JPH0167A - Method for producing 4-acetoxy-3-hydroxyethylazetidin-2-one derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to a 4-acetoxy-3-hydroxyethyl azetyl compound having a protected hydroxyl group at the 3-position and an acetoxy group at the 4-position. The present invention relates to a novel method for producing din-2-one derivatives.

4-acetoxy-8-hydroxyethylazetidine-2
-one derivatives are known to be useful as synthetic intermediates for carbapenem β-lactam antibiotics, such as chenamycin, and penem β-lactam antibiotics [for example, Raider, tetrahedron, etc.] Letters, Vol. 23, p. 2293 (1982), and Yoshida et al., Chem, Pharm, Bull, Vol. 29, p. 2899 (1981)).

(Prior Art and Problems) Conventionally, as a method for synthesizing 4-acetoxy-3-hydroxyethylazetidin-2-one derivatives, there has been a method of synthesizing from 6-aminopenicillanic acid [Yoshida et al., G! hem, P
harm, Bull, vol. 29, p. 2899 (198
1)), method of synthesis from threonine [Shiozaki et al., Tetrahedron, Vol. 89, p. 2399 (1983)], method of synthesis from aspartic acid [Raider et al., Tetrahedron Letters, Vol. 23, p. 2.293 (1982)] ,
The first prize is known.

However, in both methods, the β-lactam ring
In order to introduce an acetoxy group into the position, a heavy metal compound such as mercury acetate or lead tetraacetate, which is not suitable for industrial use, is used.

The present inventors used a novel β-lactam compound having an O-protected hydroxyethyl group at the 3-position and a silyl ether group at the 4-position (N is a phosphor group) to introduce an acetoxy group at the 4-position at low temperature. I found a manufacturing method and have already applied for it (patent application 1986-
101856). Subsequently, the present inventors conducted further studies and found that a catalytic amount of an acyl halide or a sulfonyl halide was added to the acid matrix to introduce an acetoxy group into the 4-position with a good yield at around room temperature. This led to the present invention. Details will be explained below.

(Means and effects for solving the problems) The present invention is based on the general formula (() (wherein, R1 is a hydroxyl protecting group, R2g R8s R4
represents a lower alkyl group or an aralkyl group of at to C4), a strong organic acid, a mineral acid, or a Lewis acid is combined with the general formula (IV) R8
-co -X ([V) (wherein, R8 is an alkyl group or represents an aralkyl group or a phenyl group,
X represents a halogen group), where R9 represents a general formula (V) R9-802-X (V) (wherein R9 represents an alkyl group or an aralkyl group, R represents a phenyl group, 4-acetoxy represented by the general formula (1) (wherein R1 represents a hydroxyl group-protecting group), which is characterized by reacting a base with acetic anhydride using a compound represented by a halogen group) as a catalyst. The gist of the present invention is a method for producing -3-hydroxyethylazetidin-2-one derivatives.

The β-lactam compound having a silyl ether group at the n-4 position represented by the general formula (1) has been developed by the present inventors, who have already filed a patent application (
It can be easily obtained by the method of Reaction Formula 1 as described in JP-A No. 61-18791).

Reaction formula I: R1 is the 〇-protecting group for the hydroxyethyl group at the 3-position of the β-lactam compound (1), and R1 is represented by the general formula (2
) % trialkylsilyl group represented by the formula % (in the formula, FL5t Rs * R7 represents a C1 to C6 lower alkyl group. However, R51R6 * R7 is not 01 at the same time),
rFor example, tert-butyldimethylsilyl group, triisopropylsilyl group, isopropyldimethylsilyl group,
Isobutyldimethylsilyl group, dimethyl-(l,2-dimethylpropyl)silyl group, dimethyl-(1゜1,2-
trimethylpropyl)silyl group and other tert-
Examples include butyl group, benzyl group, trichloroethoxycarbonyl group, tert-butoxycarbonyl group, p-nitrobenzyloxycarbonyl group, etc., but it is preferably stable during the reaction and can be selectively deprotected by acid treatment. tert-butyldimethylsilyl group, isopropyldimethylsilyl group, dimethyl-(1,1,2
-)dimethylpropyl)silyl group and dimethyl-(1,
2-dimethylpropyl)silyl group is preferred. In addition, R2e "8 t R4 of the β-lactam compound (1) is a 01-C4 lower alkyl group such as methyl, ethyl, isobutyl, etc., and mar is the same as an aralkyl group such as a benzyl group or p-nitrobenzyl group. Alternatively, different r groups can be selected, but preferably R2=R3=R4=methyl.

Prepared as above, the general formula (I) (wherein R1s R2* R8t R4 are the same as above)
The β-lactam compound represented by is reacted with a base and acetic anhydride to convert it into the desired 4-acetoxy-8-hydroxyethylazetidin-2-one derivative CI) (wherein R1 is the same as above). However, in this case, strong organic acids, mineral acids, Lewis acids, or the general formula (to) R8-Co-X ([%') (in the formula, g
8. The compound represented by the general formula (V) R9-802-X (V) (wherein R91
When a compound represented by (X is the same as above) acts as a catalyst, the yield is significantly improved.

Examples of strong organic acids include organic sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid, xylenesulfonic acid, mesitylenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, and pyridine sulfonic acid, trifluoroacetic acid, trichloroacetic acid, etc. It is preferable to use an organic protonic acid having a strong acidity of . Mineral acids include hydrogen chloride,
Aqueous solutions of hydrogen bromide, hydrogen iodide, phosphoric acid, nitric acid, sulfuric acid, etc. can be used. As the compound represented by the general formula GV), acetyl chloride, acetyl bromide, acetyl iodide, trifluoroacetyl chloride, etc. can be used. As the compound represented by the general formula (V), methanesulfonyl chloride, trifluoromethanesulfonyl chloride, toluenesulfonyl chloride, mesitylenesulfonyl chloride, etc. can be used. As the Lewis acid, boron trifluoride or boron trichloride is preferably used. These organic strong acids, mineral acids, Lewis acids, or compounds represented by the general formula (GV) can be prepared by acetoxylating the compound (1) with a base and acetic anhydride without adding the compound represented by the general formula (V). In this case, most of the reaction products are decomposition products in which the β-lactam ring is cleaved, and the target compound (...) cannot be obtained in a satisfactory yield.

In the 4-position acetoxylation of compound (1) in the presence of a strong organic acid, a mineral acid, a Lewis acid, a compound represented by the general formula (g), or a compound represented by the general formula (V), these n The amounts of additives, base, and acetic anhydride used, the solvent, the type of base, and the reaction temperature are factors that affect the yield. As the base, pyridines such as pyridine, picoline, and lutidine are preferred. As the reaction solvent, use the above base as a solvent, or use an organic solvent inert to compound (1) and the reaction reagent, such as methylene chloride, ethyl acetate, n-hexane, toluene, dimethylformamide, tetrahydrofuran, etc. However, it is preferable to use pyridines or dimethylformamide.

For the β-lactam compound represented by general formula (I),
0.05 to 1 mole of a strong organic acid, mineral acid, Lewis acid, compound represented by the general formula or compound represented by the general formula (V), 1 to 30 times the mole of a base, and 1 to 15 moles of acetic anhydride. It may be used within twice the molar range. The reaction temperature is preferably in the range of -80 to +50°C.

For the reaction operation, a β-lactam compound having a silyl ether group at the 4-position represented by general formula (1) is dissolved in a base such as pyridine alone or a mixed solvent of a solvent such as dimethylformamide and a base such as pyridine. , then acetic anhydride and an additive such as a strong organic acid or a mineral acid, or a Lewis acid, or a compound represented by the general formula, or a compound represented by the general formula ('V), or Perform the reaction by dividing and adding. The progress of the reaction is checked using thin layer chromatography, and when the raw materials have disappeared or become trace amounts, the reaction solution is poured into water. Next, extraction is performed with an organic solvent such as n-hexane. The organic layer is washed with an aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. The desired 4-acetoxy-3-hydroxyethylazetidin-2-one derivative is obtained by recrystallizing the crude crystals obtained by distilling off the solvent from a solvent such as n-hexane. When n-hexane is used as the extraction solvent, the 4-acetoxy-3-hydroxyethylazetidin-2-one derivative can be obtained as crystals by cooling the solution after drying. A 4-acetoxy-3-hydroxyethylazetidin-2-one derivative can also be obtained by column chromatography from the reaction mixture obtained by distilling off.

(Examples) The present invention will be described in detail below using Examples, but the present invention is not limited to these Examples.

Example 1 (SR,4R)-4-acetoxy-3-[(几)-1-
Synthesis of tert-butyldimethylsilyloxyethyl]-azetidin-2-one (3R,4R)-8-((几)1-tert-Butyldimethylsilyloxyethyl)-4-trimethylsilyloxyazetidin-2-one (mp95~96゛C1 [
α)25 9.5° (c=1.0%CjHO1s)]
Dissolve 809 waste in 1.55 g of pyridine and strain it to 0.
”C. Then, acetic anhydride 0.51g/% p-
) Add 56q of luenesulfonic acid monohydrate and incubate at 0°C for 3
Stirred for 6.5 hours. Pour the reaction solution into 80xtt of water,
Extracted with 30ml of n-hexane. Add organic layer to 5
After washing with % NaHCO3 and saturated saline, drying with anhydrous magnesium sulfate. The solvent on the P side was distilled off under reduced pressure to obtain 288 ml of white solid. When this white solid was dissolved in n-hexane and left to cool at -15°C, 19
Needle-shaped crystals with 5 capes were obtained, and based on the following physical properties, the desired crystals were obtained (
8R,4R)-4-acetoxy-8-((R)-1-t
It was confirmed to be ert-butyldimethylsilyloxyethyl]-azetidin-2-one.

(/Z) +50° (c=0.5.0H(A, )m
p 1 (17”C'HNMR (90Mf-1z, CD01s) δ
(ppm) 0.08 (6H,S), 0.84 (
9H, S), 1.20 (3H, d), 2.01 (8H
, s), 8.04 (IH, dd), 4.12 (IH
, m), 5.76 (LH, d), 6.78 (N
H) Example 2 ('(R,4R)-4-acetoxy-8-((R)-
Synthesis of 1-tert-butyldimethylsilyloxyethyl]azetidin-2-one (8R,4R)-8-((R)-1-tert-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidine-2 -on (mp95-96℃, [α)D
-9,5° (c=1.0, CHClg)) 80
6 was dissolved in 1.54 g of pyridine, and this was dissolved in -5"C
It was cooled to Then, 0.51 g of acetic anhydride/55 WIg of p-toluenesulfonic acid monohydrate was added, and the mixture was heated at -5°C for 4 hours.
The mixture was stirred for 8 hours. The reaction solution was poured into 80ml of water and extracted with 80xe of n-hexane. The organic layer was further treated with 5% Na
After washing with HOOa and saturated brine, it was dried over anhydrous magnesium sulfate. P side diameter, the solvent was distilled off under reduced pressure to obtain a white solid of 30
3111g was obtained. This white solid was subjected to high performance liquid chromatography [column YMO-backed column A-303 (
ODS), 4.6X250 silk, column temperature 15°C1
Solvent acetonitrile:water = 6:4 (v/v)
, flow rate 1.1 tst/wz, detection 210 nm), 2171F (8R,4R)-4-acetoxy-3-((R)-1-tert-butyldimethylsilyloxyethyl)azetidin-2-one was detected. It was produced (yield 78%).

Example 3 (:13R,4R)-4-acetoxy-8-((R)
Synthesis of -1-tert-butyldimethylsilyloxyethyl]azetidin-2-one (3R,4R)-3-((R)-1-tert-butyldimethylsilyloxyethyl)-4-trimethylsilyloxyazetidine- 2-one (mp95-96”C, (a)
25-9.5° (c=1.0.0H(As)) 8
01 Misaki was dissolved in 1.51*t of pyridine, and this was cooled to 9°C. Then, 0.27 m/l of acetic anhydride and 8 μl of trifluoromethanesulfonic acid were added, and the mixture was stirred at 9"C for 38 hours. After the reaction, it was treated in the same manner as in Example 2, and analyzed by high performance liquid chromatography (8R, 4R
)-4-acetoxy-8-((R)-1-tert-butyldimethylsilyloxyethyl)azetidin-2-one was produced in an amount of 179IIIg (yield: 66%).

Example 4 (SR,4R)-4-acetoxy-3-((R)-1-
Synthesis of tert-butyldimethylsilyloxyethyl]azetidin-2-one (8R,4R)-8-((R)-1-tert-butyldimethylsilyloxyethyl)-4-trimethylsilyloxyazetidin-2-one (mp95~96°C1 [α)
-9,5° (c=1.0, CH(IIs)]3
01Hg was dissolved in 1.50+wt of pyridine, 0.51 g of acetic anhydride/34 μp of a 2.75N hydrogen chloride-dioxane solution were added at room temperature, and the mixture was stirred at room temperature for 23 hours. After the reaction, it was treated in the same manner as in Example 2 and analyzed by high performance liquid chromatography to find (8R,4R)-4-acetoxy-8-((R)-1-tert-butyldimethylsilyloxyethyl)azetidine. ~168 -2-ones were produced (yield 62%).

Example 5 (8R,4R)-4-acetoxy-3-((R)-1-
Synthesis of tert-butyldimethylsilyloxyethyl]azetidin-2-one (8R, 4R) 8 ((几)-1-tert-Butyldimethylsilyloxyethyl J-4-1-limethylsilyloxyazetidine-2- On (mp95-96℃, [
α)”-9.5° (c=1.0, CHClg)]80
Dissolve 0.8q in pyridine 1.58g/, under N2 atmosphere, acetic anhydride 1.84g/, )lichloroacetic acid 80.9
Add Wjg and stir at -5°C for 40 hours. The reaction solution was poured into water and extracted with 80 g of n-hexane. The organic layer was further washed with 5% NaHOOa and saturated brine, and dried over anhydrous magnesium sulfate. After the furnace separation, the solvent was distilled off under reduced pressure to obtain 274.1q of white solid.
child. When this solid was analyzed by high performance liquid chromatography, 2. (3 liters, 4R)-4-acetoxy-8-((
R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one was produced at 241.6 m9.
This (yield 89%).

Example 6 (3R,4R)-4-acetoxy-8-((R)-1
Synthesis of -tart-butyldimethylsilyloxyethyl]azetidin-2-one (3R,4R)-:1(-((R)-1-tert-butyldimethylsilyloxyethyl)-4-)limethylsilyloxyazethyl Zin-2-one (mp95-96℃, [α
)25-9.5°(c=1.0.0f(013))
301 da was dissolved in 1.51 g of pyridine, and 0.515 g of acetic anhydride and 2 μe of phosphoric acid were added at room temperature.
Stir for hours. After the reaction, it was treated in the same manner as in Example 2 and analyzed by high performance liquid chromatography (3R
,4R)-4-acetoxy-3-[(几)-t-ter
t-Butyldimethylsilyloxyethyl]azetidine-2
-one was produced in an amount of 158q (yield 58%).

Example 7 (3R,4R)-4-acetoxy-3-((R)-1-
Synthesis of tert-butyldimethylsilyloxyethyl]azetidin-2-one Experiments were conducted in the same manner as in Example 2, in which the acid was varied. For comparison, an experiment was also conducted under conditions where no acid was added. (5.6 equivalents of acetic anhydride, 1 equivalent of pyridine, based on white)
9.7 equivalents were used, and the processing and analysis conditions were the same as in Example 2. The results are shown in Table 1.

(White (I') Margin table below 1 ε Example 8 (3R,4R)-4-acetoxy-8-((R)-1-
Synthesis of tert-butyldimethylsilyloxyethyl]azetidin-2-one Acetyl chloride, p-chloride
An experiment was conducted in which toluenesulfonyl and methanesulfonyl chloride were added. Compound (8 equivalents of acetic anhydride to white,
The treatment and analysis conditions are the same as in Example 2, using 19.7 equivalents of pyridine. The results are shown in Table 2.

(White (II') Table 2 Example 9 (3R,4R)-4-acetoxy-8-((R)-t-
Synthesis of tert-butyldimethylsilyloxyethyl]azetidin-2-one The same method as in Example 2! Therefore, we conducted an experiment to change the base. (5.6 equivalents of acetic anhydride for 1 month)
The treatment and analysis conditions were the same as in Example 2, using 0.2 equivalents of fi, p-1-luenesulfonic acid monohydrate.

The results are shown in Table 3.

(White (I') Table 3 Example 1O (3R,4R)-4-acetoxy-3-[(几)-1-
Synthesis of tert-butyldimethylsilyloxyethyl]azetidin-2-one Various solvents were investigated in the same manner as in Example 2.

Processing and analysis conditions are the same as in Example 2. The results are shown in Table 4.

(White (I) Example 11 (3R,4R)-4-acetoxy-3-((R)-1-
Synthesis of [dimethyl-(1,1,2-trimethylpropyl)silyloxy]ethyl]azetidin-2-one (3R,4R)-3-((几)-1-(dimethyl-(1
,1,2-trimethylpropyl)silyloxy]ethyl)
-4-trimethylsilyloxyazetidin-2-one 3
21Mg was dissolved in 1.51g/pyridine, and this was dissolved at 9°
Cooled to C. Then acetic anhydride 0.50g/.

Add 86” fl of p-toluenesulfonic acid monohydrate,
Stir at 9°C for 40 hours. After the reaction, it was treated in the same manner as in Example 2 to obtain a 250M1 semi-solid. This was treated with a silica gel column [n-hexane: ethyl acetate = 10: I, (V/V)], and further n
- the desired (S) by recrystallization from hexane
R,4R)-4-acetoxy-3-((R)-1-(
209 d of dimethyl-(1,1,2-1-limethylpropyl)silyloxy]ethyl]azetidin-2-one was obtained as white needle-like crystals. The physical property values are shown below.

[α] +41.57° (c = 0.5, cHCl,
)mp 80~81”C'HNM几(90MHz, CD01g) δ(pp
m ) 0.08 (6H, S ), 0.75 (6H
,8), 0.88(6)I,d), 1.20(3
FI, d), 1.60 (18, m), 2.00
(8H,S), 3.10 (1)1. dd), 4.
12 (IH, m), 5.75 (IH, d),
6.58(NH) Example 12 4-acetoxy-a-(t-(dimethyl-(1°2-dimethylpropyl)silyloxy]ethyl)azetidine-2
Synthesis of -one a-(t-(dimethyl-(l,2-dimethylpropyl))
Silyloxy]ethyl)-4-trimethylsilyloxyazetidin-2-one 1g 154I and 0.75ml pyridine
and cooled to 9°C. Then 0.0% acetic anhydride.
25111, p-) Luenesulfonic acid monohydrate 181
1v was added and stirred at 9°C for 40 hours.

After the reaction, it was treated in the same manner as in Example 2 to obtain 120 g of oil. This was treated with a silica gel column [n-hexane:ethyl acetate = 10:1, (v/v)], and
-acetoxy-3-(1-(dimethyl-(1,2-dimethylpropyl)silyloxy]ethyl)azetidine-2-
On 100q was obtained as a white solid. The physical property values are shown below.

'HNMR (90MHz, CD01.) δ(pp
m ) 0.08 (6H, S), 0.70 (IH, m)
, 0.85 (9H, d, d, d), 1.20 (
,3H,d), 1.80 (IH,m), 2.02
(8H,S), 8.10 (if(,da), 4.1
5 (LH, m), 5.80 (IH, d), 7.2
0(NH) Example 13 (:lIR,4R)-4-acetoxy-8-(1,(R
Synthesis of )-1-isopropyldimethylsilyloxyethyl]azetidin-2-one (8R,4R)-8-((R)-1-isopropyldimethylsilyloxyethyl)-4-trimethylsilyloxyazetidin-2-one 1.60 g of pyridine
and cooled to 9'C. L'te Acetic anhydride 0.53 at, p-toluenesulfonic acid.
Add 8819 and stir at 9°C for 40 hours.

After the reaction, it was treated in the same manner as in Example 2 to obtain a 210 da oil. This product was treated with a silica gel column [n-hexane:ethyl acetate = 10:1, (v/v)] and further recrystallized from n-hexane to obtain the desired (:llR,4R)-4- Acetoxy-3-((R
)-1-isopropyldimethylsilyloxyethyl]azetidin-2-one 164 cape was obtained as white crystals. The physical property values are shown below.

[α) +54.6° (c = 0.5, CjHOl
s)m992~94℃'HNMR (90MHz, CDC1g) δ(pp
m) 0.08(61(,S), 1.75(IH,m
), 1.98 (6H, d ), 1.29 ((H, d
), 2.12 ((H, S), 8.20 CIH, dd
), 4.23 (IH, m), 5.86 (IH, d),
6.50 (NH)

Claims (17)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 is a hydroxyl protecting group, R_2, R_3, R_
4 represents a lower alkyl group or an aralkyl group of C_1 to C_4), a strong organic acid, a mineral acid, a Lewis acid, or the general formula (IV) R_8-CO-X(IV) (in the formula R_8 represents an alkyl group, an aralkyl group, or a phenyl group, and X represents a halogen group) or a compound represented by the general formula (V) The general formula (II) is characterized by the reaction of a base and acetic anhydride using a compound represented by X (X represents a halogen group) as a catalyst. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R_1 represents a hydroxyl group protecting group) 4
-acetoxy-3-hydroxyethylazetidine-2-
Method for producing on derivatives. (2) R_1 is the general formula (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, R_5, R_6, and R_7 represent lower alkyl groups of C_1 to C_6. However, R_5, R_6, and R_7 are C_1) at the same time). (3) The manufacturing method according to claim 1, wherein R_1 is a tert-butyldimethylsilyl group. (4) The manufacturing method according to claim 1, wherein R_1 is an isopropyldimethylsilyl group. (5) The manufacturing method according to claim 1, wherein R_1 is a dimethyl-(1,1,2-trimethylpropyl)silyl group. (6) The manufacturing method according to claim 1, wherein R_1 is a dimethyl-(1,2-dimethylpropyl)silyl group. (7) The production method according to claim 1, wherein R_2, R_3, and R_4 are methyl groups. (8) The production method according to claim 1 or 2, wherein the strong organic acid is an organic sulfonic acid. (9) The production method according to claim 8, wherein the organic sulfonic acid is p-toluenesulfonic acid or trifluoromethanesulfonic acid. (10) The production method according to claim 1 or 2, wherein the strong organic acid is trifluoroacetic acid. (11) The production method according to claim 1 or 2, wherein the strong organic acid is trichloroacetic acid. (12) The production method according to claim 1 or 2, wherein the mineral acid is hydrogen chloride or phosphoric acid. (13) The manufacturing method according to claim 1 or 2, wherein the Lewis acid is boron trifluoride or boron trichloride. (14) The production method according to claim 1 or 2, wherein the compound represented by general formula (IV) is acetyl chloride. (15) The manufacturing method according to claim 1 or 2, wherein the compound represented by general formula (V) is p-toluenesulfonyl chloride. (16) The production method according to claim 1 or 2, wherein the base is pyridine. (17) The production method according to claim 1 or 2, wherein the base is picoline.