JPS63185994A - Production of beta-lactam compound - Google Patents

Abstract

PURPOSE:To enable production of the titled compound which is optically active in 3, 4 positions, by using an optically active amine as a catalyst when cis form in 3,4-positions of 2-azethydinone derivative which is a synthetic intermediate to carbapenem compound, etc., of antimicrobial agent is obtained. CONSTITUTION:A compound expressed by formula I (R<1> is carboxy protecting group; R<2> is lower alkyl or phenyl; R<3> is lower alkyl) is reacted with a compound expressed by the formula X-CH2COCl (X is phthalimide or azide) in an inert solvent in the presence of an optically active amine (e.g. nicotine, etc.) to provide the cis form in 3,4-positions of the aimed compound expressed by formula II. The reaction is normally carried out using the acid chloride of 1.0-1.5 equivalent and the optically active amine of 1-2 equivalent based on the compound expressed by formula II, preferably at -50 deg.C-room temperature for 30min-24hr. An optically active compound expressed by formula III is especially useful as the compound expressed by formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a 2-
The present invention relates to a method for producing azetidinone derivatives, particularly optically active forms thereof.

Formula (II) CO,R' (wherein R1 is a carboxy protecting group commonly used in the chemistry of synthetic penicillins or synthetic cephalosphorins, Rt is lower alkyl or phenyl, and R3 is lower alkyl) The compound represented and the formula (III)
) (wherein X is phthalimide or azide) and an optically inactive amine in an inert solvent,
For example, by reacting with triethylamine as a catalyst,
) (wherein R1, R2, R3 and X have the same meanings as above)
It is already known that the 3,4-cis form of the 2-azetidinone derivative represented by
91). However, in this method, optically inactive compounds are used as compounds (II) and (III), and therefore the cis form of compound (1) obtained is also optically inactive.

In addition, attempts to synthesize optically active β-lactam rings (so-called asymmetric synthesis) have been reported (for example, Canadian Journal of Chemistry, Vol. 58, p. 1605, 1980, Chemistry Letters 1).
853, 1980, etc.), but all of these are asymmetric syntheses using chiral molecular species (ChiralSyn thon) as reaction raw materials.

On the other hand, various asymmetric synthesis methods using optically active compounds as catalysts have been known so far. For example, there are examples of asymmetric synthesis using optically active bases, such as strychnine and brucine, as catalysts for the addition reaction of optically inactive alcohols to various optically inactive ketenes [translated by Yuzo Inoue et al. ,
Asymmetric synthesis, Tokyo Kagaku Dojin (1973), 296, 343
, 344, etc.].

5. Now, without using asymmetric molecular species, optically active β-
There is no known method to synthesize lactam rings.

The present invention provides the formula (II) CO2R' (wherein R' is a carboxy protecting group commonly used in the chemistry of synthetic penicillins or synthetic cephalosporins, and R2
is lower alkyl or phenyl, and R3 is lower alkyl) and the compound represented by formula (III) X CHzCOCj! (I[I
) (wherein, R1,
The present invention relates to a method for producing the cis form at the 3 and 4 positions of a compound represented by (R1, Rff and

Hereinafter, the compounds represented by formulas (I), (II), (III), etc. will be referred to as compound (I), compound (■), compound (In), etc., respectively. In addition, the optically active form regarding the 3 and 4 positions of the 3 and 4 cis form of the compound (1) is converted into a compound ('l-1).
That's what it means.

Next, the method of the present invention will be explained in more detail. R in formula (■)
The ester residue represented by 1 is a carboxyl protecting group commonly used in penicillin and cephalosporin chemistry, and includes methyl, ethyl, n-propyl, i-propyl, n-propyl,
CI~ of -butyl, sec-butyl, L-butyl groups, etc.
C3 lower alkyl group, halogenated lower alkyl group such as 2,2.2-trichloroethyl, 2.2.2-trifluoroethyl, benzyl, 0-nitrobenzyl, p-
unsubstituted or substituted aralkyl groups such as nitrobenzyl, p-methoxybenzyl group, benzhydryl group, trityl group, unsubstituted or substituted phenacyl groups such as phenacyl, p-chlorophenacyl, p-bromphenacyl, trimethylsilyl, dimethyl- Indicates a tri-lower alkylsilyl group such as t-butylsilyl. R2 or R3
The lower alkyl group represented by is methyl, ethyl,
Examples include 01-C5 linear or branched lower alkyl groups such as n-propyl, i-propyl, n-butyl, and 5eC-butyl groups.

Optically active amines include nicotine, brucine, 0-acetyl cinchonidine, 0-acetyl cinchonine, N, N-
Dimethyldehydroabiethylamine, N,N-dimethyl-α-phenylethylamine, N-methyl-2-acetoxyethylpyrrolidine, N-methyl-2-benzoyloxyethylpyrrolidine, N,N-dimethylmenthylamine and N-(di) Examples include tertiary amines such as alkyl amino acid esters. Here, as the N-alkyl group of the amino acid, there are lower alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, 5ec-butyl, and mu-butyl, and as the esters, N-
These include alkyl groups and benzyl groups similar to alkyl groups, such as N-methylproline methyl ester, N-methylproline also monobutyl ester, isobutylproline methyl ester, N,N-dimethylalanine methyl ester, N,N- Dimethylvaline methyl ester and N
, N-dimethylvaline t-butyl ester, and the like. The compound (■) and its manufacturing method are disclosed in JP-A-128-1988.
591.

Examples of inert solvents include halogenated lower alkanes such as methylene chloride, chloroform, carbon tetrachloride dichloroethane, aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, and cumene, diethyl ether, diisopropyl ether, tetrahydrofuran dimethyl cellosolve, etc. , esters such as ethyl acetate, cyclohexane, acetonitrile, methyl ethyl ketone dimethylformamide, and the like.

Compound (I[[) is usually 1.0 relative to compound (If)
~1.5 equivalents, and the optically active amine is usually used in an amount of 1 to 2 equivalents relative to compound (II).

The reaction is carried out at -50° C. to reflux, especially at -50° C. to room temperature, and is completed in 30 minutes to 24 hours.

After the reaction is completed, the optically active compound (I-1) can be isolated and purified by isolation and purification methods of general synthetic chemistry, such as extraction, chromatography, and crystallization.

The cis form of the 3.4-position of compound (1) includes the 61 form and the optically active form (1-1).

Compound (1-1) is a compound represented by either of the following two formulas.

cozR' compounds (1-1-1) and (1-1-2) are disclosed in JP-A-57
-91991 or JP-A-55-145685 by a method similar to that described in JP-A-55-145685, respectively, can lead to a compound represented by the formula % (formula %), (wherein Y is azide, phthalimide or amino), Compounds (IV-1) and (IV-2) in which Y is amino can be further acylated into compounds with antibacterial activity (
For example, JP-A-56-30976). The antibacterial activity of the final compound is determined by the i-form and (IV-2) with the skeleton of formula (IV-1).
It is far superior to the one with the skeleton. Therefore, compound (1-1-1) is usually more suitable for df form and compound (1-1-2).
) is much more useful.

Whether more of (1-1-1) or (I-1-2) can be obtained by the method of the present invention depends on the type of optically active amine, the type of solvent, the reaction temperature, etc.

tip opening EXAMPLES The present invention will be specifically explained below with reference to Examples.

Note that the optical yields (o, y, ) described in Examples were determined by the following method.

The compound (T) obtained according to the example is shown in the following reference figure (1
) Compound (IV-3) was obtained according to (JP-A-57-919
91) The compound (■) was further deesterified (see Reference Examples 1 and 2 above), and its degree of light absorption was measured (
Let the obtained value be [α) obs. ) (■) Reference diagram (1) (V) (Vl) (IV-3) [In the formula, Rl, R! and R3 have the same meanings as above, Ph
tN represents a phthalimide group] The other (+) -7β-amino-1-azabicyclo(4,
2,O]oct-2-en-8-one-2-carboxylic acid (■) (JP-A-56-30976) and N-carbetoxyphthalimide (Nefkens reagent) were reacted to form the compound (
(+)-7β-phthalimido-1-azabicyclo(4,2,0)oct-2-en-8-one-
2-carboxylic acid (see Reference Example 3), and its degree of light exposure was measured (the obtained value is defined as [α) max). The optical yield (o, y, ) was determined from the following formula.

Example 1 Cis-4-(3,3-dimethoxy-1-propene-1-
yl)-3-phthalimido-2-oxoazetidine-1-
yl-α-diethylphosphonoacetic acid, R' = tBu
, R2=Et, R''=CI!+ 3.4-position cis form of the compound] α-amino-α-diethylphosphonoacetic acid, tert-butyl ester 2.67 g (0.01 mol) and 1.43 g (1,1 equivalent it) of 4,4-dimethyl-trans-2-butinal were dissolved in 3 tan of solvent, and
ml was added and stirred at room temperature for 30 minutes. Add this solution to 17
mA! The column was passed through a column of molecular sieves, and the column was further washed three times with the same solvent for 10IllIl. The generated Schiff base [R' = "Bu in II (II),
A base (1,2 equivalent M) and 5 g of molecular sieve were added to the combined eluate and washing solution containing the compound with R" = nt and R' = CflB.

30mj of the same solvent used for Schiff base generation! 2.46 g of phthalylglycinate chloride (1,1
equivalent amount) was added dropwise to the Schiff base solution over 0.5 to 1 hour while maintaining the reaction temperature shown in Table 1. After the dropwise addition, the mixture was stirred in the chamber for 3 hours to complete the reaction. Although the title compound was contained in the reaction solution obtained in this way, the chemical yield was determined to be cis-4-(3-oxo- 1-propen-1-yl)-3-
Phthalimido-2-oxoazetidin-1-yl-α-diethylphosphonoacetic acid, tertiary butyl ester [compound represented by R' = 'Bu, R'' = Et in formula (V)] The ratio was further determined by the method described in Reference Example 2.
0) Oct-2-ene-8-oxo-2-carboxylic acid [
[compound represented by formula (■)]].

The results are shown in Table 1. The structure of the title compound was partially purified by silica gel chromatography, and was confirmed by NMR and IR, as it matched with the compound described in Reference Example 1 of JP-A-57-91991.

Table 1 Book 1 Total yield of α-amino-α-diethylphosphonoacetic acid, tertiary butyl esterophore 1, etc. *2 [α) (C〒0.5 Phosphorus N Mimorikanumashi H7
, O) As shown in Table 1, the optical rotation was measured in the same manner as in Examples and Reference Examples using optically inactive triethylamine as a base, and as a result, there was no optical rotation at all. It is clear that the production method involved asymmetric synthesis using an optically active amine, rather than asymmetric resolution in a separation and purification process such as chromatography or crystallization.

Reference example 1 cis-4-(3-oxo-1-propen-1-yl)-
3-phthalimido-2-oxoazetidin-1-yl-α
- Production of diethylphosphonoacetic acid, tertiary butyl ester 10 mff1 of an acetone solution containing p-toluenesulfonic acid (2 equivalents) was added to the reaction solution containing the crude acetal compound obtained in Example 1, and the mixture was heated for 20 to 30 minutes. Stirred.

The molecular sieve was filtered off, and the filtrate was washed successively with water, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (Wakogel C-20080 g, eluent: n-hexane/ethyl acetate-1/l) to obtain the desired product as a crystalline oil. The yield (total yield from α-amino-α-diethylphosphonoacetic acid, tertiary butyl ester) is as shown in Table 1. The structure of the title compound is disclosed in JP-A-57-
This was confirmed by matching the IR and NMR spectra described in Reference Example 2 of 91991.

Reference Example 2 Cis-7-phthalimido-1-azabicyclo[4°2.0
] Production of oct-2-ene-8-oxo-2-carboxylic acid The aldehyde compound obtained in Reference Example 1 was dissolved in a 90% aqueous methyl ethyl ketone solution, and 10% palladium on carbon [approximately 30% (W/W) to aldehyde After the completion of the reaction (usually several hours to several tens of hours), the catalyst was filtered off, dimethylethanolamine (2 equivalents to aldehyde compound) was added to the filtrate, and the mixture was stirred for 30 minutes to 1 hour. After that, it was left at room temperature overnight. The solvent was then distilled off under reduced pressure, and chloroform was added to the residue, which was washed successively with 10% citric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (Wakogel C-20020 g, eluent: chloroform). The crude product was dissolved in a small amount of chloroform, ether was added under water cooling, and the precipitated crystals were collected by suction filtration and then dried under reduced pressure to obtain the tertiary butyl ester compound of the title compound [formula (I
V-3), R' = tB! Compound represented by]
I got it. IR and NMR of this product are JP-A-57-9199.
1 corresponded to the compound described in Example 3.

Then, about 10 times the amount (v) of the tertiary butyl ester compound
/w) of formic acid was added and stirred at room temperature for 5 hours. A small amount of chloroform was added to dissolve the precipitated crystals, and then ether was added while cooling with water to precipitate the crystals. The residue was collected by suction filtration, washed with ether, and then dried under reduced pressure to obtain white crystals of the desired product.

Rf (+i = 0.23 (chloroform/methanol = 4/1) 0.39 (ethyl acetate/acetic acid = 10/1) N M R (
CDCl 3) δ: 7.85 (4H, a), 6.42
(IH, t).

5.62 (IH, d, J=5Hz), 3.7-4.2
(IH, m), 1.7 to 2.7 (411, ++)
The light absorption degree ((α) obs) of the title compound and the results of o and y calculated therefrom are as shown in Table 1.

Reference Example 3 (+)-7β-phthalimido-1-azabicyclo(4,
2,0) Production method of oct-2-en-8-one-2-carboxylic acid (+)-7β-amino-1-azabicycloC4,2゜0
] Oct-2-en-8-one-2-carboxylic acid [[α
) = +65.9 (C-0,37 phosphate buffer pH 7
, O) To 200 μm (1.1/l mole) of sodium carbonate and 3 tails of water were added and dissolved, and to this was added 480 μm of N-carbetoxyphthalimide.
(2.2 mmol) was added and the mixture was stirred for 7 hours at room temperature and then heated overnight. Insoluble matters were removed by filtration, and the filtrate was acidified with IN hydrochloric acid, and the precipitated crystals were collected by suction filtration, washed with water and ether, and then dried under reduced pressure to obtain the desired product 140.mu. (yield: 40.8%). The Rf value, IR and NMR of this compound matched those obtained in Reference Example 2. The light intensity is [α)=+42.2(
C=0.5 phosphate buffer pH 7.0), which was defined as [α) max.

In addition, an asymmetric synthesis of an optically active β-lactam ring was carried out using an optically active amine as a catalyst.

Claims (3)

[Claims] (1) Formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 is a carboxy protecting group commonly used in the chemistry of synthetic penicillins or synthetic cephalosporins, and R^
2 is lower alkyl or phenyl, R^3 is lower alkyl) and the compound represented by formula (III) X-CH_2COCl(III) (wherein, X is phthalimide or azide) Formula (I) characterized by reacting a compound with a compound in the presence of an optically active amine in an inert solvent ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1, R^ 2, R^3 and (2) The production method according to claim 1, wherein the cis form of formula (I) is further an optically active form regarding the 3- and 4-positions. (3) Formula (I) is represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2, R^3 and X have the same meanings as in formula (I)) The manufacturing method according to claim 2, characterized in that: