JPH02231471A - Preparation of 4-acetoxyazetidinones - Google Patents

Abstract

PURPOSE:To obtain the title compound which is used as an intermediate of penem antibiotics such as thienamycin or the like through simple operations in high yield with industrial advantage by reaction of an azetidinone with acetic acid and an oxidizing agent using a ruthenium compound as a catalyst. CONSTITUTION:The reaction of an azetidinone of formula I [Z is H, lower alkyl, hydroxyethyl which may be protected; Y is H, carboxyl] with acetic acid (preferably in coexistence of an acetate salt) and an oxidizing agent such as peracetic acid is carried out in an inert solvent such as anhydrous acetonitrile in the presence of a ruthenium catalyst such as a compound of the formula: RuX (X is halogen, acyloxy of R<1>COO wherein R<1> is lower alkyl or acetylacetonate), ruthenium-phosphine complex, ruthenium-carbonyl complex, ruthenium on a carrier, ruthenium-amine complex, ruthenium-olefin complex at -10 to 5 deg. for 10 minutes to 5 hours to give the subject compound of formula II.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to compounds of the following general formula [wherein Z is a hydrogen atom or a lower alkyl group] which are useful as intermediates for the synthesis of penem antibiotics represented by chenamycin. , which represents a hydroxyethyl group which may be protected.

[Conventional technology and its problems]

Benem antibiotics, represented by chenamycin, have a broad antibacterial spectrum and are therefore attracting attention as pharmaceuticals.

As a method for producing penem antibiotics, Kameya [Hete
rocycles, 1 7, 4 6 3-5
0 6 (1982)), Shibuya [[Organic Synthetic Chemistry J 4
1. 6 2 (1983)] have reported various methods, among which the above-mentioned general formula (I)
The method using 4-acetoxyazetidinones represented by the following as an intermediate is an advantageous method for producing various penem antibiotics because compound (1) can react with various nucleophiles.

Conventionally, as a method for producing 4-acetoxyazetidinones (1), a method of oxidizing 4-carboxyazetidinones with lead tetraacetate [Tetrahedron Lett
ers, 2 3. 2293 (1982)), 4
- Method for electrode oxidation of carboxyazetidinones [same,
29.1409 (1988)], a method for oxidizing 4-acetylazetidinones with methacroperbenzoic acid (
JP-A-61-50964) and a method of treating a 4-silyloxyazetidinone derivative with acetic anhydride (European Patent No. 247,378) are known.

However, in order to introduce an acetoxy group into the 4-position of an azetidinone by the above method, it is necessary to synthesize an azetidinone having a specific substituent at the 4-position and introduce an acetoxy group using this substituent as a clue. However, this method has the drawbacks that it is troublesome to produce azetidinones having a specific substituent at the 4-position, and it is difficult to convert the 4-position substituent into an acetoxy group. As a result, he was at a disadvantage.

[Means to solve the problem]

Under these circumstances, the present inventor conducted intensive research and found that an acetoxy group can be easily introduced into the 4-position of azetidinones by a reaction with acetic acid and an oxidizing agent using a ruthenium compound as a catalyst, and the present invention has been made. completed.

That is, the present invention provides a compound represented by the general formula (n) [wherein Z represents a hydrogen atom, a lower alkyl group, or an optionally protected hydroxyethyl group, and Y represents a hydrogen atom or a carboxyl group]. A method for producing 4-acetoxyazetidinones represented by the general formula (1) (wherein Z is the same as above) by reacting azetidinones with acetic acid and an oxidizing agent using a ruthenium compound as a catalyst. be.

Azetidinones (II) as raw materials of the present invention include azetidin-2-one, 3-methylazetidin-2-one,
3-ethylazetidin-2-one, 3-([)hydroxyethylazetidin-2-one, 3-methyl-4-carboxyazetidine-2-one, 3-ethyl-4-carboxyazetidine-2-one one, 3-(protected)hydroxyethyl-4-mono-ruboxyazetidin-2-one, and the like. Here, as the protecting group for hydroxyl group, those commonly used for protecting hydroxyl group in lactam compounds, such as trimethylsilyl, toluethylsilyl, tert-butyldimethylsilyl, diphenyl-te
Silyl group such as rt-butylsilyl, benzyloxycarbonyl group, p-nitropenzyloxycarbonyl group, 0
-Nitropenyl group and the like.

Among these azetidinones (II), compounds in which Z is a (protected) hydroxyethyl group and Y is a hydrogen atom are derived from, for example, acetoacetic acid [Ber, , 9 2.
1599 (1959)] is produced from the compound of the following formula (IV) according to the following reaction formula.

CO2R' (rV) (V) (Vl) COJ (■) (II-1) (n-2)
[In the formula, R2 is a carboxylic acid protecting group, R3 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a phenyl or penzyloxy group which may be substituted with a lower alkyl group or a lower alkoxy group, and R4 is a hydroxyl group protection group. In other words, compound (IV) is asymmetrically hydrogenated using a ruthenium-optically active phosphine complex as a catalyst to form compound (V).
This is hydrolyzed with dilute acid etc. to give compound (VI), which is neutralized to give compound (■), which is then lactamized to give compound (II-1>). Compound (n-2) can be obtained by protecting the hydroxyl group of .

Examples of the ruthenium compound used as a catalyst in the present invention include the following.

(1) RuXs (m) [wherein, Examples include ruthenium chloride, ruthenium tribromide, ruthenium triiodide, hydrates thereof, ruthenium acetylacetonate, ruthenium acetate, and the like.

Ruthenium complex Ruthenium-phosphine. complex HRuCl (PPhs>s. IIJuCPPhy>,
．． RutC l − (BINAP) x (NBts
). RuzCi4(TOI-BINAP)2(NETs
). Ru(0^c)z(81NAP). RuzC1<
(1.4-diphosL.HRuC l (BINA
P>x. [Ru(bpy)2(D)(PPha)) (CJ!L
)i, [Ru(bpy)*(0) (PBt3)) (
CJ! L)z, [Ru(Htro) (bpy) 2(
PPt+s) ) (C 1 b.), etc. (However, in the above compound, Bt is an ethyl group, Ph is a phenyl group, AC
represents an acetyl group, BINAP represents 2,2'-bis《diphenylphosphino)-1,1'-binaphthyl, bpy represents bipyridyl, and Tol-BINAP represents 2,2'-bis(
p-}lylphosphino)-1.1'-binaphthyl, and is used in the same manner hereinafter》 ■ Ruthenium-amine complex [:Ru(NHa)sCl) C1 2. Ru(Nt
la) scls. [Ru(CitlsNa)*(Nz)
(Ns)] Pus, [Ru(NHs)sBr]er
a. [Ru(NHs)sll I. , [ Ru (N
Hs) s (L) ] (BFs) i, (Ru(N
}Is)s(Nt)) Br, [Ru(NHs)s(N
i)] Cl 2. (Ru(NHa)s(N2))
L, Ru(NHs)ml's. RuCJ! t
(C+oLNiL '2tl20, RuCj?
i(C+oflsN2)s' 6LO. RusL(N
L) +aCl m, C Ru(bpy)*(1'Y)(LD)) (Cj
! ro, ),, Runs (Py) 2 (O^c)i, etc. (However, py in the above compound means pyridine, and will be used in the same manner hereinafter.) ■ Ruthenium ditrosyl complex Ru(No)Cj2 3 ・L ro, Ru (N
o) (NO3)s. (RuCj! (Nils)-(N
O): l C1-, [ Ru (NCO) (N}13
) 4(NO)] (C j! 04) etc.■ Ruthenium-olefin complex Ru(['sl{s) 2. Ru C (CH3)
5C51 2. RLI(Call+2), Ru(C
sLz) C1, Ru (C'-H l2) (C-H
-) etc.■ Ruthenium-rubonyl complex RLI3 (CD) I2. (RuC j!-
(CO) −) 2, RuC E 2(CD) 2 (
PPh3) 2nd Class■ Ruthenium complex κ [: RUO4]. Ba C RuL (OH)
2] etc. (3) Powdered ruthenium metal; ruthenium carriers such as ruthenium carbon, ruthenium graphite, ruthenium alumina, ruthenium silica alumina, ruthenium zeolite, ruthenium iron oxide, ruthenium zirconium monoxide, ruthenium diatomaceous earth, etc. etc.

Further, the oxidizing agent used in the present invention is not particularly limited, but for example, peroxides of various carboxylic acids,
In order of bar oxidation, highly concentrated salicy powder, ozone, cyclohexene ozonide, sodium peroxide, N-methylmorpholine-N-oxide, sodium perborate, iodosylbenzenediacetate, iodosylbenzene, sodium metaperiodate, paraperiodate. Examples include sodium iodate. Specific examples of carboxylic acid peroxides include peracetic acid, perbrobionic acid, m-chloroperbenzoic acid, and the like. These may be commercially available products, or may be prepared separately from carboxylic acid and hydrogen peroxide before the reaction. Furthermore, specific examples of peroxides include methyl ethyl ketone peroxide, methyl isobutyl ketone peroxide, cyclohexanone peroxide, methyl cyclohexanone peroxide,
Examples include diacetyl peroxide, dibrobionyl peroxide, diisobutyl peroxide, and the like. Here, when peracetic acid is used as the oxidizing agent, since peracetic acid usually contains acetic acid, there is no need to add acetic acid again, which is convenient.

In the present invention, when acetic acid is reacted, it is preferable to coexist an acetate because the yield will improve.

Such acetates include sodium acetate, potassium acetate, lithium acetate, and the like.

To carry out the present invention, the compound (■), an oxidizing agent, acetic acid, and a ruthenium compound are dissolved or suspended in a suitable solvent, and the mixture is stirred at a temperature of -10°C to 5°C for 10 minutes to 5 hours. Preferably, the reaction is carried out for about 1 hour.

Although the order and method of adding raw material compounds, catalysts, etc. are not particularly limited, it is desirable to add the oxidizing agent gradually at the end.

As the solvent, acetonitrile, methylene chloride, chlorobenzene, etc. are used. Acetic acid is l for compound (n)
It is preferable to use O to 60 times the mole, particularly 20 to 40 times the mole, and the oxidizing agent is used in an amount of 1 to 8 times the mole of compound (I[),
In particular, it is preferable to use 2 to 3 times the mole. Further, the ruthenium compound of the catalyst is 0.0% relative to compound (n). It is preferable to use 0.2 to 0.2 times the mole, particularly 0.02 to 0.1 times the mole.

The target product can be isolated from the reaction mixture by means known per se, such as recrystallization, column chromatography, etc.

〔Effect of the invention〕

As described above, the method of the present invention is an industrially advantageous method that allows the production of 4-acetoxyazetidinones (1) useful as intermediates for the production of benem antibiotics through simple operations.

〔Example〕

Next, examples and reference examples will be given and explained.

Reference example l RLI2C l − ((+) old NAP) 2 (N
Btp) Synthesis of (di[:2.2'bis(diphenylphosphino)-1.1'-binaphthyl]tetralactyruthenium triethylamine): (RuCl2(COD>) - (However, COD is 1.
It means 5-cyclocyclodiene and is used in the same manner hereinafter.

) 1 g (3.56 mmoj? ), (+
)-BINAP 2.66g (4.27 mmol1)
and 1.5 g of triethylamine are added to 100 rm1 of toluene under nitrogen atmosphere.

After heating under reflux for 10 hours, the solvent was distilled off under reduced pressure. After dissolving the crystals by adding methylene chloride, they were filtered on Celite, and the filtrate was concentrated to dryness, yielding 3.7 g of a dark brown solid Ru2Cj! 4 ((+) old NAP) 2 (Nro 1
+) was obtained.

Elemental analysis value: Cs4}1tsCj! JPJu = Ru C H P Theoretical value (%) 11.96 6B. 85 4.7
1 7J3 actual value (%) 11.68 67.6
2 4.97 6.94'H NMR (CDCf
3) δppm: 1. 30-1. 50 (t, 6
11, NCH. CII,). 3.05-3. 30
(q, 4}1, NCLCL), 6. 40-8.
60 (m, 32H, Ar-H) Reference Example 2 Synthesis of methyl (2S.3R)-2- (N-benzoylaminomethyl)-3-hydroxybutanoate: A 100 mi stainless steel plate that had been replaced with nitrogen in advance 2.5 g of methyl 2-(N-benzoylaminomethyl)-3-oxobutanoate (10 mmoj
! ) and Ruthenium-optically active phosphine complex 1 synthesized according to Reference Example 1? u2cj'-(b)-BrNAP)*(NBt-)
A solution of 84.5 mg (0.05+nmoJi!) in 17.5-methylene chloride was added, and the reaction was continued with stirring for 20 hours at 50° C. and a hydrogen pressure of 100 kg/cal. The solvent of the hydrogenated reaction product was distilled off, and the catalyst was removed from the residue by silica gel column chromatography (using a mixed solvent of n-beef sanitation and ethyl acetate as the eluent).2. 25
g of methyl (2S,3R)-2-(N-penzoinoleaminomethyl)-1-3-hydroxybutanoate was obtained.

Yield: 90%, optical purity: 98% ee (Determined using high performance liquid chromatography under the following conditions after induction into ester of (+)-α-methoxy-α-trifluoromethyl-phenylacetic acid. Column: Oevelosil
1 0 0 - 3 (4.6 ++ onX 2 5
0mm) (manufactured by Nomura Chemical), measurement wavelength IJV: 25
4nω, developing solvent: hexane/diethyl ether = 9
0/1 0, flow rate: 1 if/min).

'H NMR (CDCf,) δppm: 1. 26
(d, J: 6.25Hz, 3H), 2.62
(a+, 1N). 3.57-3.62 (m.LH).
3.73 (s.3H). 4.60-4.03 (+m.
LH), 4. 07-4. 14 (m, 1}1).
7, 02 (br, s, 1N>, 7. 41
-7. 80 (m, 5H) Reference Example 3 Synthesis of (2S,3R)-2-aminomethyl-3-hydroxybutanoic acid hydrochloride: (2S.3R)-2-(N-benzoylaminomethyl)-3-hydroxy Methyl butanoate 10.65g (4
2.43 mmoj! ) with 10% HCI aqueous solution 70-
Add and dissolve at room temperature, then heat under reflux for 4.5 hours, leave to stand at room temperature, filter precipitated benzoic acid, wash the filtrate twice with 100 d of toluene, separate the layers, and concentrate the aqueous layer under reduced pressure. By this, (2S,3R)-2-aminomethyl-
6.67 g of 3-hydroxybutanoic acid hydrochloride was obtained. Yield 93%.

H NMR (CD3ROD) δppm: 1,32 (
3}1, d. J=6.54Hz). 2.85 (IH.
m), 3. 37 (2N, m), 4. 33
(1}1, dq, J=6. 54, 4, 991
1z) Reference Example 4 Synthesis of (2S.3R)-2-aminomethyl-3-hydroxybutanoic acid: (2S,3R)-2-monoaminomethyl-3-hydroxybutanoic acid hydrochloride 6.14g (36.22 mmoβ)
Add 150rnl of acetonitrile to the solution, and add 5.0ml of triethylamine under water cooling. 05mj' (36.22 mmo
j! ) and stirred vigorously at room temperature for 2 days. The precipitated powder crystals were filtered, the residue was collected, and 100 ml of acetonitrile was added thereto, washed and filtered to obtain 4.07 g of crystalline (2S,3R)-2-aminomethyl-3-hydroxybutanoic acid. Obtained. Yield 84%.

'H NMR (CD.GD) δppm: 1. 27
(38, d. J=6. 39Hz). 2. 49
(LH, dt, J=6. 21. 6. 361
{z) ． 3. 26 (2tl. d, J=6.
36tlz). 4. 10 (IH, dq. J=
6. 21. 6. 39Hz) Reference Example 5 Synthesis of (1'R,3S)-3-hydroxyethylazetidine-2-one: (2S.3R)-2-1-aminomethyl-3-hydroxybutanoic acid 2.28g (17.14 mmol ) to 342 ml of anhydrous acetonitrile! was added to ga, and 5.49 g (20.93 mmof
) and dipyridyl disulfide 4.54g (20.6
1 mmol) was added, reacted at 55-60°C for 20 hours, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain methylene chloride-ethyl acetate-methanol (
8:8:1) to separate and purify (1' R, 3S)
-3-hydroxyethylazetidine-2-one 1.64
I got g. Yield 83%.

'H NMR (CDCj!,) δppm: 1.28
(3fl.d, J=6.311z), 2.10(II
I, Kazuha). 3. 31 (IH. ddd, J=5
, 4, 5. 2. 2. 7tlz) ,3. 36
(2N. ddd, J=5. 2. 5. 2.
2. 7tlz). 4. 21 (III, dq.
．． b6. 3, 5. 4tlz). 5. 82
(ltl, -NH) Reference Example 6 Synthesis of (1' R,3S)-3-(bee-tart-butynoredimethylsilyloxyethyl)azetidine-2-one: (1' R,3S)-3-hydroxyethino Reazetidine - 21 years old 73.88g (33.74 mmof)
Anhydrous DMF (ffl, DMF means dimethynolephonolemamide) 15mji! Add and dissolve imidazole 2.41g (35.43 mmof),
tart-butyldimethylsilyl chloride 5.34g
(35.43 m+noJ) at room temperature.
The mixture was reacted for 0 hours, poured into 100 mf of cold water, and the precipitated crystals were collected by filtration to form (1' R, 3
S) 6.5 g of -3-(1.'-tert-butyldimethylsilyloxyethyl)azetidin-2-one was obtained. Yield 84%.

[αB' -69.8° (c= 1.02 CII
Cj! 3) Optical purity 94%ee m, p. 66-68℃ 'H NMR (CDCj!.) δ ppm
:0. 09 (6H, s). 0. 88 (
9H, s). 1.21 (3H, d, J = 6.21H
z). 3.21 (III, m). 3.30(1}1,
cld, J=5.08.5.261-1z). 3.3
7 (11Lm), 4. 20 (IH, dQ. J=
5.26. 6. 21Hz). 5. 63 (I
II, -Nll) Example 1 (1' R.3R.4R)-4-acetoxy3- (
Synthesis of 1'-tert-butyldimethynoresilinoleoxyethyl)azetidin-2-one: (1' R., 3S) -3 -
(1'-tart-petinoredimethylsilyloxyethyl)azetidin-2one 0.50 g (2.
18 mmoj! ) under a nitrogen stream, add 20 i of anhydrous acetonitrile to dissolve it, and then add 0.1 g of sodium acetate.
8 g (2.18 tnmal) was added. To this solution was added 45 mg of ruthenium trichloride (0.22 mmo
Add 20d solution of 1) of anhydrous acetonyl, and -5
It was cooled to ℃. Furthermore, carefully, 40. % peracetic acid in acetic acid solution 3rnl. was dripped. Thereafter, the solvent was distilled off under reduced pressure and the product was separated and purified by silica gel column chromatography to obtain (1' R, 3 R, 4 R) -4-acetoxy-3 - (1' -tert-butyldimethylsilyl ethyl). 0.5 g of azetidin-2-one was obtained. Yield 80%.

[α] 2' + 47. 8゜ (c=0.98 CH
Cj! s) Optical purity 99.2% as 'H NMR (CDC1a) δppm: 0.08 (3
H. s). 0.09 (3B, s), 0.88 (9B
, s). 1.27 (3H, d, J=6,35}1z).
2.11 (3H, s). 3. 19 (LH. dd
．． J=3. 50. 1. 27Hz). 4. 2
3 (IH, dq. J=3.50.6.35
tlz) ,5.84(IH,d,J=1.27Hz>
, 6.40 (III, -Nil) Example 2 Synthesis of 4-acetoxyazetidin-2-one: 0.71 g of azetidin-2-one and 0.8 g of anhydrous sodium acetate
2g to 20rI1l. After suspending the suspension in acetonitrile, cool it to -5°C, add a solution of 0.26 g of ruthenium trichloride trihydrate in 10 mf of acetonitrile, and be careful to keep the reaction temperature below 0°C. Deep《40%
Acetic acid solution of peracetic acid 3.8mj! was dripped. After that, 3
Stirring was continued at 0° C. for 0 minutes.

Next, the solvent was distilled off under reduced pressure at 40°C or lower, and then purified by silica gel column chromatography (n-hexane, ethyl acetate 1:1 eluent) to obtain 0.92 g of 4-acetoxyazetidine. -2-one was obtained. Yield 71
%.

'H NMR(CDCI,)δppcn:2
．． 13 (3H.s). 3.00(IH,ddd.J=
15.26.1.40.0. 4511z). 3.
26 (l}l, ddd, J=15. 26, 4
．． 05. 2. 58Hz). 5.84 (1tl.
dd, J=4.05.1.40Hz). 7.02(i
ll.

bs, -NH) Example 3 Synthesis of 4-acetoxy 3-ethylazetidin-2-one: 3-ethylazetidin-2-one 1,0g and anhydrous sodium acetate 0.83g and methylene chloride 20ml! After adding and suspending, the mixture was cooled to -5°C, and 0.35 g of ruthenium acetylacetonate complex was added thereto. Next, add a solution of 40% peracetic acid in acetic acid, carefully keeping the reaction temperature below 0°C.3. 8d was added dropwise.

Thereafter, the same treatment as in Example 2 was carried out to obtain 1.17 g of 4-acetoxy-3-ethylazetidin-2-one. Yield 7
4.5%.

'H NMR (CDClB) δppm: 0.99 (3
)l. t. J=7.4Hz). 1.75 (2H.Tl
+). 2.10 (311, s). 3.08 (IH,
m). 5.78 (ill, d, J=1.25Hz).
6. 55 (Ill. bs. -Ntl) Example 4 (BiR.3R.4R) -4 Iccho Setoxy 3-(1'-
Synthesis of (]'R.3S)-3-(1'-hydroxyethyl)azetidin-2-one: Add 12 ml of methylene chloride to 0.3 g of (]'R.3S)-(1'-hydroxyethyl)azetidin-2-one and 0.21 g of anhydrous sodium acetate. After the suspension was cooled to -5°C, a solution of 68 mg of ruthenium trichloride trihydrate in acetic acid (.2 ml) was added.

Thereafter, 155 mg of (1'R.3
R. 4R)-4-acetoxy-3-(1'-hydroxyethyl)azetidine-2-one was obtained. Yield 12%.

However, the eluent for column chromatography used for purification was methylene chloride-ethyl acetate-methanol (20:
20:1) mixed solution.

'H NMR (CDCJ 3) δppm: 1. 25
(3H.d.J=6.7Hz). 2. 08(
3H, s). 3, IT<ill, m). 4.16
(LH.m). 5.81(l}I,m), 7.09
(IH, bs, -NH) Example 5 (1' R, 3R, 4R) -4-acetoxy 3- (
Synthesis of 1'-tart-butyldimethylsilyloxyethyl)azetidin-2-one: (biR,33)-3-(1'-tert-butyldimethylsilyloxyethyl)azetidin-2-one 10
．． 53 g and 3.58 g of anhydrous sodium acetate in 40
After suspending the suspension in 0d of acetonitrile, it was cooled to 0°C, and a 200rd acetonitrile solution of 1.14g of ruthenium trichloride trihydrate was added. Thereafter, the same treatment as in Example 2 was carried out to obtain 10.5 g of (1'-R.3R.4R)-4-acetoxy-3 (1'-tart-butyldimethylsilyl-oxyethyl)azetidine-2-one. Yield 80%. However, the eluent for silica gel chromatography used for purification was n-hexane-ethyl acetate (
4:1) mixed solvent.

'H NMR (CDC1s) δppm: 0.08 (3
H,s). 0.09 (3H.s). 0.88 (9
11,s). 1.27 (3H, d, J=6,35}1z
). 2.11 (311, s), 3. 19 (11
{, dd. J=3. 50. 1. 27Hz)
．． t. 23 (1N. dq. J=3.50.
6. 35Hz). 5.84(l}I, d, J=1.
271{z). 6.40 (111.8H) Example 6 Synthesis of 4-acetoxyazetidin-2-one; 0.3 g of 4-carboxyazetidin-2-one, 0.43 g of anhydrous sodium acetate and 100 m of 5% ruthenium-carbon
g was suspended in a mixture of 12-1 methylene chloride and 4 Fnl acetic acid, and then cooled to -3°C. Add to this the reaction temperature θ
40% peracetic acid in acetic acid solution 1, carefully keeping the temperature below °C.
lmt' was added dropwise, and then stirred at 0° C. for 1 hour.

After separating the catalyst by suction filtration, the solvent was distilled off under reduced pressure. 20 d of n-hexane was added to this, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 7 g of 4-acetoxyazetidin-2-one OJ. Yield 82%.

Example 7 (1' R.3R.4R)-4-acetoxy3- (
Synthesis of 1'-tart-butyldimethylsilyloxyethyl)azetidin-2-one: (1' R,3S,4R)-3- (1'-tert
Butyldimethylsilyl (oxyethyl)-4-carboxyazetidine - 21 OJg, anhydrous sodium acetate 0.
After suspending 18 g and 30 mg of 5% ruthenium carbon in a mixture of methylene chloride IOd and acetic acid 3-,
Cooled to -3°C. Thereafter, the same treatment as in Example 6 was carried out, and n-
Hexane5rnI! Recrystallized from 0.21 g of (1'
R, 3R. 4R)-4-acetoxy-3-(beete
rt-butyldimethylsilyloxyethyl)azetidine-2-one was obtained. Yield 66%.

Examples 8 to 18 (1' R,3R.4R-4-acetoxy3-(
Synthesis of 1'-tert-butyldimethylsilyloicethyl)azetidin-2-one: The reaction was carried out according to Example 1, except that the catalyst and reaction conditions were changed as shown in Table 1 below. The results are shown in Table 1.

Examples 19-34 Synthesis of 4-acetoxyazetidin-2-one: Examples 19-34 except that the catalyst and reaction conditions were changed as shown in Table 2 below.
30 is based on Example 2, and Examples 31 to 34 are based on Example 6.
The reaction was carried out according to.

The results are shown in Table 2.

Margins below Table 2 Ru (acac) s: Ruthenium acetylacetonate Example 35 (1' R.3R.4R)-4-acetoxy 3( 1
Synthesis of '-tert-butyldimethylsilyloxyethyl)azetidine-2-one: (1'R.3S)-3-(1'-tert-butyldimethylsilyloxyethyl)azetidine-2-one 100 mg (0.44 mmol), anhydrous sodium acetate 36 mg (0.44 auooj!
) and ruthenium trichloride trihydrate 1 2 mg (0
．． 04 mmoj! ) was added to lrn1 acetic acid and dissolved. To this, 167 mg of m-chloroperbenzoic acid was added at room temperature.
(0.97 mmoj!) was added in solid form in small portions over the course of 1 hour. After that, stirring was continued for 4 hours, and the reaction solution was mixed with IOmj! of water and extracted twice with 5 rods of n-hexane. The combined n-hexane layers were added to a saturated aqueous sodium bicarbonate solution lOrn1. and 10 d of saturated saline, then dried by adding anhydrous magnesium sulfate, filtered, distilled off the solvent under reduced pressure, and subjected to silica gel column chromatography to obtain F) n-hexane-ethyl acetate (4
: Purification was performed using the mixed solvent of 1), and 86rag of (
1'R. 3R,4R)-4-7 Setoxy3-(
1'-tert-butyldimethylsilyloxyethyl)azetidin-2-one was obtained. Yield 68%.

Examples 36-45 (1'R,3R.4R)-4-acetoxy 3(1'
Synthesis of -tert-butyldimethylsilyloxyethyl)azetidin-2-one: Using the same raw materials as in Example 35, changing the type of oxidizing agent and performing the same operation, (1' R, 3R, 4R) -4-acetoxy 3 was synthesized. - (1'-tert-butyldimethylsilyloxyethyl)azetidine-2-one was synthesized. The results are shown in Table 3.

The following margin Example 46 (1' R, 3R, 4R)-4-acetoxy 3-(1
Synthesis of '-hydroxyethyl)azetidin-2-one: (1' R,3S)-3- (1' -hydroxyethyl)azetidin-2-one 1.0 g (8.7 mmoβ
》, anhydrous sodium acetate 0.649g (7.91mm
of) in 40-methylene chloride under nitrogen atmosphere. Cool to -5°C, κ[RLI04]65. 64m
g (0.322 mmol) and 1260 mmol of acetic acid, followed by 3.34 g (17.58 mmol) of 40% peracetic acid.
ol) was added dropwise over 5 to 10 minutes so that the liquid temperature did not rise above 2°C.

Thereafter, the mixture was stirred at -5 to 0°C for 2 hours. The reaction solution was concentrated, and 0.0% of the target substance was purified by silica gel column chromatography using methylene chloride-ethyl acetate-methanol (3:8:1). 687 g was obtained. Yield 45.6%.

Example 47 (BiR,3R,4R)-4-acetoxy 3-(1'-
Synthesis of hydroxyethyl) azetidine-2-one: converting the catalyst from K[RL104] to Ba[RuO, (Oft)
The reaction was carried out according to Example 46 except that the reaction mixture was changed to [Z]. 102,-95 mg (0.32 mmo) of the target substance
1) Obtained. Yield: 19. 75%.

Example 48 (1' R.3R,4R)-4-acetoxy3- (
Synthesis of 1'-tart-butyldimethylsilyloxyethyl)azetidin-2-one: (1'R.3S)-3-(1'-tert-butyldimethylsilyloxyethyl)azetidin-2-one 1.02 g ( 4J67 mmol) and 4 g (4.146 mmol) of anhydrous sodium acetate OJ are added to 40-methylene chloride under a nitrogen atmosphere. Cool to -5°C, K[RLI04]32. 96mg (0.16
15 mmoA) and acetic acid 12. After adding Omf, 1.7 g (8.95 mmol) of 40% peracetic acid was added dropwise over 5 to 10 minutes so that the liquid temperature did not rise above 2°C. Thereafter, the mixture was stirred at -5 to 0°C for 1 hour.

Concentrate the reaction solution, add 20 ml of ethyl acetate, and add 2 ml of diluted sodium chloride water.
0d was added to make it alkaline and the liquid was separated. Furthermore, the aqueous layer was extracted twice with ethyl acetate and combined with the previously separated ethyl acetate. The ethyl acetate solution was dried by adding anhydrous magnesium sulfate and concentrated to obtain 1.08 g of the crude target substance. Yield 3
8. 86%.

Example 49 (1'R,3R.4R)-4-acetoxy3-(1
'-tert-butyldimethylsilyloxyethyl)
Synthesis of azetidine-2-one: The catalyst was κ[RuO. ] to Ba [RuOt (0 old,
] The reaction was carried out according to Example 48 except that the reaction was changed to Crude target substance 51. 7mg (0.162mmo 1
) was obtained. Yield 58.8%.

Example 50 (IR.3R.4R)-4-acetoxy 3-(1'
Synthesis of -tart-butyldimethylsilyloxyethyl)azetidin-2-one: (1' R,3S)-3- (1' -tert-butyldimethylsilyloxyethyl)azetidin-2-one 2.0 g (8. 73 mmol), anhydrous sodium acetate 0.72 g (8.78 mmol), Ru3 (
co) 12 9 3 mg (0.145 mmoj2
) and 100ml of acetic acid! and at room temperature oxygen 901/
3. Ozone was generated using an ozone generator at 3. 15g
/hr for 3 hours. Then filter, concentrate,
100 ml of ethyl acetate was added, and after neutralization with 50 d of 5% sodium bicarbonate solution, the mixture was separated. Furthermore, the aqueous layer was extracted twice with methylene chloride, and 100 mj of ethyl acetate, which had been separated previously, was added! The mixture was combined and concentrated to obtain 1.15 g of the crude target substance. n-hexane-ethyl acetate (8:l) by silica gel chromatography
unreacted (1' R.3S)-3- (1' -te
0.21 g of rt-butyldimethylsilyloxyethyl) azetidine-2-one and 0.05 g of the target substance were obtained. Yield 1,79%.

that's all Applicant: Takasago Fragrance Industries Co., Ltd.

Claims (1)

[Claims] 1. The following general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) [In the formula, Z is a hydrogen atom, a lower alkyl group, or an optionally protected hydroxyethyl group and Y represents a hydrogen atom or a carboxyl group] General formula (I) characterized in that azetidinones represented by the following are reacted with acetic acid and an oxidizing agent using a ruthenium compound as a catalyst ▲Mathematical formula, chemical formula, table, etc. ▼(I) [In the formula, Z is the same as above] A method for producing 4-acetoxyazetidinones represented by: 2. The ruthenium compound has the following general formula (III) RuX_3(III) [wherein, X is a halogen atom, R^1COO (however, R^1
The method for producing 4-acetoxyazetidinones according to claim 1, which is a compound represented by acyloxy or acetylacetonate represented by (represents a lower alkyl group). 3. The 4-acetoxyazetyl compound according to claim 1, wherein the ruthenium compound is a ruthenium complex selected from ruthenium-phosphine complexes, ruthenium-amine complexes, ruthenium-nitrosyl complexes, ruthenium-olefin complexes, ruthenium-carbonyl complexes, and ruthenium oxo complexes. Method for producing ginones. 4. The method for producing 4-acetoxyazetidinones according to claim 1, wherein the ruthenium compound is ruthenium metal or a ruthenium carrier.