X

5 J-V .J-cl <0-V

0 u co2r "P03

10 years, mostly CHO

v I

Y 2 R ° "

Y ^ - \ _ rSCg2 γ H

--f 3 γ_ ^ SC-X

15 /] - Y ο ^ · Ν \ ^ ° Η

CO, R "I

1 CO2R "20 ^ base v SOC1- ψ Ψ ^ o

Y-, Y II

V_SC-X

25 ΥΝγ ^ c02R "C02R" 30 rt Λ P0-,. . x-c- Θ 3.

Base 7071 7 1 1

° O

Y ~ ^ sc-x YS_ ^ sc-x pT «ΓΤ 5 QJ-N \ ^ P03 -N \ ^ p03 co2r" CO2Rh 10 b = ring nitrogen protecting group

In Method II, the 4-trityl-thio-2-azetidinone ring nitrogen is protected with a conventional, easily removable protecting group such as triorganosilyl (e.g., trimethylsilyl or tert-butyldimethylsilyl), methoxymethyl-15-methoxyethoxymethyl, tetrahydropyranyl, etc., tetrahydropyranyl. coupling to the 1-position of the azetidinone is accomplished by reacting the appropriate electrophile with the N-protected azetidinone in the presence of a strong base. At this point, the method branches into two 20 routes.

In the second route, the N-protected intermediate is deprotected by conventional methods (e.g., acid hydrolysis) to form an ester, chlorinated with a hydroxy ester, converted from a chloroester to a phosphorane, converted to a phosphorane-heavy metal mercaptide, and cyclized to the mercaptide.

O

n with X-C-Θ.

In an alternative route, the N-protected azetidinone is converted to a heavy metal mercaptide, the mercaptide is acylated at 30 O

II

with X-C-®, the N-protecting group is removed, the liberated azetidinone is reacted with a glyoxylate ester, chlorinated and the chloroester is reacted with phosphine to form phosphorane.

The antibacterial penem derivatives of formula I described above can be prepared from 12 7071 7 compounds of formula II by cyclizing a compound of formula II in an inert organic solvent at a temperature slightly above room temperature and reflux, followed by the compound is hydrogenated.

The following examples illustrate the invention. All temperatures are in degrees Celsius. The following abbreviations are used in the examples: CSI chlorosulfonyl isocyanate 10 pet.ether ether petroleum ether b.p. boiling point NMR nuclear magnetic resonance spectroscopy h hour ether diethyl ether (unless otherwise indicated 15 Celite Johns-Manville Products Corporation trademark PNB p-nitrobenzyl mp melting point LAH lithium aluminum hydride 20 n-BuLi n-butyllithium MIBK methyl isobutyl

Et C2H5 ~

Tr -C (C6h5) 3

Me ch3 25 THF tetrahydrofuran

Ph phenyl DMF dimethylformamide TEA triethylamine PNBG p-nitrobenzylglyoxylate 30 THP tetrahydropyranyl TFA trifluoroacetic acid HMPT hexamethylphosphoric triamide (or HMPA) LDA lithium diisopropylamide 35 Ac CH3CO-

Ms CH 3 SO 2 DMAP 4-dimethylaminopyridine

II

13 7071 7

Preparation of intermediates according to the invention

Example 1 (1'R, 3S, 4R and 1'S, 3R, 4S) -4- (2-azidoethoxy) acetylthio-3- (1'-hydroxyethyl) -1- (p-nitrobenzyl-2 "-triphenyl) 5-phosphoranylidene-2 "-acetate) -2-azetidinone /

JMe3niCl / E «- 3N

10 F »· / ** ^ Γ, ΐ * 3» ™ -

to PNS C0, PNB

k /

OH

Λ ·· π / 5ΥΝ, Α / Ν3 15 0 ^ Υ ^ Φ3

CO FNB

To a stirred solution of 820 mg (1.16 mmol) of 20 (1'R, 3S, 4R and 11S, 3R, 4S) -silver-2- (1'-hydroxyethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone-4-thiolate in 20 mL of THF was added sequentially at -15 ° (methanol-ice bath) under nitrogen with 0.1648 mL (4.66 mmol, 4 02 equivalents) of triethylamine, 0.589 mL (4.64 mmol, 4.00 equivalents) of chlorotrimethylsilane and 81.2 mg (1.12 mmol) of imidazole. The mixture was stirred for 18 hours (overnight) at room temperature and then cooled to -10 to 15 °. 0.220 mL (2.72 mmol) of pyridine was added followed by a solution of 372 mg (2.27 mmol, 1.96 equivalents) of 2-azidoethoxyacetyl chloride in 20 mL.

C ^ C ^ stitches. Stirred for one hour at room temperature. After the precipitate was isolated by filtration, the filtrate diluted with EtOAc was washed successively with 1N hydrochloric acid, brine, saturated sodium bicarbonate solution and brine, dried over sodium sulfate, evaporated to give 748 mg of an oil. This was dissolved in 147071 7 of moist CH 2 Cl 2 (20 mL + 3 drops of water) and treated with two drops of trifluoroacetic acid for 30 minutes at room temperature. The mixture was washed with saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, evaporated to give 695 mg of a crude oil. This was purified by column chromatography (15 g SiO 2, eluent EtOAc-CH 2 Cl 2 1: 1) to give 538 mg (0.739 mmol, 63.7% yield) of the title compound as a yellowish oil, 1 HMR (CDCl 3) δ: 1.22 (d, J = 6 Hz, CH 3-1 '), δ 5.6 (2d, H-4) and 7.3-8.4 ppm (aromatic H 5), IR (neat) δ max: 3420 (OH), 2100 (-N3), 1750 (C = O) and 1690 cm-1 (thioester), Rf = 0.20 (CH2Cl2-EtOAc 1: 1).

Example 2 4- (2 * -Azidoethoxyacetylthio) -1- (p-nitrobenzyl-15 2 "-triphenylphosphoranylidene-2" -acetate) azetidinone * p "· 5 * 5 Pyr / CH 2 Cl 2 t 2 0

25 CO PNB

To a stirred solution of 7.96 g (12.0 mmol) of silver 1- (p-nitrobenzyl) -2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thiolate in 100 mL of CH 2 Cl 2 , 1.94 ml (24.0 mmol) of pyridine, a solution of 2.23 g (13.6 mmol) of 2-azidoethoxyacetyl chloride in 20 ml of CH2Cl2 was added at 0-5 and under nitrogen. and the mixture was stirred for two hours at room temperature. After removal of the precipitate by filtration, the filtrate was evaporated and the residual oil was purified by column chromatography (160 g SiO 2, eluent EtOAc-CH 2 Cl 2 1: 1) to give 4.216 g (6.17 mmol, 51.471 mmol, 51.4%) of the title phosphorane as a yellowish solid. foam. Crystallization from CH 2 Cl 2: ether (1: 9) gave the title compound, m.p. 123-129 ° (decomposes), IR (nujol) ν max: 2090 (-N3), 1755 (β-lactam) and 1690 cm-1 (thioester). Analysis Calculated for C 59.74 H 4.42 N 10.26 S 4.69, Found: C 59.33 H 4.49 N 9.69 S 5.19 . TLC (EtOAc): Rf = 0.55.

Example 3 4- (21-Azidoethylthioacetylthio) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidine-10-non-1 ' SCCH2SCH2CH2N3 o d'— n.

° f = PPh3 σ ^ r = PPh3

15 CGOPNB COOPNB

A solution of 15.7 mmol of silver 1- (p-nitrobenzyl 1'-triphenylphosphoranylidene-1'-acetate) -2-azetidinone-4-thiolate and 1.6 mL (19.8 mmol) pyridine in 200 mL of CH 2 Cl 2 was treated by dropwise addition over 0.25 h of a solution of 3.64 g (20.3 mmol) of 21-azidoethylthioacetyl chloride in 50 mL of CH 2 Cl 2. The reaction mixture was stirred for 1.5 h at 23 °, filtered and the solid was washed with CH 2 Cl 2. The filtrate and washings were combined and washed with 0.1 N HCl solution, water, saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated on a rotary evaporator to give an orange syrup. Column chromatography (300 g silica gel G-60, eluent EtOAc in Cl 2 Cl 2, 0-40%) gave 7.7 g, 70% of the crude compound after evaporation of the solvent. Recrystallization from CH 2 Cl 2-ether-petroleum ether gave the title compound, m.p. 150-151 °, decomposes. Analysis for C 34 H 30 N 5 O 6 S 2 P: Calculated: C 58.36 H 4.32 N 10.01 S 9.17, Found: C 58.64 H 4.36 N 10.03 S 9.25, 35 IR (KBr) V> max: 2100 (s, N3), 1750 (s, / 3-1 actam C = 0), 7071 7 16 1675 (s, C = 0), 1655 (s, C = 0), 1610 (s, aromatics) and 1440 cm -1 (s, P-Ph).

Example 4 (1'R, 3S, 4R and 1'S, 3R, 4S) -4- (2-azidoethoxyacetyl-5-thio) -3-1'-hydroxyethyl) -1 - (}} trimethylsilylethyl-2 " - triphenylphosphoranylidene-2 "-acetate) -2-azetidinone

QH OH

^ SAg SCOCH ^ OCH ^ CH ^ N ^ 1 ° CO2 ^ V / 'S \

1.54 mL (11.8 mmol) of trimethylsilyl chloride was added to a stirred suspension of 2.48 g (3.34 mmol) of silver 3- (1'-hydroxyethyl) -1- (β-trimethylsilylethyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate, 136 mg (2.0 mmol) of imidazole and 1.64 mL (11.8 mmol) of triethylamine in 60 mL of THF at 0 ° . The mixture was stirred for 18 hours at 23 °. 60 ml of methylene chloride were added, the mixture was cooled to -15 °, 1.32 ml (16.4 mmol) of pyridine and 1.43 g (8.70 mmol) of β-azidoethoxyacetyl chloride were added, and the mixture was stirred for 0.5 ml. hours at -15 °. 60 ml of ether, 60 ml of ethyl acetate and 20 ml of 1M hydrochloric acid were added. The precipitate was removed by filtration and the organic phase was washed with 100 ml of 0.1M hydrochloric acid, 100 ml of 1% sodium bicarbonate solution and saturated sodium chloride solution. Evaporation of the dried solution gave the crude title product as an oil, yield 85%.

30 IR ^ max '* 1755 1695 cm ~ 1 ·' 17 7071 7

Preparation of final products of formula I Example I

a) (1'R, 5R, 6S and 1'S, 5S, 6R) -p-Nitrobenzyl-6- (1'-hydroxyethyl) -2- (2-azidoethoxymethyl) penem-3-carboxyl-5-hydrate______ OH 011 Y ^ / v Λ r '"' i- ° toluene * | f> S \ ~ 10 o Νγ · Ρ03 Δ ° N" \

COjPNB COjPNB

A solution of 490 mg (0.673 mmol) of (1'R, 3S, 4R and 1'S, 3R, 4S) -4- (2-azidoethoxy) acetylthio-3- (1'-hydroxyethyl-15-yl) -1- (p-nitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone in 80 ml of toluene was gently heated to reflux for three hours. Evaporation of the solvent in vacuo gave an oily residue which was purified by column chromatography (10 g SiO 2, eluent 20-10% EtOAc in CH 2 Cl 2), crystallized from CH 2 Cl 2 -ether to give 202 mg (0.449 mol, 66.6% yield) of the title compound as pale yellow crystals. (CDCl 3) δ: 1.35 (3H, d, J = 6.5 Hz, CH 3-1 '), 2.18 (1H, broad, OH), 3.2-3.9 (5H, m , -CH 2 - and H-6), 3.9 to 4.5 (1H, m, H-1 ·), 4.45 to 4.72 to 4.75 to 5.02 (2H, type AB) , CH 2 2 2), 5.02 to 5.25 to 5.35 to 5.57 (2H, AB-type, -CH 2 Ar), 5.62 (1H, d, J = 1 Hz, H-5) and 7.42 -

7.65 - 8.13 - 8.28 ppm (4H, A2'B2 ', aromatic Hs), IR

(nujol) Vmax: 3460 (-OH), 2210 (-N3), 1765 (β-lactam) and 1680 cm-1 (ester). An analytical sample was obtained by continuing 30 crystallizations, m.p. 107-108 ° (CHOClO-ether), UV (EtOH) o. : 2 max max 264 (δ = 12000) and 323 ir (u = 9200), Rf = 962 (CH 2 Cl 2 - EtOAc 1: 1), analysis C 18 H 19 N 5 O 7 S: Calculated: C 48.10 H 4.26 N 15 , 88 S 7.13, found: C 47.81 H 4.18 N 15.00 S 7.16.

ie 7071 7 b) (1'R, 5R, 6S and 1'S, 5S, 6R) -6- (1'-hydroxyethyl) -2- (2-azidoethoxymethyl) penem-3-carboxylic acid-OH J "5 oP ^ hCH2O2C2C3- '

CO ΡΝΈ COjH

A solution of 180 mg (0.400 mmol) of 10 (1'R, 5R, 6S and 1'S, 5S, 6R) -p-nitrobenzyl-6- (1'-hydroxyethyl) -2- (2-azidoethoxypenem-3) was stirred. carboxylate in 18 mL of THF, 19 mL of ether, 18 mL of water and 180 mg of 10% palladium on carbon and hydrogenated (H 2, 3.85 kp / cm) for 2.5 h at room temperature. The filtrate was washed with EtOAc, lyophilized to give 84.4 mg (0.293 mmol, crude yield 73.2%) of the title compound as an impure, yellowish powder: UV (H 2 O) 305.5 (fc = 4800) and 255 m 2. u (€ = 3800) This powder was purified by HPLC (Waters C ^ g Micro Bondapack Reverse 20 Phase 30 cm x 10 mm, eluent 1% CH 2 CN in water) to give 44.7 mg (0.155 mmol, yield 38 .8%) of the title compound as a white powder. 1 HMR (D 2 O) δ = 1.34 (3H, d, J = 6.4 Hz, CH 2 -1 '), 3.26 (2H, m, -CH 2 N), 3.82 (2H, m, -OCH 2 CH 2 -), 3.94 (1H, dd, J 6-1 = 6.2 Hz, J 6 -5 = 1.4 Hz, H-6), 4.2 - 4.4 (1H, m , 25 H-1 '), 4.52 - 4.70 - 4.84 - 5.02 (2H, type AB, CH2 ~ 2 ) and 5.81 ppm (1H, d, J = 1.3 Hz, H-5), IR (KBr tablet), max: 3420 (OH), 3000-2600 (broad, CO 2 H), 1765 ( 3-lactam) and 1575 cm -1 (-CO 2 H), UV (H 2 O) * max: 306 (€ = 5300) and 258 m -1 (t = 3600).

30 Example II

a) p-Nitrobenzyl 2- (2-azidoethoxy) methylpenem-3-carboxylate-35 I-1 X toluene i - r "" '\ JJ * -s—'

CO 2 PMO CO 2 PNB

li 19 7071 7

A solution (4.13 g, 6.04 mmol) of the phosphorane of Example 2 in 200 ml of toluene was heated at reflux for 1.5 hours under nitrogen. After removal of insoluble matter, the solvent was evaporated in vacuo, the residual oil was purified by column chromatography (80 g SiO 2, eluent 5% ether in benzene) to give 2.44 g (6.02 mmol, 99.6%) of the title compound. as a yellowish oil. This was used in the next step. Crystallization from CH 2 Cl 2 -ether (1: 9) gave an analytical sample of 10, m.p. 88-89.5 °, 1 HMR (CDCl 3) δ: 3.35 (2H, t, J = 5 Hz, -OCH--), 3.47 (1H, dd, J = 16 Hz, jr = 2 Hz, 2 gem 'trans C, -H), 3.67 (2H, t, J = 5 Hz, -CH-NJ, 3.85 (1H, dd, J 6 23 gem 16 Hz, Cg-H), 4, 73 (2H, ABq, J = 16.19, C 1 -C 14), 5.30 (2H, ABq, J = 13.5, 9, -OCH_Ar), 5.63 (1H, dd, J. = 2 Hz, z trans 15 Jcj, s = 3.5 Hz, C5-H), 7.50 - 7.63 - 8.1 2 - 8.27 ppm (4H, A2, B2 ', aromatic H5), IR ( nujoli) ν max: 2100 (-N3), 1785 (β-lactam) and 1695 cm-1 (ester), UV (EtOH); λ max: 263 m 2 (t = 12000), 320.5 m u (ε, 9600), TLC (benzene-ether 1: 1), Rf = 0.60.

B) 2- (2-Aminoethoxy) methylpenem-3-carboxylic acid O'XVcH ^ CH ^ VP ": C .....-

\ o PUB CO H

25 2

A solution of 1.62 g (4.00 mmol) of the above azo ester in 50 ml of dimethoxyethane was mixed with 50 g of any ether, 50 g of water and 1.62 g of 10% palladium on carbon (Engelhard) and hydrogenated for 2.5 hours at room temperature (H 2: 385 kp / cm). After removal of the catalyst by filtration, the aqueous layer was washed with 2 x 50 mL of ether and then 1 x 50 mL of EtOAc. The aqueous layer was lyophilized to give 817 mg (3.34 mmol, 83.6%) of the title amino acid as a yellowish powder, UV (H 2 O) macg: 304 (E, = 5000). This material was purified by HPLC (Waters, C 2 g Micro Bondpak Reverse Phase 30 cm x 10 mm, eluent 1% CH 2 CN in water) to give 432 mg (1.77 mmol, 44.2%) of the title amino acid as a white solid. powder. HMR (D 2 O) δ: 3.19 - 3.9 (4H, m, -OCH-CH NH), 3.54 (1H, dd, J = 16.9 Hz, J. = 1.9 Hz, 2 2 2. gem trans C (H), 3.88 (1H, dd, J = 16.8 Hz, J = 3.7 Hz, C, -H), 6 gem 'cis δ 4.52 - 4, 70-4.83-5.01 (2H, AB-type, C2-CH2O-) and 5.77 ppm (1H, dd, Jcis = 3.6 Hz, Jtrang = 1.9, C1-4-U), IR (KBr tablet) λmax: 1770 (β-lactam) and 1580 cm-1 (-CO 2 H), UV (H 2 O) λmax: 3.04 m 2 u (ε = 5400), 256 m 3100).

1 0 Example III

a) p-Nitrobenzyl 2-aminoethylthiomethylpenem-3-carboxylate_

.S ^ CH SCH CH N

jzT - O ^ C = PPh, ° \

[3 COOPNB

COOPNB

A suspension of 4.5 g (6.43 mmol) of 4- (2'-azidoethylthioacetylthio) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene acetate) -2-azetidinone in 375 ml of toluene was added. The reaction mixture was cooled to 23 ° and the solvent was evaporated on a rotary evaporator to give an orange syrup. The crude material was purified on a silica gel column) (90 g of silica gel G-60, eluent ether-petroleum ether 1: 1: 1). -3: 2) The pure material was obtained as a yellow syrup, 2.2 g, 81% IR (neat) ν max: 2100 (s, N 2), 1785 (s, β-lactam 30 C = O) , 1705 cm-1 (s, PNB C = 0), 1 HMR (CDCl 3) δ: 2.53 - 2.90 (m, 2H, H-1 "), 3.30 - 3.67 (m, 3H, H 2 O ", H-6 trans), 3.98 (ABq, Ja_b = 14.8 Hz, 2H, H-1 '), 5.32 (ABq, Ja_fa = 13.0 Hz, 2H, CH 2 -PHNO 2), 5.66 (dd, Jh_5 H_6 cis = 3.6 Hz, Jh_5 h_6 trans = 1.9 Hz, 1-H, H-5), 7.58 (d, JHo_Hm = 8.8 Hz, 2H, 35 Ho , PNB) and 8.19 ppm (d, Ju = 8.8 Hz, 2H, Hm, PNB).

rilTl-Rio

II

21 7 071 7 b) 2-Aminoethylthiomethylpenem-3-carboxylic acid JZI ^ -CH2SC "* c" ^ - "ojlX ^ CK25c'oc" 2n "3t COOPNB CO (^

To a solution of 45 mg (0.11 mmol) of p-nitrobenzyl 2-azidoethylthiomethylpenem-3-carboxylate in 5 mL of dimethoxyethane was added 5 mL of ether, 5 mL of water, and 45 mg (0.11 mmol) of 10 -% of palladium carbon. The reaction mixture was hydrogenated at 23 ° under a hydrogen pressure of 3.15 kp / cm 2 for 3.0 hours and filtered through a pad of Celite. The layer was washed with water, the filtrate and washings were combined and diluted with ether. The aqueous phase was isolated, washed with ether and lyophilized. The crude product (20 mg) was purified by HPLC, 5 mg, 18%. IR (KBr): 1765 (C = O,

1 _ 1 ITlclKS

1600 cm (broad, COO), HMR (D 2 O) δ: 2.70 - 3.00 (m, 2H, H-1 "), 3.15 - 3.45 (m, 2H, H-2"), 3.49 (dd, Jgem = 16.8 Hz, 20 j _ = 1.7 Hz, H-7 trans), 3.85 (dd, J = 16.8 Hz, 6.5 trans' gem '' J6 -5 cis = 3.4 Hz / H-6 cis) · 4'05 ^ q, J _b = 14 ^ 6 Hz, 2H'H-1) and 5.74 ppm (dd, J5_6 cis = 3.4 Hz , J5_6 trans =

1.7 Hz, 1H, H-5), UV * max: 307 (ζ = 4330), 250 (ε = 3282). Example IV

(A) (1'R, 5R, 6S and 1'S, 5S, 6R) - [3-trimethylsilylethyl 2- [3-azidoethoxymethyl-6- (1'-hydroxyethyl) penem-3-carboxylate ( isomer B) __

OH OH

A solution of 1.3 g of the phosphorane of Example 4 in 200 ml of toluene was heated to reflux for 22 hours. Evaporation of the solvent on a rotary evaporator gave the crude title product. Chromatography on 40 g of silica gel eluting with increasing amounts of ether in hexane gave the crystalline title compound in 65% yield. IR,:

* 1 IIMR nia.KS

5 1760 and 1700 cm-1, showed the product to be contaminated with the second isomer.

b) (1'R, 5R, 6S and 1'S, 5S, 6R) -2- [N-azidoethoxymethyl-6- (1'-hydroxyethyl) penem-3-carboxylic acid (isomer B) 10 ohm - * JIX ^ h2 ° cVV :, 1 5

A solution of 3 mL (1.5 mmol) of anhydrous tetrabutylammonium fluoride in THF was added to a solution of 155 mg (0.37 mmol) of the above ester in 2 mL of THF at 0 ° C. After 5 minutes at 0 °, 10 ml of water and 10 ml of ethyl acetate were added, the mixture was acidified to pH 3 with 1M hydrochloric acid and the phases were separated. The organic phase was extracted with 0.05 M sodium bicarbonate solution, the aqueous extracts were acidified to pH 3 with hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried, evaporated on a rotary evaporator, the residue triturated with ether to give 27 mg of the crude title compound as a solid, yield 28%. IR ν max: 3500, 1785, 1670 cm -1, 1 H NMR (CDCl 3) δ: 1.30 (3H, d, J = 6.5, 0.1 H -1), 2.22 (1H, OH), 3.1-3.9 (5H, 30 m, CH 2 and H-6), 3.9-4.4 (1H, m, H-1 '), 5.60 (1H, d, J = 1, H-5).

23 7071 7 c) (1'R, 5R, 6S and 1'S, 5S, 6R) -6- (11-hydroxyethyl) -2- (2-aminoethoxymethyl) penem-3-carboxylic acid

OH

5 Λ -__ Λ f \ -CH ^ 0CHncn ^ mn

CO2H CO2H

A solution of 150 mg of the above azido compound in 15 ml of THF, 15 ml of ether and 15 ml of water was hydrogenated on a Parr shaker with 150 mg of 10% palladium on carbon at an initial hydrogen pressure of 4, 2 kg / cm. After 3 hours, the catalyst was removed by filtration through Celite, the aqueous phase was washed with ethyl acetate, lyophilized to give the crude title compound. Purification by HPLC (Waters, C 2 g Micro Bondapack Reverse Phase) gave 46.7 mg of pure title compound, which was the same as the previously prepared sample prepared by hydrogenation / hydro-genolysis of the corresponding azido-p-nitrobenzyl derivative.

Claims (4)

A 70-azetidinone derivative used as an intermediate in the preparation of therapeutically useful penem-5 derivatives of the formula w \ \> - (Alk) -A- (Alk ') - NH 2 J- CO 2 H 1 wherein Alk is C 1-2 alkylene, A is O, S or SO, Alk 1 is C 2-4 alkylene and Y is hydrogen or lower alkyl which may be substituted by hydroxy, characterized in that it has the formula O Y. ^ SC- (Alk) -A- (Alk ') - N3 20. N P (Q), II O Y 3 co2r "wherein Y, Alk, A and Alk 'have the same meaning as above, R" 25 is an easily cleavable ester-forming group and Q is phenyl or lower alkyl.