NO179446B - Process for the preparation of propargylazetidione compounds - Google Patents

Description

According to the parent application (91.1368, patent 178624), new 2-substituted alkyl-3-carboxy carbapenems with the formula

where

R<1> is an R<4> B group where R<4> is a hydroxyl group, benzyloxycarbonyloxy or tertbutyldimethylsilyloxy, and B is a C 1 -C 4 alkylene group;

R<2> is hydrogen;

R<3> is hydrogen, a straight or branched chain lower alkyl group or a water-soluble cation selected from lithium,

sodium and potassium;

X is F, Cl, Br or I; and

Y is CO2H or CO2<R16>;

there

R<16> is a lower alkyl group with a straight or branched chain.

With regard to the production and effect of the aforementioned compounds, reference is made to the parent application.

This invention relates to a method for the production of starting materials for use in the production of the compounds of formula I.

According to the invention, a compound with formula is produced:

there

R<1> is an R<4> B group, where R<4> is tert-butyldimethylsilyloxy; and

B is a C 1 -C 4 alkylene group,

R<5> is H or CH2COOH

The method is characterized by turnover of a compound

with formula:

where R<1> is as defined here above with there

R<22>= Cl, Br or I;

with magnesium or zinc in the presence of a Lewis acid,

to form a compound of formula XX wherein R<5> is H,

and optionally reacting said compound with R<23>CH2C02H where R<23> is chlorine, bromine, iodine or toluenesulfonyl, in the presence of a base selected from the group consisting of lithium bis(trimethylsilyl)amide, lithium hydride or sodium hydride, in a mixed solvent system selected from diethyl ether:N,N-dimethylformamide, toluene:N,N-dimethylformamide and tetrahydrofuran:N,N-dimethylformamide, to form a compound wherein R<5> is -CH2-COOH.

The procedure can be illustrated as follows:

Step 2 is used if you want a compound where R<5> is

CH2COOH.

The invention is described more carefully in connection with the following specific examples.

Example 1

r3S- r3alpha( S*) . 4beta11- 3- Tl- r r( 1 . 1- dimethylethyl)-dimethylsilyloxylethyl]- 4-( 2- propyl)- 2- azetidinone

To a dry three-necked round flask equipped with a mechanical stirrer, 1000 ml addition funnel and thermometer, 146.6 g of zinc and IL tetrahydrofuran are added. The suspension is stirred at 0° under an argon atmosphere while 800 ml of diethylaluminum chloride (1.8M in toluene) is added via cannula. A solution of 320 g of [3S-[3alpha(S<*>), 4beta]-4-(acetyloxy)-3-[l-[[(1,1-dimethylethyl)-dimethylsilyl]-oxy]ethyl]-2 -azetidinone and 168 ml of propargyl bromide (80% toluene solution) in 800 ml of tetrahydrofuran are added via addition funnel over 90 minutes and the reaction mixture is stirred at 0°C for 2 hours, then at room temperature overnight. The reaction mixture is cooled to 0°C and 200 ml of pyridine is added dropwise over 50 minutes. The solution is filtered through diatomaceous earth washing with dichloromethane. The filtrate is concentrated in vacuo to IL and the solid is dissolved in dichloromethane. The resulting solution is added over 45 minutes to a stirred 3L ice/water slurry and stirring is continued for a further 30 minutes. The solution is filtered through aqueous magnesium silicate and the filtrate is evaporated to give 196.6 g (66.9%) after recrystallization from heptane.

<1>H NMR (CDCl 3 ) S 0.078 (s, 6H), 0.877 (s, 9H), 1.23 (d, 3H), 2.05 (t, H), 2.54 (m, 2H), 2.90 (m, H), 3.86 (m, H), 4.21 (m, H), 5.98 (br s, OH).

IR (KBr) 1702, 1754 cm"<1>.

Example 2

r3S- r3alpha( S* 0 . 4betal1- 3- f I- T r 1. 1- dimethylsilvl1)-dimethylsilvl1oxy] ethyl1- 2- oxo- 4-[ 2- propynyl- l-azetidine- acetic acid

A 4.48 g suspension of pre-washed sodium hydride (50% dispersion in oil) in 200 ml anhydrous tetrahydrofuran is cooled in an ice bath under argon. A solution of 10 g of azetidinone prepared in Example 1 and 6.22 g of bromoacetic acid in anhydrous tetrahydrofuran is added to this suspension over the course of 30 minutes. The resulting reaction mixture is stirred for a further 20 minutes, then 16 ml of dry dimethylformamide is added dropwise. The ice bath is then removed and the suspension is stirred overnight at room temperature. 100 ml of IN hydrochloric acid is slowly added to the suspension, followed by 200 ml of water. The product is extracted in 3 x 300 ml of ethyl acetate. The organic phase is washed with 2 x 200 ml water, 2 x 200 ml saline solution, dried over magnesium sulfate and filtered. The filtrate is evaporated and gives, after recrystallization from hot hexane, 10.9 g of product (90.2%). Temp. 86-88°C.

<1>H NMR (CDCl 3 ) S 0.068 (d, 6H), 0.895 (s, 9H), 1.24 (d, 3H), 2.07 (m, H), 2.6 (m, 2H), 2.97 (m, H) , 3.98 (m, H) , 4.1 (q, 2H) , 4.2 (m, H) , 7.8 (br s, OH).

IR (KBr) 1702, 1755 cm"<1>.

Claims (1)

Procedure for the preparation of a compound of formula: there R<1> is an R<4> B group, where R<4> is tert-butyldimethylsilyloxy; and B is a C₁-C₁ alkylene group, R<5> is H or CH2COOH characterized by reacting a compound of formula: where R<1> is as defined here above with whereR2<2> = Cl, Br or I; with magnesium or zinc in the presence of a Lewis acid, to form a compound of formula XX where R5 is H, and optionally reacting said compound with R<23>CH2CO2H where R<23> is chlorine, bromine, iodine or toluenesulfonyl, in the presence of a base selected from the group consisting of lithium bis(trimethylsilyl)amide, lithium hydride or sodium hydride, in a mixed solvent system selected from diethyl ether:N,N-dimethylformamide, toluene:N,N-dimethylformamide and tetrahydrofuran:N,N-dimethylformamide, to form a compound wherein R<5> is -CH 2 -COOH.