DE3408196A1 - CARBAPENEM INTERMEDIATE COMPOUNDS, METHOD FOR THE PRODUCTION AND THE PROCESSING THEREOF - Google Patents

Description

PROF. DR. DR. J. REITSTOT-f EFf ·· * "- ©" R. WERFER KINZEBACH DR. ING. WOLFRAM BUNTE (, _βΒ8 -, _Β7β )

REITSTÖTTER. KINZEBACH & PARTNER POST BOX 78Ο. D-BOOO MUNICH 43

PATENT LAWYERS APPROVED REPRESENTATIVES AT THE EUROPEAN PATENT OFFICE EUROPEAN PATENT ATTORNEYS

TELEPHONE: (OBS) 2 7t SS 83 TELEX: Ο52152Ο8 ISAR D BAUERSTRASSE 22. D-8OOO MUNICH ΛΟ

March 6, 1984

OUR ACTS = M / 25. OUR REF:

REFERENCE: RE

Bristol-Myers Company 345 Park Avenue, New York 10154 U.S.A.

Carbapenem intermediates, process for their preparation and for their further processing

POSTAL ADDRESS; D-8OOO MUNICH 43. POST BOX 7ΘΟ

Μ / 25 010 C G-

The invention relates to new intermediate compounds, a process for their production and for their processing an important intermediate used in the synthesis of thienamycin and other carbapenem antibiotics is used.

The antibiotic thienamycin of the formula

10

-COOH

15th

was originally obtained by fermentation of Streptomyces cattleya (see U.S. Patent 3,950,357). Thienamycin is an exceptionally potent broad spectrum antibiotic that has remarkable activity against various Pseudomonas species owns. These organisms are extremely resistant to ß-lactam antibiotics.

Because of the exceptional biological activity of thienamycin, a large number of derivatives have been made manufactured. Although attempts have been made to synthesize derivatives in which the hydroxyethyl group is replaced by various other substituents in the 6-position of the carbapenem ring system, the hydroxyethyl group still becomes the preferred 6-position substituent for optimal activity viewed.

Since the fermentation processes for the production of thienamycin and its derivatives are unsatisfactory, have been various methods for total synthesis in the literature

• ft *

Μ / 25 010

door (see, for example, US Pat. No. 4,287,123, 4,269,772, 4,282,148, 4,273,709, 4,290,947 and the European Patent application 7973). Although the different manufacturing processes have different starting materials use, but they proceed via a common diazo intermediate compound of the formula

N-H

N.

(I)

wherein R _{1 represents} a common carboxyl protecting group. One of the most preferred carboxy-protecting groups for intermediate I is the p-nitrobenzyl group, which can be easily removed by catalytic hydrogenation after the final carbapenem product has been formed.

Attempts have recently been made to prepare intermediate I from the readily available compound 6-APA (followed by thienamycin and other carbapenem derivatives). Karady et al. report, for example, in J.Am.Chem.Soc. 103 (22): 6765-6767 (1981), one such procedure leading to the intermediate diazo compound of the formula

OOCH,

34Q8196

M / 25 010

leads, where P is t-butyldimethylsilyl. With this one Process uses the O-protected azetidinone of the formula

OP H

with an enol silyl ether of benzyl 2-diazoacetoacetate the formula

OSi (CH ₃ J ₃

implemented.

In Tetrahedron Lett., 22 (22): 2293-2296 (1982), the preparation of the diazo intermediate is of the formula

BUT

described. 4-Acetoxy-3- (1-hydroxyethyl) -2-azetidinone is used using a Lewis acid catalyst with the corresponding silyl enol ether of the formula

OSi (CH ₃ ) ₃

CO ₂ CH ₂

M / 25 010 ψ -

alkylated.

Yoshida et al. describe in Chem. Pharm. Bull 29 (10): 2899-2909 (1981), a further production process for converting the compound 6-APA into the O-protected one Azetidinone of the formula

.CH, to ^10/3

OSi-C (CH ₃ J ₃

^CH 3

H
_L- «OCOCH ₃

The latter compound can be prepared by the method described in the aforementioned Tetrahedron Lett is described, converted into a diazo intermediate compound of the formula I.

Since the diazo intermediate of formula I with a p-nitrobenzyl ester protecting group is a preferred carbapenem intermediate it would be desirable to have a method available that would allow this to occur easily accessible azetidinone compounds of the general

formula

II
where L is a common leaving group, such as a halo

M / 25 010

gene or acetoxy group, and P a common hydroxyl protective group, like a triorganosilyl group, mean be converted into the corresponding p-nitrobenzyl ester intermediate of the formula I.

Since the alkylation of ketones catalyzed by Lewis acids with silyl enol ethers is described in the literature is [cf. e.g. Tetrahedron Lett. 23 (22); 2295-2296 (1982) and also Tetrahedron Lett. 2J> (4): 379-382 (1982)], one might have expected that the desired p-nitrobenzyl ester intermediate I or a hydroxy-protected derivative thereof by Lewis acid catalyzed alkylation of a suitable one Azetidinone compound II with an enol silyl ether of p-nitrobenzyl diazoacetoacetate of the formula

III

-ίο χ

wherein R, R and R are each independently a C ₁ _ ^ - alkyl group, can produce. Unfortunately, however, this known process for the preparation of the compounds of the formula III cannot be used if a p-nitrobenzyl protective group is used. Therefore, in the known process for the preparation of enol silyl ethers of diazoacetoacetates, a diazoacetoacetate ester of the formula

...

M / 25 010

10 15 20 25

wherein EL means a carboxyl protecting group to one Enolsily! Etherester

,1

2 ■?
R and R- 'each independently of one another

where R,

NEN C ^ _{-i! f} alkyl radical, silylated, using a triorganosilyl halide silylating agent and working in the presence of a strong base; ie one works, for example, with trimethylchlorosilane using a lithium base, such as lithium hexamethyldisilazide. If the p-nitrobenzyl ester is used in this known silylation process, the strong base required for enolate formation is due to the highly reactive methylene group with the p-nitrobenzyl ester

30th

35

* a ν »

M / 25 010

incompatible. When using weaker organic Bases such as trialkylamines with the triorganosilyl halide silylating agent however, the desired enol silyl ether is not obtained.

The object of the present invention is therefore to provide a siliconization process for production of the p-nitrobenzylsilyl enol ether of the general formula III

CO ₂ CH ₂

III

12 ^ 5

wherein R, R and R ^ are each independently one Mean C ^ λ-alkyl group, from the intermediate compound of the general formula IV

CO ₂ CH ₂

Successful preparation of intermediate III would then lead to the preparation of the important carbapenem intermediate of formula Ia

M / 25 010

OH

A.

ANH C / N

Yes

or a hydroxy-protected derivative thereof, by an intermediate compound of formula III with a suitable, O-protected azetidinone of general formula II

OP

II

where P and L have the meanings given above, reacted and, if desired, then removed the hydroxy protective group.

The invention relates to new intermediate carbapenem compounds of the general formula III

CO ₂ CH ₂

(in)

<ü V «W <- *

M / 25 010

Sr

12 3
wherein R, R and R each independently represent a ^c -i λ-alkyl radical.

The invention also relates to a process for the preparation of the intermediate compounds of the general Formula III, which is characterized in that a compound of the formula IV

(IV)

with a silyl triflate of the general formula V

R ¹
R ² -Si-0S0 ₂ CF ₃

(V)

wherein R ₁ R and R ^ are each independently a C ₁ ^ -alkyl radical, reacted in an inert, organic solvent and in the presence of an organic base.

The invention also relates to a method for Preparation of an intermediate compound of the general formula Ib

(Ib)

. " ^: 3Τθ8196

Μ / 25 010

.45-

wherein R is a hydrogen atom or a customary hydroxy protecting group means that is characterized in that a compound of the general formula II

"" L

(II)

where R is a customary hydroxy protecting group and L is a customary leaving group such as acetoxy, propionyloxy, t-butyryloxy or chlorine group, mean in an inert, organic solvent and in the presence a Lewis acid catalyst with a silyl enol ether of the general formula III

CO ₂ CH ₂

(IH)

wherein R, R and R ^ each independently represent a C _{1 -Zf} -alkyl radical.

It has surprisingly been found that one can use the p-nitrobenzyl-diazoacetoacetate intermediate of formula IV 30

CO ₂ CH ₂

(IV)

M / 25 010

successfully into the corresponding enol silyl ether intermediate of the general formula III

(III)

// V ^^ CO ₂ CH ₂ - ^ ^ V-NO ₂

in which R, R and R- ⁷ each independently represent a C _{1 - / f} -alkyl group, can be converted by reacting a compound of the general formula IV with a triorganosilyl triflate silylating agent of the general formula V

R ²

R ² ^ i-OSO-CF, (V)

β ^{2 3}

12 3

wherein R, R and R ^ have the meanings given above, in an inert organic solvent and in the presence of an organic base. The replacement of the well-known sllyl chloride by the silyl triflate silylating agent makes it possible that instead of the known strong bases, an organic base, such as a Trialkylamine, e.g. This facilitates the production of the desired silyl enol ether intermediate III made possible in high yield, although the highly reactive one in the p-nitrobenzyl unit Methylene group is present.

The reaction of intermediate IV with the triorganosilyl triflate silylating agent one leads in

M / 25 010

an inert, organic solvent by, for example, in methylene chloride, tetrahydrofuran, carbon tetrachloride, dioxane, dimethoxyethane, diethyl ether or chloroform; is carried out at a temperature of about -40 ° to about +30 ⁰ C. Conveniently, the reaction is carried out at a temperature of about 0 to 5 ° C.

The triorganosilyl triflate compound can be any trialkylsilyl trifluoromethyl sulfonate be. However, it is preferred to use a commercially available compound such as trimethylsilyl trifluoromethylsulfonate or tert-butyldimethylsilyl trifluoromethylsulfonate. That a particularly preferred silylating agent is tert-butyldimethylsilyl-trif luo rme thylsulfonate.

Suitable organic amine bases which can be used together with the triorganosilyl triflate silylating agent include: diisopropylethylamine, DBU (i, 8-diazabicyclo [5.4.0] undec-7-en), DBN (1,5-diazabicyclo [4.3 .0] non-5-ene and especially TrI- (C ₁ ^) - alkylamines (e.g. trimethylamine, triethylamine, tributylamine, tripropylamine) ·

In general, the organic base, the triorganosilyl triflate, is used and the intermediate compound IV in approximately equimolar amounts, with the base in a small amount Excess is present. The particularly preferred molar ratio of intermediate compound IV: triorganosilyl triflate: Base is about 1: 1.2: 1.4.

The process described above gives the desired intermediate silyl enol ether compounds general formula III in high yields.

M / 25 010
1

Particularly preferred, new intermediate compounds of the general formula III are those which trimethylsilyl-5 or have tert-butyldimethylsilyl protecting groups.

The invention also relates to further processing of the intermediate compounds prepared according to the invention of the general formula III to the known diazo intermediate compound Ia. To do this, you set an interim connection III with a suitable, O-protected azetidinone of the formula II in an inert, organic Solvents such as methylene chloride, chloroform, carbon tetrachloride, dioxane, diethyl ether, 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, Aluminum chloride, tin (IV) chloride or iron (III) chloride, around. The preferred solvent is methylene chloride and the preferred catalyst is zinc chloride.

The azetidinone compounds of the formula II are known compounds or can be prepared by known processes. The hydroxyalkyl group of these compounds is protected by the usual hydroxy protective groups. Although the specific protecting group used is not critical and can be selected from a large number of such known compounds, it is preferred to use a triorganosilyl protecting group _f such as a trimethylsilyl or tert-butyldiraethylsilyl group since these groups can be easily removed by treatment with methanolic HCl or with fluoride ions (eg tetra-butylammonium fluoride / tetrahydrofuran) can remove. Suitable hydroxy protecting groups can also be mentioned: p-Nitrobenzyloxycarbonyl, which is catalyzed by

J A-Uö I at)

-Λ * A ! R: 'UO'O " ^: t

M / 25 010 f * T

table hydrogenation can remove, allyloxycarbonyl, which can be removed by Pd (PtfL) f -catalyzed reaction, and 2-Trih.aloethoxycarbonyl (-CO ₂ CH ₂ CX ^, where X = Cl or Br), which can be obtained by treatment with Zn - Can remove acetic acid in methanol. The leaving group L can be any conventional leaving group, for example a halogen atom (for example chlorine atom) or an acyloxy group (for example an acetoxy-propionyloxy or t-butyryloxy group). However, preference is given to using an acetoxy group. In general, it is preferred to add an excess of the silyl enol ether III to the azetidinone II.

After the alkylation to form the hydroxy-protected Diazo intermediate can then remove the protective group by known processes, wherein the desired intermediate compound Ia is obtained. The abovementioned triorganosilyl protective groups are particularly preferred, because they can be easily removed without destroying the rest of the molecule.

The diazo intermediate compound of the formula Ia can be converted into thienamycin or into various types by known processes convert other carbapenem derivatives with useful antibacterial activity.

The following examples serve to illustrate the invention.

M / 25 010 1

example 1

Preparation of p-nitrobenzyl-2-diazo-3-trimethylsilyl-5- oxy-3-butenoate

A. p-nitrobenzyl acetoacetate

CO ₂ Et + HIGH ₂ - "- ^TO1UO1

O ₂ PNB

A mixture of 140 g (1.08 mol) of ethyl acetoacetate and 153 g (1.00 mol) of ρ-nitrobenzyl alcohol (washed with diethyl ether before use) in 1 1 of toluene is slowly distilled and 900 ml of the solvent is collected over a period of 15 h. After cooling, the insoluble material is removed by filtration through gelite, washed with toluene and evaporated in vacuo, 280 g of a crude oil being obtained. This oil is crystallized at 5 ° C in 280 ml diethyl ether to give 181.55 g (0.766 mol; 76.6% yield). Of the title compound as white crystals mp erhältι 40 to 42 ⁰ C.

IR (film) J _v : 1740 (ester), 1715 (C = O), 1515 and 1345 (NO ₂ ) cm ^-1

¹ H NMR (CDCl ₃ ) S ϊ 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, -CO ₂ CH ₂ Ar), 7.53 (2H, d, J = 9 Hz, ArH groups) and 8.23 ppm (2H, d, J = 9 Hz, ArH groups)

34U8 Ί

M / 25 010

Rf = 0.45 (diethyl ether).

An analytical sample was obtained by recrystallization from toluene-hexanes: melting point 47 to 49 ° C

Analysis: for C ₁₁ H ₁₁ NO ₅

Calculated: C 55.70% H 4.67% N 5.91% found: 55.59 4.62 5.85.

10

B. p-nitrobenzyl 2-diazo-5-ketobutenoate

TsN ₃

CO ₂ PNB

To a solution of 134.6 g (0.568 mol) of p-Nitrobenzylacetoacetat and 79.0 ml (0.568 mol) of triethylamine in 340 ml CH CN ₇₅ is added during 15 min under nitrogen atmosphere at 0 to 5 ⁰ C 130 g (0.639 mol) of p-Toluenesulfonyl azide (97% pure), during which time the title compound will precipitate. The cooling bath is removed and the mixture is stirred for 3 h at room temperature. The mixture is then cooled in an ice bath for 30 minutes and the precipitate is filtered off, which is _{washed with 75 ml of cold CH 3} CN and then with 200 ml of cold diethyl ether. It is then dried and 135.06 g (0.514 mol) of the title compound (90.4% yield) is obtained as a pale yellow

30 powder.

¹ H-NMR (CDCl ₃ ) 6 : 2.50 (3H, s, -CH ₃ ), 5.38 (2H, s,

-CO ₂ CH ₂ Ar), 7.53 (2H, d, J = 9 Hz, aromatic H) and 8.27 ppm (2H, d, J = 9 Hz, aromatic H)

35

M / 25 010

IR (CH ₂ Cl ₂ ) v? _max : 2130 (N ₂ ), 1720 (ester), 1655 (C = O),

1520 and 1350 cm " ¹ (NO ₂ )
Rf = 0.65 (ethyl acetate).

C. p-Nitrobenzyl -2-diazo-3-trimethylsilyloxy-3 "" butenoate

OSiMe,
OH 3

° ^Tf

Triethylamine
^N 2

To a suspension of 236 mg (1 mmol) p-Nitrobenzyla-diazoacetoacetate and 0.15 ml (1.08 mmol) of triethylamine in 2 ml CH ₂ Cl ₂ are added under nitrogen atmosphere at 0 to 5 ⁰ C 0.22 ml of trimethylsilyl trifluoromethylsulphonate and stir the mixture for 30 min. 30 ml of dry hexane are added to this clear, yellow solution and the reaction mixture is stirred for 10 min in
Dissolves 50 ml of dry hexane. The insoluble material is filtered through gelite and the filtrate is concentrated in vacuo
a, whereby 277 mg (0.90 mmol; yield 90%) of the
Title compound is obtained as yellow crystals.

IR (film) ^ _max : 2100 (N ₂ ), 1705 (ester), 1520 and
1345 cm " ¹ (NO ₂ )

¹ H-NMR (CDCl ₃ ) ^ i 0.27 (9H, s, -SiMe ₃ ), 4.23 (1H, d,
J = 2 Hz, vinyl proton), 4.93 (1H, s, J = 2 Hz,
Vinyl proton), 5.32 (2H, s, -CO ₂ CH ₂ Ar), 7.48 (2H, d, J = 9 Hz, aromatic protons) and 8.23 ppm
(2H, d, J = 9 Hz, aromatic protons).

J 4Ub I yb

Μ / 25 010 1

Example 2

Production of p-nitrobenzyl-2-diazo-3-tert.-butyl dimethyls i Iy loxy-3-buteno at -

To a suspension of 26.30 g (0.10 mol) of p-nitrobenzyl-ct-diazoacetoacetate and 14.57 g (20.00 ml; 0.14 mol) of triethylamine in 200 ml of dry methylene chloride are added at 2 ^° C. during 31.72 g (27.50 ml; 0.12 mol) of tert-butyldimethylsilyl trifluoromethylsulfonate over a period of 30 min under a nitrogen atmosphere, the mixture is then stirred for 1 h at 2 ^° C. and the clear, orange-colored solution is diluted with 50 ml of methylene chloride , washed with 3 x 200 ml of water and then with 100 ml of sodium chloride solution, dried (Na2S0 ^) and concentrated to give 37.40 g (0.099 mol; yield 99%) of the title compound as a yellow solid.

25th

¹ H-NMR (CDCl ₃ , EM-36OA, 60MHz) i: 0.26 (6H, s, Si (CH ₃ J ₂ ), 0.96 (9H, s, SiC (CH ₃ ) ₃ ), 4, 25 (1H, d, J = 2.5 Hz, 4-H), 4.97 (1H, d, J = 2.5 Hz, 4-H), 5.32 (2H, s, -CO ₂ CH ₂ Ar), 7.48 (2H, d, J = 9.0 Hz, ArH groups) and 8.22 ppm (2H, d, J = 9.0 Hz, ArH groups) IR (FiIm) O _n ,: 2090 (N ₉ , 1694 (ester), 160 (C = C) and 1344 cm " ¹ (NO ₂ ).

M / 25 010

Example 3

Preparation of (3S, 4R) -3 - [(iR) -Hydroxyethyi; J-4- [3- (4-nitrobenzyloxy) -carbonyl-2-oxo-3-diazopropyl] -a2etidine-

2-on

10 15

OSi 4-

1 I I

I osi

OCOCH.

ZnCl.

20 25 30

35

CO ₂ P-NB

A solution of 144 mg (0.5 mol) (1'R, 3R, 4R) · 3- (1'-tert .-Butyldimethylsilyloxyethyl) -4-acetoxyazetidin-2-one) in 4 ml of methylene chloride and then 350 mg (0.93 mmol) of solid 4-nitrobenzyl-2-diazo-3-tert-butyldimethylsilyloxy-3-butenoate, the mixture is stirred 4.5 h under nitrogen at room temperature, the mixture is diluted with 50 ml of ethyl acetate, washed with 2 × 25 ml of saturated sodium bicarbonate solution and then with 30 ml of sodium chloride solution, dried (Na ₂ SO ^) and concentrated, whereby a crude, oily, yellow solid is obtained, which is purified by column chromatography [30 g SiO ₂ , eluted

ο η υ υ ι

M / 25 010

with methylene chloride / ethyl acetate (4: 1)], whereby 198 mg (0.405 mmol; 81% yield) of the title compound are obtained as an oil, which is identical to a sample prepared by a known method (TLC, ¹ H-NMR).

Example 4

Preparation of (3S, 4R) -3 - [(1R) -Hydroxyethyl] -4- [3- (4-nitrobenzyloxy) -carbonyl-2-oxo-3-diazopropyl] -azetidin-2-one

CO ₂ PNB

IN.HCl / methanol

CO ₂ PNB

To a solution of 72 mg (0.15 mmol) (3S, 4R) -3 - [(1R) - (tert-butyldimethylsilyloxy) ethyl] -4- [3- (4-nitrobenzyl- oxy) carbonyl-2-oxo-3-diazopropyl] -azetidin-2-one in 1.0 0.2 ml of 1N aqueous HCl are added to ml of methanol and the mixture is stirred the mixture for 2 h at room temperature. After this time, thin layer chromatography (TLC) (ethyl acetate) shows that the implementation is complete. During this time the title compound precipitates. This is filtered off and rinses them with cold CH ^ OH / ^ O (9: 1) and then with cold diethyl ether, giving 43 mg (0.11 mmol; yield 7390) the title compound is obtained as a white solid. The title compound is obtained in a similar manner

M / 25 010

from (3S, 4R) -3 - [(1R) - [(2,4-tri-tert-butylphenoxy) -dimethylsilyloxy) -ethyl] -4- [3- (4-nitrobenzyloxy) -carbonyl-2-oxo -3-diazopropyl] -azetidin-2-one.

Example 5

Preparation of (3S, 4R) -3 - [(iR) - [(2,4,6-tri-tert-butylphenoxy) -dimethylsilyloxy] -ethyl] -4- [3- (4-nitrobenzyl) -oxycarbonyl- 2-oxo-3-diazopropyl1 »azetidin-2-one

OSi-4-I I

O ₂ PNB

ZnCl.

CO ₂ PNB

The title compound is produced in an 84% yield (3R, 4R and 4S) -4-acetoxy-2 - [(1R) - [(2,4,6-tri-tert-butylphenoxy) -dimethylsilyloxy] -ethyl] -2-azetidinone according to the above for the corresponding t-butyldimethylsilyl derivative described procedure.

¹ H-NMR

₃ 80MHz) <f: 0.26 (3H, s, SiMe), 0.40 (3H, s, SiMe), 1.27 (9H, s, t-Bu), 1.41 (18H, s, ( t-Bu) ₂ ), 2.92 (1H, dd, J _3-1 = 4.7 Hz, J _{3. 4} = 2.5 Hz, 3-H), 2.97 (1H, dd, J _acc = 17.6 Hz, ^ «^ ₄ = 9.6 Hz, 1" -H _b ), 3.40 (1H, dd, J _gem = 17.6 Hz,

3.5 Hz, 1 "-H _a ), 3.98-4.24 (1H, m, 4-H), ^a 4.32-4.57 (1H, br.s, NH), 7.22 (2H, s, ArH of the ether), 7.52 (2H, d, J = 8.7 Hz, ArH of the ester) and 8.25 ppm (2H, d, J = 8.7 Hz, ArH of the ester)

IR (pure) V ⁷ _m ·. 3300 (br., NH), 2137 (-Np), 1755 (β ^ lactam), 1720 (ester), 1651 (C = O) ,,, 1523 and 1345 cm " ¹ (NO ₂ ).

Claims (1)

M / 25 010 Claims Compounds of the general formula III (III) wherein R ¹ , R ² and R ^ are each independent of one another a C _- . ^ -Alkyl radical 2. A compound of Claim 1 having the formula: OSi (CH ₃ J ₃ CO ₂ CH ₂ 25 3- A compound according to claim 1 having the formula: CH-, OSi-C (CH ₃ ) ₃ CH. CO ^ C 2 ^CH 2 4. A process for the preparation of the compounds according to any one of claims 1 to 3 _t characterized in that a compound of the general formula IV: M / 25 010 (IV) with a silyl triflate of the general formula V: R ¹
R ² -Si-0S0oCF, 12th wherein R, R and (V) have the meanings given above, in an inert organic solvent and reacted in the presence of an organic base. 5. The method according to claim 4, characterized in that the reaction is carried out at a temperature of about -40 ° to approx. + 30 ° C. 6. The method according to claim 4 or 5, characterized in that the organic 'base is a C ^ _ ^ - Trialkylamine and methylene chloride as a solvent used. 7. Process for the preparation of the compounds of the general formula .: M / 25 010 wherein R is a hydrogen atom or a customary hydroxy protecting group means, characterized in that a compound of the general formula II OJT (II) wherein len, L a usual leaving group and λ ι
R represents a common hydroxy protecting group in an inert organic solvent and in the presence of a Lewis acid catalyst with an enol silyl ether of the general formula III CO ₂ CH ₂ (III) wherein R, R and R each independently represent a C, ^ -alkyl group, converts and, if desired removed the hydroxy protecting group to give the corresponding hydroxyethyl intermediate. 8. The method according to claim 7, characterized in that that the leaving group L for Μ / 25 010 0-CCH stands. 9. The method according to claim 7 or 8, characterized in that ZnCl _{2 is} used as the Lewis acid catalyst. 10. The method according to any one of claims 7 Ms 9> characterized in that the solvent used is methylene chloride. 11. The method according to any one of claims 7 to 10, characterized in that one is used as the hydroxy protecting group a tert-butyldimethylsilyl, trimethylsilyl or (2,4,6-tri-tert-butylphenoxy) -dimethylsilyl group is used.