JPS62252785A - 4-substituted beta-lactam compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is (protected) hydroxyl or (halogen-substituted) alkyl; R<2> is H or alkyl; R<3> is (substituted) aromatic group; X is O, S, sulfinyl, sulfonyl or NR<4> (R<4> is H, alkyl or phenyl); Y is O, S or NR<5> (R<5> is H, alkyl or phenyl)]. EXAMPLE:(R)-2-[(3S, 4R)-3-((R)-1-t-butyldimethylsilyloxyethyl)-2-oxoazetidin-4-yl] propionic acid 2-benzothianolinonamide. USE:A synthetic intermediate for carbapenem derivative useful as an antibacterial substance. PREPARATION:The compound of formula I can be produced by reacting the compound of formula II (Z is acetoxy, etc.) with the compound of formula III in the presence of a tertiary amine and boron triflate or tin triflate in an inert solvent (e.g. CH2Cl2).

Description

[Detailed Description of the Invention] Object of the Invention Carbapenem derivatives with no substitution at the 1-position are known to exhibit strong antibacterial activity, and several methods for their synthesis have already been reported (J, Am, Chen.

Soc, 102 6181 (1980), Te
trahadron Lat, s, 252793 (
198]. Compounds (1) and (2) are important intermediates in these synthetic methods.

(In the formula, R1 represents an optionally protected hydroxyl group or an alkyl group optionally substituted with a halogen atom,
R represents an alkyl group or a heterocyclyl group which may be substituted with an amino group. ) The present inventors investigated a simple synthesis method for compounds (1) and (2), and synthesized the compound (3) described below.
was found to be a synthetic intermediate of compounds (1) and (2).

On the other hand, among carbapenem derivatives having an alkyl group at the 1-position, those whose coordination is R'''C have strong antibacterial activity.
It is known to have superior chemical and in vivo stability compared to carbapenem derivatives with no substitution at the 1-position (Hetarocycles 21 1 (1984)).
)). Therefore, it is desired to develop a method for selectively synthesizing alkyl-substituted carbapenems having an R coordination at the 1-position. The inventors investigated various methods of synthesizing the compound and found that the compound (3) described below is an important intermediate for the synthesis, thereby completing the present invention.

Structure of the Invention The present invention relates to a synthetic intermediate (3) for carbapenem derivatives.

In the formula, R1 represents an optionally protected hydroxyl group or an optionally substituted alkyl group with a halogen atom,
R2 represents a hydrogen atom followed by an alkyl group, and R! ,t
@ Indicates an aromatic ring group formed by combining two adjacent carbon atoms, which may have a substituent, or an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, or an NR' group (
R' is a hydrogen atom, an alkyl group or t is an oxygen atom, a sulfur atom, or an NR5 group (
R5 represents a hydrogen atom, an alkyl group or a phenyl group)
shows.

The alkyl groups in R1, R2, R4 and R5 of compound (3) are the same or different and are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl, t-butyl, and pentyl.

Examples include impentyl and S-pentyl, and preferably a C7 to C4 alkyl group.

The protecting group for the hydroxyl group which may be protected as a substituent in R1 is, for example, an acyl group, an aralkyl group, an alkyloxycarbonyl group, an aralkyloxycarbonyl group, an alkenyloxycarbonyl group, an alkyloxymethyl group, a substituted ethyl group, a trialkyl group. A silyl group or a diphenylalkylsilyl group is opened, preferably an aralkyloxycarbonyl group, an alkenyloxycarbonyl group or a trialkylsilyl group.

The aforementioned acyl groups are, for example, formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, phthyryl, 4
-) luoyl, 4-anisoyl, 4-nitrobenzoyl or 2-nitrobenzoyl. Aralkyl groups include, for example, benzyl, 4-methoxybenzyl, 2-
Nitrobenzyl, 4-nitrobenzyl, diphenylmethyl or triethylsilyl. Alkyloxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, 2.2.2
-) Lichloroethoxycarbonyl or 2-trimethylnosilylethoxycarbonyl. Aralkyloxycarbonyl groups include, for example, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4
-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl t fC 4-nitrobenzyloxycarbonyl. Examples of the alkenyloxycarbonyl group include vinyloxycarbonyl and allyloxycarbonyl. Alkyloxymethyl groups include friends such as methoxymethyl, t-butoxymethyl, 2-
An example of methoxyethoxymethyl is 2.2.2-trichloroethoxymethyl. Examples of the substituted ethyl group include 1-ethoxyethyl, 1-methyl-1-methoxyethyl or 2.2.2-trichloroethyl. Trialkylsilyl groups include, for example, trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, t
-butyldimethylsilyl or triisopropylsilyl. Diphenylalkylsilyl group fC
Examples include diphenylmethyl and diphenylethyl.

The halogen atom of the substituent in R1 is, for example, fluorine,
Examples include chlorine or bromine.

Together with two adjacent carbon atoms of R3, * indicates two adjacent carbon atoms). These aromatic ring groups may have one or two substituents that are the same or different as shown below.

Examples include alkoxy groups such as , halogen atoms such as chlorine or bromine, or nitro groups.

Compound (3) has various isomers even at its asymmetric carbon. The present invention includes one or a mixture thereof.

Particularly suitable compounds of compound (3) include compound (3') shown in the following table.

In the table, TBS represents t-butyldimethylsilyl, TMS represents trimethylsilyl, PNZ represents 4-nitrobenzyloxycarbonyl, and ALZ represents allyloxycarbonyl.

The object compound (3) of the present invention can be produced by the method described below.

In the above formula, R', R2, R', X and Y have the same meanings as above, and 2 is acetoxy, propionyloxy, pivaloyloxy, valeryloxy, hexanoyloxy, ethylhexanoyloxy, heptanoyloxy, octanoyloxy, = indicates a leaving group such as a fatty acyloxy group such as cytyloxy or decanoyloxy or a benzenesulfonyl group.

Reagents used in the reaction include tertiary amines and boron triflate or tin triflate.

Examples of tertiary amines include diimpropylethylamine, diisopropylmethylamine, triethylamine, 1-ethylpiperidine, 1-methylmorpholine, 1-
Ethylpyrrolidine, 1,4-diazabicyclo[2,2,
21 octane, 1°5-diazabicyclo(5,4,0)
undecene-5 or 1,5-diazabicyclo(4,3
, 0) cyclic or chain amines such as nonene-5.

Boron for poron triflate is dibutyl boron,
Cifuropyrporone, diethylboron, diimpropylboron, diisobutylboron, dicyclohexylboron,
Examples include dicyclopentylboron, cyclopentylboron, and 9-borabicyclo(3,3,1)nonyl.

The solvent used in this reaction is not particularly limited as long as it does not participate in this reaction, but methylene chloride,
Preferred are halogenated hydrocarbons such as chloroform and dichloroethane, ethers such as diethyl ether and tetrahydrofuran, and hydrocarbons such as benzene and toluene. The reaction temperature is usually -78°C to 60°C, preferably -10°C to 20°C.

The reaction time varies depending on the raw material compounds and reaction reagents, but is usually 2 to 24 hours.

After completion of the reaction, the target compound can be isolated from the reaction mixture according to conventional methods. For example, after adding water to the reaction mixture to terminate the reaction, the target compound is extracted with an organic solvent that is immiscible with water, such as the above-mentioned reaction solvent or ethyl acetate, and the solvent is distilled off from the extract. A pure product can be obtained by purification using column chromatography or the like.

Effects of the Invention The object compound e) of the present invention is an important synthetic intermediate of carbapenem derivatives, which are useful antibacterial substances. That is, when compound (3) is hydrolyzed, carboxylic acid (6) is obtained. Compound (6) can be converted into dicarbabenem derivative (9) by the method disclosed in JP-A-51-123182. Also, compound (3) gold mercaptan (7)
When reacted with, thioester (8) is obtained.

Compound (8) can be converted into cicarbabenem derivative (9) by the method disclosed in JP-A-59-51286.

EXAMPLES The present invention will be explained in more detail with reference to Examples and Reference Examples below.

Example 1 3-propionylbenzoxazolin-2-one (36
2Q) t' Anhydrous methylene chloride (3d) yc, dibutylboron reflux at 0°C under nitrogen atmosphere) (2,
1d) and diisopropylethylamine (4aas)
was added and stirred for 30 minutes. (38,4R)-4- at 0°C
7 Setoxy 3-((R)-1-1-butyldimethylsilyloxyethyl]azetidin-2-one (28719)
km aqueous methylene chloride (2-) and then added zinc bromide (50+9). After stirring overnight at room temperature, the mixture was poured into water and extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.

The residue was subjected to silica gel column chromatography.
Developed with hexane/ethyl acetate-271 and (→-2-
((3S.

(S
) -2-C(3S, 4R)-2-okine-3-(
A 6:1 mixture of (R)-1-t-butyldimethylsilyloxy)azetidin-4-yl]propionic acid 2-benzoxacillinone amide was obtained. Main house■
Material; NMR (cocz3) δ ppm: 0
．． 08 (6H, s), 0.89 (9H,
s), 1.24 (3H, d, J=7Hz).

1.35 (3H, d, I-THz), 3.06 (I
H.

dd, Jw 4, 2 Hz),
3.9-4.5 (3H, m).

6.1 (I H, br, s), 7.
1-7.4 (3H, m).

7.8 ~8.3 (I H, m) Engineering R (C1 (
C23) cm-': 3420, 179G
, 1770 Example 2 3-propionylbenzothiasolin-2-one (41
4119) in anhydrous methylene chloride (3-) and dibutylboron tri7late (2-
2mA) and diimpropylethylamine (420μ
) and stirred for 30 minutes. At 0℃ (3S, 4R)
-4-acetoxy-3-((→-1-1-butyldimethylsilyloxyethyl)azetidin-2-one (287
119) was dissolved in anhydrous methylene chloride (2 m) and added.
Zinc bromide (50119) was then added. After stirring at room temperature for one day, the mixture was poured into water and extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, it was subjected to vacuum chromatography and developed with hexane/ethyl acetate port 271 to give (6)-2-((33,4PL)-3-((R)
-1-1-butyldimethylsilyloxyethyl)-2-
Oxoazetidin-4-yl]propionic acid 2-benzothiazolinone amide 26019 was obtained.

NMR (CDC4) a ppm: O, C7 (6H
, s), 0.90 (9EI, S), 1.2
3 (3Ei, d, J-7FIZ), 1.33 (
3Ef, 4. Jm7Hz), 3.11 (, IH, dd
, Jx5,2-Hz'), 3.9~4.5 (3H
, m), 6.82 (I H, br, s)
.

7.1-7.6 (3H, m), 8.0-8.3
(I H, m) 工R(cHcts) き-': 3
450, 1760 j1695 Example 3 Stannath trifluoromethanesulfonate (460■)
was dissolved in anhydrous methylene chloride (211 tl) and dissolved in N-ethylpiperidine (165 μm) 1 at 0°C under nitrogen atmosphere.
and stirred for 10 minutes. At 0°C, 3-propylbenzoxazolin-2-one (191 ml) was dissolved in anhydrous methylene chloride (1d) and stirred for 15 minutes. At 0°C (3S.

4R)-4-acetoxy-3-((R)-1-1-butyldimethylsilyloxyethyl]azetidin-2-one (280 μl) was dissolved in anhydrous methylene chloride (1 ml), and then zinc bromide ( After stirring at room temperature for one day, pour into pH 7 glue/acid buffer, add ethyl acetate, and remove the resulting precipitate by filtration through Celite. After drying the organic layer over anhydrous magnesium sulfate, The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and developed with hexane/ethyl acetate = 2/1 to give (R)-2-((3S,4Et)-3-((R)- 1
-t-butyldimethylsilyloxyethyl)-2-oxoazetidin-4-yl]propionic acid 2-benzoxacillinone amide and (S)-2-((3s,4R))
A 2:1 mixture of -3-(1)-1-t,-butyldimethylsilyloxyethyl)-2-oxoazetidinon-4-yl]zolopionic acid 2-benzoxacylinonamide 116w1 gold was obtained.

IR (CDCt3) 3420, 1790.1770
m-' Example 4 Stannath trifluoromethanesulfonate (46511
1v) N-ethylpiperidine (165 μm>
1 and stirred for 10 minutes. At 0°C, 3-gropionyl inzothiazolin-2-one (207 ml) was dissolved in anhydrous methylene chloride (1 ml) and stirred for 15 minutes. (38,4B)-4-acetoxy-3-((R)-1-
t-Butyldimethylsilyloxyethyl]azetidine-
2-one (14411Ig) was dissolved in anhydrous methylene chloride (1d
) and then added zinc bromide (25 ft). After stirring at room temperature for 1 day, a phosphoric acid solution (pH 7) was added, and ethyl acetate was added. The raw p-hole precipitate was removed by filtration, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and developed with hexane/ethyl acetate = 171 to give (n)-2-((3s, 4p)
-3-((p)-1-t-butyldimethylsilyloxyethyl)-2-oxoazetidin-4-yl]propionic acid 2-benzothiazolinoneamide and (S)-2-(
(38,4B)-3-((R)-1-t-butyldimethylsilyloxyethyl)-2-oxoazetidine-4-
144 η of a 2:1 mixture of propionic acid 2-benzothiazo 1 nononamide was obtained.

IR(CDCt5)cIrL, 3450, 1760
, 16953-Glopionylpenzoxazoline-2
-on (482■) and in the same manner as in Example 1, C
I()-((38,4B)-3-((R)-1-t-butyldimethylsilyloxyethyl)-2-oxoazetidin-4-yl]propionic acid 2-naphtho[2°3]
Oxacylinone amino 1 and (s)-((3s,4n)-3
-((Fl)-1-t-butyldimethylsilyloxyethyl)-2-oxoazetidin-4-yl]zolopionic acid 2-nando(2,3)oxasilinoneamide 4:
1 mixture was obtained in an amount of 75 cm.

Main product: NMFI (CDCt,)δI)pm: 0.08(6
H, s), 0.89 (9H, s), 1.25 (3E, d
, J = 7Hz), 1.37 (3H, d, J = 7H
z ), 3.12 (I H, dd r J =4.2
Hz).

3.9-4.5 (3H, m), 6.1 (IH, br
, s), 7.3-8.1 (5H, ro), 8.
49 (IH, d, J = IHz) IR (CHCL3) l
-”: 3400, 1790, 13605-t-7
'Til-3-propionylbenzoxazolin-2-one (4'94 mq) was used in the same manner as in Example 2, (
R)-((3S,4R)-3-((R)-, i-t-
5-1-Butyl-2-butyldimethylsilyloxyethyl-2-oxoazetidin-4-yl]propionic acid
-Benzoxacillinone amide 386rIv was obtained.

NMR (CDCtρδppm: 0.07 (6H,
s ), 0.87 (9H.

S), 1.24 (3H, d, J=7Hz), 1.32
(,9H,s), 1.35 (3H,d, J=6Hz),
3.06 (IH, aa, J=4.2Hz), 3.9-4
．． 5 (3H, s), 6.6 (LH, br, d), 7
．． 08 (LH, d, J=9Hz), 7.30 (IH, d
d, J=9.2Hz), 8.14(IH, d, J=2H
z) IR (4C!3”lJm-1: 3430, 17
95, 1765.

Example 7 5-chloro-3-propionylbenzoxazoline-2
-on (451■) using gold, in the same manner as in Example 2, (
R)-((38,4R)-3-((El)-1-1--
1Tyldimethylsilyloxyethyl)-2-oxoacetinon-4-yl]propionic acid 5-chloro-2-benzooxasilinonamide 339 was obtained.

NMR (CDCt3) δppm: 0.09 (6H, s)
, 0.88 (9H, s), 1.24 (3H, d,
J = 7E(z), 1.35(3H, d, J = 7Hz
), 3.06 (IH, dd,, T = 4°2 Hz),
3.9-4.5 (3)1, m), 6.68 (
I H, br, s), 7.0-7.4 (2H, rn
), 8.0-8.2 (IE, rn)IR(C
FCl2) α-': 3430, 1800.1765 Reference example 1 Su(R)-2-1: (38,4R)-3-((匈-1-1
゜-Butyldimethylsilyloxyethyl)-2-oxoazetidin-4-yl]propionic acid 2'-benzothiazolinoneamide (313 mg) ffi methanol (3-
) and IN aqueous sodium hydroxide solution (2mj)t
- and stirred overnight at room temperature. After washing with ethyl acetate, the mixture was made acidic with dilute hydrochloric acid. After extraction with ethyl acetate and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain (R
)-1-((38,4R)-3-((R)-1-t-butyldimethylsilyloxyethyl]-2-oquinazetedin-4-yl)propionic acid (205 NIg) was obtained.

NMR (CD3.OD) δppm: 0.07 (3
H,s),,0.08 (3[(,s),0.89 (
9H,s), 1.18 (3F(,d,J=6Hz),
1.21 (3H, d, J-7Hz), 2.58 (
IF(.

q'Jint8t, J! 7H2), 3.00 (I
H, t, J = 2t (z) j3.8G (1H, dd
, J-7,2 [(z), 422 (1H, dq.

J=6.2Hz) IR (KBr) Cm, 3450, 3300
, 1720(R)-2-1:(38,4R)-3-((
R)-1-1-7'Tyldimethylsilyloxyethyl)
-2-oxo-azetidin-4-yl]propionic acid 2
-benzoxacillinone amide and (s) -2-[:(
3s,4R)-2-((1-1-t-butyldimethylsilyloxyethyl)-2-oxo-2-azetidin-4-yl]propionic acid 2-benzoxacylinone amide 6=1 mixture.

(30 tsp) was dissolved in methanol (1-), 0.5N hydroxide solution (1-) was added, and the mixture was stirred at room temperature for 4 days. After washing with ethyl acetate, the mixture was made acidic with dilute hydrochloric acid. After extraction with ethyl acetate and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain (R)-1-C(38,
4R)-3-((R)-1-1-butyldimethylsilyloxyethyl-2-oxoazetidin-4-yl)propionic acid and (S)-1-((3B, 4R)-3-
A (6:1) mixture of ((R)-1-t-7'' tildimethylsilyloxyethyl,)-2-oxoazetidin-4-yl]propionic acid was obtained.

IR(KBr)an: 3450. 3300
．． 1720 Reference direction 3 Water-accumulated sodium (2N9) Suspended in t-anhydrous tetrahydrofuran (0.2m), 3-(s)-Merka 7
')-1-(4-Nitrobenzyloxycarbonyl)pyrrolidineC25M9)k Anhydrous tetrahydrofuran (0,
3ml) and stirred for 5 minutes. enemy)-2-
((3S,4R)-3-((R)-1-1-butyldimethylsilyloxyethyl)-2-oxoazetidin-4-yl]propionic acid 2-benzothiazolinoneamide (4 mg) i anhydrous tetrahydrofuran (0 ,5d)K
The mixture was added and stirred at room temperature for 1 hour. The reaction mixture was subjected to thin layer chromatography on silica gel and developed with ethyl acetate/hexane = 2/1 to obtain (sulfur-2-((3S,
4R) -s-((odor-1-1-butyldimethylsilyloxyethyl)-2-oxoazetidin-4-yl)propionic acid (8) -1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-yl thioester 3ys
I got yt.

IR(CHCt5) an-': 3400, 17
60, 1690 Reference Example 4 (R)-2-((3s, 1)-3-((n)-t-1-
butyldimethylsilyloxyethyl)-2-oquinazetinon-4-yl]propionic acid 2-pe/zooxazolinonamide and (S)-2-((38,4R)-3-(
(R)-1-t-butyldimethylsilyloxyethyl)
-2-oxoazetidin-4-yl)propionic acid 2
- 15=1 mixture of benzoxacillinone amides (23
5mq)? In the same manner as in Reference Example 3, (R)-2
-((38,4R)-3-((R)-1-t-butyldimethylsilyloxyethyl)-2-oxoazetidine-
4-yl]propionic acid (S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthioester 180η was obtained.

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 represents an optionally protected hydroxyl group, a group, or an alkyl group optionally substituted with a halogen atom, R^2 represents a hydrogen atom or an alkyl group, and R^3
represents an aromatic ring group formed by combining two adjacent carbon atoms which may have substituents, and X represents an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group or an NR^4 group (R^ 4 represents a hydrogen atom, an alkyl group, or a phenyl group), and Y represents an oxygen atom, a sulfur atom, or an NR^5 group (R^5 represents a hydrogen atom, an alkyl group, or a phenyl group). A β-lactam compound having the following.