DE3210092A1 - METHOD FOR CONVERTING AN OPTICALLY ACTIVE OR RAZEMIC ALCOHOL - Google Patents

Description

- 5 description;

The invention relates to a new process for reversing the chiral center that carries the hydroxy function, in optically active or racemic alcohols in ß-lactam systems, which gives a very high yield.

The importance of the chiral center bearing the hydroxy function in β-lactam compounds is in the literature well documented. The very potent antibiotic thienamycin (IV)

OH

SCH ₂ CH ₂ NH ₂ COOH

(IV)

has the (8R, 6S, 5R) configuration (Schönberg et al., J. Am. Chem. Soc. 100. 6491 to 6499). On the other hand, all members of the important family of olivanic acids only show the 8S configuration (Basker et al., J. Antib. 22,

25 878 to 884).

Furthermore, the newer penem class of type (V) shows:

COOH

. . ·. ': ■ ■ 3210032 - β -

a strong antibacterial activity in its (8R) configuration and a dramatic decrease in its (8S) isomer (Pfaendler et al, J. Am. Chem. Soc. 102. 2039-2043). A mild method of converting an S (or R) alcohol to its R (or S) isomer that is compatible with the β-lactam function is therefore of extreme importance. Indeed, the synthesis of this class of compounds usually yields R and S mixtures.

10

The invention relates to a new, completely stereospecific Process for converting an optically active or racemic alcohol of formula (I):

Oh

20th

(D!

into its epimer of opposite configuration the carbon atom bearing the hydroxy group, regardless of the configurations that the others have Have carbon atoms.

This route results in a stereochemically complete reversal at such a carbon atom in molecules with the important ß-lactam function, those with high chemical yield takes place.

In the formula (I), R represents hydrogen or lower alkyl, preferably methyl, ethyl, isopropyl, X and Y together form a radical of the type:

SCHoCH-NHR

VI

CH

wherein η is 0, 1 or 2. R "represents hydrogen, halogen, hydroxy (free or protected), amino (free or protected), carbamoyloxy, OR, OCOR, NHCOR, SR or a group SR" ¹ , where R " ^{1 is} a five-membered heterocyclic ring, e.g.

is. R ^IV stands for hydrogen, lower alkyl, benzyl, substituted benzyl, trichloroethyl, acetonyl, phenyl, benzhydryl or an enzymatically labile radical which brings favorable pharmacokinetic properties, and R stands for a suitable protective group, such as (CH,), Si or COR.

The method according to the invention can also be based on azetidinone derivatives of the general formula (I) can be used in which X represents hydrogen, lower alkyl, alkenyl, Alkynol, a suitable removable group such as Cl, Br, OAc, N (Et,) ,, SR or a radical of the type (cf. DE-OS 3 006 273):

OAc

R "

OAc

COOR

where η is O or 1, R ^{1 is} hydrogen, a suitable protecting group, such as (CH,), Si, Ms, CH ₂ Hi, CO ₂ CH ₂ HiNO ₂ and R, R "and η are as above have given meanings, and Y is hydrogen,

2Q (CH,), Si or the following groups:

CH-

COOR

IV

R "

OR ¹

COOR

IV

SR

COOR

COOR

IV

stands in which R ¹ , R "and R ^{IV have} the same meanings,

as indicated above, have R for hydrogen or a

suitable protecting group, such as COOCHpCCl ,, and Z is a hydroxyl, chlorine or = PPh, group.

The reaction proceeds according to the following scheme:

Level (A)

I (S)

Ii (S)

^. H. .R level (b) \ V. ■ · "

CF ₃ SO ₂

vStage e (B)

H OH

I (R) itufe (A)

Step (A) involves the conversion of the optically active (R or S) alcohol (I) to the corresponding triflate (II): The reaction may be carried out in solvents such as methylene chloride or chloroform in the temperature range of -80 to 0 ⁰ C (preferably -20 ° C) and using a

- ίο -

equimolar mixture of (CF ^ SOp) oO or CF, SOpCl and a base such as pyridine or imidazole in a ratio to the alcohol of up to the stoichiometric amount be carried out to a 2 or 3-fold excess.

After a short work-up, as described in the example, crude (II) (R or S) for stage (B) used. Step (B) is preferably carried out in aqueous acetone for a few hours at room temperature Tetrahydrofuran or a methylene chloride / water mixture, the best mixture being methylene chloride, acetone and water.

The invention is illustrated in the example.

example

Methyl-6af (8s) -1-trifluoromethylsulfonyloxyäthylJ-3-penicillanate-S-oxide:

" ¹ U

<7 'COOCH-

A solution of 7.8 ml of trifluoromethanesulfonic anhydride in 90 ml of dry methylene chloride was added dropwise to a solution of 5 ml of dry pyridine in 180 ml of dry methylene chloride which had been cooled under nitrogen to -10 ⁰ C. After stirring for 20 minutes, a solution of 6 g of methyl 6a - [(8s) -1-hydroxyäthylJ-3-penicillanate-S-oxide in 90 ml of dry methyl

- 11 -

j lene chloride was added dropwise to the mixture and more Stirred at −10 ° C. for 15 min. The reaction mixture was poured into 450 ml of ice-cold water. After separating the two phases, the aqueous phase was washed with methylene

5 chloride extracted.

The organic extracts were washed with cold water, concentrated to 300 ml and used for the next stage without further purification.

IR (CH ₂ Cl ₂ ): 1795, 1760 cm

¹ H NMR (CDCl ₃ ): 1.25 (s, 3H, 0-Cg ₃ ); 1.71 (s, 3H, β- (1.76 (d, J = 6.5 Hz, 3H, OT ₃ -CH); 3.81 (s, 3H, COOCH ₃ ); 3.96 (dd, J = 2.0, 2.5 Hz, 1H, 1 ^ 6); 4.52 (s, 1H, H ^ 4.94 (d, J = 2.0 Hz, H ^); 5.45 (m , 1H, CHO).

b)

Methyl 6a- [ (8R) -1-hydroxyethylJ-3-penicillanate-S-oxide:

CHo

H COOCH.

. CH ₃ -CH ₃

"COOCH-

240 ml of a water / acetone (4: 6) mixture and 10 ml 10% aqueous sodium bicarbonate solution was added to the given solution obtained in the previous example. The mixture was stirred at room temperature overnight and then concentrated to a small volume in vacuo (to remove the acetone). After adding salt water

The mixture was extracted with methylene chloride. The organic extracts were washed with salt water and dried. After evaporation of the solvent, 5.8 g of a yellowish foam remained. The cleaning by column chromatography (silica gel, methylene chloride / ethyl acetate mixtures as eluent) gave 5.4 g of the pure title compound (total yield 90Ji).

¹ H NMR (CDCl3,): 1.25 (s, 3H, CC-CjJ ₃ ); 1.36 (d, J = 6.5 Hz, 3H, CH ₃ CH); 1.70 (s, 3H, B-CH _3); 3.56 (dd, J = 2.0, 6.5 Hz, 1H, H ₁ (S); 3.72 (s, 3H, COOCYes ₃ ); 4.35 (dq, J = 6.5, 6 , 5 Hz, 1H, CJOH); 4.49 (s, 1H, H ^); 5.00 (d, J = 2.0 Hz, 1H, H-5).

Claims (1)

PATENT LAWYERS AND APPROVED REPRESENTATIVES BEFORE THE EUROPEAN PATENT OFFICE DR. WALTER KRAUS D I PLO M C H EM I K ER · D R.-l N S. AN N EKÄTE WEISERT DIPL-ING. SPECIALIZATION CHEMISTRY IRMGARDSTRASSE 15 D-BOOO MUNICH 71 TELEPHONE O H 9/79 7 O 77-7Θ 7O 78 TELEX O5-5121 & 6 kpotd TELEGRAM CRAUS PATENT 3233 WK / rm FARMITALIA CARLO ERBA S.p.A. Milan / Italy Process for converting an optically active or mix alcohol Claim Process for converting an optically active or racemic alcohol of formula (I): in which R represents a hydrogen atom or lower alkyl, X and Y together represent a radical of the type _J ³ COOR rv COOR rv . CH where η has the value 0, 1 or 2, R "is hydrogen, halogen, free or protected hydroxy, free or protected amino, carbamoyloxy, OR, OCOR, NHCOR, SR or a group SR" ¹ , where R ™ means a five-membered heterocyclic ring which contains up to 4 heteroatoms from the group nitrogen, oxygen and sulfur, R ^IV for hydrogen, lower alkyl, benzyl, substituted benzyl, trichloroethyl, acetonyl, phenyl, benzhydryl or an enzymatically labile residue ^ the favorable pharmacokinetic properties gives, R is a suitable protecting group, such as (CH,), Si or COR, or X is hydrogen, lower alkyl, alkenyl, alkynyl or a suitable removable group, e.g. Cl, Br, OAc, N (Et, ) ,, SR or a remainder of the type OAc S ν. OR ' COOR where η is O or 1, R ^{1 is} hydrogen, a suitable protective group such as (CH,), Si, Ms, CH ₂ Ph, CO ₂ CH ₂ PhNO ₂ , and R, R "and η are as defined above have, and Y stands for hydrogen, (CH,), Si or the following groups: CH, OR ' COOR IV R " COOR IV SR COOR IV R " COOR wherein R ¹ , R "and R have the meanings given above, R is hydrogen or a suitable protective group, such as COOCH ₂ CCl ₃ , and Z is a hydroxy, chlorine or = PPh, group, in its epimer of the opposite configuration the carbon atom carrying the hydroxyl group, characterized in that one la) the alcoholic function in the corresponding Converts trifluoromethanesulfonate and b) the resulting trifluoromethanesulfonate hydro-5 lysed to free alcoholic function to get back.