JPS63208569A - Production of 4-acetoxy-3-hydroxyethylazetidin-2-one derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a synthetic intermediate for carbapenem beta-lactam antibiotic substance and penem beta-lactam antibiotic substance, in high yield, by reacting a beta-lactam compound with a base and acetic anhydride in the presence of a specific catalyst. CONSTITUTION:A beta-lactam compound of formula I (R1 is OH-protecting group; R2-R4 are 1-4C lower alkyl or aralkyl) is made to react with a base (e.g. pyridine) and acetic anhydride using a compound of formula II (R5 is 1-6C lower alkyl or phenyl; X is halogen or CF3SO2O; n is 1-4) as a catalyst to obtain the objective compound of formula III. The reaction is carried out either by using the base as the reaction solvent or in an organic solvent such as dimethylformamide at -30-+50 deg.C. The compound of formula II is e.g. trimethylchlorosilane. The amounts of the compound of formula II, the base and acetic anhydride are 0.05-1mol., 1-30mol. and 1-15mol. per 1mol. of the compound of formula I, respectively.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to 4-acetoxy-3-hydroxyethylazetidine, which has a hydroxyethyl group with 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 -2-one derivatives.

4-acetoxy-3-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., Chemical and Pharmaceutical Bulletin (Chem, Pharm, Bull), Vol. 29,
2899 pages (1981)).

(Prior art and problems) Conventionally, a method for synthesizing 4-acetoxy-3-hydroxyethylazetidin-2-one derivatives from 6-aminopenicillanic acid [Yoshida et al., Chem, Ph.
arm, Bull, vol. 29, p. 2899 (
1981): Method of synthesis from threonine [Shiozaki et al., Tetrahedron, vol. 39, p. 2899 (198
8)], method of synthesis from aspartic acid [Leider et al., Tetrahedron Letters, Vol. 23, p. 2293 (19
82)] etc. are known.

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

The present inventors have developed a production method in which an acetoxy group is introduced into the 4-position at a low temperature using a novel β-lactam compound having an 0-protected hydroxyethyl group at the 8-position and a silyl ether group at the 4-position (N is unprotected). I have already filed an application (Patent Application No. 6l-1
01856).

After that, the present inventors conducted further studies and found that the general formula (1) % formula %) (1) (in the formula, R5 represents a lower alkyl group of cl-C6 or a phenyl group, and X represents a catalytic amount) By adding a compound represented by a halogen group or an aF3so2o group (n=1 to 4), a method was discovered to introduce an acetoxy group into the 4-position in a good yield at around room temperature, leading 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 (1) (wherein, R1 is a hydroxyl protecting group, R2, aa tR4 are C1 to C4 lower alkyl groups, or aralkyl groups). A β-lactam compound represented by the general formula (1) % formula % ( ) (wherein R5 represents a lower alkyl group of 01 to C6 or a phenyl group, and X represents a halogen group or a CF35020 group). n = 1 to 4) as a catalyst, a base and acetic anhydride are allowed to react,
The gist of the present invention is a method for producing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative represented by the general formula (III) (wherein R1 represents a hydroxyl protecting group).

The β-lactam compound having a silyl ether group at the 4-position represented by general formula (1) can be easily obtained by the method of reaction formula I, as the present inventors have already applied for a patent (Japanese Patent Application Laid-Open No. 61-18791). can.

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 (I
V) a trialkylsilyl group represented by Si R7(IV) (wherein R6+ R7+ R8 represents a C1 to C6 lower alkyl group. However, R6y R7t ag is not C1 at the same time);
For example, tert-butyldimethylsilyl group, triisopropylsilyl group, isopropyldimethylsilyl group, isobutyldimethylsilyl group, dimethyl-(1,2-dimethylpropyl)silyl group, dimethyl-(1,1,2-)
-dimethylpropyl)silyl group and other tert-
A butyl group, a benzyl group, a trichloroethoxycarbonyl group, a tert-butoxycarbonyl group, a p-nitrobenzyloxycarbonyl group, etc. are preferred, but they are preferably stable during the reaction and can be selectively deprotected by acid treatment. tert-butyldimethylsilyl group, isopropyldimethylsilyl group, dimethyl-(1,1゜2-
trimethylsilyl)silyl group and dimethyl-(1,2-
Dimethylpropyl)silyl group is preferable.

Moreover, R2t Ra+ R of β-lactam compound (1)
4 can be selected from the same or different groups from 01 to C4 lower alkyl groups such as methyl, ethyl, isobutyl, or aralkyl groups such as benzyl group and p-nitrobenzyl group, but preferably R2=18=R4= Methyl is the best.

The β-lactam compound represented by the general formula (1) (where R1#R2pRBpR4 is the same as above) prepared as above is reacted with a base and acetic anhydride to obtain the desired 4-acetoxy-3 -Hydroxyethylazetidin-2-one derivative (III) (wherein R
, are the same as above), but at this time, the general formula (II) (Rs )4-n-s 1(X)n(II) (where R
When a compound represented by (5, x, n are the same as above) acts as a catalyst, the yield is significantly improved.

Examples of the compound represented by the general formula (N) include trimethylsilyltrifluoromethanesulfonate, trimethylhalosilane, triethylhalosilane, triisopropylhalosilane, tripropylhalosilane, triphenylhalosilane, diphenylmethylhalosilane, ter
t-Butyldiphenylhalosilane, tert-butyldimethylhalosilane, isobutyldimethylhalosilane, isopropyldimethylhalosilane, dimethyl-(1,
1,2-trimethylpropyl)halosilane, dimethyl-
(l.

2-dimethylpropyl)halosilane, tert-butylmethylphenylhalosilane, etc., or dimethyldihalosilane, diphenyldihalosilane, methylpropyldihalosilane, etc., or methyltrihalosilane, ethyltrihalosilane, propyltrihalosilane, butyltrihalosilane etc., or tetrachlorosilane, etc. can be used.

When compound (1) is acetoxylated with a base and acetic anhydride without adding the above compound (1), most of the reaction products are decomposition products in which the β-lactam ring is cleaved, and the target compound (I ) cannot be obtained in a satisfactory yield.

In the 4-position acetoxylation of compound (1) in the presence of these compounds represented by general formula (1), compound (
I), the amount of 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, the base mentioned above can be used as a solvent, or an organic solvent inert to compound (1) and the reaction reagent, such as methylene chloride, ethyl acetate, n-hexane, toluene, dimethylformamide, tetrahydrofuran, etc. can be used. However, it is preferable to use pyridines or dimethylformamide.

For the β-lactam compound represented by general formula (1),
The compound represented by general formula (II) may be used in an amount of 0.05 to 1 mole, the base in a 1 to 30 mole amount, and acetic anhydride in a 1 to 15 mole amount. The reaction temperature is -8()-4-)
A range of 50°C is preferred.

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 the compound represented by the general formula (1) are added all at once or in portions to carry out the reaction. 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. Then n-
Extraction is performed with an organic solvent such as hexane. The organic layer is washed with an aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. The crude crystals obtained by distilling off the solvent were
- By recrystallizing with a solvent such as hexane, the desired 4-
An acetoxy-3-hydroxyethylazetidin-2-one derivative is obtained. When n-hexane is used as the extraction solvent, the 4-acetoxy-3-hydroxyethylazetidin-2-one derivative can also be obtained as a crystal by cooling the solution after drying. In addition, a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative can also be obtained by column chromatography from the reaction mixture after distilling off the solvent.

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

Example 1 (SR,4R)-4-acetoxy-3-C(R)-l
Synthesis of -tert-butyldimethylsilyloxyethyl]azetidin-2-one (8R, 4 liters) -8-C(R)-tert-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidin-2-one Cmp 95-96°C.

Dissolve I in 7.6 mJ of pyridine and add 2.5 ml of acetic anhydride under nitrogen atmosphere! ,) Limethylchlorosilane 0.12
m1! was added and stirred at 9°C for 41 hours. Add the reaction solution to 1 part water
Pour into 50m/150ml of n-hexane! Extracted with. The organic layer was further washed with 5% NaHOO3 and saturated brine, and then dried over anhydrous magnesium sulfate. After separating F, the solvent was distilled off under reduced pressure to obtain 1.250.9 of a white solid. A part of 1.000.9 of this white solid was dissolved in n-hexane, and after removing the insoluble matter, it was left to cool at -15°C.
A needle-shaped crystal of 90m, 9 was obtained, and the desired (3R24R)-4-acetoxy-8-C(R) was obtained from the following physical properties.
It was confirmed that it was -1-tert-butyldimethylsilyloxyethyl]azetidin-2-one.

[α] +50° (CO, 5, CHCl8) mp10
7℃ 'HNMR (90MHz, CDC1a) δ (ppm
) 0.08 (6H, S), 0.84 (9H, S).

1.20 (8H, d), 2.01 (8H, s).

8.04 (LH, dd), 4.12 (IH, m).

5.76 (IH, d), 6.73 (Nu) A part of the above white solid was also subjected to high performance liquid chromatography [column YMO-backed column A-808 (ODS), 4.
6x250 mm, column temperature 15°C, solvent acetonitrile:water = 6:4 (r).

Flow rate 1.1 rnI! /nl 1 n, detection 210n
m], a total of 1.014JF (8R,4
R)-4-acetoxy-8-C(R)-1-tert-
Butyldimethylsilyloxyethyl]azetidin-2-one was produced (yield 74%).

Example 2 (3R,4R)-4-acetoxy-3-C(R)-l
Synthesis of -tert-butyldimethylsilyloxyethyl]azetidin-2-one (3 liters, 4R) -3-C(R)-1-tert-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidine-2 -on 302m, 9 with methylene chloride 0.74 ml! Dissolve in 0.77 ml of pyridine.
0.27 ml of acetic anhydride! After adding, under nitrogen atmosphere,
Trimethylchlorosilane 0.012ml! was added and stirred at room temperature for 17 hours. Add the reaction solution to 80ml of water! Pour it inside;
Extracted with 80 m/n-hexane. Add 5% more organic layer
After washing with NaHCOa and saturated brine, it was dried over anhydrous magnesium sulfate.

After separating F, the solvent was distilled off under reduced pressure to obtain 262m of F as a white solid. This solid was analyzed by high performance liquid chromatography (3R2□4B)-4-acetoxy-8-C(R
) 98r# of -1-tert-butyldimethylsilyloxyethyl]azetidin-2-one was produced (yield 36%).

Example 3 (8R,4R)-4-acetoxy-8-[:(R)-1
Synthesis of -tert-butyldimethylsilyloxyethyl]azetidin-2-one In the same manner as in Example 1, experiments were carried out in which Compound (II) was varied in various ways. For comparison, an experiment was also conducted under conditions in which Compound (II) was not added. The treatment and analysis conditions were the same as in Example 1, using 5.6 equivalents of acetic anhydride and 19.7 equivalents of pyridine with respect to compound (r). The results are shown in Table 1.

(1') (II') Table 1 Example 4 (IR,4R)-4-acetoxy-8-C(R)-1-
Synthesis of tert-butyldimethylsilyloxyethyl]azetidin-2-one An experiment was conducted in which the base was changed in the same manner as in Example 1. The treatment and analysis conditions were the same as in Example 1, using 5.6 equivalents of acetic anhydride and 0.2 equivalents of trimethylchlorosilane with respect to compound (r).

The results are shown in Table 2.

Table 2 Example 5 (3・几,4R)-4-acetoxy-3-[: (R)
Synthesis of -1-[dimethyl-(1,1,2-trimethylpropyl)silyloxy]ethyl]azetidin-2-one (8R,4R)-+3-C(R)-1-(nidimethyl-
(1,1,2-trimethylpropyl)silyloxy]ethyl)-4-trimethylsilyloxyazetidin-2-one 520ml, 9 in pyridine 2.44ml! and cooled to 9° C. under nitrogen atmosphere. Then 0.81 m of acetic anhydride
1! , trimethylchlorosilane 0.039ml! was added and stirred at 9°C for 40 hours. After the reaction, it was treated in the same manner as in Example 1 to obtain 401m, 9 semi-solid. This product was treated with a silica gel column [n-hexane:ethyl acetate: 1 O: 1, (V/V): 1] to obtain the desired (8R,5R)-4-acetoxy-8-[:(R)
-1-(nidimethyl-(1,1,2-trimethylpropyl)silyloxy]ethyl]azetidin-2-one 838
mIi was obtained as white needle-like crystals. The physical property values are shown below.

[α] +41.5° (CO,5, CHCl3)
mpso~81℃ IHNMR (90MHz, CDOIB) δ
(ppm) 0.08 (6H, s), 0.75 (6H
,s).

0.88 (6H, d), 1.20 (8H, d).

1.50 (IH, m), 2.00 (3H, s).

3.10 (IH, dd), 4.12 (IH, m).

5.75(LH,d), 6.5L(NEI) Example 6 (8R,4R)-4-acetoxy-8-C(R)-1-
Isopropyldimethylsilyloxyethyl]azetidine-
Synthesis of 2-one (:(R,4R)-8-((R)-1-isopropyldimethylsilyloxyethyl)-4-trimethylsilyloxyazetidin-2-one 801 m, 9 with pyridine 1.5
The solution was dissolved in 8 ml and cooled to 9°C under nitrogen atmosphere. Next, 0.52ml of acetic anhydride! , trimethylchlorosilane 0
．． 025m1! was added and stirred at 9°C for 40 hours. After the reaction, it was treated in the same manner as in Example 1 to obtain a semi-solid of 229 mJ. This was applied to a silica gel column [n-hexane:ethyl acetate = 10:1, (v/v)
] to obtain 176 ml of the desired (3R,4R)-4-acetoxy-3-C(R)-1-isopropyldimethylsilyloxyethyl]azetidin-2-one as white crystals. The physical property values are shown below.

Ca) +54.6°(CO,5,CHCl3)m
I) 92-94°C 'HNMR (90MHz, CD01g)'δ
(pI)m) 0.08(6H,s), 1.75(I
H, m).

1.98 (6H, d), 1.29 (aH, d).

2.12 (8H, s), 3.20 (IH, dd).

4.28 (IH, m), 5.86 (IH, d).

6.50(NH) Example 7 4-acetoxy-8-(1-[nidimethyl-(1°2-
dimethylpropyl)silyloxy]ethyl]azetidine-
Synthesis of 2-one a-[''1-1 dimethyl-(1,2-dimethylpropyl)silyloxy]ethyl]-4-trimethylcycloxyazetidin-2-one aoom, y as pyridine 1.4
7m1! and cooled to 9° C. under nitrogen atmosphere. Then 0.49 mj' of acetic anhydride, 0 of trimethylchlorosilane
．． 023m1! was added and stirred at 9°C for 40 hours. After the reaction, it was treated in the same manner as in Example 1 to obtain a 201m, 9 semi-solid. This product was added to a silica gel column [n-
Hexane:ethyl acetate=10:1. (v/v)] to obtain the desired 4-acetoxy-3-[:1-(dimethyl-(1,2-dimethylpropyl)silyloxy]ethyl]azetidin-2-one 175m, 9 as a white solid. Obtained.

The physical property values are shown below.

'HNMR (90MHz, CDCIg) δ(1)
I) m) 0.08 (6H, S), o, 7o (in,
m).

0.85 (9H, d, d, d), 1.20 (3H, d'
).

1.80 (IH, m), 2.02 (8H, S).

3.10 (IH, dd), 4.15 (IH, m).

Claims (12)

[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). represents a C_1 to C_6 lower alkyl group or phenyl group, and X is a halogen group or CF_3SO_
Indicates 2O group. The general formula (III) is characterized by the action of a base and acetic anhydride using a compound represented by n=1 to 4) as a catalyst. There are mathematical formulas, chemical formulas, tables, etc.
III) 4-acetoxy-3-hydroxyethylazetidine-2 represented by (wherein R_1 represents a hydroxyl protecting group)
-Method for producing one derivative. (2) R_1 is the general formula (IV) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) (In the formula, R_6, R_7, R_8 represent lower alkyl groups of C_1 to C_6. However, R_6, R_7, R_8
is not C_1 at the same time. ) The manufacturing method according to claim 1. (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 manufacturing method according to claim 1, wherein R_2, R_3, and R_4 are methyl groups. (8) The manufacturing method according to claim 1 or 2, wherein the compound represented by general formula (II) is trimethylchlorosilane. (9) The manufacturing method according to claim 1 or 2, wherein the compound represented by general formula (II) is trimethyliodosilane. (10) The manufacturing method according to claim 1 or 2, wherein the compound represented by general formula (II) is trimethylsilyltrifluoromethanesulfonate. (11) The manufacturing method according to claim 1 or 2, wherein the base is pyridine. (12) The manufacturing method according to claim 1 or 2, wherein the base is picoline.