JPS6284057A - Production of 4-acetoxy-3-hydroxyethylazetidine-2-one derivative - Google Patents

Abstract

PURPOSE:A beta-lactam with a silyl ether in the 4-position is allowed to react with acetyl nitrate to convert 4-silyl ether into acetoxy group, when necessary, followed by deprotection to give the titled substance, which is useful as an intermediate of antibiotics. CONSTITUTION:Acetyl nitrate is allowed to act on a beta-lactam of formula I (R<1> is a group protecting hydroxyl group such as t-butyldimethylsilyl); R<2>-R<4> are lower alkyl, phenyl, aralkyl; R<5> is N-protecting group) at -40-0 deg.C, then, when needed, the N-protecting group is removed to give a compound of formula II (R<6> is H, or N-protecting group). Acetyl nitrate is obtained by gradually adding dropwise fuming or conc. nitric acid into acetic anhydride at temperature lower than 15 deg.C. The amount of acetyl nitrate is 1-20mol per mol of the compound of formula I, acetic anhydride is 1-100mol and conc. sulfuric acid as a catalyst is 0.01-10mol.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel method for producing 4-acetoxy-3-hydroxyethylazetidin-2-one derivatives.

In recent years, since the discovery of chenamycin, various carbapenems have been discovered and synthesized, and their development is progressing due to their excellent antibacterial activity and β-lactamase inhibitory action. In addition, its skeletal analog, penem, has the same anti-depressant properties and is also being studied because it can be administered orally. In order to express these activities, 1-position is required at the 6-position.
It is important to have a hydroxyethyl group. Also,
As an important method for synthesizing these skeletons, a method of ring-closing the 4- and 1-positions of a β-lactam compound to derive carbapenems and penems is widely used.

Therefore, 4-hydroxyethyl having 1-hydroxyethyl or a protected hydroxyl group at the 8-position and a dehydrogenation group, especially an acetoxy group, which is easily substituted with carbon or sulfur compounds at the 4-position.
-acetoxy-3-hydroxyethylazetidine-2-
On derivatives are known as important and useful intermediates in carbapenem and penem synthesis reactions.

(Prior art and problems) Conventionally, as a method for synthesizing 4-acetoxy-8-hydroxyethylazetidin-2-one derivatives, a method of synthesizing from 6-aminopenicillanic acid [Yoshida et al., Chemical & Pharma Co., Ltd. Steikal Burzchin (Ohem,
pharm, Bull, ), 29 volumes.

2899 pages (1981)], method of synthesis from threonine [Shiozaki et al., Tetrahedron
edron), volume 89, page 2899 (1988
2009], Method of Synthesis from Aspartic Acid [Raider et al., Tetrahedron Letters]
Lett, ), 23%, 2893 pages (
1982)] are known. However, all of these methods have the disadvantage of using industrially undesirable heavy metal compounds such as mercury acetate and lead tetraacetate to introduce the 1-acetoxy group at the 4-position of the β-lactam ring. Ta. In order to solve these drawbacks, the inventors of the present invention continued their intensive research and found that 8-8-
Patent Application No. 189797 (1982) to discover a method for producing a new β-lactam compound having a hydroxyl-protected 1-hydroxyethyl group at the 4-position and a silyl ether at the 4-position)
Furthermore, they discovered a simple method for converting the 4-position of this β-lactam compound into an acetoxy group, and completed the present invention.

The details will be explained below.

(Means and effects for solving the problem) (In the formula, R1 is a hydroxyl protecting group, R2, R3, and R4 are cl-c
4 lower alkyl group, phenyl group or aralkyl group,
A β-lactam compound represented by the general formula
The present invention relates to a method for producing a 4-acetoxy-8-hydroxyethylazetidin-2-one derivative represented by n)(i) R1 (wherein R1 is the same as above and R6 represents hydrogen or an N-protecting group).

The β-lactam compound represented by the general formula (I) has already been filed by the present inventors (Patent Application No. 18979, filed in 1982).
No. 7) β-lactam compound (I') (R1°R1!, R1,
R4 is the same as above) by introducing an N protecting group R5.

(1') This operation is performed because the yield is generally higher if N is protected when acetyl nitrate is used next. At this time, as a protecting group introduction reagent, H, R5-x
(x is halogen) can be used. R6・-X is generally a β-lactam N protecting reagent such as oxalyl chloride such as trimethylsilyl chloride, t-butyldimethylsilyl chloride, isopropyldimethylsilyl chloride, inbutyldimethylsilyl chloride, and triisopropylsilyl chloride. Among them, trimethylsilyl chloride and t-butyldimethylsilyl chloride are preferred.

For the reaction, the compound (R5 and 15-X) is reacted with DMF,
The mixture is mixed in an inert organic solvent such as dichloromethane or THF, and the treatment is completed within several hours to about one day at room temperature to the boiling point of the solvent. Distill the solvent and extract.

By normal operations such as washing with water, the desired β-lactam compound (I
) is obtained.

As the hydroxyl group-protecting group R1, a trialkylsilyl group represented by the general formula (III) j--si-R9(In) (wherein H7, IL8, and R9 represent a C1 to C4 lower alkyl group) ,
For example, t-butyldimethylsilyl group, inpropyldimethylsilyl group, triisopropylsilyl V group, inbutyldimethylsilyl group, etc., as well as t-butyl group, benzyl group, trichloroethoxycarbonyl group, t-butoxycarbonyl group, benzyloxy Examples include carbonyl group, p-nitrobenzyloxycarbonyl group, etc., but monobutyldimethylsilyl group and isopropyldimethylsilyl group are preferable because they are more stable during the reaction and can be selectively deprotected by acid treatment etc. .

Furthermore, the substituent R2*IL8+ R' of the 4-position silyl ether of the β-lactam compound is methyl, ethyl,
cl − such as inpropyl, isobutyl, t-butyM, etc.
c4 lower γ alkyl group, phenyl group, or aralkyl group such as benzyl or p-nitrobenzyl group,
or different groups can be selected, but preferably R2=R
8=R4=methyl is preferred.

By reacting acetyl nitrate with the compound represented by the general formula (I) (in which Bl, R2, R8, R4 and 5 are the same as above) prepared as above, the silyl ether at the 4-position was converted into an acetyl ether. group, and then, if necessary, by removing the protecting group of N, the general formula (II) (wherein R1 is the same as above, R6 is hydrogen or protecting N) A compound represented by (indicating a group) is obtained. Acetyl nitrate can be obtained by slowly dropping fuming nitric acid or concentrated nitric acid into acetic anhydride under cooling, preferably below 15° C., according to a known method.

At this time, it can be diluted with an inert solvent such as a halogenated hydrocarbon. Note that it is desirable to add concentrated sulfuric acid before dropping nitric acid as a reaction catalyst.

The solution of acetyl nitrate obtained in this way and the compound (
In the outer tube in which I) is reacted, the reaction temperature is 0°C to room temperature, preferably -40°C to 0°C, and the amount of acetyl nitrate is 1 to 20 times the mole of compound (I), and acetic anhydride is added. is 1
~100 times the mole, and concentrated sulfuric acid may be used in an amount of 0.01 to 10 times the mole. As the solvent, an inert solvent such as a halogenated hydrocarbon can be used, but usually the same solvent as that used to prepare acetyl nitrate may be used. To carry out the reaction, a solution of compound (I) is slowly added dropwise to a cooled solution of acetyl nitrate, and once compound (I) has disappeared, the reaction solution can be treated with an ordinary organic solvent and water. . On this occasion,
It is desirable to use alkaline water or a buffer solution and to perform the treatment at a low temperature so that I)H in the reaction solution does not become strongly acidic. Then, when the solvent is distilled off, β- with an acetoxy group at the 4-position
A lactam compound is obtained, but the type of N protecting group R5,
Depending on the reaction and processing conditions, R5 may be eliminated, a mixture of a compound with R6 attached and a compound with R5 eliminated, or a compound with R6 attached may be obtained. If it is necessary to remove the protecting group of N, a conventional method can be used to remove the protecting group. The represented compound is obtained. Or, again,
When deriving these into carbapenems and penem compounds, it is also possible to carry out a deprotection operation and introduce an arbitrary protecting group, if necessary, by a known method.

Regarding the removal of the N protecting group, it is often desirable to remove only the N protecting group without removing the protecting group 1 of the hydroxyethyl group at the 3-position. In this case, specifically, when the protecting group of N is a trialkylsilyl group, for example, a t-butyldimethylsilyl group, tetrabutylammonium chloride, tetrabutylammonium chloride, tetramethylammonium chloride and potassium fluoride may be used. The combined reagents can be reacted in the presence of acetic acid using THF, dichloromethane, etc. as a solvent, or in the case of a more unstable trimethylsilyl group, an additional amount of pyridinium p-)luenesulfonate can be reacted in a THF-water solvent. A known method may be used, such as acting with

Compound (II) thus obtained can be purified by crystallization from n-hexane, petroleum ether, etc., or by silica gel chromatography.

(Examples) Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited only to these Examples.

Example 1 (81,4B)-4-acetoxy-8-C(R)-l
Synthesis of -tert-butyldimethylsilyloxyethyl]-azetidin-2-one (8m, 4m) -a-C(n)-1-tert-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidine-2 -On i, oo, p in DMF10m
l! 1.05 JI of triethylamine and 0.82 JI of trimethylsilyl chloride were dissolved in the solution. After adding p and stirring at room temperature for 6 hours, 1. Dilute with 60ml of hexane and cool with water to 60ml of 6% NaHOOs water! After separating the water layer at 0°, the organic layer was mixed with 10% citric acid-6% 1aHcO8 mixture (1) H4) 60ml! .

60ml of saturated salt water! After washing with
ert -butyldimethylsilyloxyethyl]-4-trimethylsilyloxy-1-trimethylsilylazetidin-2-one at 1.05! I got it.

Acetic anhydride 5.89. p 1,2-diku ooz tough 5rn
l! of concentrated sulfuric acid into a water-cooled medium. l
mI! Add 0.8ml of fuming nitric acid (specific gravity 1.52) while maintaining the liquid temperature at 10-15℃! was dripped. After the dropwise addition was completed, the temperature was maintained at 0 to 10'C for 1 hour, and then cooled to -40C (dry ice-acetone bath).

To this, (8R,4R)-8-((R)-1-tert
-Butyldimethylsilyloxyethyl]-4-trimethylsilyloxy-1-trimethylsilylazetidin-2-one A solution of 1.05,9 in 21 m/2-dichloroethane was added dropwise over 1 hour. As is, -4
After reacting at 0'C for 8 hours, the reaction solution was diluted with hexane 85
0m/, ethyl acetate 150ml! , 500 ml of pH 7 phosphoric acid solution (0.5M)! into the mixture at once. After separating the aqueous layer, the organic layer was separated using 5% NaHOO
g 500ml of water! , 10% citric acid-5% NaHOOa
Mixed solution (pH 4) 500m7. 200ml of saturated salt water!
After washing with water and drying with magnesium sulfate, the solvent was distilled off to obtain a pale yellow oil. this is(
8 liters, 4 liters)-4-acetoxy-8-CCTL)-1
-tert-butyldimethylsilyloxyethyl/I/]-
1-trimethylsilylazetidin-2-one (!: (
3B.

4B)-4-acetoxy-a-C(R)-t-te
Note, which was a mixture of rt-butyldimethylsilyloxyethyl]-azetidin-2-one (molar ratio 1:2), T
HF80ml! And 15m1 of water! Dissolve in a mixture of p-
) Add 8 Gmy of pyridinium luenesulfonate, and add 80
Stir for a minute. Add hexayssomI to the reaction solution! and ethyl acetate #15QmI! and 500 ml of water! , 5% Na
After washing with 3,500 m of HCO and 200 m of saturated brine, the organic layer was distilled off, leaving a pale yellow solid (
8B,4R)-4-acetoxy-8-C(R)-1-t
0.88.9 of ert-butyldimethylsilyloxyethyl]-azetidin-2-one was obtained. By recrystallizing this from n-hexane, the desired β-lactam (8R941L)-4-acetoxy-8-[(R)-
i -tert-butyldimethylsilyloxyethyl]-
Azetidin-2-one was obtained as 0.27.9m colored needles.

[α) = +50° (C = 0.5, OH(31
g).

m¥), 107-108℃ IH-NMR (90MHz, CDC1g), δ (ppm
): 0.08 (6H, 8), 0.84 (9H, 8).

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

8.04 (IH, da), 4.12 (IEl, m).

5.76 (IH, d), 6.78 (NEI) Example 2 (8R,4B)-4-acetoxy-8-((R)-1-
Synthesis of tert-butyldimethylsilyloxyethyl]-azetidin-2-one 6.89 JI of acetic anhydride was added to 1,2-dikuooz Tough 5rr.
IJ! of concentrated sulfuric acid o-i
mI! was added, and 0.8 ml of fuming nitric acid (specific gravity 1.52) was added dropwise while roughly maintaining the liquid temperature at 10 to 15°C. After completion of the dropwise addition, stirring was continued for 80 minutes, and then the reaction solution was cooled with water. In this, (8B, 4B)-8-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-trimethylsilyloxy-1-trimethylsilylazetidine-2 synthesized in the same manner as in Example 1 was added. -On 0
．． 98. A solution prepared by dissolving F in 21 mJ of 1,2-dichloroethane was added dropwise over about 1 hour. After continuing to stir for 3 hours, the reaction solution was diluted with 150 ml of hexane and 850 mA's of ethyl acetate. , pEI 7 phosphate buffer (0,5M
) 500 mJ was poured into the mixture at once. After separating the suiseki, the organic layer was treated with 500 mJ of 5% NaHCO3 water.
10% citric acid-5% NaHCOs mixture (pH 4) 5
00mJ.

After washing with 200 ml of saturated saline solution and drying over anhydrous magnesium sulfate, the solvent was distilled off to leave a pale yellow oil with 0.8 mL of water.
8! I got i. This was crystallized in n-hexane to obtain the desired β-lactam 0.18.9 as colorless needle crystals. The properties of each were the same as those shown in Example 1.

Example 8 (8R,4B)-4-acetoxy-8-[: (R)-
Synthesis of 1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one (8R,4R)-8-C(IL)-1-tert-butyldimethylsilyloxyethyl)-4-)limethylsilyloxyazethi Zin-2-one Dissolved in 1.00,9'Q dichloromethane tomz and added 0.00% triethylamine.
89. li' and jer t-butyldimethylsilyl chloride 0.61. p was added thereto, and the mixture was stirred at a constant temperature for 6 hours. After the reaction, a 5% aqueous NaHOO3 solution was added to this solution, and the aqueous layer was separated, and the organic layer was washed successively with I) H8 diluted hydrochloric acid and saturated brine. After drying over hot water magnesium sulfate, the solvent was distilled off to obtain a brown liquid. This was purified by silica gel chromatography (hexane:ether = 100:8) and (8R94R)-8-C(R)-1-tert-butyldi-1-y-lsilyloxyethyl)-4-)limethyl 0.80Ii of silyloxy-1-tert-butyldimethylsilylazetidin-2-one was obtained as a colorless liquid.

Acetic anhydride 2.70.9 to 1.2-dichloroethane 2.5
ml and cooled with water, 0.05 nlz
of concentrated sulfuric acid was added, and 0.4 ml of fuming nitric acid (specific gravity 1.52) was slowly added dropwise while maintaining the liquid temperature at 10 to 15°C. Thereafter, it was kept at 0 to 10°C for 80 minutes, cooled to -40°C, and (8R,4R)-8-
[(R)-1-tert-butyldimethylsilyloxyethyl)-4-trimethylsilyloxy-1-tert-butyldimethylsilylazetidin-2-one 0.61.
F to 1,2-dichloroethane 11ml! was added dropwise over 1 hour. After keeping at -40°C for 1 hour and reacting at -80°C for 2 hours, the reaction solution was mixed with 210 mJ of hexane, ethyl acetate A/ 9 Q mj', p
E[7(7) was poured at once into a mixture of 800 m/m of phosphate buffer (0.5 M). After removing the aqueous layer, the organic layer was
%NaHCOB water, 10% citric acid - 6% NaHOOB
The mixture (pH 4) was washed successively with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 0.82 fl of a pale yellow oil. This was purified by silica gel chromatography (hexane:ether=10:1),
(8R,4B)-4-acetoxy-8-[: (R)
-1-tert-butyldimethylsilyloxyethyl)
-1-tert-butyldimethylsilylazetidine-2
-one 0.22 g was obtained as a colorless oil. This is T
I (F) dissolved in 20 ml! of tetra-n-butylammonium fluoride o, is, g.

0.07 pg of acetic acid was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off and 50 mJ of ethyl acetate was added! 5% NaHCOa
Water 5 Q rllI! was added, the aqueous layer was separated, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off and recrystallized from n-hexane to obtain the desired β-lactam 0.18.9 in the form of colorless needles. The properties of each were the same as those shown in Example 1.

Example 4 (8R,4)-4-acetoxy-s -C(R)-1
Synthesis of -inpropyldimethylsilyloxyethyl]azetidin-2-one 8- [(R) -1-isopropyldimethylsilyloxyethyl]-4-)limethylsilyloxyazetidine-2
-On 1.50m (8R, 4B) body: (88, 48)
Body = 5:1:l to 15ml dichloroethane! Dissolve in
0.65F of triethylamine and 1.0G, p of tert-butyldimethylsilyl chloride were added, and the mixture was stirred at room temperature for 14 hours. Dichloromethane 59ml! After diluting with 5
%NaHC! OB50ml! , diluted hydrochloric acid (pH 4), and saturated brine in this order, and dried over anhydrous magnesium sulfate.

The solvent was distilled off to give 8-((R)-1-inpropyldimethylsilyloxyethyl)-4-)limethylsilyloxy-
1-tert-butyldimethylsilylazetidine-2-
On 1.56.9 was obtained as a yellow oil.

Acetic anhydride 5.8Sl 1.2-diku aoz Tough 5ml!
After adding 0.2 m/ml of concentrated sulfuric acid, the mixture was cooled to an internal temperature of 10 to 16°C. Smoking glass while maintaining that temperature! ! (Specific gravity 1.52) 0-8m1! about 1.5
After the mixture was added dropwise over a period of time, stirring was continued for 2 hours.

This was cooled to -80°C, and 8-C(R)-1-isopropyldimethylsilyloxyethyl]-4-trimethylsilyloxy-1-tert-butyldimethylsilylazetidin-2-one 1.5611.2- A solution dissolved in 80ml of dichloroethane was added dropwise over about 1.5 hours, and stirring was continued for about 8 hours. The reaction solution was diluted with 850ml of hexane.
1! , ethyl acetate 150m/, pH 7 (7) phosphate buffer (0, 1M) 500ml! The mixture was poured all at once into a water-cooled container.

After separating the aqueous layer, the organic layer was mixed with 5% NaHC! 08 water ao.

ml! , 800ml of 10% citric acid-5% NaHCOB mixture (pH 4)! and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a yellow oil 0.90.9%. This 4-acetoxy-8-
The oil containing C(R) -t-isopropyldimethylsilyloxyethyl) -l -tert-butyldimethylsilylazetidin-2-one was directly poured into 20 ml of dichloromethane! Dissolved in 0.8711 tetramethyl acetic acid
Ammonium chloride 0.84, p, and potassium fluoride 0.18.9 were added, and the mixture was stirred in a suspended state. After reacting at room temperature for 8 hours, the reaction solution was diluted with 5% NaHCO3.
The mixture was poured into 100 mJ of water and 80 mJ of DIKU00/Tan, and after stirring for a while, the aqueous layer was removed and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The target β-lactam obtained ((8R,4R):
By crystallizing a pale yellow oil containing (8S, 4R)=5:1:l from hexane! 0, lR, 4R) 0
．． 21 g were obtained as rust-colored needles.

(a)”! +54.2° (C=0.5, CHC
! 18) mp, = 92-94°C lH-NMR (90MHz, CD01B) δ(pp
m): 0.04 (6H, 1), 0.90 (7H).

1.28 (8H, d), 2.06 (8H, 8).

8.18 (IH, dd), 4.18 (IH, m).

Claims (11)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 is a hydroxyl protecting group, R^2, R^3, R
^4 is a lower alkyl group, phenyl group, or aralkyl group of C_1 to C_4, and R^5 is a protecting group for N) is treated with acetyl nitrate, and then, if necessary, N General formula (II), which is characterized by the elimination of the protective group of N
A method for producing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative represented by: (2) R^1 is the general formula (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, R^7, R^8, R^9 represent lower alkyl groups of C_1 to C_4 ) The manufacturing method according to claim 1. (3) The manufacturing method according to claim 1, wherein R^1 is a t-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^5 is a trimethylsilyl group. (6) The manufacturing method according to claim 1, wherein R^5 is a t-butyldimethylsilyl group. (7) The production method according to claim 1, wherein R^6 is hydrogen. (8) The manufacturing method according to claim 1, wherein R^6 is a t-butyldimethylsilyl group. (9) The manufacturing method according to claim 1, wherein R^6 is a trimethylsilyl group. (10) The manufacturing method according to claim 1, wherein R^2, R^3, and R^4 are methyl groups. (11) General formula (I') ▲Mathematical formulas, chemical formulas, tables, etc.▼(I') (In the formula, R^1 is a hydroxyl protecting group, R^2, R^3, R
^4 is C_1 to C_4 lower alkyl group, phenyl group,
or an aralkyl group) and R^5
By reacting a reagent represented by -X (R^5 is a protecting group for N, X is a halogen), the 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 is C_1 to C_4 lower alkyl group, phenyl group,
or an aralkyl group, R^5 represents a protecting group for N), and then the compound (I)
is treated with acetyl nitrate, and then, if necessary, N
By removing the protective group of the general formula (II) ▲Mathematical formula, chemical formula, table, etc.▼(II) (In the formula, R^1 is a hydroxyl protecting group, R^6 is hydrogen or N
A method for producing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative represented by: