FR2542317A1 - CARBAPENEM INTERMEDIATE COMPOUNDS AND PROCESS FOR PREPARING THE SAME - Google Patents

Abstract

THE PRESENT INVENTION CONCERNS NEW INTERMEDIATE COMPOUNDS OF CARBAPENEM PRESENTING THE FORMULA: (CF DRAWING IN BOPI) IT ALSO AIMS IN PARTICULAR A NEW PROCESS FOR THE PREPARATION OF THE INTERMEDIARY RESPONDING TO THE FOLLOWING FORMULA: (CF DRAWING IN BOPI) PRODUCTS ARE USEFUL IN THE SYNTHESIS OF THIENAMYCIN AND OTHER CARBAPENEM ANTIBIOTICS.

Description

2 42317

  The present invention relates to a new process for producing a key intermediate used

  in the synthesis of thienamycin and other anti-

biotic carbapenem.

  It also covers the compound or intermediate product

obtained by this process.

  The antibiotic thienamycin of formula

OH H

o =

SCH 2 CH 2 NH 2

NOT

O COOH

  was originally obtained by fermentation of Streptomyces

  cattleya as described in U.S. Patent No. 3,950,357.

  Thienamycin is a broad-spectrum and exceptionally potent antibiotic with significant activity against a variety of Pseudomonas species, which have been known to be resistant to

P / lactam antibiotics.

  Due to the outstanding biological activity of thienamycin, a large number of derivatives have been prepared although attempts have been made to synthesize derivatives with various substituents and other than hydroxyethyl at the 6-position of the carbapenem system or ring, the hydroxyethyl group is still considered the most advantageous substituent 6 for obtaining

an optimum activity.

  Since the fermentation methods for preparing thienamycin and its derivatives have been unsatisfactory, several methods of total synthesis have been described in the literature (see, for example, U.S. Patents 4,287,123, 4,269,772, 4,282,148; , 4,273,709, 4,290,947 and European Patent Application No. 7973) Although the various synthetic methods use different starting materials, they pass through a common diazo intermediate, having the formula

OH H

> X O

N-H 02 R

I

  wherein R 1 represents a conventional group protecting the carboxyl function One of the most preferred groups

  protecting the carboxyl function, for the intermediate product

  I is the p-nitrobenzyl group which can be immediately removed by catalytic hydrogenation after

  formation of the ultimate carbapenem product.

  Recent attempts have been made to synthesize Intermediate I (and subsequently thienamycin and other carbapenem derivatives) from readily available 6-APA. See Karady et al., For example, in J Am Chem Soc. 22): 6765-6767 (1981), which describe such a method, which produces the diazo intermediate of formula

0 P H

s -Z O

T N COOCH 2 X

  in which P is t-butyldimethylsilyl by displacement of the O-protected azetidinone, of formula

OP H

  With an enol silyl ether of benzyl 2-diazoacetoacetate having the formula O Si (CH 3) 3 Co 2 CH 2 Ke

N 2

  N 2 The publication "Tetrahedron Lett 23 (22): 2293-2296 (1982) describes the preparation of the diazo intermediate of formula

OH H

7 oo

OOCH

  N 22 from 4-acetoxy-3- (1-hydroxyethyl) -2-azetidinone by Lewis acid catalysed alkylation with the corresponding silyl enol ether of formula O Si (CH 3) 3

NO 2 CH 2 CH

  N 2 Yoshida et al., In the publication Chem Pharm. Bull 29 (10): 2899-2909 (1981) describe another process

  to convert 6-APA to azetidinone 0-

  protected formula CH 3 O Si-C (CH 3)

\ H

  IOCOCH 3 which can be converted to a diazo intermediate of formula I by the method described in the aforementioned publication Tetrahedron Lett Since the intermediate product diazo

  of formula I having a protective group of p-nitro-

  benzyl ester is a preferred intermediate of carbapenem,

  it would be desirable to have a process for

  form the immediately available azetidinone compounds

general formula

QP H

The

  Wherein L is a conventional group which is removed, such as halo or acetoxy and P is a conventional hydroxyl protecting group, such as triorganosilyl, to the corresponding intermediate product of pnitrobenzyl ester, of formula I. the Lewis acid catalyzed alkylation of ketones such as their silyl enol ethers has been described in the literature (see for example Tetrahedron Lett 23 (22): 2293-2296, 1982 and also Tetrahedron Lett 23 (4): 379-382 ( 1982), it could be expected that the desired p-nitrobenzyl ester I intermediate or a hydroxy-protected derivative thereof could be prepared by Lewis acid catalyzed alkylation of a suitable azetidinone compound. II with a pnitrobenzyl diazoacetoacetate enol silyl etherpresenting the formula

R 1

Oi R 2 \ R 3

  C 02 CH 2 N 02

1.5 N 2

N 2 III

  in which R 1, R 2 and R 3 are each independently a C 1 -C 4 alkyl group. Unfortunately, however, the inventors have found that the known method for preparing the compounds of formula III does not work when a protecting group of The method of the prior art for preparing enol silyl ethers of diazoacetoacetates, therefore, uses the silylation of a diazoacetoacetate ester of the formula ## STR2 ## wherein R 1 is a carboxyl protecting group on the enol silyl ether ester R 1 i 2 O Si R 1 R 3

C 02 R 1

  wherein R 1, R 2 and R 3 are each independently C 1 -C 4 alkyl, using a triorganosilylated halide silylating agent in the presence of a strong base, for example trimethylchlorosilane with a base of

  lithium such as lithium hexamethyldisilazide.

  When this silylation process according to the prior art is used with the p-nitrobenzyl ester (CH 2) 2

N 2

  the strong base necessary to form the enolate is incompatible with the pnitrobenzyl ester because of the methylene group which is highly reactive.

  weaker organic bases such as trialkyl-

  amines with the triorgano halide silylating agent

  silylated, however, does not produce the desired enol silyl ether.

  The object of the present invention was to provide a silylation method for producing p-nitrobenzyl silyl-enol ether N 2

C 02 CH 2 / NO 2

  Wherein R 1, R 2 and R 3 are each independently C 1 -C 4 alkyl from the intermediate

C 02 CH 2 NO 2

  N 2 IV The successful preparation of intermediate III would then allow the preparation of the key intermediate of carbapenem OH H Ia or a hydroxyl-protected derivative of this intermediate, by reaction of intermediate III with an azetidinone O-protected of formula OP H _ LH II in which P and L are as defined above, after which the group is eliminated, if desired;

protecting the hydroxyl function.

  The subject of the present invention is essentially new intermediate products of carbapenem having the formula v R 1

1 2

O Si-R

CO CH 2 NO 2

/ 2 2

  N 2 III in which R 1, R and R 3 are each independently

a C 1 to C 4 alkyl group.

  The invention also relates to a process for the preparation of an intermediate of formula III which consists in reacting a compound of formula

O

  Co 2 c H 2 N O 2 N 2 IV with a trifluoromyl silyl trifluorom of formula R 2 IR -Si-O 502 CF 3 R 3 V wherein R 1, R 2 and R 3 are each independently a C 1 -C alkyl group 4, in an inert organic solvent

  and in the presence of an organic base.

  Another object of the invention is to propose a process for the preparation of an intermediate of formula

OR H

\ AH

H

  Wherein R is hydrogen or a conventional hydroxyl protecting group, which process comprises reacting a compound of the formula ## STR2 ## wherein R is a conventional group protecting the hydroxyl and L function. is a conventional group which is removable or separable, such as acetoxy, propionyloxy, tbutyryloxy or chloro, in an inert organic solvent and in the presence of a Lewis acid catalyst with a silyl enol ether of formula R 1 O If R 2

C 02 CH 2 "NO 2

  Wherein R 1, R 2 and R 3 are each independently C 1 -C 4 alkyl. The present invention is based on the discovery of

  unexpectedly that the intermediate compound of diazoaceto

  p-nitrobenzyl acetate of formula Co 2 CH 2 O NO 2 N 2 IV

  could be successfully transformed into the intermediate product

  corresponding diol of enol silyl ether, of formula R 1 Oki-R 2 / R Co 2 CH 2 e N O 2 N 2 III in which R 1, R 2 and R 3 are each independently a C 1 -C 4 alkyl group, by reaction of the compound IV with a silylation agent of trifluoromethylsulfonate-triorganoslyl, of formula

R 2 S-O SO 2 CF 3.

  At 33 in which R 1, R 2 and R 3 are as defined above, in an inert organic solvent and in the presence of a base

  The use of the sylylation agent of trifluoromethyl-

  silyl sulphonate instead of the silylchloride reagent according to the prior art allows the use of an organic based such as a trialkylamine for example tri (C 1 -C 4) alkylamine 3 instead of the strong bases of the prior art thus making it possible to successfully form the desired silyl enol ether intermediate III in high yield despite the presence of the highly reactive methylene group in the p-nitrobenzyl moiety. The reaction of Intermediate IV with the triorganosilyl trifluoromethyl sulfonate sylylation agent is carried out in an inert organic solvent such as methylene chloride, tetrahydrofuran, carbon tetrachloride, dioxane, dimethoxyethane, diethyl ether or chloroform at a temperature between about -400 C and about + 301 ° C. More conveniently, the reaction is allowed to develop at a temperature of

between about 0 and 5 C.

  The triorganosilyl trifluoromethylsulfonate may be any trialkylsilyl trifluoromethylsulfonate, but is preferably a commercially available reagent such as trimethylsilyl trifluoromethylsulfonate or tert-butyl dimethylsif trifluoromethylsulfonate.

  The most preferred silylating agent is trifluoro-

  tert-butyl dimethylsilyl methylsulfonate.

  Organic amine bases such as

  diisopropylethylamine, DBU (1,8-diazabicyclo l 5,4,

  undec-7-ene), D 4 N (1,5-diazabicyclo [4,3,0] n-5-ene) and especially tri (C 1 -C 4) alkylamines (by

  trimethylamine, triethylamine, tributyl-

  amine, tripropylamine) are suitable for use with the triorganosilyl triflate silylating agent. In a general way we make react the base

  triorganosilyl trifluoromethylsulfonate and the

  IV in roughly equal amounts

  molars, the base being used in slight excess

  preferred molar ratio of intermediate IV: trifluoromethyl-

  triorganosilyl sulfonate: base is about 1: 1.2: 1.4.

  The desired silyl enol ether intermediates of the general formula III are formed in high yields using the method described above. Among the novel intermediates within the scope of formula III, the most preferred compounds are those having the functional protecting groups.

  trimethylsilyl or tert 7 butyl dimethylsilyl.

  Once the intermediates of formula III are prepared, they can be used, following another

  aspect of the present invention for preparing the intermediate

  Thus, Intermediate III is reacted with a suitable O-protected azetidinone of Formula II in an inert organic solvent such as methylene chloride, chloroform, carbon tetrachloride, dioxane, diethyl ether, chloroform, carbon dioxide, dioxane, diethyl ether and the like. tetrahydrofuran or dimethoxyethane, in the presence of a Lewis acid catalyst such as zinc chloride, zinc iodide, zinc bromide, titanium tetrachloride, magnesium bromide, boron trifluoride, chloride

  aluminum, stannic chloride or ferric chloride.

  A preferred solvent is methylene chloride and a

  The preferred catalyst is zinc chloride.

  The azetidinone compounds of formula II are known compounds or can be prepared by known methods. The hydroxyalkyl group of such compounds is protected by a conventional hydroxy protecting group Although the particular protecting group used is not critical, and can be selected from a large number of such groups known in the art, it is preferred to use a triorganosilyl protecting group such as trimethylsylyl or tert-butyl dimethylsilyl, since such groups are immediately removable by treatment with methanolic HCl or methanol. Fluoride (e.g. tetra-n-butylammonium fluoride / tetrahydrofuran) Other examples of suitable hydroxyl protecting groups include p-nitrobenzyloxycarbonyl which can be removed by catalytic hydrogenation, the allyloxycarbonyl group which can be removed by reaction.

  catalyzed by Pd (P 03) 4, and the 2-trihaloethoxy group

  carbonyl (-C 2 CH 2 CX 3 o X = Cl or Br) which can be removed by treatment with Zn-acetic acid in methanol The group which eliminates L can be any conventional separable group such as halo (for example chloro) or acyloxy (for example acetoxy, propionyloxy or

  t-butyryloxy) but is more preferably acetoxy.

  Generally, it is preferred to add an excess of silyl enol

ether III to azetidinone II.

  Following the alkylation reaction to form the hydroxyl-protected diazo intermediate, the protecting group may be subsequently removed by known methods to provide the desired intermediate. The protecting groups of triorganosilyl, as mentioned above are especially preferred because they can be easily removed without

  dislocation of the remaining part of the molecule.

  The diazo intermediate Ia can be converted by known methods into thienamycin and various other

  carbapenem derivatives with anti-

useful bacterial.

  The following examples will illustrate, without the

limit, the present invention.

EXAMPLE 1

  Preparation of p 2-nitrobenzyl 2-diazo-3-

  trimethylsilyloxy-3-butenoate A p-nitrobenzyl acetoacetate

O

C 02 and + HOCH 2 02 toluene

C 2 O GNP

  A mixture of ethyl acetoacetate (140 g, 1.08 mole) and p-nitrobenzyl alcohol (153 g, 1 mole, wash with diethyl ether before use) in toluene (1 L) was slowly distilled, 900 ml. After cooling, all the insoluble materials were removed by filtration through celite, washed with toluene and evaporated in vacuo to obtain 280 g of a crude oil. This oil was crystallized at 50.degree. diethyl ether (280 ml) to give 181.55 g (0.766 moles, 76.6% yield) of the title compound as a white, slightly tinted crystals: mp 40-42 (IR) (film) m. ester, 1715 (C = O), 1515 and 1345 (NO 2) cm 1, 1 H NMR (CDCl 3): 1.98 (s, impurity), 2.32 (3H, s, CH 3), 3, 62 (2H, s, -COCH 2 CO 2 R), 5.08 (s, impurity), 5.28 (2H, s, -C 2 CH 2 Ar), 7.53 (2H, d ", J = 9 Hz, Ar H), and

  8.23 ppm (2H, "d", J = 9Hz, Ar H); Rf 0.45 (diethyl ether).

  An assay sample was obtained by recrystallization from toluene-hexanes: mp 470-490 ° C. Analysis: Calculated for C 11 H 11 N O 5: C, 55.70; H, 4.67;

N, 5.91

found: C, 55.59; H, 4.62;

N, 5.85.

  B p-nitrobenzyl 2-diazo-3-ketobutenoate 0 o Ts N 3 O 2 PNB and 3 N / CH 3 CN C PNB

N 2

  To a solution of p-nitrobenzyl acetoacetate (134.6 g, 0.568 mole) and triethylamine (79 mL, 0.568 m)

  in CH 3 CN (340 mL) was added at 0-5 ° C under atmospheric pressure.

  Nitrogen of p-toluenesulfonyl azide (130 g, 0.639 mole, 97% purity) over a period of 15 minutes During this period, the title compound began to precipitate The cooling bath was removed and the mixture was stirred at room temperature for 3 hours The mixture was cooled in an ice bath for 30 minutes and the precipitate was filtered, washed with cold CH 3 CN (75 ml) and then cold diethyl ether (200 ml), and dried to give 135.06 g (0.514 mol, 90.4% yield) of the title compound as a pale yellow powder: 1 H NMR (CDCl 3): 2.50 (3H, s, -CH 3), 5.38 (2H, s, -C 2 CH 2 Ar), 7.53 (2H, "d", J = 9Hz, aromatic Hs) and 8.27 ppm (2H, "d", J = 9 Hz, aromatic Hs); R (CH 2 C 2) max: 2130 (N 2), 1720 (ester), 1655 (C = O), 1520 and 1350 cm (No 2);

Rf 0.65 (ethyl acetate).

  C p-nitrobenzyl 2-diazo-3-trimethylsilyloxy-3-

  butenoate O Si Me 1 J 5 C 02 PNB TMS O Tf CO PNB

2 X / 2

triethylamine

2 1 M 2

  To a suspension of p-nitrobenzyl (-diazoaceto)

  acetate (236 mg, 1 mmol), and triethylamine (0.15 mL, 1.08 mmol) in CH 2 Cl 2 (2 mL), trimethylsilyl trifluoromethylsulfonate (0.22) was added at 0 ° -5 ° C. ml) under a nitrogen atmosphere and the mixture was stirred for 30 minutes to this light yellow solution was added dry hexane (30 ml) and the reaction mixture was stirred for 10 minutes After removal of the oily deposit, the The hexane solution was evaporated in vacuo to give a yellow solid which was redissolved in dry hexane (50 ml). The insoluble material was filtered through celite and the filtrate was evaporated in vacuo to give 277 mg (0, g). 90 mmol, 90% yield) of the title compound, as yellow crystals: IR (film) O max 2100 (N 2), 1705 (ester), 1520 and 1345 cm-1 (NO 2); NMR H (CDCl3): 0.27 (9H, s, -SiMe3), 4.23 (1H, d, J = 2Hz, vinyl proton), 4.93 (1H, d, J = 2 Hz, vinyl proton), 5.32 (2H, s, -C 02 CHH 2 Ar), 7.48 (2H, "d", J = 9Hz, aromatic protons), and 8.23 ppm (2H, "d", J = 9Hz,

aromatic protons).

EXAMPLE 2

  Preparation of p-nitrobenzyl 2-diazo-3-tert-

  butyl dimethylsilyloxy-3-butenoate oosi COe 2 i-NBTBDMS O Tf / O 2 P-NB o 10 N (C 2 H 5) 3

N 2 N 2

  To a suspension of p-nitrobenzyl C

  acetate (26.30 g, 0.10 mmol) and triethylamine (14.57 g, 20 mL, 0.14 mole) in dry methylene chloride (200 mL) were added at 2 ° C. butyl dimethylsilyl trifluoromethylsulfonate (31.72 g, 27.50 ml, 0.12 mol)

  during a period of 30 minutes under a nitrogen atmosphere.

  The mixture was then stirred at 2 ° C. for 1 hour.

  The light orange solution was diluted with methylene chloride (50 ml) and washed with water (3 x 200 ml) then with brine (100 ml), dried (Na2O4), and evaporated to give 37, 40 g (0.099 mol, 99% yield) of the title compound as a yellow solid: 1 H NMR (CDCl 3, EM-360 A, 60MHz) &: 0.26 (6H, m.p. s, Si (CH 3) 2), 0.96 (9H, s, Si C (CH 3) 3), 4.25 (1H, d, J = 2.5Hz, 4-H), 4 , 97 (1H, d, J = 2.5 Hz, 4-H), 5.32 (2H, s, -C 02 CHH 2 Ar), 7.48 (2H, d, J = 9 Hz, Ar H) and 8.22 ppm (2H, "d", J = 9Hz, Ar H); I R (film) max 2090 (N 2), 1694

  (ester), 1600 (C = C) and 1344 cm-1 (N 02).

EXAMPLE 3

  Preparation of (3S, 4R) -3 (1R) -hydroxyethyll

  4 1 (4-nitrobenzyloxy) carbonyl-2-oxo-3-diazo

  propyll azetidin-2-one O Si 4 l \ a 02 PJNB

O OCOCH 3 N

r 0 N Zn C 12 of H H O O Si N 2

"C 02 PC 2 P-B

0. I \ H O

  To a suspension of anhydrous zinc chloride (34 mg, 0.5 mmol) in methylene chloride (2 ml),

  a solution of (1 'R, 3 R, 4 R) -3- (1' -tert-

  butyldimethylsilyloxyethyl) -4-acetoxy-azetidin-2-one (144 mg, 0.5 mmol) in methylene chloride (4 ml),

  then 4-nitrobenzyl-2-diazo-3-tert-butyl-

  solid dimethylsilyloxy-3-butenoate (350 mg, 0.93 mmol) under a nitrogen atmosphere The mixture was stirred at room temperature under nitrogen for 4.5 hours. The mixture diluted with ethyl acetate (50 ml) was washed with saturated sodium bicarbonate (2 x 25 ml) and then brine (30 ml), dried (Na2O4) and evaporated to give an oily yellow crude solid product which was purified by column chromatography (Si 2.30 g), elution with methylene chloride: ethyl acetate 4:13 to give 198 mg (0.405 mmol, 81%) of the title compound as an identical oil (tlc, H NMR) with an authentic sample prepared according to a published process S

EXAMPLE 4

  Preparation of (3S, 4R) -3C (1R) -hydroxyethyll

  3- (4-nitrobenzyloxy) carbonyl-2-oxo-3-

  diazopropyl 3-azetidin-2-one Osi + N C 02 PNB HC 1 1 W / methanol

OH N 2

2 GNP 2 O \ H

  To a solution of (3 S, 4 R) -3-ú (1 R) - (tert-butyl-

  dimethylsilyloxy) ethyl-3- (4-nitrobenzyloxy) carbonyl-

  2-oxo-3-diazopropyl 3-azetidin-2-one (72 mg, 0.15 mmol) in methanol (1 mL), 1N aqueous HCl (0.2 mL) was added and the mixture was stirred at room temperature for 2 hours during which time tlc (ethyl acetate)

  indicated that the reaction was complete.

  During this period, the title compound was precipitated. This was filtered and rinsed with cold CH 3 HH (9: 1) and then cold diethyl ether to give 43 mg (0.11 mmol, 73% yield) of title compound as a white solid The title compound was obtained in a manner similar to

  from (3S, 4R) -3 {(1R) 1 (2,4,6-tri-tert-butyl)

  phenoxy) dimethylsilyloxyl ethyl-4-t 3- (4-nitrobenzyloxy) -

  carbonyl-2-oxo-3-diazopropyl azetidin-2-one.

2 542317

* 20

EXAMPLE 5

  Preparation of the (3 S, 4 R) -3 J (1 R) -t C (2,4,6-

  tri-tert-butylphenoxy) dimethylsilyloxyl etyl

  4-TL 3 (4-nitrobenzyl) oxycarbonyl-2-oxo-3-

  diazopropy 13 azetidin-2-one 081-0 bl O Si-O N 2

1 O O 2 PNBPN

  The title compound was prepared in a yield of 84% from (3L, 4R and 4S) -4-acetox Y-3 (1R, 1H). 2,4,6-tri-tert-butylphenoxy) -dimethylsilyloxy I ethyl-2-azetidinone by the method described above for the corresponding derivative of t-butyl dimethylsilyl: 1 H NMR (CDCl 3, 80 M Hz). 0.26 (3H, s, Si Me), 0.40 (3H, s, Si Me), 1.27 (9H, -s, t-Bu), 1.41 (18H, s). , (t-Bu) 2), 2.92 (11 i, dd, J 3 = 1, = 4.7 Hz, J 3-4 -2.5 Hz, 3-H), 2.97 (1H , dd, J, e = 17, 6 Hz, pH 9.6 Hz, 1 "1-Hb), 3.40 (1H, dd, Jge = 17.6 Hz, J 1, 4 =, Hz, 1 "1-Ha) 3) 842 1, m 4 -H, 432-, 57 (a 1 H l '-) e 5,3-5 (2H, s, -CO 2 CH Ar),, 95 ( 1H, br, s, Nil), 7.22 (2H, s, Ar H ether), 7.52 (2H, dl ', J = 8.7Hz, Ar H1 of 1H). ester) and 8.25 ppm (2H, 11d, J = 8.7 Hz, Ar H1 of the ester): IR (pure) mx 3300 (br, NH), 2137 (-N 2 ), 1755 (A / 3lactamia), 1720 (ester),

  1651 (C = O) 1523 and 1345 cm 1 (No 2).

  Naturally, the invention is in no way limited to the described embodiments which have been given only by way of example and it includes all the technical equivalents of the means described as well as their combinations if they are carried out according to

his mind.

R E V E N D I CATI ONS

  1. Compound having the formula R 1

I 2

O Si-R

1 \ R 3

CO 2 CH 2 02

  in which R 1, R 2 and R 3 are each independently

a C 1 -C 4 alkyl group.

  A compound according to claim 1 having the formula O Si (CH 3) 3 C O 2 CH 2 j NO 2 N 2 3. A compound according to claim 1 having the following formula Si-C (CH 3) C c 2 Q 2 NO 2 N 2 4. Process for the preparation of a compound of formula R 1

I R 2

C CH NO 2

  Wherein R 1, R 2 and R 3 are each independently C 1 -C 4 alkyl, which process is characterized in that it comprises reacting a compound of formula o o N

2 CH 2 22

-N 2

  with a trialkylsulfonate trifluoromethylsulfonate of formula R -Si-O 502 CF 3 R 3 in which R 1, R 2 and R 3 are as defined above, in an inert organic solvent and in the presence of a

organic base.

  5. Process according to Claim 4, characterized in that the reaction is carried out at a temperature of between approximately -40 ° C. and + 300 ° C. 6. Process according to Claim 4 or 5,

  characterized in that the organic base is a trialkyl-

  amine Cç-C 4, and the solvent is methylene chloride.

  7. Process for the preparation of a compound of formula OR 4 H z

> CH 2 N 02

  wherein R 4 is hydrogen or a conventional hydroxyl protecting group, which process is characterized by reacting a compound of formula

OR 4 'H

NOT

  wherein L is a conventional group which is removed or separated and R 4 is a conventional hydroxyl protecting group in an inert organic solvent and in the presence of a Lewis acid catalyst with a silyl enol compound ether of formula R 1 I l 2 O Si R 3

C 02 CH 2 4 NO 2

  Wherein R 1, R 2 and R 3 are each independently C 1 -C 4 alkyl and, if desired, removing the hydroxyl protecting group to obtain

  the corresponding intermediate of hydroxyethyl.

  8. Process according to claim 7, characterized in that the group L which eliminates is the group: o O Il

-0-CCH 3

  9. Process according to claim 7 or 8, characterized in that the Lewis acid catalyst

is Zn C 12.

  10. Process according to claim 7, 8 or 9, characterized in that the solvent is methylene chloride. Process according to claim 7, 8, 9

  or 10, characterized in that the protecting group.

the hydroxyl is a tert-butyldimethylsilyl group,

  trimethylsilyl or (2,4,6-tri-tert-butylphenoxy) dimethyl-

  silyl. Process according to Claim 4, characterized by the production of the compounds corresponding to the following formulas: O Si (CH 3) 3

X C 02 CH 2 / N 02

  N 2 and CH Si-C (CH 3 CH 3 X Co 2 CH 2 "NO 2