CA1220215A

CA1220215A - Carbapenem intermediates

Info

Publication number: CA1220215A
Application number: CA000447155A
Authority: CA
Inventors: Yasutsugu Ueda; Guy Roberge
Original assignee: Bristol Myers Co
Current assignee: Bristol Myers Co
Priority date: 1983-03-07
Filing date: 1984-02-10
Publication date: 1987-04-07
Also published as: JPH09176113A; FR2542317A1; BE899085A; JPS59170096A; CY1447A; JPH0564157B2; MY8800117A; DE3408196A1; GB2136009B; IT8419891A0; FR2542317B1; DE3408196C2; IT1175944B; HK84588A; JPH0827168A; GB2136009A; GB8405878D0

Abstract

ABSTRACT

A new process is disclosed for preparation of the known carbapenem intermediate of the formula

Description

3L2~ S

BACKGROI~D OF THE INVENTION
_ . _ 1. Field of the Invention _ The present invention is directed to a new process for producing a key intermediate used in the synthesis of thienamycin and other carbapenem ~ntibiotics.

.. . . . . . .

2. Description of the Prior ~rt The antibioti~ thienamycin of the formula OB H
~L ~ ~ SCH2CH2N82 ~ ~ ~00 was originally obtained by fermentation of 5treptomyces ~ y~
as descri~ed in ~.S. Pate~t 3,950,357. Thienzmycin is a~
ex~eptionally pote~ broad-spectrum antibiotic which possesses notable activity against various Pseudomonas species, organisms whi~h have been notoriously resistant to ~-lactam antibioticsr Because of the exceptional biological activity of thienamycin, a large number o~ derivatives have been prepzred.
While attempts have been made to synthesize deri~atives with various substituents other than hydroxyethyl at the 6-position of the carbapenem ring system, the hydroxye~hyl group is still considered the most advantageous 6-substituent for optLmum activity.

Since ferm ntation procedures to prepare thienamycin and derivatives thereof ha~e been unsa~isfactory, several total synthesis procedures have been reported in the literature (see, for example, ~.S~ Patents 4,287,123, 4,269,772! 4,282,148, 4,273,709, 4,230,947 and European Patent Application ~973).
While the Yarious synthetic procedures utilize different start-~L22~2~ S

ing materials, they go through a common diazo intermediatehaving the fo~mula OH ~3 ~ N ~ C2Rl where Rl represents a conventional carboxyl-protecting group.
One of the most pre~erred carboxyl-protecting groups for inter-mediate I is the p-nitrobenzyl group which can be readily removed by catalytic bydrogenation after formatio~ of the ultimate carbapenem product.

Recently attempts have been made to synthesize inter-mediate I (and subseguently thiPnamyci~ and other carbape~em derivatives) from readily available 6-APA. ~arady et al., for example, in J._Am. Chem. So~. 103~22): 6765-6~67 (1981) dis-close one such process which produces the diazo intermediate of the formula OP H
~.~ fO
~ N ~ OOCH2 ~

where P is t-butyldimethylsilyl by displaceme~t of the O-protected azetidinone of the formula OP H
Cl N ~

s . -4-wi~h an enol silyl ether of benzyl 2-diazoacetoacetate ha~ing the formula - ~ 2 2 Tetrahedron Lett. 23(22): 2293-2296 (1982) discloses the preparation of the diazo intermediate of the formula OH H
~'~~

2 ~

from 4-acetoxy-3~ hydroxyethyl)-2-azetidinone by ~ewis acid catalyze~ alkylation with the corresponding silyl enol ether of the ~onmula ~co2~::H2~3 ~2 ~ oshida et al. in Chem. Pharm. Bull. 29(10): 2B99-2909 (1981) report another synthetic procedule ~or converting 6-APA
to the O-protected azetidinone o~ the formula OSi-C(C~3)3 \CH3 H
` ~ OCOCH3 N\

, Zl~

which can be converted to a diazo intermediate o~ Formula I by the process disclosed in ~he abo~e-mentioned Tetrahedron Lett.
reference..
Since the diazo intermediate of Formula I having a p-nitr~benzyl ester protecting group is a preferred carbapenem intermediate, it would be desirable to have a process for converting readily available azetidinone compounds of the general formula P H
L
N~
H

II --where L is a conventional leaving group such as halo or acetoxy and P is a conventional hydroxyl-protecting group such as triorganosilyl to the corresponding p-nitrobenzyl ester inter-mediate of Foxmula I.

Since the Lewis acid catalyzed alkylation of ketones as their silyl enol ethers has been described in the literature (se~, for example, Tetrahedron Lett. 23(22): 2293-2296, 1982 and also Tetrahedron Lett. 23(4): 379-382, 1982), it might be expected that the desired p-nitrobenzyl ester-intermediate I or hydroxy-protected deri~ati~e thereof could be prepared by Lewis acid catalyzed alkylation of an appropriate azetidinone compound II
with an enol silyl ether o~ p-nitrobenzyl diazoacetoacetate having the formula . --6--Rl . R2 ~!C}I~ O~

III

wherein Rl~ R2 ~nd R3 are each independently Cl~C4 alkyl.
~nfortunately, however, the present inventors have found ~hat ~he known meth~d of preparin~ compou~ds of Formula III does not work when a p-nitrobenzyl protecting group is desired. Thus, the prior art method ~or preparing enol silyl ethers of diazo-acetoacetates employs silylation o~ a diazoacetoacet2te ester o~ ~he ~ormula . ~f 2 1 wherein Rl is a carboxyl-protecting gxoup t~ the en~l silyl eth~r ester . R
O `~;--R2 ~C2~1 ' wherein Rl, R2 and R3 are each independently Cl-C4 alkyl by use o~ a triorganosilyl halide silylating ag~nt in the presence of a strong base, e.g. trimethylchl~rGsilane with a lithium bace such as lithium hexamethyldisilazide. When this prior art silylation procedure is e;rployed with ~che p-a~itrobenzyl ester ~2Z~

2CE~2~ N02 the strong base needed to ~orm ~he enolate is incompatible wi~h the p-nitrobenzyl ester because of the highly reactive methylene group. ~se of weaker organic bases such as trialkylamines with ~he triorganosilyl halide silylating agent, however t d~es not produce the desired enol silyl ether.

It was the object of the present invention to pr~vide a silylation procedure fox producing the p~nitrobenzyl silyl enol ether Rl 2 o~i ~

// ~ C02CH2 ~ 2 III

wherein Rl, R and R are each independently Cl-C4 alkyl from the intermediate , C2CH2~o2 :~V

~L~Z~S

Successful preparation of intermediate III would ~hen allow preparation of the key carbapenem lntermediate OB
,l~
N2~J~ Co2C~I2~3No2 Ia or a hydroxyl-protected derivative thereof by reaction of ~nter-mediate III with a suikable O-protected azetidinone of ~he formula OP
L
,s~Nb wherein P and L are as defined above followed by remov21, if desired, o~ the hydroxyl-~rotecting group.

~2~

SUMMARY OF THE INVENTION

The present invention provides novel carbapenem intermediates having the formula Rl o~i ` R2 ~"" C02C~2~Mo2 lII
wherein Rl, R2 and R3 are each independently Cl-C4 alkyl.

Also provided by the present inven-tion is a process for the preparation of an intermediate of Formula III which comprises reacting a compound of the formula O

C02 C H2 ~o2 IV

with a silyl triflate of the formula ~,1 ~ OSO~CF3 wherein Rl, R2 and R are each independently Cl-C~ alkyl in an inert organic solvent and in the presence of an organic base.

s Still further provided by the presen-t invention is a process for the preparation of an intermediate of the formula OR
~` ~

o ~ ~ N2 ~ 02C~2 ~ No2 wherein R is hydrogen or a conventional hydroxyl-protecting group, which process comprises reacting a compound of -the formula oR4 H

L
~ N \

wherein R4 is a conventional hydroxyl-pro-tecting group and L is a conventional leaving group such as acetoxy, propionyloxy, -t-butyryloxy or chloro in an inert organic solvent and in the presence of a Lewis acid ca-talyst with a silyl enol e-ther of the formula Rl ogi--R2 co2c~2~3NO2 -~=i, III
, zz~
--ll--wherein R~, R2 and R3 are each independently Cl-C4 alkyl.

DETAILE:D DESCR:rPTION
.

The pres~ inven~ion is based on the unexpected dis-co~ery that the p-nitrobenzyl diazoacetoacetate intermediate of the formula Co2~H2~02 IV
.
could ~e successfully converted to the correspo~ding enol silyl ether intenmediate o~ the fo~mula .

0~ R2 2CH2 ~ ~2 III

wherein Rl, R2 and R3 are ea~h independently Cl-C~ al~yl by reaction of C~mpound IV with a triorganosilyl triflate silyl~ting agent of the formula Rl R -S -oS02CF3 R
V

wherein Rl, R2 and R3 are as de~ined above in an inert organic solvent and in the presence of an organic baseO Vse o~ the silyl ~riflate silylating agent instead of the prior art silyl-chloride reagent a~lows use of an organic base such as a tri-alkylamine le.g. tri(Cl-C4)alkylamine~ instead o~ the prior art strong bases, ~hus 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 triorgan~-silyl triflate silylating agent is carried out in an inert organic solvent such as methylene chloride, tetrahydrofuran, carbon tetrachloride, dioxane, dimethoxyethane, diethyl ether or chloxoform at a temperature in .the range of fr~m about -40C
to about ~30C. Most conveniently t~e reaction is allowed to take place at a temperature in the range o~ from about 0-~C.

me triorganosilyl triflate may be any trialkylsilyl triflusromethylsulfonate but is preferably a commercially a~ail-able reagent such as trimethylsilyl trifluoromethylsulfonate or ert-butyl dimethyls lyl trifluorome~hylsul~onate. The m~st preferred silylating agent is tert-butyl d~methylsilyl trifluoro-.methylsulfonate. .

. Organic amine bases such as diisopro yle~hylamine, DBU
(1,8-~iazabicyclo~5.4.0]unde~-7-ene), D3N (1,5-diazabicyclo-[4-3.0]non-5-ene) and especially tri (cl-c~ ) alkylamines (e.g.
trimethylamine, triethylamine, tributylamine, tripropylamine) are suitable for use with the tri~rganosilyl trif~ate silylating agent.

Generally the organic base, triorganosilyl triflate and intermediate IV are reacted in approximately e~uimolar amounts with the base being used in slight excess- The most pre~erred molar ratio o~ intermediate IV: triorganosilyl tri~lat~
base is about 1:1.2:1.4.

~;22~2~ ~

The desired silyl enol ether intermediates of general Formula III are formed in high yields by use of the above-described process.

Of the novel intermediates included within ~he scope of Formula III, the most preferred compounds are th~se having the trimethylsilyl or tert-butyl dimethylsilyl ~rotecting groups.

Once intermediatPs of ~ormula III are prepared, they may be used in a further aspect of the present invention to prepare the known diazo intermediate Ia. Thus, intermediate III
is reacted with a suitable O-protected ~zetidinone of the ~ormula II in an inert organic solvent such as methylene chlori~e, chloroform, carbon tetrachloride, dioxane, diethyl ether, tetrahydrour~n or dime~hoxyethane in the presence of a Lewis acid catalyst such as zinc chloride, zi~c iodide, zinc bromide, titanium tetrachloride, magnesium bromide, boron trifluoride, aluminum chloride, stan~ic chloride or ferric chloride. A
preferred solvent is methylene chloride and a pxeferred catalyst is zinc chloride.

Azetidinone compounds of ~ormula II are known compounds or may he prepared by ~n~wn methods. The hydrox~aIkyl group o~
such comp~unds is protected by a conyentional hydroxy-protecti~g group. While the particular pro~ecting group used is n~t critical and ~ay be selected from a large number of such groups known in the art, it is preferred to use a triorgan~silyl protect-ing group such as trimethylsilyl or tert-butyl dimethylsilyl since such groups are readily removable by treatment with methanolic ~Cl or with fluoride ion (e.g. tetra-n-butyl ammonium fluoride/tetrahydrofuran). ~ther examples of suitable hydroxy-protecting groups include p-nitrobenzyloxycarbOnYl which can be removed by catalytic hydrogenation, allyloxycarbonyl which can be removed by Pd(p03~4-catalyzed reaction and 2-trihaloethOxy-carbonyl (-C02CH2CX3 where X=Cl or Br) which may be re~oved by treatment with Zn-acetic acid in methanol. The lea~ing group L
may be any conventional leaving group such as halo ~e.g. chloro) or acyloxy (e.g. ace~oxy, propionyloxy or t-butyryloxy) but is most preferably acetoxy. ~enerally it is preferred to add an excess of the silyl enol ether III to the azetidinone II.

~ 2Q~

~ ollowing the alkylation reaction to form the hydroxyl-protected diazo intermediate, the protecting group may be subsequently removed by known methods so as t~ provide the desired intermediate Ia. Triorganosilyl protecting groups, as mentioned above, are especially preferred because they may be readily removed without disruption of the remaining portion of the molecule~

Diazo intermediate la may be converted by known methods to thienamycin and various other carbapenem deri~ati~es having useful antibacterial activity.

The following examples illustrate but do not limit the scope of the present in~ention.

~xample 1 - P e aration of -~itrobenz 1 2-diazo-~-r p _ p ~ . y_ _rimethylsilyloxy-3-butenoate A. p-Nitrobenzyl acetoacetate ~ C02Et }IC~t:H2~o2 ~ toluene o ~1 / \ j/C02PNB

A mixture of ethyl acetoacetate (140 g, l.OB mole) and p-nitrobenzyl alcohol (153 g, l.00 mole; was washed with diethyl ether prior to use) in toluene (l L) was slowly distilled, 900 ml of the solvent being collected over a period of 15 hours.
After cooling, any insoluble material was removed by filtration ~ZZ~2 3L~

over Celite , washed with toluene and evaporated in vacuo to obtain 280 g of a crude oil. This oil was crystallized at 5C
from diethyl ether (280 ml) to yield 181.55 g (0.766 mole, 76.6%
yield) of the title compound as off-white crystals: mp 40-42C;
ir (film)~ max 1740 (ester), 1715 (C=0), 1515 and 1345 (N02) cm ; Hmr (CDC13) S : 1.98 (s, impurity), 2.32 (3H, s, CH3),

3-62 (2H, s, -COCH2C02R), 5.08 (s, impurity), 5.28 (2H, s, -C02CH2Ar), 7.53 (2H, "d", J=9 Hz, ArH's), and 8.23 ppm (2H, "d", J=9 Hz, ArH's); Rf 0.45 (die-thyl ether). An analytical sample was obtained by recrystallization from toluene-hexanes:
mp 47-49C.

Anal. calc d for CllHllN05: 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 O

/~ C02PNB v-~/ca]cN /~C02PNB

To a solution of p-ni-trobenzyl acetoacetate (134.6 g, 0.568 mole) and triethylamine (79.0 ml, 0.568 mole) in CH3CN
(340 ml) was added at 0-5C under a nitrogen atmosphere p-toluenesulfonyl azide (130 g, 0.639 mole; 97% pure) over a period of 15 minutes. During this period the title compound started precipitating. 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 percipitate was filtered, washed with cold CH3CN (75 ml) and then cold diethyl ether (200 ml), and dried to yield 135.06 g (0.51~ mole, yield 90.4%) of -the title compound as pale yellow powder:
Hmr (CDC13) ~ : 2.50 (3H, s, -CH3), 5.38 (2H, s, -C02CH2Ar), 7.53 (2H, "d", J=9 Hz, aromatic Hs) and 8.27 ppm (2H, "d", J=9 Hz, aroma-tic Hs); ir (CH2C12) ~max 2130 (N2), 1720 (ester), 1655 (C=0), 1520 and 1350 cm (N02); Rf 0.65 (ethyl acetate).

-~ trade mark ~ ,~

2~S ~, ~
-16- .

C. p-Nitrobenz~l 2-diaz~-3-trLmethylsilyloxy-3-butenoate O OSiMe3 ~U~ C02PNB . .//\ ~02PNB
~ triethylamine To a suspensisn of p-nitrobenzyl ~-diazoacetoacetate (236 mg, 1 mmole) and triethylamine ~0~?5 ml, 1.08 mmole) in CH2C12 (2 ml) was added at 0-5~C trime~hylsilyl trifluoro-methylsul~onate (0.22 ml) under a nitrogen abmospbere and the mixture was stirred for 30 minutes, To t~is ~lear yellow solution was added dxy hexanes ~30 ml) a~d the reaction mixture was stirred for 1~ minutes. After removing the vily deposit, the hexanes soluti~n was evaporated in acuo to yield yellow .
solid ~hich was redissolved in dry hexane~ (50 ml). The insoluble m~terial was filtered over Celit~ and the filtrate was e~a~orated ~n ~acuv t~ obtain 277 mg ~0.90 mmole, yield 90%) of the title compound as yell~w crystals: ir (film) ~max 2100 (~2)~ 1705 (ester), 1520 and 1345 cm 1 ~No23; lHmr (CDC13) ~: 0.27 (9~, s, SiMe3), 4.23 (lH, d, J=2 Hz, vinyl proton),

4.93 (1~, d, J-2 Hz, vinyl proton), 5.32 (2H, s, -C02CH2Ar), 7.4~ (2H, ~d~, J--9 Hz, aromati~ prot~ns3~ and B.23 pp~ (2~, "dn, . J--9 Hz, aromatic protons).

. EXample 2 Preparatio~ p-Ni~ ~ ~3-tert-butyl d~methylsilyloxy-3-buten~ate o osi +
2P-NB TBD~S OTf ~ 02P-NB
N(C2H5)3 N2 ~ ~L trade mark : , ..

~22~t;

To a suspension of p-nitrobenzyl ~-diazoacet~acetate ~2 6 . 30 q, O .10 mole) and triethylamine (14 . 57 g, 20 . 0~ ml, D .14 m~le) in dry ~ethylene chloride (200 ml) was added at 2~C tert-butyl dimethylsilyl trifluor~methylsulfonate ~31.72 g, 27.5~ ml, O.12 mole) over a 30 minute period under a nitrogen atmosphere, The mixture was then stirred at 2 C ~r one hour. The clear orange solution was diluted with methylene:.chloride (50 ml) and washed with water (3 x 200 ml) and then brine ~1~0 ml), dried (Na2S04) and evaporated, yielding 37.40 g (0.099 mole, yield 99%~ of the title compound as a yellow solid: ~mr (CDC13, EM-360A, 60 MHz) ~: 0.26 (6H, s, Si(C~3)2), 0.96 (9H, s, SiC(CH3)3), 4.25 (1~, d, J=2.5 Hz, 4-H), 4.97 (lX, d, J=2.5 Hz, 4-H), 5~32 (2H, s, -CO2CH2Ar), 7.48 ~2H, "dn, J=9.0 Hz, Ar~'s) and 8~22 ppm ~2H, "d~, J=9~0 Hz, Ar8's); ir (film) ~max 2090 tN2), 1694 (ester), i600 (C=C) and 1344 ~m 1 (N02).

~x~ . . ..
Preparation of (3S,4R)-3-~ y~roxyethyl3-4-13-(4-nitrobenzvloxY)carbonyl-2-oxo-3-diazo~ro~ylJazetidin-~-one osi +
0l i + ~C02P-N13 J",~C)CC>CH3 __ ~
~ ~C12 OSi+ N2 ~CO2P-~B

3122~ S ~D

T~ a suspension of anhydrous zinc chloride (34 mg, 0.25mmole), in methylene chloride ~2 ml) was ad~ed a solution of (l'R, 3R, 4R)-3-(1'-tert-butyldimethylsilyloxyethyl~-4-acetoxy-azetidln-2-on~ (144 mg, 0.5 mmole) in methyl~ne ~hloride (4 ml) foll~wed by solid 4-nitrobenzyl-2-diazo-3-~ert butyldimethyl-silyloxy-3-butenoate (350 mg, 0.93 mmole) under a nitrogen atmosphere~ m e 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 (Na2S04) and evaporated, yielding a crude oily yellow solid which was purified by column chroma- -tography. [(sio2~ 30 g) eluted with methylene chlorid~:ethyl acetate 4:1] to obtain 198 mg ~0.405 mmole, 81%) of ~he title compound as an oil identical (tlc, l~mr) with an authentic sample prepared by a published procedure.

... . . . .

Prepar~tio~ ~f..(35,AR) -3-.I (lR)~Hydxoxye~hyI]-4-l3-(4-nltrobenz~loxy)carbonyl-2-oxo-3-diazopropyl3 azetidin-2-one OSi+ N~
~C02PNB lN I~Cl/methanol o~

~ 2 OH .
CO;~PNB
N
0~
To a solution of (3Sr4R)-3-[(lR)-(tert-butyldimethyl-silyl~xy)ethyl3-4-[3-(4-nitrobenzyloxy~carbonyl-2-~xo-3-diazopropyl]azetidin-2-one (72 mg, 0.15 mmole) in methanol (1~0 ml) was added lN aqueous HCl (0.2 ml) and ~he mixture was stirred at room temperature for 2 hours by which time tlc (ethyl acetate) indicated that the reactiOn was complet2d.

~ 21[3i~LS

Durlng this period the title compound was precipitated. This was filtered and rirlsed with cold CH30H-~20 (971) and then cold diethyl ether to obtain 43 mg tO.ll mmole, yield 73%) ~f the title compound as a white solid. The title compound was similarly obtained from (3S,4R)-3-{(lR)-I(2,4,6-tri-tert-~butylphenoxy)dimethylsilyloxy~e~hyl~ 4-~3-(4-nitrobenzyloxy) carb~nyl-2-oxo-3-diazopropyl~azetidin-2-one. ~'-xample 5 Prepar~tion D~ . (3S,4R?-3-.~(lR- I (2., ~, 6-~ri-ter~
butylphenox~)dimeth~lsilyloxy~ethyI}~
4-13-(4-nitrobenzyl)oxycarbonyl-2-oxo- -3-diaz~propyl~azetidin-~-one ~ ~ J ~ ~c02P~

The title cc~mpound was prepared in 84 ~6 yield from (3R,4 and 4S)-4-acet~xy-3-{(lR-1(2,4,6-tri-tert-butylphenoxy)-dimethylsilyloxy] ethyl }-2-azetidinorle by the method described ab~ve for the corresponding t-~utyl dimethylsilyl-derivative:
Hmr (CDC13, 80 MHz) ~: 0.26 (3H, s, SiMe), 0.40 (3H, s, SiMe), 1.27 (9H, s, t~Bu) ~ 1.41 (18H, s, (t Bu)~), 2.92 tlH, dd, J3 1~=
2 5 Hz 3-~I), 2.97 (lH, dd, ~em-17~6 Hz, Jl"b--4 9.6 Hz, l"-Hb), 3.40 (lH, dd, ~gem~17~6 Hz, Jln _4=3.5 Hz, l"-Ha), 3.98-4.24 (lH, m, 4-H), 4.32-4.57 (lH, m,- l'-H), 5.3~ (2H, s, -CO2CH2Ar), 5.95 (1~, br s, ~), 7.22 (2H, s, ArH's of the ether), 7.52 (2~1, rd", J~8.7 Hz, Ar~'s o~
the ester) and 8.25 ppm (2H, ~d!' ~ J=8.7 Hz, ArH's o~ the ester):
ir (neat) ~max 3300 (br, NH), 2137 (-N2), 1755 (~-lactam), 1720 (ester), 1651 (C=O), 1523 and 1345 cm (N02).

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the formula wherein R1, R2 and R3 are each independently C1-C4 alkyl, which process comprises reacting a compound of the formula with a silyl triflate of the formula wherein R1, R2 and R3 are as defined above, in an inert organic solvent and in the presence of an organic base.

2. The process according to Claim 1 wherein the reaction is carried out at a temperature of from about -40°C to +30°C.

- Page 1 of Claims -

3. The process according to Claim 1 wherein the organic base is a C1-C4 trialkylamine, and the solvent is methylene chloride.

4. The process according to Claim 2 wherein the organic base is a C1-C4 trialkylamine, and the solvent is methylene chloride.

5. A compound having the formula wherein R1, R2 and R3 are each independently C1-C4 alkyl, when prepared by the process of Claim 1, Claim 2 or Claim 3, or by obvious chemical equivalents thereof.

6. A compound having the formula wherein R1, R2 and R3 are each independently C1-C4 alkyl, when prepared by the process of Claim 4 or by an obvious chemical equivalent.

- Page 2 of Claims -

7. A process for the preparation of a compound of the formula which process comprises reacting a compound of the formula with a silyl triflate of the formula in an inert organic solvent and in the presence of an organic base.

8. The process according to Claim 7 wherein the reaction is carried out at a temperature of from about -40°C to +30°C.

9. The process according to Claim 7 wherein the organic base is a C1-C4 trialkylamine, and the solvent is methylene chloride.

- Page 3 of Claims -

10. The process according to Claim 8 wherein the organic base is a C1-C4 trialkylamine, and the solvent is methylene chloride.

11. A compound having the formula when prepared by the process of Claim 7, Claim 8 or Claim 9 or by obvious chemical equivalents thereof.

12. A compound having the formula when prepared by the process of Claim 10 or by an obvious chemical equivalent.

13. A process for the preparation of a compound of the formula - Page 4 of Claims - -23-which process comprises reacting a compound of the formula with a silyl triflate of the formula in an inert organic solvent and in the presence of an organic base.

14. The process according to Claim 13 wherein the reaction is carried out at a temperature of from about -40°C to +30°C.

15. The process according to Claim 13 wherein the organic base is a C1-C4 trialkylamine, and the solvent is methylene chloride.

16. The process according to Claim 14 wherein the organic base is a C1-C4 trialkylamine, and the solvent is methylene chloride.

17. A compound having the formula - Page 5 of Claims -when prepared by the process of Claim 13, Claim 14 or Claim 15 or by an obvious chemical equivalent thereof.

18. A compound having the formula when prepared by the process of Claim 16 or by an obvious chemical equivalent.

19. A process for the preparation of a compound of the formula wherein R4 is hydrogen or a conventional hydroxyl-protecting group, which process comprises reacting a compound of the formula wherein L is a conventional leaving group and R4' is a conventional hydroxyl-protecting group in an inert organic - Page 6 of Claims -solvent and in the presence of a Lewis acid catalyst with an enol silyl ether compound of the formula wherein R1, R2 and R3 are each independently C1-C4 alkyl, and, if desired, removing the hydroxyl-protecting group to obtain the corresponding hydroxyethyl intermediate.

20. The process according to Claim 19 wherein the leaving group L is

21. The process according to Claim 19 wherein the Lewis acid catalyst is ZnCl2.

22. The process according to Claim 20 wherein the Lewis acid catalyst is ZnC12.

23. The process according to Clairn 19 wherein the solvent is methylene chloride.

- Page 7 of Claims -

24. The process according to Claim 20 wherein the solvent is methylene chloride.

25. The process according to Claim 21 wherein the solvent is methylene chloride.

26. The process according to Claim 22 wherein the solvent is methylene chloride.

27. The process according to Claim 19, Claim 20 or Claim 21 wherein the hydroxyl-protecting group is tert-butyldimethylsilyl, trimethylsilyl or (2,4,6-tri-tert-butylphenoxy) dimethylsilyl.

28. The process according to Claim 22, Claim 23 or Claim 24 wherein the hydroxyl-protecting group is tert-butyldimethylsilyl, trimethylsilyl or (2,4,6-tri-tert-butylphenoxy) dimethylsilyl.

29. The process according to Claim 25 or Claim 26 wherein the hydroxyl-protecting group is tert-butyldimethylsilyl, trimethylsilyl or (2,4,6-tri-tert-butylphenoxy) dimethylsilyl.

- Page 8 of Claims -