FR2579595A1 - PROCESS FOR THE PREPARATION OF AZETIDINONE DERIVATIVES - Google Patents

Abstract

THE INVENTION CONCERNS THE PREPARATION OF AZETIDINONE DERIVATIVES OF FORMULAS IA ANDOU IB (CF DRAWING IN BOPI) OBTAINED AND ELIMINATION OF THE PROTECTIVE GROUP R OF THE DIASTEREOMERIC PAIR OF FORMULA II: (IN FORMULAS III AND II, R IS AS DEFINED ABOVE) OBTAINED BY OXIDATION AND ISOLATION OF THE DIASTEREOMERIC MIXTURE OF THE COMPOUNDS OF FORMULAS IA AND IB, OR, IF DESIRED, SEPARATION OF THE COMPONENT OF FORMULA IA FROM THE COMPONENT OF FORMULA IB BY SELECTIVE CRYSTALLIZATION.

Description

The present invention relates to a new process for preparing d.

  : seen from azetidinone of formulas (la) OH H1H I Coszz H, COOCH

C, 2 3

HHla NH and / or (Ib)

OH H H

13 CH2COOCH.I

H3C lb NH

  The trans compounds of formulas (Ia) and (Ib) are diastereo-

  mrs, which differ from each other in the configuration of the hydroxyl group.

  LP term "diastereomeric" is used here and throughout the description and the

  claims to refer to the racemic modifications of given diastereomers. According to the prior art, the diastereomers of formula (Ia) are prepared from a pvranone derivative containing the Cree hydrogen atoms; in the desired configuration ("lactone"), while the diastereomer of formula (Ib) is obtained by the transisomerization of the diastereomer of formula (Ia) and converted into thienamvcin (European patent

  840), which is a well known broad-spectrum antibiotic.

  The compounds of similar structure (azetidinone-

  benzhydryl-acetic acid esters) from trans-type intermediates.

  azetidinone in the form of a diastereomeric mixture according to the beige patent

N 899 936.

  It has been found experimentally that the acidic treatment followed by the reduction of the azetidinone derivatives of formula (IV) ## STR2 ##

\ C / H

C CH2 COOCH3

  Or wherein R 3 is a protecting group which can be removed by oxidation, said compound of formula (IV) being a mixture of cis and trans isomers, gives only compounds of formula (II) = ccH H

I C CH2 COOCHI

H 3 é1112

H NX

GOLD

  before a trans configuration (R is as defined above). We found

  further that after removal of the protecting group R from the diastereo-

  The method of the present invention provides that the diastereomer of formula (Ia) can be selectively crystallized, which is advantageous in that during synthesis, unlike the process described in European Patent No. 62,840, it is not It is necessary for the azetidinone intermediates to be converted to the corresponding pyranone derivatives containing the critical substituents in the desired configuration and then to convert said pyranone to the target azetidinone compound, instead the desired configuration is developed.

  on the skeleton azetidinone itself.

  In the case of the structurally similar compounds described in Belgian Patent No. 899 936, the components of the diastereomeric mixture obtained can not be separated by selective crystallization as in the process according to the invention, and the separation can be carried out only by chromatography. The invention relates to a method for the preparation of the azetidinone derivatives of formulas (Ia) OH NH O and / or (Ib)

OH H H

I C | 12 COOCH3

H3C b

H M

H NH

  by ai) treatment of a compound of formula (IV)

\ / C H H

CH2 COOCR3

GOLD

  (R is a protective group which can be removed by oxidation), which is a mixture of cis and trans isomers, with an acid and reduction of the compound of formula (III) ## STR2 ##

I II

H3 C X CH2 COOCH3I

H3 R

  0NR obtained and removal of the protective group R of the diastereomeric pair of formula (II) in the formulas (III) and (II) R is as defined above) obtained by oxidation and isolating the diastereomeric mixture of the compounds of formulas (Ia) and (Ib), or, if desired, separating the component of formula (Ia) from the component of formula (Ib) by selective crystallization, or a2) reduction of a compound of formula (III), and removal of the protective group R from the diastereomeric pair of formula (II) (in formulas (III) and (II) R is as defined above) obtained, by oxidation, and isolation of the diastereomeric mixture of the compounds of formulas (Ia) and (Ib), or if desired, separation of the component of formula (Ia) from the component of formula (Ib) by selective crystallization, or

  a3) removal of the protective group R from the diastereo-

  of formula (II) (R is as defined above) and isolation of the diastereomeric mixture of compounds of formulas (Ia) and (Ib) obtained, or if desired, separation of the component of formula (Ia) from with the formula component

  (Ib) by selective crystallization.

  In the process according to the invention, an isomeric mixture of a compound of formula (IV) is used as starting material, which can be prepared as follows: A isomeric mixture cistrans of formula (VII) is subjected to hydrolysis ) C / H> / COOC, Hs V II H3 C Ns

GOLD

  described in US Pat. No. 4,434,099. The azetidinone-carboxylic acid isomeric mixture of formula (VI) is then reacted.

\ H /

H3C / XCOOH I

  R with a carboxyl activator and then with diazomethane. The isomeric mixture of diazoketone of formula (V) o is then subjected

\ /, H H

H3C XCHCOCHN2

H3C V

GOLD

  obtained at a rearrangement of diazoketone (that is to say to a diazo exchange) in the presence of water, and the acetic azetidinone acetic acid derivatives obtained are converted into a cis-trans isomeric mixture of formula (IV) with diazomethane . In the general formulas (VII), (VI) and (V), R represents a protecting group which can be removed by oxidation. The transformation

  (VII) -> (VI) .. '(V) --- (IV) will be specified in more detail in the examples.

  The ethylenecetal group of the compounds of formula (IV) is removed by acid treatment. For this purpose, for example, sulfonic acid, e.g. ex. p-toluenesulfonic acid. a silyl halogen, p. ex. a silyl halide formed from a mixture of sodium iodide and silicon tetrachloride or sodium iodide and trimethyl silicon chloride, or a mineral acid, preferably perchloric acid. Decetalization is preferably conducted in a mixture of a suitable organic solvent, preferably a ketone, e.g. ex. acetone or a chlorinated hydrocarbon and acetonitrile. The reaction mixture is then neutralized and, if desired,

  the compound of formula (III) is isolated.

  The compound of formula (III) is then reduced. The reduction is preferably conducted with a complex metal hydride, preferably alkali metal / tetrahydridoborate (III). The compound of formula (II) obtained has a trans configuration, that is to say during the transformation

  (IV) --- (II) from a cis compound a trans isomer is obtained.

  Then, the protective group R of the compound of formula (II) obtained is removed by oxidation. R is preferably benzyl or phenyl substituted by one or more methoxy groups. The dimethoxybenzyl group can be removed with a peroxydisulfate oxidizing agent, while for the removal of the methoxyphenyl group the combination of a

cerium (IV) salt and an acid.

  The oxidation gives a mixture of the diastereomers of formulas (Ia) and (Ib) which is isolated, or. preferably, the major part of the diastereomer of formula (Ia) is isolated by selective crystallization. The crystallization is

  preferably conducted in dichloromethane. It can be separated by chromato-

  the mixture of the diastereomers of formulas (Ia) and (Ib) remaining in

  the mother liquor. The compounds of formulas (Ia) and (Ib) are racemates.

  The invention will be specified by the following nonlimiting examples.

EXAMPLE 1

  34.8 g (0.0918 mol) of a mixture of cis- and trans-

  ethyl- / 1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine

  carboxylate / in 50 ml of pyridine, and to the solution is added 3.67 g (0, 0918 mol) of sodium hydroxide dissolved in 100 ml of water. The mixture is stirred at room temperature for 12 hours, after which 500 ml of water are added to the solution, which is then extracted with three parts of 1 ml of diethyl ether. The phases are separated, the aqueous phase is adjusted to pH 1 with a concentrated aqueous hydrochloric acid solution and then extracted with three 100 ml portions of dichloromethane. The dichloromethane phase is dehydrated with anhydrous magnesium sulfate, filtered and the filtrate is evaporated. Yield: 28.7 g (89%) of an acid mixture

  trans- and cis-11- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo

2-azetidine-carboxylic acid.

EXAMPLE 2

  a) 28.7 g (0.816 mol) of a mixture of cis- and

  trans- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine

  the carboxylic acid prepared according to Example 1 in 290 ml of dry tetrahydrofuran, and 13.6 ml (0.097 mol) of triethylamine are added to the solution and then

  while cooling with ice, 9.5 ml (0.097 mol) of ethyl chloroformate.

  The reaction mixture is cooled to -15 ° C. and after stirring for a minute the precipitated triethylamine salt is filtered off under an argon atmosphere. To the filtrate is added diazomethane prepared from 36.75 g (0.245 mol) of N-methyl-N-nitrosourea and dissolved in 370 ml of

  cold diethyl ether. The reaction mixture is allowed to warm to room temperature.

  ambient temperature while stirring, and after two hours it is evaporated

  to dryness under vacuum. The evaporation residue is subjected to chromatography

  graphisur column. (Adsorbent: 400 g of silica gel G, eluent: mixture: 1 of dichloromethane and acetone). Yield: 16.3 g (53.3%) of a mixture

  cis and trans-4- (diazoacetyl) -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxol)

2-yl) -2-azetidinone.

  IR (film): 2900, 2110, 1760 cm -1.

  b) The product of step a) is dissolved in a mixture of 800 ml of peroxide-free tetrahydrofuran and 320 ml of water, and the solution is irradiated with a high-pressure mercury lamp (HPK 125) in 8 times. , in a Pyrex apparatus, under an argon atmosphere, up to

  that the starting compound is exhausted. The reaction mixtures are evaporated.

  combined with a volume of 300 ml, is made up to 1200 ml with water, and made alkaline with about 20 ml of a 10% aqueous solution of hydroxide

  sodium. The mixture is then extracted with three 200 ml portions of dichloromethane.

  methane. The aqueous phase is acidified to pH 2 with a concentrated aqueous solution.

  hydrochloric acid, and the acid solution is extracted with three 160 ml portions of dichloromethane. The combined extract is dehydrated with sulfate

  anhydrous magnesium, filtered and the filtrate evaporated to 50 ml.

  To the concentrated solution is added a solution of diazomethane prepared from 6.0 g of N-nitroso-N-methyl-urea in 60 ml of ether, while cooling with ice water. When the evolution of nitrogen is complete, the excess diazomethane is decomposed with acetic acid and

  the reaction mixture is evaporated.

  Yield: 11.2 g (68%) of a mixture of cis- and trans-methyl- / 1- (2,4-dimethoxy)

  benzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine acetate /. IR (film): 3000-2840, 1750, 1720 (flexion) cm c) The product of step b) is dissolved in 250 ml of acetone and to the solution is added 5 ml (0.056 mol) of 70% perchloric acid aqueous solution while cooling with ice water. The mixture is stirred under ice-cooling for one hour, after which 5.22 g (0.062 mol) of sodium bicarbonate is added, and stirring is continued for a further 5 minutes. The reaction mixture is evaporated to dryness in vacuo. 150 ml of absolute methanol are added to the residue and then with stirring

  and cooling with ice-water, 0.92 g (24.5 mol) of tetrahydrido-

  borate (III) / sodium. The mixture is stirred for one hour with cooling with ice water, after which its pH is adjusted to 7 with acetic acid and the mixture is evaporated. The residue is suspended in 200 ml of dichloromethane, which is extracted with two fractions of 25 ml of water and then ml of saturated aqueous sodium chloride solution. The organic phase is dehydrated with anhydrous magnesium sulfate, filtered, and

  evaporate the filtrate. The residue is subjected to column chromatography.

  (Adsorbent: silica gel G, eluting agent: 10: 1 mixture of dichloromethane

and acetone, 200 kPa).

  Yield: 6.1 g (54%) of a mixture of methyl-1- (2,4-dimethoxybenzyl) -3 (SR) -

  1 (RS and SR) -hydroxyethyl-4-oxo-2 (RS) -azetidine-acetate3-1 IR (film): 3430, 1750, 1720 cm -1 H-NMR (CDCl3): 1.29 d and 1 , 33 d (3H, J = 6.5 Hz), 2.60-3.78 m (2H), 2.7 s diff (1H), 2.88 dd and 2.94 dd (1H, J = 2 , 5 Hz and 6.5 Hz), 3.71 s (3H), 3.75-4.00 m (1H),

  4.11 quintuplet and 4.14 quintuplet (1 H, J = 6.5 Hz), 6.5 s diff (1H).

EXAMPLE 3

  2.7 g (8 mMoles) of isomeric mixture of methyl-

  1- (2,4-Dimethoxybenzyl) -3 (SR) -1- (RS and SR) -hydroxyethyl-4-oxo-2 (RS) azetidine

  acetate in a mixture of 40 ml of acetonitrile and 10 ml of water. To the solution is added in four equal parts, while stirring and under reflux, under a

  argon atmosphere, a solution of 8.65 g (32 mMoles) of dipotassium persulfate

  (K2S2 O8) and 11.4 g (64 mMoles) of disodium biphosphate in 40 ml of water. The reaction mixture is refluxed for another hour

  while stirring, and evaporated under vacuum, on a bath at 50 ° C.

  The evaporation residue is treated with 50 ml of dichloromethane, the dichloromethane solution (MgSO 4) is dehydrated and subjected to column chromatography (adsorbent: 50 g of silica gel G, eluting agent

  7: 2 mixture of dichloromethane and acetone, 200 kPa).

  Yield: 1.06 g (80.2%) of a mixture of methyl-f (2RS3SR) -3- / 1 (RS and M) -

  hvdroxyéthyl / -2-azetidine acetate}. The resulting mixture of diastereomers is dissolved in 2-3 ml

  dichloromethane, and the precipitated crystalline 1SR diastereomer is isolated.

  Yield: 0.29 g (21%) of methyl- (2RS, 3SR) -3- / 1 (SR) -hydroxyethyl / -2-azetidine

acétatel.

Melting point: 87 C.

  IR (KBr): 3300, 3200, 1720 cm -1H NMR (CDCl3) δ: 1.32d (3H, J = 6.5Hz); 2.69 d (2H, J = 7.0 Hz); 2.82 s (1H, diffuse); 2.94 dd (1H, J = 2.5 Hz and 6.0 Hz); 3.71 s (3H); 3.85 dt (1H, J = 2.5 Hz

  and 7.0 Hz); 4.11 quintuplet (1H, J = 6.5 Hz); 6.5 s (1H, diffuse).

  The evaporation of the mother liquor obtained when the crystalline 1SR diastereomer is isolated gives a mixture of the diastereomers of formulas

(Ia) and (Ib).

  IR (film): 3500-3100 (diffuse), 1760-1720 cm-1 If desired, the components can be separated by chromatography

  of the diastereomeric mixture above.

Claims (4)

  1. Process for preparing azetidinone derivatives of formulas (Ia) OH H H c ^^^^^^^ C H20COOCH3 H3C A NH and / or (Ib) OH H H 1! C CH COOCH H C 2   NH o in which one proceeds in which one proceeds by al) treatment of a compound of formula (IV) C H H3 C <CH2 COOCH3 H3C 2IV   N (R is a protective group which can be removed by oxidation), which is a mixture of cis and trans isomers, with an acid and reduction of the compound of formula (III) CH 2 COOCH 3 H3C I gold 0 N R   obtained and elimination of the protective group R of the diastereomeric pair of formula (II) OH H H H CH2 COOCH3 H 3C H 0 N   O (in the formulas (III) and (II) R is as defined above) obtained, by oxidation, and isolation of the diastereomeric mixture of the compounds of formulas (Ia) and (Ib). or, if desired, separating the component of formula (Ia) from the component of formula (Ib) by selective crystallization, or a2) reducing a compound of formula (III), and removing the protecting group R from the diastereomeric pair of formula (II) (in the formulas (III) and (II) R is as defined above) obtained, by oxidation, and isolation of the diastereomeric mixture of the compounds of formulas (Ia) and (Ib), or it is desired to separate the component of formula (Ia) from the component of formula (Ib) by selective crystallization, or   a3) removal of the protective group R from the diastereo-   of formula (II) (R is as defined above) and isolation of the diastereomeric mixture of compounds of formulas (Ia) and (Ib) obtained, or if desired, separation of the component of formula (Ia) from with the formula component   (Ib) by selective crystallization.   2. Process according to claim 1, variant ala of the process, wherein the acid treatment of the compound of formula (IV) is carried out with perchloric acid. 3. Process according to claim 1, variant al) or a2) of the process, in which the reduction of the compound of formula (III) with a hydride is carried out. complex metal.   4. Method according to claim 1, variant a1), a2) or a3) of the process, o   the diastereomer of formula (Ia) is crystallized from dichloromethane.