JPH0316357B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula The present invention relates to a method for producing a penem-3-carboxylic acid derivative having the following. In the above formula (), R ¹ is a hydrogen atom, an alkyl group, or an R ⁴ A- group (wherein R ⁴ represents a hydroxyl group, an alkoxy group, an acyloxy group, a trialkylsilyloxy group, an alkylthio group, or an acylamino group, and represents an alkylidene group which may be substituted with trifluoromethyl), and R ² represents an alkyl group, an alkenyl group, an aralkyl group, an aryl group, or an R ⁵ -B- group (wherein R ⁵ represents a hydroxyl group, an alkoxy (B represents an alkylene group), and R ³ represents a carboxyl group-protecting group. , Y represents an oxygen atom, a sulfur atom, a methylene group or an alkyl-substituted methylene group, and the R ² -Y- group may represent a methyl group. In the general formula (), R ¹ is preferably a hydrogen atom, such as methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, sec-
A linear or branched lower alkyl group such as butyl, tert-butyl, n-pentyl, isopentyl, or an R ⁴ A- group (wherein R ⁴ is a hydroxyl group, such as methoxy, ethoxy, n-propoxy, Lower alkoxy groups such as isopropoxy, lower aliphatic acyloxy groups such as acetoxy, propionyloxy, n-butyryloxy, isobutyryloxy or benzyloxycarbonyloxy, p-nitrobenzyloxycarbonyloxy, o-nitrobenzyloxy Acyloxy groups such as aralkyloxycarbonyloxy groups such as carbonyloxy, tri-lower alkylsilyloxy groups such as tert-butyldimethylsilyloxy, e.g. methylthio, ethylthio, n
- lower alkylthio groups such as propylthio, isopropylthio, lower aliphatic acylamino groups such as acetylamino, propionylamino, n-butyrylamino, isobutyrylamino or benzyloxycarbonylamino, p-nitrobenzyloxycarbonylamino, o - indicates an acylamino group such as an aralkyloxycarbonylamino group such as nitrobenzyloxycarbonylamino, A is methylene, ethylidene, propylidene, butylidene, bentylidene, 2,2,2
- indicates an alkylidene group which may be substituted with a trifluoromethyl group such as trifluoroethylidene and 3,3,3-trifluoropropylidene. )
and R ² is preferably, for example, methyl, ethyl,
Straight-chain or branched lower alkyl groups such as n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, such as allyl, 2-butenyl, 3- Straight-chain or branched lower alkenyl groups such as methyl-2-butenyl and 2-pentenyl; for example, lower alkyl groups such as methyl, ethyl, n-propyl, and isopropyl in an aromatic ring;
Lower alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy or aralkyl groups such as benzyl, phenethyl, phenylpropyl with or without substituents such as halogen atoms such as fluorine, chlorine and bromine, e.g. Aromatic rings are substituted with lower alkyl groups such as methyl, ethyl, n-propyl, and isopropyl, lower alkoxy groups such as methoxy, ethoxy, n-propoxy, and isopropoxy, or halogen atoms such as fluorine, chlorine, and bromine. an aryl group such as phenyl or an R ⁵ B- group with or without the presence of a hydroxyl group, e.g. a lower alkoxy group such as ^methoxy , ethoxy, n-propoxy, isopropoxy, e.g. acetoxy, propionyloxy, Lower aliphatic acyloxy groups such as n-butyryloxy and isobutyryloxy, lower alkoxyoxalyloxy groups such as methoxalyloxy, ethoxalyloxy, and n-propoxalyloxy, or benzyloxycarbonyloxy and p-nitrobenzyloxy Acyloxy groups such as aralkyloxycarbonyloxy groups such as carbonyloxy, lower alkylsilyloxy groups such as tert-butyldimethylsilyloxy, carboxyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl; lower alkoxycarbonyl groups such as benzyloxycarbonyl, aralkyloxycarbonyl groups such as p-nitrobenzyloxycarbonyl, such as methylthio, ethylthio, n-propylthio,
lower alkylthio groups such as isopropylthio,
For example, acetylamino, propionylamino, n
- lower aliphatic acylamino groups such as butyrylamino, isobutyrylamino, or acylamino groups such as aralkyloxycarbonylamino groups such as benzyloxycarbonylamino, p-nitrobenzyloxycarbonylamino, o-nitrobenzyloxycarbonylamino; and B represents a linear or branched lower alkylene group such as methylene, ethylene, trimethylene, propylene, tetramethylene, and pentamethylene. ), and R ³ is preferably, for example, methyl, ethyl, n-propyl, isopropyl, n
- straight-chain or branched lower alkyl groups such as butyl, isobutyl, tert-butyl, such as methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, isobutoxymethyl; lower alkoxymethyl groups such as acetoxymethyl, propionyloxymethyl, n-butyryloxymethyl, isobutyryloxymethyl, lower aliphatic acyloxymethyl groups such as pivaloyloxymethyl, such as 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-
n-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-n-
a 1-lower alkoxycarbonyloxyethyl group such as butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl, for example a benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl group or a phthalidyl group, and Y is oxygen atom, sulfur atom or methyl,
It is a methylene group which may be substituted with a lower alkyl group such as ethyl, n-propyl or isopropyl, and the R ² Y- group may represent a methyl group. In addition, in the compound having the above general formula (), there are optical isomers and stereoisomers based on asymmetric carbon atoms, and all of these isomers are shown by a single formula, but by this, The scope of the description of the present invention is not limited. however,
Preferably, a compound can be selected in which the carbon atom at the 5th position has the same coordination as that of penicillins, that is, the R coordination. The manufacturing method included in the present invention will be explained in detail below. Starting materials are general formula (In the formula, R ¹ , R ² , R ³ and Y have the same meanings as described above, and X represents an oxygen atom or a sulfur atom.)

When expressed in combination with [Formula], a [(alkyl)thio]thiocarbonyl]thio group such as X=S,=S,
=S, [(alkoxy)thiocarbonyl]thio group such as Y=O, [(alkyl)thiocarbonyl]thio group such as X=S, Y=CH ₂ -, X=O,
[(alkylthio)carbonyl] like Y=S
The thio group is represented by an (alkoxycarbonyl)thio group such as X=O, Y=O, or an acylthio group such as X=O, Y=CH ₂ -, and these compounds are described in the literature [S.
Oida, A. Yoshida, T. Hayashi, N. Takeda, T.
Nishimura and E. Ohki, J. Antibiotics 33 , 107
(1980); I.Ernest, J.Gosteli, C.W.Greengrass,
W.Holick, DEJackman, HRPfaendler, and
R.B.Woodward, J.Am.chem.Soc., 100 , 8214
(1978)] General formula obtained by synthesis according to the method of (In the formula, R ¹ , R ² , In the presence, 1 to 4 equivalents of an alco represented by the general formula XCOCOOR ^{3 (} ) (wherein, It can be prepared by reacting with xalyl halide. In ^the reaction in the method of the present invention, ^the above-mentioned raw material, that is, the azetidinone ^derivative represented by the general formula ( or a dialkylamino group), or a phosphite ester such as trimethyl phosphite or triethyl phosphite, or a phosphite amide such as tris(dimethylamino)phosphine. This method produces a penem-3-carboxylic acid derivative represented by: In carrying out this reaction, the solvent to be used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol, ethanol, propanol, and isopropanol, and ethers such as tetrahydrofuran and dioxane are used. , esters such as ethyl acetate and butyl acetate, aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and methylene chloride, dialkyl fatty acid amides such as dimethylformamide and dimethylacetamide, and acetonitrile. Nitriles such as these and mixed solvents of these organic solvents are suitable. The reaction temperature is not particularly limited and can usually be carried out at room temperature to around 150°C, but preferably 50° to 150°C.
Heat it nearby. The time required for the reaction varies mainly depending on the type of raw materials and reaction temperature, but it is approximately 5
The duration ranges from hours to 4 days. After the reaction is completed, the target compound () of this step is collected from the reaction mixture according to a conventional method. For example, after removing insoluble matter from the reaction mixture if necessary, washing with water,
It can be obtained by drying and distilling off the solvent and excess reagent. The target compound thus obtained can be further purified, if necessary, by conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography, etc. In this reaction, when the starting compound () is brought into contact with the trialkyl phosphite or triamide phosphite represented by the above general formula () in a solvent at a relatively low temperature from room temperature to about 90°C, the general formula (In the formula, R ¹ , R ² , R ³ , R ⁴ , X and Y have the same meanings as described above.) A ylide compound represented by the formula can be obtained, but it is not possible to purify it as it is. This also includes a method in which the desired penem-3-carboxylic acid derivative (2) is obtained by heat treatment without heating. The heating temperature in this case is 100 to 150℃, and the reaction time is about 4
hours to 48 hours. The compound having the general formula () obtained by the present invention belongs to penem derivatives having double bonds at the 2- and 3-positions of penicillin, and has various substituted alkyl groups, alkylthio, or alkyloxy groups at the 2-position. A group of compounds, with the general formula ()
Protecting groups for hydroxyl and amino groups and carboxylic acid protecting groups contained in R ¹ and R ² shown in
By removing R ³ by known methods,
For example, it is an important synthetic intermediate that can lead to penem-3-carboxylic acids which are useful as pharmaceuticals and have excellent antibacterial activity as described in Japanese Patent Application No. 54-44050. The present invention is superior to conventional methods for producing penem derivatives in the following points. As a method for producing penem derivatives, the method shown in the following reaction formula (JP-A-52-71460, JP-A-53-137951
and Japanese Unexamined Patent Publication No. 119486/1986) are known. In the formula, X and Y represent an oxygen or sulfur atom or a methylene group. That is, azetidinone derivative 1 is reacted with glyoxylic acid ester to form adduct 2, which is halogenated with thionyl chloride to form chloride 3,
Compound 3 is reacted with triphenylphosine in the presence of a base to give 4, followed by heating of compound 4 to give the penem derivative 5. In this method, compounds 2 to 4 can be reacted continuously in one reaction vessel, so it can be considered as one step, and penem derivative 5 can be obtained from compounds 1 to 3 steps. On the other hand, the method for producing penem derivatives of the present invention is a method of synthesizing according to the following reaction formula. That is, azetidinone derivative 1 is oxalylated to form oxalimide 6, compound 6 is reacted with a phosphite derivative (P(OR ⁴ ) ₃ ) to form compound 7, and 7 is heated to obtain penem derivative 5. In this method, there is no need to isolate compound 7, so penem derivative 5 can be obtained from compound 1 in two steps. Furthermore, by this method, penem derivative 5 can be obtained from compound 1 in good yield. As described above, while the conventional method can obtain Compound 5 from Compound 1 in three steps, the production method of the present invention can obtain Compound 5 from Compound 1 in two steps. Therefore, this production method is a superior method for producing penem derivatives compared to conventional methods. In addition, in the production method of the present invention, compound 5 is obtained from compound 7 even when heated at 80°C, whereas compound 5 is hardly obtained even when compound 4 is heated to 100°C, and compound 5 is obtained even when heated to about 120°C. Compound 5 is then obtained.
In general, it is thought that lower temperatures produce fewer by-products in chemical reactions, and from this point of view as well, the production method of the present invention is superior to conventional methods. In addition, the reaction time of this method is shorter than that of conventional methods. In other words, in this method, the reaction time required to obtain 5 from 1 is approximately 5 hours, whereas in the conventional method, the reaction time required to obtain 4 from 3 is approximately 40 hours; The reaction time is approximately 15 hours. Therefore, the present method is superior to the conventional method as a method for commercially producing penem derivatives. Example 1 2-methylpenem-3-carboxylic acid methyl ester A 1 ml solution of 40 mg (0.17 mmol) of N-methoxalyl-4-acetylthioazetidin-2-one and 65 mg (0.52 mmol) of trimethyl phosphite in dioxane was heated at 95°C in a nitrogen stream for 15 hours, and then
Heat to reflux for 2.5 hours. The residue after the solvent was distilled off was separated and purified by preparative thin layer chromatography [developing solvent: benzene-ethyl acetate (5:1)] to give 8 mg.
(yield 23%) of the target product is obtained as crystals. When recrystallized from a hexane-ethyl acetate mixed solvent, the melting point
Gives needle-shaped crystals at 79.5-80℃. Elemental analysis value as C ₈ H ₉ NO ₃ S Calculated value: C, 48.22; H, 4.55; N, 7.03; S, 16.09 Actual value: C, 48.40; H, 4.59; N, 6.99; S, 16.08 IR spectrum ν ^Nujol _nax cm ^-1 : 1768, 1707, 1581 NMR spectrum (CDCl ₃ ) δppm: 2.30 (3H, s), 3.36 (1H, dd, J = 172Hz),
3.75 (1H, dd, J = 12, 4Hz), 3.77 (3H, s),
5.68 (1H, dd, J=4,2Hz) Example 2 2-Methylpenem-3-carboxylic acid p-nitropenzyl ester N-p-nitrobenzyloxyoxalyl-4
-Acetylthioazetidin-2-one 84mg
(0.24mmol) and trimethyl phosphite 238mg
(1.92 mmol) in 11 ml of ethyl acetate solution under nitrogen stream.
After stirring at 65°C for 24 hours, the solvent and volatile substances were distilled off at 60°C under reduced pressure to give crude 4-acetylthio-1-
112 mg of [1-(p-nitrobenzyloxycarbonyl)trimethoxyphosphoranylidenemethyl]azetidin-2-one are obtained. A catalytic amount of p-hydroquinone is added to 112 mg of the phosphorane thus obtained, dissolved in 10 ml of xylene, and heated to 105 DEG C. for 21 hours under a nitrogen stream. After distilling off the solvent, the residue was separated and purified by preparative thin layer chromatography [developing solvent: ethyl acetate-benzene (1:8)] to obtain 37 mg (48%) of the desired product. When recrystallized from methylene chloride-ether, the melting point is 132-135℃.
Needle crystals are obtained. This product was manufactured by Woodward et al, J.Am.Chem.Soc. 101 6296
(1979)] (melting point 130~
132℃), IR spectrum, and NMR spectrum match. Example 3 (5R,6S)-2-(2-p-nitrobenzyloxycarbonylaminoethyl)-6-[(R)-1
-tert-butyldimethylsilyloxyethyl]
Penem-3-carboxylic acid p-nitrobenzyl ester (3S,4R)-N-p-nitrobenzyloxyoxalyl-4-(3-p-nitrobenzyloxycarbonylaminopropionylthio)-3-[(R)
A 17 ml solution of ethyl acetate containing 130 mg (0.18 mmol) of -1-tert-butyldimethylsilyloxyethyl]azetidin-2-one and 180 mg (1.45 mmol) of trimethyl phosphite was stirred at 65°C under a nitrogen stream for 26 hours.
The solvent and volatile substances were distilled off under reduced pressure at 60°C to give the crude (3S,4R)-4-(3-p-nitrobenzyloxycarbonylaminopropionylthio)-3-
155 mg of [(R)-1-tert-butyldimethylsilyloxyethyl]-1-[1-(p-nitrobenzyloxycarbonyl)trimethoxyphosphoranylidenemethyl]azetidin-2-one is obtained. Add a catalytic amount of p-hydroquinone to this, and xylene 15
ml for 24 hours at 105° C. under nitrogen flow. After distilling off into a solvent, the residue was separated and purified using preparative thin layer chromatography [developing solvent: benzene-ethyl acetate (1:1) mixed solvent] to obtain 43 mg (yield 35%) of the target product as an oil. Obtain it as a substance. IR spectrum ν ^liq _nax cm ^-1 : 3400, 1797, 1700-1740 NMR spectrum (CDCl ₃ ) δppm: 0.05 (3H, s), 0.08 (3H, s), 0.80 (9H, s),
1.16 (3H, d, J=6.5Hz), 2.8~3.5 (4H, m),
3.70 (1H, dd, J=4, 1.5Hz), 4.20 (1H,
m), 5.18 (2H, s), 5.14 (1H, d, J=15
Hz), 5.38 (1H, d, J = 15Hz), 5.60 (1H, d,
J=1.5Hz), 7.3-8.4 (8H) Example 4 2-Butylthiopenem-3-carboxylic acid p-nitrobenzyl ester N-methoxalyl-4-[(butylthio)thiocarbonyl]thioazetidin-2-one 171mg
(0.53mmol) and trimethyl phosphite 132mg
(1.06 mmol) in 3.5 ml of acetonitrile is stirred at 55°C in a nitrogen stream for 16.5 hours. The residue after the solvent was distilled off was separated and purified by preparative thin layer chromatography [developing solvent: benzene-ethyl acetate (10:1)] to obtain 39 mg (yield 27%) of the desired product as crystals. When recrystallized from ethanol, the melting point is 100 ~
Gives plate crystals at 101.5℃. Elemental analysis value C ₁₁ H ₁₅ NO ₃ S ₂ Calculated value: C, 48.32; H, 5.53; N, 5.12 Analysis value: C, 48.14; H, 5.52; N, 5.03 IR spectrum ν ^Nujol _nax cm ^-1 ; 1769 , 1702 NMR spectrum ( _CDCl3 ) δppm: 0.96 (3H, t-like), ~1.6 (4H, m), 2.99 (2H,
t, J = 7Hz), 3.49 (1H, dd, J = 17, 2
Hz), 3.84 (3H, s), 3.86 (1H, dd, J=17,
4Hz), 5.74 (1H, dd, J=4,2Hz) Example 5 2-Butylthiopenem-3-carboxylic acid p-nitrobenzyl ester N-p-nitrobenzyloxyoxalyl-4
- A solution of 116 mg (0.26 mmol) of [(butylthio)thiocarbonyl]thioazetidin-2-one and 260 mg (2.10 mmol) of trimethyl phosphite in 14 ml of ethyl acetate is stirred at 70°C under a nitrogen stream for 22 hours. After distilling off the solvent, 131 mg of the residue was subjected to column chromatography using 6 g of silica gel, and the objective was to obtain a substance with a melting point of 128 to 129°C from the portion eluted with benzene-ethyl acetate (20:1 to 10:1). 36 mg (yield 35
%) as crystals. This product is Japanese Patent Application No. 53-81658 (Japanese Patent Application No. 55-9034)
A compound obtained by the intramolecular Witzteich reaction of 4-[(butylthio)thiocarbonyl]thio-1-[1-(p-nitrobenzyloxycarbonyl)triphenylphosphoranylidenemethyl]azetidin-2-one described in The melting point, infrared absorption spectrum, and nuclear magnetic resonance spectrum match. IR spectrum ν ^nujol _nax cm ^-1 ; 1786, 1677 nmr spectrum (CDCl ₃ ) δppm; 0.93 (3H, t, J = 6Hz), 2.98 (2H, t, J =
7Hz), 3.50 (1H, dd, J=17, 2Hz), 3.91
(1H, dd, J = 17, 3.5Hz), 5.26 (1H, d, J
= 14Hz), 5.55 (1H, d, J = 14Hz), 5.77 (1H,
dd, J=3.5, 2Hz), 7.70 (2H, d), 8.32
(2H, d) Example 6 (5R, 6S)-2-[[2-(p-nitrobenzyloxycarbonylamino)ethyl]thio]-6
-[(R)-1-tert-butyldimethylsilyloxyethyl]penem-3-carboxylic acid p-nitrobenzyl ester (3S,4R)-N-p-nitrobenzyloxyoxalyl-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[2-(p-nitrobenzyloxycarbonylamino)ethyl] [thio]thiocarbonyl]thioazetidin-2-one
71mg (0.093mmol) and trimethyl phosphite 92mg
(0.74 mmol) in 9 ml of toluene in a nitrogen stream,
Heat and stir at 65-75°C for 34 hours. The residue after distilling off the solvent is separated and purified using preparative thin layer chromatography (developing solvent: chloroform-ethyl acetate (5:1)) to obtain 31 mg (47%) of the target product as an oily substance.This product The IR and NMR spectra match those of the compound described in Japanese Patent Application No. 54-44050. IR spectrum ν ^nujol _nax cm ^-1 : 1780, 1710, 1670 nmr spectrum (CDCl ₃ ) δppm: 0.03 (3H, s ), 0.07 (3H, s), 0.80 (9H, s),
1.20 (3H, d, J=6Hz), 3.04 (2H, m),
3.38 (2H, t, J = 5Hz), 3.66 (1H, dd, J =
4,2Hz), 4.12 (1H, m), 5.04 (1H, d, J
= 14Hz), 5.10 (2H, s), 5.37 (1H, d, J =
14Hz), 5.57 (1H, d, J=2Hz), 7.38 (2H,
d, J=9Hz), 7.50 (2H, d, J=9Hz),
8.58 (4H, d, J = 9Hz) Example 7 2-Methylthiopenem-3-carboxylic acid p-nitrobenzyl ester and 2-methoxypenem-3-carboxylic acid p-nitrobenzyl ester

【formula】

[Formula] N-p-nitrobenzyloxyoxalyl-4
- A solution of 256 mg (0.67 mmol) of [(methoxy)thiocarbonyl]thioazetidin-2-one and 495 mg (3.99 mmol) of trimethyl phosphite in 33 ml of ethyl acetate is stirred at 65°C under a nitrogen stream for 22 hours. The solvent and volatile substances were distilled off under reduced pressure to obtain 307 mg of crude 4-[(methoxy)thiocarbonyl]thio-1-[1-(p-nitrobenzyloxycarbonyl)trimethoxyphosphoranylidenemethyl]azetidin-2-one. obtain. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1760, 1637, 1603, 1513, 1341 A solution of 307 mg of this crude phosphorane and 32 ml of xylene containing a catalytic amount of p-hydroquinone was heated at 130°C under a nitrogen stream.
Heat for 18 hours and evaporate the solvent. The residue was analyzed by preparative thin layer chromatography (developing solvent: benzene).
42 mg of 2-methylthiopenem derivative (yield 18%, based on N-p-nitrobenzyloxyoxalyl derivative) and 8 mg of 2-methoxypenem derivative (yield
3.6%, based on the N-p-nitrobenzyloxyoxalyl derivative), respectively, are obtained as crystals. When the 2-methylthio derivative obtained here is recrystallized from acetone, needle-shaped crystals with a melting point of 165-166°C are obtained. Elemental analysis value C ₁₄ H ₁₂ N ₂ O ₅ S ₂ Calculated value: C, 47.71; H, 3.43; N, 7.95; S, 18.20 Actual value: C, 47.77; H, 3.45; N, 7.83; S, 18.14 IR spectrum ν ^KBr _nax cm ^-1 : 1800, 1683 NMR spectrum (CDCl ₃ ) δppm: 2.54 (3H, s), 3.51 (1H, dd, J=16, 2Hz),
3.84 (1H, dd, J=16, 3.5Hz), 5.24 (1H, d,
J=14Hz), 5.47 (1H, d, J=14Hz), 5.73
(1H, dd, J = 3.5, 2Hz), 7.62 (2H, d, J
= 8.5Hz), 8.22 (2H, d, J = 8.5Hz) In addition, when the 2-methoxypenem derivative is recrystallized with a chloroform-benzene mixed solvent, the melting point is 196
Prism crystals at ~198°C are obtained. Elemental analysis value as C ₁₄ H ₁₂ N ₂ O ₆ S Calculated value: C, 50.00; H, 3.60; N, 8.33 Actual value: C, 49.98; H, 3.60; N, 8.16 IR spectrum ν ^KBr _nax cm ^-1 : 1788, 1689, 1603, 1563, 1508, 1339 NMR spectrum (CDCl ₃ ) δppm: 3.43 (1H, dd, J = 17, 2Hz), 3.86 (1H, dd,
J=17, 3.5Hz), 4.03 (3H, s), 5.16 (1H,
d, J=14Hz), 5.42 (1H, d, J=14Hz),
5.66 (1H, dd, J=3.5, 2Hz), 7.56 (2H, d,
J=9Hz), 8.20 (2H, d, J=9Hz) Example 8 (5R,6S)-2-[[(R)-1-methyl-2-
(p-nitrobenzyloxycarbonylamino)
ethyl]thio]-6-[(R)-1-tert-butyldimethylsilyloxyethyl]penem-3-carboxylic acid p-nitrobenzyl ester (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[(R)-1-
Methyl-2-(p-nitrobenzyloxycarbonylamino)ethyl]thio]thiocarbonyl]thio-1-(p-nitrobenzyloxalyl)azetidin-2-one 374 mg (0.48 mmol) and trimethyl phosphite 475 mg (3.83 mmol) ) dioxane 40
ml solution is stirred at 75° C. for 91 hours under nitrogen flow. The solvent was distilled off, and the residue was subjected to preparative thin layer chromatography [developing solvent, benzene: ethyl acetate = 1:
2], and then repurified by preparative thin layer chromatography [developing solvent, chloroform:ethyl acetate = 8:1] to obtain 92 mg of the target product (yield 26%).
I got it. Recrystallize from benzene, melting point
A pure product with a temperature of 163-164°C was obtained. IR spectrum ν ^KBr _nax cm ^-1 : 3400 (br.), 1785,
1735, 1690 Specific rotation [α] ²⁵ _D +29.6° (C = 0.47, CHCl ₃ ) NMR spectrum (CDCl ₃ ) δppm: 0.03, 0.06 (6H, s), 0.83 (9H, s), 1.23
(3H, d, J=6Hz), ~1.3 (3H, m), 3.45
(3H, m), 3.71 (1H, dd, J=4, 1.5Hz),
4.2 (2H, m), 5.17 (2H, s), 5.18 (1H, d,
J = 14.5Hz), 5.38 (1H, d, J = 14.5Hz), ~
5.4 (1H, m), 5.61 (1H, d, J = 1.5Hz), 7.48
(2H, d), 7.60 (2H, d), 8.16 (4H, d) Reference example 1 N-methoxalyl-4-acetylthioazetidin-2-one 4-Acetylthioazetidin-2-one 977mg
(6.74mmol) and triethylamine 1.02g
(10.1 mmol) of methoxalyl chloride in 20 ml of methylene chloride solution while stirring under ice cooling.
(10.1 mmol) and keep at the same temperature for 20 minutes. The reaction solution was diluted with methylene chloride and added to phosphate buffer (PH
7) Wash and dry. After distilling off the solvent, the residue was subjected to column chromatography using 20 g of silica gel, and benzene-ethyl acetate (10:1 to
Collect the portion eluted with the 9:1) mixed solvent to obtain 1.40 g (90% yield) of the target product as crystals. Recrystallization with acetone-diisopropyl ether mixed solvent yields prismatic crystals with a melting point of 69-70.5°C. Elemental analysis value as C ₈ H ₉ NO ₅ S Calculated value: C, 41.56; H, 3.92; N, 6.06; S, 13.87 Actual value: C, 41.49; H, 3.88; N, 6.06; S, 13.93 IR spectrum ν ^Nujol _nax cm ^-1 : 1812, 1746, 1720, 1701 NMR spectrum (CDCl ₃ ) δppm: 2.39 (3H, s), 3.23 (1H, dd, J = 18, 4Hz),
3.81 (1H, dd, J=18, 6.5Hz), 3.92 (3H,
s), 5.81 (1H, dd, J = 6.5, 4Hz) Reference example 2 N-p-nitrobenzyloxyoxalyl-4
-acetylthioazetidin-2-one 4-acetylthioazetidin-2-one under ice cooling
In a solution of 1.19 g (8.2 mmol) in methylene chloride in 16 ml,
Triethylamine 1.08g (10.7mmol), p-nitrobenzyloxyoxalyl chloride 2.60g
(10.7 mmol) were added one after another and stirred at the same temperature for 35 minutes. Then, after diluting with methylene chloride, it is washed twice with phosphate buffer (PH7.0) and dried. After distilling off the solvent, the residue was subjected to column chromatography using 25 g of silica gel. The fraction eluted with a mixed solvent of benzene-ethyl acetate (10:1) was collected and recrystallized from benzene-diisopropyl ether to yield 2.50 g (85%) of the desired product as needle-shaped crystals, melting point 117-118°C. It will be done. Elemental analysis value as C ₁₄ H ₁₂ N ₂ O ₇ S Calculated value: C, 47.73; H, 3.43; N, 7.95; S, 9.10 Actual value: C, 47.94; H, 3.46; N, 8.01; S, 8.99 IR Spectrum ν ^Nujol _ax cm ^-1 1803, 1747, 1718, 1702, 1602, 1522, 1350 NMR spectrum (CDCl ₃ ) δppm: 2.31 (3H, s), 3.21 (1H, dd, J = 18, 4Hz),
3.76 (1H, dd, J = 18, 6Hz), 5.39 (2H, s),
5.71 (1H, dd, J=6,4Hz), 7.59 (2H, d,
J=9Hz), 8.23 (2H, d, J=9Hz) Reference example 3 (3S,4R)-N-p-nitrobenzyloxyoxalyl-4-(3-p-nitrobenzyloxycarbonylaminopropionylthio)-3 −
[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one (3S,4R)-4-(3-p-nitrobenzyloxycarbonylaminopropionylthio)-3-
[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one 150mg
(0.29mmol) and triethylamine 89mg
(0.88 mmol) in methylene chloride was cooled to -10°C, and while stirring, 214 mg (0.88 mmol) of p-nitrobenzyloxyoxalyl chloride was added.
Hold at the same temperature for 30 minutes. Then, ice-cold phosphate buffer and methylene chloride are added, and the organic layer is washed with water. After drying, the solvent is distilled off and the residue is subjected to silica gel column chromatography. The portion eluted with a benzene-ethyl acetate (3:1) mixed solvent was collected to obtain 148 mg (yield 70%) of the desired product as crystals. IR spectrum ν ^Nujol _nax cm ^-1 : 1805, 1745, 1730, 1715, 1700 NMR spectrum (CDCl ₃ ) δppm: 0.05 (3H, s), 0.10 (3H, s), 0.91 (9H, s),
1.21 (3H, d, J=7Hz), 2.7-3.8 (5H, m),
4.12 (1H, m), 5.20 (2H, s), 5.39 (2H, s),
5.78 (3H, d, J = 4Hz), 7.45 (2H, d, J =
9Hz), 7.51 (2H, d, J=9Hz), 8.14 (2H,
d, J = 9Hz), 8.18 (2H, d, J = 9Hz) Reference example 4 N-methoxalyl-4-[(butylthio)thiocarbonyl]thioazetidin-2-one 235 mg (1.0 mmol) of 4-[(butylthio)thiocarbonyl]thioazetidin-2-one and 151 mg (1.5 mmol) of triethylamine in 4 ml of methylene chloride.
183 mg (1.5 mmol) of methoxysalyl chloride in solution
Add while stirring under ice-cooling, and continue stirring for 30 minutes. After diluting the reaction solution with methylene chloride, it is washed with phosphate buffer (PH7) and dried. The residue after the solvent was distilled off was subjected to column chromatography using 6 g of silica gel, and the portion eluted with benzene was collected to obtain 262 mg (yield: 82%) of the desired product as an oily substance. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1820, 1755, 1710 NMR spectrum (CDCl ₃ ) δppm: 0.88 (3H, t-like, J=6Hz), ~1.5 (4H,
m), 3.25 (1H, dd, J=17, 3.5Hz), 3.33
(2H, t, J=7Hz), 3.89 (3H, s), 3.89
(1H, dd, J = 17, 6Hz), 6.15 (1H, dd, J
=6,3.5Hz) Reference example 5 N-p-nitrobenzyloxyoxalyl-4
-[(butylthio)thiocarbonyl]thioazetidin-2-one 226 g (0.96 mmol) of 4-[(butylthio)thiocarbonyl]thioacetidin-2-one and 132 mg (1.31 mmol) of triethylamine in 7 ml of methylene chloride.
Cool the solution to -15°C and add 316 mg of p-nitrobenzyloxyoxalyl chloride while stirring.
(1.30mmol). After stirring at the same temperature for 30 minutes, dilute with methylene chloride and add phosphate buffer (PH7).
wash with After drying, the solvent was distilled off and the residue was subjected to column chromatography using 11 g of silica gel, and the portion eluted with a mixed solvent of benzene-ethyl acetate (20:1 to 15:1) was collected to give 390 mg (yield 88
%) of the desired product as an oily substance. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1820, 1761, 1713, 1603, 1517, 1342 NMR spectrum (CDCl ₃ ) δppm: 0.91 (3H, t-like), ~1.6 (4H, m), 3.29 (1H,
dd, J = 17.5, 4Hz), 3.34 (2H, t, J = 7
Hz), 3.93 (1H, dd, J=17.5, 6Hz), 5.45
(2H, s), 6.19 (1H, dd, J=6.4Hz),
7.67 (2H, d, J = 8.5Hz), 8.31 (2H, d, J
=8.5Hz) Reference example 6 (3S,4R)-N-p-nitrobenzyloxyoxalyl-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[2-(p-
Nitrobenzyloxycarbonylamino)ethyl]thio]thiocarbonyl]thioazetidine-
2-on (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[2-(p-
A solution of 100 mg (0.18 mmol) of nitrobenzyloxycarbonylamino)ethyl]thio]thiocarbonylthio]thioazetidin-2-one and 54 mg (0.53 mmol) of triethylamine in 3 ml of methylene chloride was cooled to -10°C, and p-nitrobenzyloxyoxalyl was added. Add 130 mg (0.53 mmol) of chloride and keep at the same temperature for 20 minutes. ice-cold phosphate buffer (PH7),
Methylene chloride is sequentially added, and the organic layer is washed with water and dried. 209 mg of the residue after solvent distillation was added to 5 g of silica gel.
The fraction eluted with a benzene-ethyl acetate (15:1) mixed solvent was collected and 106 mg (yield 77%) of the desired product was obtained as an oily substance. IR spectrum ν ^CHCl3 _nax cm ^-1 3460, 1823, 1769, 1730, 1607, 1517, 1353 NMR spectrum (CDCl ₃ ) δppm: 0.00 (3H, s), 0.10 (3H, s), 0.83 (9H, s),
1.23 (3H, d, J=6Hz), ~3.6 (4H, m),
4.40 (1H, td, J=6,4Hz) 5.16 (2H, s),
5.40 (2H, s), ~5.4 (1H, m), 6.72 (1H, d,
J=4Hz), 7.50 (2H, d, J=9Hz), 7.56
(2H, d, J=9Hz), 8.19 (2H, d, J=9
Hz), 8.23 (2H, d, J = 9Hz) Reference example 7 N-p-nitrobenzyloxyoxalyl-4
-[(methoxy)thiocarbonyl]thioazetidin-2-one A solution of 250 mg (1.41 mmol) of 4-[(methoxy)thiocarbonyl]thioazetidin-2-one and 185 mg (1.83 mmol) of triethylamine in 6 ml of methylene chloride was cooled to -10°C, and with stirring, 447 mg of p-nitrobenzyloxyoxalyl chloride ( 1.83 mmol) and further stirred for 20 minutes. Ice-cold phosphate buffer (PH7) and methylene chloride were sequentially added to the reaction solution.
Wash the organic layer with water. After drying, the solvent was distilled off and the residue was subjected to column chromatography using 11 g of silica gel.
20:1) Collect the portion eluted with a mixed solvent to obtain 536 mg (yield 99%) of the target product as an oily substance. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1821, 1762, 1717, 1605, 1520 NMR spectrum (CDCl ₃ ) δppm: 3.26 (1H, dd, J=17, 4Hz), 3.86 (1H, dd,
J = 17, 6Hz), 4.16 (3H, s), 5.36 (2H,
s), 5.81 (1H, dd, J=6,4Hz), 7.53 (2H,
d, J = 8 Hz), 8.16 (2H, d, = 8 Hz) Reference example 8 (3S, 4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[(R )-1
-Methyl-2-(p-nitrobenzyloxycarbonylamino)ethyl]thio]thiocarbonyl]thio-1-(p-nitrobenzyloxalyl)acetidin-2-one (3S,4R)-3-[(R)-tert-butyldimethylsilyloxyethyl]-4-[[[(R)-1-methyl-2-(p-nitrobenzyloxycarbonylamino)ethyl]thio] thiocarbonyl]thioazetidin-2-one 326 mg (0.57 mmol) and triethylamine 172 mg (1.70 mmol) in methylene chloride 10
ml solution was cooled to -10°C in a salt-ice bath, and 416 mg (1.71 mmol) of p-nitrobenzyloxalyl chloride was added with stirring under a nitrogen stream. at the same temperature
After stirring for 25 minutes, add 10 ml of phosphate buffer (PH7), extract with chloroform, and wash with water. After drying the extract, the solvent was distilled off, the residue was subjected to column chromatography using 5 g of silica gel, and the portion eluted with a mixed solvent of benzene-ethyl acetate (15:1) was collected, yielding 385 mg of the target product ( Yield: 87%) was obtained as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1815, 1760, 1720,
1607, 1511 NMR spectrum (CDCl ₃ ) δppm: 0.10 (6H,
s), 0.83 (9H, s), 1.21 (3H, d, J=6
Hz), 1.43 (3H, d, J=7Hz), 3.2-3.7 (3H,
m), 4.0-4.6 (2H, m), 5.13 (2H, s), 5.34
(2H, s), 6.70 (1H, d, J=4Hz), 7.43
(2H, d), 7.50 (2H, d), 8.13 (2H, d),
8.17 (2H, d)

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a hydrogen atom, an alkyl group, or
R ⁴ A- group (wherein R ⁴ represents a hydroxyl group, an alkoxy group, an acyloxy group, a trialkylsilyloxy group, an alkylthio group, or an acylamino group,
represents an alkylidene group optionally substituted with a trifluoromethyl group. ), R ² is an alkyl group, alkenyl group, aralkyl group, aryl group, or R ⁵ B- group (wherein R ⁵ is a hydroxyl group, an alkoxy group, an acyloxy group, a trialkylsilyloxy group, a carboxyl group, an alkoxy represents a carbonyl group, aralkyloxycarbonyl group, alkylthio group, or acylamino group, B represents an alkylene group), R ³ represents a carboxyl group protecting group, X represents an oxygen atom or a sulfur atom, and Y represents an oxygen atom, a sulfur atom, a methylene group or an alkyl-substituted methylene group, and the R ² -Y- group may represent a methyl group. ] A general formula characterized in that an azetidin-2-one derivative having the following is heated with a phosphorous triester or a phosphorous triamide. (In the formula, R ¹ , R ² , R ³ and Y have the same meanings as described above.) A method for producing a penem-3-carboxylic acid derivative having the following formula: 2 General formula [In the formula, R ¹ is a hydrogen atom, an alkyl group, or
R ⁴ A- group (wherein R ⁴ is a hydroxyl group, an alkoxy group,
Acyloxy group, trialkylsilyloxy group,
Indicates an alkylthio group or an acylamino group, A
represents an alkylidene group optionally substituted with a trifluoromethyl group. ), R ² is an alkyl group, alkenyl group, aralkyl group, aryl group, or R ⁵ -B- group (wherein R ⁵ is a hydroxyl group, an alkoxy group, an acyloxy group, a trialkylsilyloxy group, a carboxyl group, an alkoxy represents a carbonyl group, aralkyloxycarbonyl group, alkylthio group or acylamino group, B represents an alkylene group), R ³ represents a protecting group for the carboxyl group, X represents an oxygen atom or a sulfur atom, and Y represents a It represents an oxygen atom, a sulfur atom, a methylene group or an alkyl-substituted methylene group, and the R ² -Y- group may represent a methyl group. ] is reacted with a trialkyl phosphite or triamide phosphite having the general formula (R ⁴ ) ₃ P (wherein R ⁴ represents an alkoxy group or a dialkylamino group). general formula (In the formula, R ¹ , R ² , R ³ , R ⁴ , X and Y have the same meanings as described above.) Producing a phosphorus-ylide compound having the following formula, isolating it, and then heating it. A general formula characterized by (In the formula, R ¹ , R ² , R ³ and Y have the same meanings as described above.) A method for producing a penem-3-carboxylic acid derivative having the following formula. 3 General formula [In the formula, R ¹ is a hydrogen atom, an alkyl group, or
R ⁴ A- group (wherein R ⁴ is a hydroxyl group, an alkoxy group,
Acyloxy group, trialkylsilyloxy group,
Indicates an alkylthio group or an acylamino group, A
represents an alkylidene group optionally substituted with a trifluoromethyl group. ), R ² is an alkyl group, alkenyl group, aralkyl group, aryl group, or R ⁵ -B- group (wherein R ⁵ is a hydroxyl group, an alkoxy group, an acyloxy group, a trialkylsilyloxy group, a carboxyl group, an alkoxy represents a carbonyl group, aralkyloxycarbonyl group, alkylthio group or acylamino group, B represents an alkylene group), R ³ represents a protecting group for the carboxyl group, X represents an oxygen atom or a sulfur atom, and Y represents a represents an oxygen atom, a sulfur atom, a methylene group or an alkyl-substituted methylene group, and the R ² -Y- group may represent a methyl group; R ⁴
represents an alkoxy group or a dialkylamino group. ] A general formula characterized by heating a phosphorus-ylide compound having (In the formula, R ¹ , R ² , R ³ and Y have the same meanings as described above.) A method for producing a penem-3-carboxylic acid derivative having the following formula.