AU620982B2 - A process for the preparation of penem compounds - Google Patents
A process for the preparation of penem compounds Download PDFInfo
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- AU620982B2 AU620982B2 AU53906/90A AU5390690A AU620982B2 AU 620982 B2 AU620982 B2 AU 620982B2 AU 53906/90 A AU53906/90 A AU 53906/90A AU 5390690 A AU5390690 A AU 5390690A AU 620982 B2 AU620982 B2 AU 620982B2
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- alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/06—Preparation by forming the ring or condensed ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Description
pp.Tergau i.I. Lapice To the Commissioner of Patents j w Form COMMONWEALTH OF AUSTRALIA PAT ENTS ACT 1952.69 COMPLETE SPECIFICATION
(ORIGINAL)
Class mnt. Class Application Number: Lodged: Cornplew Specificati on Lodged: Accepted: Published! Priority Rela;ted Art Name of Applicant H-OECHST ATIENGESELLSCKAFr 'Address of Applicant Actual Inventor Bruningstra~se, D-6230 of Germany Frankfurt/Main 80, Federal Republic KARL-HEINZ BUDT, WALTER DURCKHEIMER, GERD FISCHER, ROLF HORLEIN, REINER KIRRSTEITER, and~ RUDOLF LAITRELL WATERMARK PATENT TRADEMARK ATTORNEYS.
LOCKED BAG NO. 5, HAWTHORN, VICTORIA 3122, AUSTRALIA Address for Service Complete Specification for the Invention entitled: A PROCESS FOR THE PREPARATION OF PENEM CCt4POUNDS The following statement Is a full description of this Invention, Including the best method of performing It known to us 1.
-A
1 I- r I .T HOECHST AKTIENGESELLSCHAFT HOE 89/F 135K Dr. v.F./PP Description A process for the preparation of penem compounds The invention relates to a process for the preparation of penem compounds.
4ti I 4r t0r 0444 lIC 0D 00( 0 0 ohIO 0 0000 0 00a a0, 4 0 0 00 o15 o Penem derivatives of the formula I are valuable compounds with antibiotic properties. A synthetic process disclosed in the literature for penem derivatives I entails intramolecular cyclization of azetidinone derivatives of the formula II with trialkyl phosphites. However, this process often provides only poor yields. Moreover, the reaction is slow and requires elevated reaction temperatures, for example reflux in toluene. Under these reaction conditions there is frequently partial inversion of configuration at C-5, which results in undesired (5S,6S)-penems.
It has now been found that the described disadvantages of the known process can be avoided if dialkyl alkylphosphonites are used in place of trialkyl phosphites for the 20 cyclization reaction. These novel reagents permit the reaction temperatures to be lower, for example room temperature, and result in shorter reaction times. Higher yields and purer products are achieved thereby. In addition, the undesired isomerigation to (5S,6S)-penems is avoided. The dialkyl alkylphosphonates and dialkyl alkylthiophosphonates formed as by-products can be removed in a straightforward manner.
Hence the invention relates to a process for the preparation of penem derivatives of the formula I, in which the preferred configuration is (5R,6S) p ,-0 F i f.4 7, -2- 31 j and in which R' denotes hydrogen,, (C-C 4 -alkyl, (C-C2) -alkoxy, (C-C)-alkylthio, phenoxy, phenyl (the phenyl rings being unsubstituted or substituted once or twice by carboxyl, (C, 1
-C
4 -alkoxycarbonyl, allyloxycarbonyl, aminocarbonyl (C-C)-alkylaminocarbonyl, cyano, F, [1 Cl or Br), (C 3
-C
8 -cycloalkyl, (C 3 -Cr,)-cycloalkyloxy,
(C
5 -C)-oxacycloalkyl (saturated or singly or doubly unsaturated), (C 3 -Cr,)-oxocycloalkyl, (C 3 -C-1,-bis-
(CI-C
3 )-lyoy -ylakl (C 3
-C
5 -I (Cl-C 3 -alkylino]-cycloalkyl, (C-C 8 -[arylimino 3cycloalkyl,
(C
3
-C
6 -hydroxyiminocyc loalkyl, (C 3
-C
6
-(C-C
3 -alkyloxyimino) -cycloalkyl, in which the cycloalkyl radical is unsubstituted or substituted once or twice by Cl-C 3 -alkyl, preferably methyl, by (Cl-C 3 -4 alkoxy, preferably methoxy, by halogen, preferably chlorine, or by methylene and is saturated or can contain one or two double bonds, V 0t 4 R 2 denotes hydrogen or a customary carboxyl protective group which can be eliminated by hydrolysis, photolysis, oxidation, reduction or enzymatically, R 3 denotes hydrogen, -alkyl, -alkenyl, (Cl-C)-alkoxy, (C-C 7 -cycloalkyl, phenyl, 2-oxo-1,3dioxolyl, triazolyl, thiazolyl, amino, acylaxnino or alkoxy.
Suitable and particularly preferred substituents are the following: Ri hydrogen, (C 1
-C
4 )-alkyl (for example methyl, ethyl, hydroxymethyl and axinomethyl) (Cl-C4) -alkoxy (for example methoxy and ethoxy), (C.-CO)-alkylthiot (for example methylthio, ethylthio, and propylthio),F phenoxy (for example 4-c arboxamidophenoxy or 4cyanophenoxy), phenyl (for example 4is~ I. III S-C-R j -3carboxamidophenyl or 4-cyanophenyl), saturated or unsaturated (C 5 -oxacycloalkyl (for example tetrahydrofuryl or furyl), (C4-C 6 )-oxocycloalkyl (for example 1-oxo-3-cyclobutyl), 3hy4droxyiminocyclobutyl, 3-methoxyiminocyclobutyl and 3 ,3-dimethoxycyclobutyl.
R
3 l-hydroxyethyl (in which the OH group is free or protected by trimethylsilyl, diphenyl-tert butylsilyl, allyloxycarbonyl, trichioroethyloxycarbonyl or 4-nitrobenzyloxycarbonyl), (C 1
-C
3 )-alkoxy (for example methoxy or ethoxy), (C 1
-C
3 -alkenyl, for example triazolylethylene or thiazolylethylene.
The (Cl-CA) -alkylI and (C,-C 4 -alkoxy groups in the substitutent R' are either unsubstituted or substituted once or twice by hydroxyl, (Cl-C) -alkoxy, (Cl-C 4 -acyloxy, am1inio, (Cl-C4) -alkylamino, -acylamino, mercapto,F (C-C)-alkvylthio or heterocytcLylthio, for example thiazolyl-, thiadiazolyl-, pyridylthio.
tt 4 4 Phenyl. nuclei are liks,%wise unsubstituted or substituted once or twice by carbo.Nyl, (CI-C 4 ,)-alkoxycarbonyl, allyloxycarbonyl, aminocarbonyl, (C 1
-C
4 -alkylaminocarbonyl, cyano or halogen, preferably F, Cl, Br.
The (C- 4 -alkyl and -alkoxy groups in R 3 are 'j either unsubstituted or substituted by hydroxyl, (Cl-CA) alkoxy, (C-CO-acyloxy, amino, (Cl-C 4 )-alkylamino, (C 1
-C
4 acyl amino, mercaptoo (Cl-CO)-alkylthio or heterocyclylthio, it being possible for an OH group to be free or protected by trimethylsilyl, diphenyl-tert.-butylsilyl, allyloxycarbonyl, trichioroethoxycarbonyl. or 4nitrobenzyl.oxyca.-bonyl.
Xn the procopss 6ccording to the invention, the compounds of the formula I are prepared by reacting a compound ofF the formula II rU -4-
X
S R in which X denotes uxygen or sulfur, and R1, R 2 and R 3 have the above meaning, with a trivalent organic phosphorus compound of the formula III 5 F F.
F F F F F F
R
6 P 4
NOR
F 4 15 in which R6 denotes (C 1
-C
4 -alkyl, for example mtthy1, ethyl or trifluoromethyl, phenyl which can be substituted by.
(Cl-C 3 )-alkyl or (C-C 3 -alkoxy, and R 4 and R 5 are identical or different and denote (Cl-C4)alkyl, allyl, benzyl, or phenyl which can be substituted by (C-C 3 )-alkyl or (Cl-C)-alkoxy.
The reaction between a compound II and a compound III can be carried out in a suitable organic solvent, for example in tetrahydrofuran, ethyl acetate, an aromatic hydrocarbon such as benzene, toluene or xylene, or a halogenated hydrocarbon such as dichloromethane, trichioromethane or 1,1, 2-trichloroethane.
The reaction temperature can vary between +10 0 C and 160 0
C,
preferably between +20*C and +70 0
C.
The concentration of the compound II, to be cyclized is between 1 mol/1 and 100 mmol/l, preferably between 2 mmol/l and 20 mmol/l.
equivalents, relative to II.
The compounds of the formulae II and III are known or can be prepared by processes disclosed in the literature.
The examples which follow serve to illustrate the invention further.
Example 1 fi i 1 4-Nitrobenzyl (5R,6S)-6-[(1R)-tert.-butyldimethylsilyl- 0 oxyethyl (4-aminocarbonylphenoxy)penem-3-carboxylate 130 mg (0.2 mmol) of (3S,4R)-4-[(aminocarbonyl)-phenoxythiocarbonylthio3-3-[(lR)-tert.-butyldimethylsilyloxyethyl) 4-nitrobenzyloxycarbonyl)-azetidin-2-one were dissolved in 90 ml of CHC13 under an argon atmosphee at 55°C. To this was added within 30 minutes a solution of mg (0.8 mmol) of dimethyl methylphosphonite CH 3 P(OCh3) 2 in 10 ml of CHCI 3 and, after addition was complete, the mixture was then stirred for 2 hours and, after cooling, worked up. Extraction with 1 N aHCO 3 solution, 1 N KHSO 4 solution and water was carried out, and the organic phase was dried with magnesium sulfate and concentrated in S« vacuo. The crude product provided, after flash chromatot graphy (SiO 2 70-200 pm 10 H.O; first toluene ethyl acetate 20 1, then 1 1 for elution), the title compound in 83 yield.
The compounds I listed in Table 1 were obtained analogously from the starting substances II listed in Table 2 under the reaction conditions listed in Table 3.
pW_ data on the pene. I according to the invention Exampl e RIR 2 1 H-NMR (COC1 3 8 (p"pm) -OAt QLCONH2 PNB -CH(OTBOMS)CH 3 2 D.O CONH2 3 0O44Q'CNH 2 -C11 2 CH=C11 2
CH
2
CH
2 S iMe 3 8.17, 7.55 (4H1, AA-88', J=8.7 Hz, aromat. H -of P118); 7.83, 7.21 (411 AA'BB', J=8.8 aromat. H of benzamide); 5,65 (1H, d, J=1.4, H1-5); 5.38, 5.21 (2H, AR, J=13.8, Benzyl-11); 4.41-4,42 (lIN, m, -CH(OTBDMS)-); 3.76 (1IN, dd J=1.4. 4.8, 11-6); 1.25 (3H1, d, J=6.2, CH 3 0.82 (9H, s. tert.-Butyl-H); 0.09, 0.05 (6H1, 2 x s, Si(C11 3 2 7 J3. 7.21, (411, M'BB'1, J=8.8, aromat. HI ofbenzamlde; 5.78-5.94 (111, m, 5.62 (1H, d. J1I.i, 5.40-5.17 (2H1, m, =C1 2 4.66 !211, m, COZ-C11 2 4.25 (1IN, -CII(OTBDMS)-); 3.71 (111, dd, J=1.4, 4.8, 11-6); 1.25 (3H1, d, J=6.2, CH 3 0.88 (91, S, tert.-Butyl-1); 0.09, 0.05 (611, 2 x s, Si(C11 3 2 7.BZ, 7.20 AAMBB', J=8.8. aromat. H Of benzamlde); 5.61 (IN1, d. J=1.4, 11-5); 4-20-4.30 (311, m, -CH(OTBDMS)- and 'C1 2
CH
3.72 (1IN, dd, J=1.4, 4.8, 11-6); 1.25 (3H11d, J=6.2, C11 3 0.96 (2H1, m, CH 2 Si); 0.87 (911, s, tert.-utyl-1); 0.1-0.01 (total 1511, 3 x s, Si(C11 3 3 TBDMS t-butyldimethylsilyl Me Methyl PNB para-Nitrobenzy! IRON -buyldmetylslyl Me Metyl 118= pra-itrbeny'! TE 1,1,2-Trlchloroethane fl77
U'
*E 4 a 4 4 *i o Table I Continuation a a a 4 a a a *OQ 0 a 0 rro orr o rr a -a a fi n P a -a n r r i r^ Example R1 R 2 R3 1 1-NMR (COCI) 8 (ppm) 4 0C1 3
-CH
2 CH=C1 2 -CH(OTBDMS)CH3
OCH
3 6
OCH
3
PNB
-CHCH
2 SiMe 3 5,.85-6.02 (1M, m, 5.55 (1H, d, J=1.4, 5.43-5.17 (total2f, m, C14 2 4.65 (2H, m, C0 2 -C1 2 4.25 (1H, m, -CH(GTBDMS)-);.4.00 (3H, s, OCH 3 3.65 (1H, dd, J=1.4, 4.8, 1,25 (3H, d, J=6.2,
CH
3 0.90 (9H, s, tert-Butyl-H); 0.10 (6H.
2 x s, Si(C1 3 2 8.20, 7.60 (4H,AA'88, J=8.7 Hz, aromat. H of PNB); 5.61 (11, d, J=1.4, 5.39 and 5.19 (2H, ABq, 14Hz, Benzyl-H); 4.25 (1N, m, -CH(OTBDMS)-); 4.04 (3H, s, OCH 3 3.71 (11, dd, J=1.4, 4.8, 046); 1.27 (3H, d, J=6.2), C1 3 0.82 tert.-Butyl-H); 0.09, 0.05 (6H, 2 x s, Si(CH 3 2 5.52 (1H, d. J=1.4, 4.25 (total3H, m, -CH(OTDBMS)-, CH 2 -OCO); 4.00 s, 0C1 3 3.65 (1H, dd, J=1.4, 4.8, 1.25 (3H, d, J=6.2, CH 3 1.05 m, CH 2 Si); 0.90 (9, s, tert.-Butyl-H); 0.5-0.1 (15, 3 x s, Si(C1 3 3 8.29, 7.59 AA'BB', J=8.7 Hz, aromat H of PNB); 5.55 (1H, d, J=1.4, 5.39and 5.19 (2H, ABq, 414z, Benzyl-H); 4.72 (11, m, 4.25 (11, m, -CH(OTBOS)-); 3.66 (1H, dd, J=1.4, 4.8, 2.0-1.5 (total8H, Cyclopentyl-CHZ); 1.27 (3H, d, J=6.2, CH3-); 0.82 (9H, s, tert.-Butyl-H); 0.08, 0.05 k6H, 2 x s, Si(CH 3 2 7 0[J -PHN so i -i L- -I Table I Continuation Exapl eR R2 R 1H NMR NEW (POm) -M -013 8 0Q 9
SCH
3 PNB -CH(OTBDMS)CH3 -C4 2 C1--CH2 8.19, 7.61 (4H, AA'BB', J=8.7Hz, aromat. H of PNB); 5.55 (1H, d, J=1.4, 5.29 and 5.19 (2H, ABq, 14Hz, Benzyl-H); 4.21-4-12 (total.',NI m, 1'-CH and -CH(OTBDMS)-); 3.66 (14, dd, J=1.4, 4.8, 2.05-1.3 (total 1014, m, Cyclohexyl-C1 2 1.27 (3H, d, J=6.2,
CH
3 0.82 (9H, s, tert.-Btuyl-H); 0.08, 0.05 (6H, 2 x s, Si(C1 3 2 5-85-6.02 (1H, m, 5.61 (1H, d, J=1.4, 5.43, 5.37, 5.22, 5.19 (tt12H, 4 x d, CH 2 4.70 m, C0 2
-CH
2 4.22 (11, m, -CH(OTBDS)-); 3.68 (1H, dd, J=1.4, 4.8, 2.51 s, SCH 3 -123 (3H, d, J=6.2, CH3); 0.88 (94, s, tert.-Outyl-H); 0.10 (6H, 2 x s, Si(C1 3 2 8.21, 7.51 (4H, AA'BB', J=8.7 Hz, aromat. H of PNB); 5.66 d, J=1.4, 5.41and 5,21 (2H, ABq, 14Hz, Benzyl-H); 4.25 (1H, m, -CH(OTBOS)-); 3.71, 1H, dd, j1.4, 4.8, 2.52 (3H, s, SC1 3 1.25 (3H, d, J=6.2,
CH
3 0.82 (9H, s, tert.-Butyl-H); 0.09, 0.05 2 x s, Si(CH3) 2 5.59 (lI, d, J=1.4, 4.0-4.31 (zus.
3H, m, -CH(OTBDMS)-, C14f-0C0); 3.66 (114 dd, J=1.4, 4.8, 2.50 (3 s, SCH 3 1.21 (3H, d, J=6.2, CU 3 1.08 (2H, m, C 2 Si); 0.89 (9H, s, tert.-Butyl-H); 0.01-0.11 3 x s, Si(U1 3 2 SC4 3
PHD
11 SC14 3 -CH2CH2SiIe3
-L
rr ,nn ~rr rr .4 Table I Continuation Example RI R 2
R
3 1 H-NMR (CODC1 3 8 (29
IOQ
-CH
2
CH
2 S IMe3 -CH(OTBDMS)CH3
-CH
2
CH
2 SiMe 3 5.52 and 5.45 (totallH, d, J=1.4, 5.42-5.35 (1H, m, 4.31-4.15 (totl1H, M, -CH(OTBOMS)- andZH2-OCa); 4.03-3.77 (2H, m, 5'-CH 2 3.64 (1H, m, 2.51-2.34 (1H, 2 2.05-1.71 (3H, m, 3',4'-CH 2 1-25 (total3H, m, CH 3 1.08 (2H, m, 0.87 (9H, m, CH 2 Siand tert.-Butyl-H); 0.09-0.11 (15H, m, Si(CH 3 3 7.68, 7.52, 6.5. (total3H, 3 x m, Furyl-H); 5.56 (1H, d, J=1.4; 4.34-4.21 (total3H, m, -CH(OTBDMS)-fnd. C1 2 -OCO); 3.69 (1H. dd, J=1.4, 4.8, 1.28 (314, d, J=6.2, C143-); 1.10 (2H, m, CH 2 Si); 0.91 (9H, m, tert.-Butyl-H); 0.01-0.11 (15, 3 x s, Si(C1 3 3 7.50, 7.39 (totaiSH, 2 x m, Phenyl-H); 5.69 (1H, d, J1.4. 4.31 (1H, m, -CH(OTBD45)-); 4.19 (2H, m, C1 2 -OCO); 3.78 (1H, dd, J-1.4, 4.8, 1.32 d, J=6.2, 0.93 (totalllH m, CH 2 Siand tert.-PAyl-H); 0.01-0.11 (15, 3 x s, Si(C11 3 3 -0-
-CI
2 C1 2 SiMe3 Compound 0140 is prepared fram 2 dIfferent precursors in Example 14 and 1, 6-.Mw I It a 4 I Table I Continuation a -1 a -r I OCb rr F- 4 r r r 4 LI nri ni-~C
LI-
S: Example R 2 3 16 O CO 2
CH
2 CH=CH -C 2 CHZSiie 3
-CH(OTBDMS)C"
3 1 H-NIR (CODC 3 8 (ppm) 17 is 19 KXH H 3:
-CH
2
CH
2 Site 3
SCH
2
CH=CH
2
-CH
2
CH
2 SiMe 3 8.06, 7.53 (4H, AA'BB, J=8.8 Hz, aromat. H); 6.1-5.94 (1H4, m, 5.71 (1H, d, J=.4, 5.44-5.20 (2H, m, =CH 2 4.84 (2H, m, C0 2
-CH
2 /Allyl); 4.27 (1H, m, -CH(OTBDMS)-); 4.16 (2H, m, CO 2
CH
2 /T4SE); 3.78 (19, dd, J=1.4, 4.8, 1.28 d, J=6.2, CH 3 0.91 (9H, s, tert.-Butyl-H); 0.11-0.01 4 x s, Si(CH 3 2 5.58 J=1,4 Hz, 4.52 1H, Cyclobutyl); 4.25 (in, 3H, C02CH 2 and CHCH 3 3.70 (dd, J=5 andlHz, 3.15-3.5S-(m, 4 Cyclobutyl-H); 1.28 (3H, d, J=6Hz, CHCH 3 1.08 (Mn, 2H, CH 2 0.88 9H, tert.-Outy1-H); 0.18 6H, Si(CH 3 2 0.06 9H4, Si(CH 3 3 5.86-6.03 1P=CH); 5.61 fd, 7=14z, 5.22-5.45 2=C" 2 4.72 2H, C02CH 2 4.51 19, Cyvclobutyl); 4.25 CHCH 3 3.72 (dd, J=5 and 1 Hz, 3.15-T55 (m, 4-Cyc'lobutyl-H); 1.28 (3H, d, J=6Hz, CHCH 3 0.88 9H, tert.-Butyl-H); 0.10 6fflSi(CH 3 2 5.52 JlHz, 4.2-4.32 3H, CO 2
CH
2 und CHCH 3 4.0-4.14 19, Cyclobutyl); 3-67 (dd, J=5 and 1Hz, 3.15 and 3.16 (je s, 2 x 3H, OCH 3 2.5-2.7 2H, Cyclobutyl); 2.1-2.22 2H, Cyclobutyl), 1.28 (3H, d, .!-f6Hz, CHCH 3 1.08 2H, CH Si); 0.88 s, 9H, tert.-Butyl-H), 0.10 6H, Sif CH3)2); 0.06 9H, Si(C9 3 3 1~ rr rr P~ i L L-L) LL -C Table 2 Starting compounds R S1 0 2t tC R Example R2 R3X 1 0 ~CO4H 2 *PNB -CH(OTBDMS) S 2 -0 ~CONH 2
-CH
2
CH=CH
2
S
CtO~'CNH -CH 2
CH
2 Si Me3 S t t t4 OCH 3
-CH
2 CHi=CH 2
S
1 5 OCH 3
-N
6 OCH 3
-CH
2
CH
2 SiI~e3
S
7O1j 0PNB
S
8-PNB gg s 9 SH 3
-CH
2
CH=CH
2
S
-12- Example RI R2 R3X
SCH
3 -PNB of s 11 SCH 3
-CH
2
CH
2 SiMe3 s 12 -CHZCH 2 Si~e3 0 13 1A -CH 2
CH
2 SiP~e 3 0 I 14 -CHZCH 2 SiMe 3 0
-CH
2
CH
2 SiMe 3 s 16 .C0CH 2 CH=CH2~ -CH 2
CH
2 SiMe 3 0 17 -0-CH 2
CH
2 SiMe 3 0 18 -CI 2 CH=CHZ 0 19 H3-CH 2
CH
2 Si~e 3 0 a a p a a a 0 0 a a aa-0 en a a a a a.
a oa a 4
SCR
Conc. ~~Temp.Recintm(hYel% Examle Reagant III Equivalents of III Cffo.) Solvent Oq)Ratintm(h il
CH
3 P(OCH3)2
K
CH
3
P(OC
2 H5:,Z CHC1 3 1.1-2-TCE CHC1 3 if It It 'i to 2 1 2 0,5 0,5 2 3 3 6 1 1 2,5 0 0
P.
rt 0 Ms 0 rt 0 Ft 0
I.&
0 CI43P(OCII3)2- CHPN2')
Claims (4)
1. A process for the preparation of a penemn compound i in which R 5 S 0 CO 2 R 2 R1 denotes hydrogen, (Ci -C 4 )-alkyl, (CI-Cl 2 )-alkoxy, (Ci -C 1 2 )-alkylthio, phenoxy, phenyl (the phenyl rings being, unsubstituted or substituted once or twice by carboxyl, (Cl-C 4 )-alkoxycarbonyl, allyloxycarbonyl, aminocarbonyl, V (Cl-C 4 )-aikylaminocarbonyl, cyano, F, CI or Br), (C 3 -Cs)-cycloalkyl, (C 3 -C 6 cycloalkyloxy, (C 5 -C 6 )-oxacycloalkyl (saturated or singly or doubly #1 t cycloalkyl, (C 3 1 -C 3 )-alkyllmino]-cycloalkyl, (Cs-C6)-[aryliminO]- cycloalkyl, (C 3 -Cre)-hydroxyinocycloalkyl, (C 3 -C6)-(C 1 -C 3 -alkyloxyimino)- cycloalkyl, in which the cy',Ioalkyl radical Is unsubstituted or substituted once or twice by Cl-C 3 -alkyl, by (C 1 -C 3 )-alkoxy, by halogen, or by methylene and Is saturated or can contain one or two double bonds, the (CI-C 4 )-alkyl and (Ci-C 4 alkoxy groups in the substituent RI 1 are either unsubstituted or substituted once or twice by hydroxyl, (C 1 -C 4 )-alkoxy, (Cl-C 4 )-acyloxy, amino, (Cl-C 4 )-alkyl- amino, (C 1 -C 4 )-acylamlno, mercapto, (C 1 -C 4 )-alkylthlo or heterocyclylthio, 44: 4 2 denotes hydrogen or a customary carboxyl protection group which can be eliminated by hydrolysis, photolysis, oxidation, reduction or enzymatically, R3 denotes hydrogen, (CJ-C 4 )-alkyl, (CI-C 4 )-alkenyl, (Cl-C 4 )-alkoxy, (C 4 -C 7 cycloalkyl, phenyl, 2-oxo-1 ,3-dioxolyl, triazolyl, thlazolyl, amino, acylamino 31 or alkoxy, the (Cl-C 4 )-alkyl and (Cl-C 4 )-alkoxy groups in R 3 are either unsubstituted or substituted by hydroxyl, (C C 4 )-alkoxy, (C 1 -C 4 -acy loxy,0 amino, (C 1 -C 4 )-alkylamino, (Cj-C 4 )-acylamlno, mercapto, (C 1 -C 4 )-alkylthlo or heterocyclylihio, It being possible for an OH group to be free or protected by trimethylsilyl, diphenylbtert.-butylsilyl, allyloxycarbonyl, trichioroethoxy- carbonyl or 4-nitrobenzyloxycarbonyl which comprises reactino a compound of the formula ii 0A _t TO T x 002 R in which X denotes oxygen or sulfur, and Ri, R2 and R3 have the above meaning, with a trivalent organic phosphorus compound of the formula iii CR4 R 6 -P in which R6 denotes (C-C 4 )-alkyl, phenyl which can be substituted by (Cl-C 3 )-alkyl or (Ci C 3 )-alkoxy, and R4 and R5S are Ideontical or different and denote (C 4 )-alkyl, allyl, benzyl, or phenyl which can be substituted by (01-03)-alkyl or (01-03)-alkoxy.
2. The process as claimed in claim 1, wherein the reaction of compound ii with 113: is carried out in an organic solvent.
3. The process as claimed In claim 1, wherein the reaction is carried out. -It between 100C and +1 60c00.
4. The process as claimed In claim 1, wherein R1 denotes hydrogen, (Cij1C 4 )-alkyl, (Ci-04 )-alkoxy, (Ci -C 3 )-alkylthio,j phenoxy, phenyl (the phenyl nuclei being substituted by (Ci -C 4 )-alkoxy- carbonyl, aminocarbonyl or cyano), (C 5 -0 6 )-oxacycloalkyl, (04-06) oxocycloalkyl, 3-hydroxyiminocyclobutyl, 3-methoxyimlnocyclobutyl, 3,3- dimethoxycyclobutyl, 3- methoxy-2-cyclobu ton-1 -yI, 2-msihoxy-1 cyclobuten-1 -yl and 4-methoxy-3-cyclohexen-1 -yl, the (CI -C 4 )-alkyl and (CI-C34)-alkoxy groups In the substituent Ri are either unsubstituted or Atubstituted once or twice by hydroxyl, (C 1 -0 4 )-alkoxy, (CI-C 4 )-acyloxy, .Jo 16 amino, (C 1 -C 4 )-alkyl-amino, (Ci -C 4 )-acylamino, mercapto, (Ci -C 4 alkylthio or heterocyclylthio, R 3 denotes 1-hydroxyethyl (in which the OH group s free or protected by trimethylsilyl, diphenyl-tert.-butylsilyl, allyloxycarbonyl, trichloroethoxy- carbonyl or 4-nitrobenzyloxycarbonyl), -C 3 )-alkoxy, (Ci -C 3 )-alkenyl, C, C3)-alkoxy groups in R3 are either unsubstituted or substitued by hydroxyl, (Ci- C 4 )-alkoxy, (Cl-C 4 )-acyloxy, amino, (Ci -C 4 )-alkylamino, (01-04) acylamino, mercapto, (Cl-C 4 )-alkylthio or heterocyclylthio, it being possible for an OH group to be free or proteoted by trimethylsilyl, diphenyl-tert.-butyl- silyl, allyloxycarbonyl, trichloroethoxycarbonyl or 4-nitrobenzyloxycarbonyl. c C C C 4 C I $1 4i #1 S C C C IC I S C S S S III C CISSSI I C 1141 C S C S C C CC C C I I C *t C 4 TI,, DATED this 17th day of December, 1991. HOECHST AKTIENGESELLJSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BUR WOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA AU005390690.WPC
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3914389 | 1989-04-29 | ||
| DE19893914389 DE3914389A1 (en) | 1989-04-29 | 1989-04-29 | Prodn. of penem antibiotics - by reacting 4-acyl:thio-1- oxalyl-2-azetidinone cpds. with phosphonite di:ester |
| DE3917287 | 1989-05-27 | ||
| DE19893917287 DE3917287A1 (en) | 1989-05-27 | 1989-05-27 | Prodn. of penem antibiotics |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU5390690A AU5390690A (en) | 1990-11-01 |
| AU620982B2 true AU620982B2 (en) | 1992-02-27 |
Family
ID=25880482
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU53906/90A Ceased AU620982B2 (en) | 1989-04-29 | 1990-04-27 | A process for the preparation of penem compounds |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0399228A1 (en) |
| JP (1) | JPH02306978A (en) |
| KR (1) | KR900016224A (en) |
| AU (1) | AU620982B2 (en) |
| CA (1) | CA2015580A1 (en) |
| FI (1) | FI902110A0 (en) |
| NO (1) | NO173871C (en) |
| PT (1) | PT93893A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU652954B2 (en) * | 1990-08-20 | 1994-09-15 | Asubio Pharma Co., Ltd. | Antibacterial penem esters derivatives |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3839987A1 (en) * | 1988-11-26 | 1990-05-31 | Hoechst Ag | PENEM DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
| WO1992003443A1 (en) * | 1990-08-20 | 1992-03-05 | Suntory Limited | Antibacterial penem compounds |
| GB9216102D0 (en) * | 1992-07-29 | 1992-09-09 | Smithkline Beecham Plc | Pharmaceutical substances |
| ATE522521T1 (en) | 2002-03-26 | 2011-09-15 | Nippon Soda Co | METHOD FOR PRODUCING A CYCLIC CONNECTION |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2144743A (en) * | 1983-08-11 | 1985-03-13 | Erba Farmitalia | Process for the preparation of penems |
| AU7004287A (en) * | 1986-03-17 | 1987-09-24 | Schering Corporation | 2-heterocyclylthio penems |
| AU7676687A (en) * | 1986-08-12 | 1988-02-18 | Hoechst Uk Ltd. | Preparation of antibacterial 7-oxo-4-thia-1-azabicyclo(3,2,0)hept-2-ene derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0275002A1 (en) * | 1987-01-09 | 1988-07-20 | Hoechst Aktiengesellschaft | Process for the production of 7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene derivatives |
-
1990
- 1990-04-25 EP EP90107815A patent/EP0399228A1/en not_active Withdrawn
- 1990-04-26 FI FI902110A patent/FI902110A0/en not_active Application Discontinuation
- 1990-04-27 PT PT93893A patent/PT93893A/en not_active Application Discontinuation
- 1990-04-27 CA CA002015580A patent/CA2015580A1/en not_active Abandoned
- 1990-04-27 AU AU53906/90A patent/AU620982B2/en not_active Ceased
- 1990-04-27 JP JP2115038A patent/JPH02306978A/en active Pending
- 1990-04-27 NO NO901893A patent/NO173871C/en unknown
- 1990-04-27 KR KR1019900005962A patent/KR900016224A/en not_active Application Discontinuation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2144743A (en) * | 1983-08-11 | 1985-03-13 | Erba Farmitalia | Process for the preparation of penems |
| AU7004287A (en) * | 1986-03-17 | 1987-09-24 | Schering Corporation | 2-heterocyclylthio penems |
| AU7676687A (en) * | 1986-08-12 | 1988-02-18 | Hoechst Uk Ltd. | Preparation of antibacterial 7-oxo-4-thia-1-azabicyclo(3,2,0)hept-2-ene derivatives |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU652954B2 (en) * | 1990-08-20 | 1994-09-15 | Asubio Pharma Co., Ltd. | Antibacterial penem esters derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| FI902110A0 (en) | 1990-04-26 |
| PT93893A (en) | 1990-11-20 |
| NO173871B (en) | 1993-11-08 |
| NO901893D0 (en) | 1990-04-27 |
| JPH02306978A (en) | 1990-12-20 |
| KR900016224A (en) | 1990-11-13 |
| CA2015580A1 (en) | 1990-10-29 |
| EP0399228A1 (en) | 1990-11-28 |
| AU5390690A (en) | 1990-11-01 |
| NO901893L (en) | 1990-10-30 |
| NO173871C (en) | 1994-02-16 |
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