DK174361B1 - 6-silyl:oxy-ethyl-2-oxo-penam-3-carboxylate(s) prepn. - from 2-tri:phenyl:methyl:thio-3-silyl:oxy-2-oxo-azetidinyl-acetate derivs. - Google Patents

Abstract

(A) Prepn. of penam derivs. of formula (IV) comprises: (a) reacting an azetidinone deriv. of formula (I) with a molar excess of silver nitrate in presence of molar excess of pyridine in an inert solvent at -25 to +25 deg. C, then treating with hydrogen sulphide to give an azetidine deriv. of formula (II); (b) acylating with 1 molar equiv. of p-nitrophenyl chloroformate in presence of 1 molar equiv. 4-(dimethylamino)pyridine in an inert solvent at -25 to + 25 deg. C to give an azetidinone of formula (III); and (c) reacting with molar excess of lithium hexamethylolsilylamide at -50 to -100 deg. C to give (IV); where R = CH2CX=CH2, CH2CH2SiMe3, p-nitrobenzyl or ester forming gp. which is hydrolysable in vivo; X = H or Cl; R1 = silyl protecting gp. (IC) may then be: (d) reacted with 1 molar equiv. triflic anhydride in presence of a molar excess of diisopropylethylamine in an inert solvent at -40 to -90 deg. C to give a soln. of a cpd. of formula (V); and either: (e) reacted with at least 1 molar equiv. of HSR2 at 0 to -90 deg. C to give a penem of formula (VI); or (e') reacted with at least 1 molar equiv. of (R6R5CH)2Cu(CN)nLin+1 at -60 to -100 deg. C to give a penem of formula (VI'); Where R2 = e.g. 1-4C alkyl, (1,3-dioxacyclopent-4- or 2-yl)methyl, (2-oxo-1,3-dioxa cayclopent-4-yl)methyl, (1-methyl-2-imidazolyl) methyl, etc.; Q = OH, p-nitrobenzyloxycarbonylamino, piperidino, pyrrolidino, morpholino or 4-allyloxycarbonylpiperazino; R5 = H or 1-8C alkyl; R6 = H, Me, 1-8C alkoxy or OR7; R7 = hydroxyprotecting gp.; or R5 + R6 = (CH2)mO(CH2)p; m and p = 0-5; provided that m + p is at least 3; and n = 0-1.

Description

in DK 174361 B1

The present invention relates to an efficient multistage process for the preparation of penem compounds having the general formula (6 ') of claim 1. The compounds of formula (61) are useful as precursors to 5 different antibiotic penem compounds specified by formula (7 ') shown below in Scheme 3.

Hitherto, a number of processes have been described for the preparation of penem antibiotics substituted at the 2-10 position with an alkyl group or a thioether group, -SR 2, as in formulas (6) and (6 '). For thioether compounds (6) and (7), two of the more general of these processes are illustrated in Schemes 1 and 2. In Scheme 1, an alternative intermediate to the silver salt of the mercaptan is the mercaptan itself described by Zn / H + reduction of the tritylated thiol (Girijavallabhan et al., J. Antibiotics, 39, 1182 (1986), U.S. Patent No. 4,584,133). Menard et al. also in the U.S. Patent No. 4,272,437 discloses processes related to the processes of Scheme 2, which 20 processes were used more generally for the synthesis of compounds (6 ') and (7') as well. For example, intermediates of type (K) were reacted with an acylating agent such as R5R5CH-COCl to form compounds structurally related to (L) which are then heated to seal the ring and thus to form compounds (6 '). and (7 '). See also published application EP 199,446, wherein compounds of the type (6 ') and (7') below, in which and R6 are defined together, are prepared in a similar manner.

30 2 DK 174361 B1

Scheme 1

Η H

Rd J_ ¢ ^ 3 Kd_L_ / SCf, 3

5 pa ICH2CO2Re pH

* - ™ J-s-Λ

O O CO 2 R

(A) (B) 10 »

Rd T_ ^ s

AgN03 "" Η ClCORf - >> l _ „-, e -►

O CO 2 R

(C)

S

1 '1

RdJ_ / S / ^ 'ORf 20 h strong base w -N- ^

O 2 CO 2 R

(D)

H

25 w

RdJ'_ _►

C02RQ

3 ° (E)

Rd - -S'v ^ 'SR9 I-N-v e O C0 ^ Re 35 * (F) 3 DK 174361 B1

References: Girijavallabhan et al., J. Antibiotics, 39, 1182 (1986), U.S. No. 4,584,133, wherein:

OH

Rd ",

H

Re = -CH2CH = CH2,

Rf = beta-naphthyl,

Ro = C2 H9, CH2 N, etc. , 15

Xa = "leaving group".

DiNinno et al., U.S. Patent No. 4,610,823 (1986); Leanza et al., Tetrahedron, 39, 2505 (1983), where 20 i

* X

Ra = CH3 =

H

25

Re = -CH2CH = CH2 or -CH2 ØO2,

Rf = CeHs, R ° = alkyl, aralkyl, etc., 30

Xa = "leaving group".

4 DK 174361 B1

See also Girijavallabhan et al., U.S. patents Nos. 4,443,373 and Nos. 4,530,793 for an alternative synthesis of the compounds (E), wherein CH 3 CHOH-, and Re represents CH 2 CH = CH 2 or CH 2 CH 2 Si (CH 3) 3, from compound (A).

5 DK 174361 B1

Scheme 2

Η H

5 Ra T_ SCØ ^ f_.SC03 -¾. h CHOC00R °

H _2 H OH

I-NH * * J-N-f.

c02Rb fG) (H) 10

Raj-_ £ S03

S02C12 li £ 1 03P

- * - ► -N-. -in-►

15 C02R

(IN)

Η H

"A_I _ ^ SCØ," a? ^ SAg t 1- £ 20 R Λ -_► H, «> 3 -M —— <b ^ -N-v" b o co2ru nCO2r ° (J) (K)

25 * JL

Ra_T_ ^ S SEt CICSjEi \ .po, CH3C6H5 "- * '- N-3 b" vS3- *

O ^ CO2RD

30 iL) · 6 DK 174361 B1% Ho

Ra - / S''Y ^ SEt oa f ^ Sv ^ SEt s LM »T ~ h i C ° 2Rb 0 ^ N ^ C02Rb (M) (N)

H

10 * aJ_ ^ His S * C

_S! sh __>. I 1 CO 2 Rb (O) 15

Reference: 20 DiNinno et al., Tetrahedron Letters, 23, 3535 (1982), where i

j-SiO

Ra - CHs =

25 H

Rb = -CH 2 CH = CH 2,

Rc = -CH (CH 3) 2, -CH 2 CH 2 OH, etc.

30 *: These steps presumed on the basis of footnote 16 reference to UK 2,042,514.

7 DK 174361 B1

See also Ganguly et al./J. Antimicrob. Chemo., 9, Supplement C1 (1982), using several similar steps in a different sequence. Ghosez et al., Tetrahedron Letters, 39, 2493 (1983), have described the synthesis of 2- oxopenam compounds from penicillin G and the conversion of the same to 2-alkoxypenem derivatives of penicillin G. In Japanese Public Application No. 84,115,788 ( Chem. Abst., 97; 34979y, Derwent Abst. 78700D) similarly describes the conversion of hydroxy and carloxy protected 6- (1-hydroxyethyl) -2-oxopenam compounds to the corresponding alkoxy analogs.

Additional alternative methods for the synthesis of penem compounds include the methods described by Dextraze 15 et al., U.S. Patent No. 4,769,451; Pirie et al., U.S. Patent No. 4,751,297; Volkmann et al., U.S. patent no.

4,739,047; Brighty, U.S. Patent No. 4,695,626; Brighty et al., U.S. Patent No. 4,782,145; Perrone et al., J, Org.

Chem., 51, 3413 (1986); Batastini et al., U.S. patent no.

20,631,150; UK Patent Application No. 2,187,448; Alpegiani et al., U.S. Patent No. 4,577,016, and Franceschi et al., J.

Antibiotics, 36, 938 (1983).

In the literature, there have been numerous reports on the formation of 2-oxocarbapenem compounds and 3-oxocepham compounds for 2- (alkylthio) -2-carbapenem compounds and 3-alkylthio-3-cephem compounds via enolic esters: 30/174361 B1 8 / / -O ► J-or1 io "j COORh COORh 5 (Q)

R ^ SH

1 '10 ΓΠ · i-.1 h COORn m 15 where is a traditional carboxy protecting group / R1 is e.g. diphenyl or diethylphosphoryl, tosyl / mesyl or trifluoromethanesulfonyl. See, e.g. Sletzinger et al., Tetrahedron Letters, 21, 4221 (1980); Andrus et al., J.

Am. Chem. Soc., 106, 1808 (1984); Evans et al., Tetrahedron Letters, 26, 3787 (1985) and 27, 3119 (1936) and U.S. Pat. Patent No. 4,673,737; Ratcliffe et al., 21, 31 (1980); same place 1979, 4947; Salzmann et al., Same site, 21, 1193 (1980); Melillo et al., Same site, 21, 2783 (1980);

Iimori et al., J. Am. Chem. Soc., 105, 1659 (1983). However, the chemistry observed with these carbapenem ketone groups has generally been inapplicable to the thiolactone carbonyl group in 2-oxopenem compounds. The reaction of methyl chloride or mesyl anhydride with e.g. a compound of the type (4) below produces a compound of the type 30

, H

H

H · SO_CH,; / ~ N- <2 3

O 2 CO 2 R

(S) w 9 while either tosyl chloride or triflyl chloride and a compound of the type (4) produce a compound of the type

5 or 1 H

z "sv ^ ° H ^ H. Cl ^ -N— <

CT C02R

10 (T)

It has recently been specifically stated in published European Patent Application No. 257,419 that a compound of the type (4) below was reacted with diphenylphosphoryl chloride to form the in situ diphenylphosphoryl ester which was further reacted with a phenol to form a compound of types 20 ca3caioR \ _

I I

J-N-t 2

O COOR

(U) 25 in a very small yield. This application provides no specific support for the alleged wider use of other potential enol ester-forming reagents, such as triflyl chloride, which is actually a known chlorinating agent, not a triflate ester-forming reagent (see above and Hakimelahi et al., Tetrahedron Letters, 1979, p. 3643-3644).

10 DK 174361 B1

We have now found an efficient multistage process for the synthesis of penic antibiotics, which is summarized in Scheme 3. Accordingly, the process of the invention is peculiar to the characterizing part of claim 1.

In Scheme 3, the various variable symbols are defined as follows: R represents -CH2CX = CH2, -CH2CH2Si (CH3) 3, p-nitrobenzyl or a traditional radical that forms an ester which is hydrolyzed under physiological conditions, X represents H or Cl, R 1 is a traditional protecting group of the sylyl type and R 5 and R 2 are defined separately, where hydrogen or (C 1 -C 6) alkyl, R 6 represents hydrogen, methyl, (C 1 -C 6) alkoxy or OR7, R7 is a traditional hydroxy protecting group and R8 represents hydrogen, (Cx-C5) alkoxy or OH, or R5 and R6 are defined together and represent - (CH2) mO (CH2) p- where m and p each is 0 or an integer of from 1 to 5, assuming that the sum of m and p is at least 3 and 20 R5 and R8 correspond to R5 and R6 except that when R8 is defined separately from R5, the meaning OR7 with OH.

Scheme 3 25 Γ 1 OR1 OR1 yy g

/ • kl_ / scø3: AJ

30 H Γη α3Η03, 8 Ta I-Ν-ν J-Ν-.

C02R ο- "C02R

(1) 11 DK 174361 B1

Scheme 3 (continued) OR1 5 - ^ SH o HS H \ CIC-O- ^ VnO, - -? _> H _l ^ L_ £ _s> ^ iN-, base ^ O co2r (2) 10 OR1 0 s' C0- {J) ^ Oi H% H Strong base ^ yNv ''>

CO 2 R

(3) OR1 + f + niV0 'l1 (F, CS0?>, 0 ^ N - U base ^^ co2r (4) OR1 S ^ oso2cr3

H ^ I

H 1

I-N-L

0i> co2R

(S)

Scheme 3 (continued) 12 DK 174361 B1 (5) (R5R6CH) 2Cu (CN) n 5 1

OR

I H 5 6

^ CHR ^ R

Η I ^ I

H 1 -► -> i-N-

CO, R

10 υ 2 (6 ')

OH

A. f / chr5r8 -r ^ T (or a corresponding 15 H t "I ester hydrolyzed Ή I-jj-under physiological

O * COOH

conditions) (7 1) 20

Traditional radicals that form esters that are hydrolyzed under physiological conditions have become as common in the beta-lactam field as pharmaceutically acceptable salts. As in the case of numerous other beta-lactam antibiotics, such "pre-drug" esters are commonly used orally to enhance gastrointestinal absorption. Once absorbed, they are hydrolyzed in vivo to form the corresponding penic acid. Preferred ester radicals are -CHR 2 OCOR 4 or -CHR 30 CO 2 R 4, where r 3 represents hydrogen or methyl, and represents (C 1 -C 6) -alkyl, especially pivaloyloxymethyl and 1- (ethoxycarbonyloxy) ethyl.

13 DK 174361 B1

Among the traditional protecting silyl groups are trimethylsilyl and dimethyl-t-butylsilyl. The latter is most preferred because of the ease of insertion and removal, while at the same time having excellent stability as a protecting group during the various other process steps of the present invention.

Preferred values for -CHR ^R® also found in the prior art are methyl, hydroxymethyl, 2-10 tetrahydrofuryl, 2-tetrahydropyranyl or methoxymethyl. The hydroxymethyl group is often further reacted to produce e.g. a carbamate

The present invention, which is readily practiced, provides an efficient process for the preparation of penemanti biotics of formula (7 ').

In the first step of this process, a triphenylmethylthio compound of formula (1) is reacted in the presence of two 20 or more molar equivalents of a weakly basic amine such as pyridine and in the dark with silver nitrate (at least one mole equivalent, usually in excess). , for example, 1.5-2 molar equivalents) to produce the silver salt of the corresponding mercaptan. This reaction is generally carried out in a reaction inert solvent such as methanol. The temperature is not critical, but lower temperatures, e.g. from -25 ° C to 25 ° C is generally preferred, where from 0 to 5 ° C is particularly convenient and satisfactory. Generally without isolation, the intermediate silver salt 30 is directly converted with excess hydrogen sulfide gas to the raercaptan.

Silver is recovered as the sulfide by filtration and the mercaptan (2) is recovered from the mother liquor by conventional methods such as extraction and solvent evaporation.

14 DK 174361 B1

As used herein, the term "reaction inert solvent" refers to a solvent which does not react with starting materials, reagents, intermediates or products in a manner that adversely affects the yield of the desired product.

In the second step, the mercaptan (2) is reacted with substantially one mole equivalent of 4-nitrophenyl chloroformate to give the intermediate of formula (3). This step is carried out in the near room of substantially one mole equivalent of a tertiary amine, preferably diisopropylethylamine and / or dimethylaminopyridine, usually in a reaction inert solvent such as tetrahydrofuran, and is preferably carried out at a lower temperature, e.g. from -25 ° C to 25 ° C, conveniently at 0-15 5 ° C. If desired, the intermediate (3) is isolated and characterized by traditional methods. However, it is simply preferred to use the initially obtained solution of the compound of formula (3) directly in the next step.

In the third step, the intermediate (3) is cyclized in the presence of a strong base to produce the desired 2-oxopenem of formula (4), a known compound, e.g. when R represents allyl. This step is preferably carried out on a solution of the compound of formula (3) in a reaction inert solvent such as tetrahydrofuran. The preferred strong base is lithium hexamethyldisilylamide in the same reaction-inert solvent, usually used in a large molar excess (e.g., 3-5 molar equivalents). This base, conveniently purchased as a 1 M solution in tetrahydrofuran, is generally diluted (e.g., from about 0.1 to 0.2 M) with tetrahydrofuran and cooled to a low temperature (e.g., from -50 ° C to -100 ° C, conveniently at -78 ° C, the temperature of a bath of acetone and dry ice). A solution of the compound of formula (3) in the same solvent is added portionwise, maintaining the same low temperature. The reaction, which is substantially complete after the addition is complete, is conveniently quenched with acetic acid excess and 2-oxopenem (4) is isolated by conventional methods of concentration and extraction.

In the next step, 2-oxopenem (4) is reacted with freshly distilled triflinic anhydride, usually in a small molar excess, at reduced temperature (from 0 ° C to -90 ° C, conveniently at -78 ° C) in a reaction inert. solvent, such as methylene chloride, in the presence of a molar excess (usually 4-6 molar equivalents) of a tertiary amine, preferably diisopropylethylamine. If desired, the resulting enolic triflate ester of formula (5) is isolated by chromatography of the reaction mixture on silica gel and the compound is characterized. However, this is unnecessary since the reaction solution is suitable for direct reaction with an appropriate reagent in the next step.

In the fifth step of the present sequence, a solution of the appropriate cuprous salt is reacted: (R 1 R 2 CH) 2 CU (CN) n 25 Lin + 1, where R 5 and R 6 have the opposite meaning and n is 0 or 1, in the same or another reaction inert solvent, with the triflate ester (5) similarly to produce penem intermediates of formula (6 '). However, when R 6 is a hydroxy protecting group, it is generally preferred to use a cuprous salt where n is 0.

When R is a conventional radical that forms an ester when hydrolyzed under physiological conditions, and in the absence of a hydroxy protecting group in the radical r5r6CH, the antibiotic penem compound is obtained by traditional removal of the protective silyl group, e.g. by methods specifically exemplified below. When R represents -CH2CX = CH2, -CH2CH2Si (CH3) 3 or p-nitrobenzyl, a further traditional chemical step is needed to produce the acidic antibiotic penem compound of formula (7 ') or its pharmaceutically acceptable salt .

When R represents -CH kis (triphenylphosphine) palladium, in which the alkali metal salt is directly formed by the antibiotic penem compound.

When R represents -Cl 2 Cl 2 Si (CH 3) 3, the group is best removed simultaneously with the protective dimethyl-t-butylsilyl group, preferably by using a molar excess of tetrabutylammonium fluoride in a reaction inert solvent such as tetrahydrofuran.

When R represents p-nitrobenzyl, the group is usually removed by conventional hydrogenolysis over a noble metal catalyst, preferably palladium, e.g. palladium-on-carbon.

When the side chain contains a traditional hydroxy protecting group R7, it is also removed by traditional methods. The preferred groups of this class are methoxymethyl, benzyloxymethyl and tetrahydropyranyl which are hydrolyzed with aqueous acid and / or by hydrogenation.

The mercaptans required by the present reaction sequence are known or obtainable by conventional methods. Preferred methods for the synthesis of 3S-mercaptothiolane-1R oxide are described specifically below.

The antibiotic penem compounds of formula (7 ') as well as their pharmaceutically acceptable salts and esters are used in drugs according to methods described in the references set forth above.

The following examples illustrate the invention.

EXAMPLE 1 2- (4R-mercapto-3S- (IR- (dimethyl-t-butylsilyloxy) ethyl) -2-azetidinon-1-yl) acetic acid aryl ester of formula (2)

A solution of 20 g (33.2 mmol) of 2- (4R- (triphenylmethylthio) -3S- (IR- (dimethyl-t-butylsilyloxy) ethyl) -2-azetidinon-1-yl) acetic acid aryl ester of formula (1) ( Jeff et al., "Tetrahedron, Vol. 39, 2505-2513, 1983; U.S. Pat.

4,610,823) in 600 ml of methanol was cooled to 0 ° C and treated with 5.94 ml (73 mmol) of pyridine. The subsequent portion of the reaction sequence was performed with the reaction flask protected from light. To the solution was added solid silver nitrate (10.2 g, 60 mmol) and the reaction mixture was allowed to stir for 1.5 hours while maintaining the temperature at 0 ° C. When the reaction was complete, hydrogen sulfide gas was slowly introduced with constant stirring. The dark mixture was then filtered through celite to obtain silver sulfide and the filtrate was concentrated. The organic residue was partitioned between ethyl acetate and brine. The layers were separated and the aqueous phase was re-extracted with fresh ethyl acetate. The combined organic layers were dried over sodium sulfate and then evaporated to give the title product used directly in the next step.

EXAMPLE 2 2 "(4R- (4-nitrophenyloxycarbonylthio) -3S- (1R- (1-methyl-t-butylsilyloxy) ethyl) -2-azetidinon-1-yl) acetic acid aryl ester of formula (3) prepared a solution of 4.06 g (33.2 mmol) of dimethylaminopyridine and 6.69 g (33.2 mmol) of 4-nitrophenyl chloroformate in 700 ml of THF. The solution was cooled to 0 ° C and treated with a solution of whole portion of the title product from the above example in 60 ml of THF and a separate portion of 5.78 ml (33.2 mmol) of diisopropylethylamine in 60 ml of THF The addition took 0.5 hour and a white precipitate formed. of the mixture for 5 minutes, the reaction mixture was filtered to exclude atmospheric moisture, and the filtered solution of the present title product was placed in an addition funnel and immediately used in the next step.

Part of this solution, after filtration through a small portion of silica gel using CDCl 3 as the eluent, was characterized by 1 H-NMR (300 MHz) which showed delta: 8.22 (2H, d, J = 8 Hz) , 7.29 (2H, d, J = 8 Hz), 5, 74-5, 89 (1H, ddd, J = 18 Hz, J = 12 Hz, J = 6 Hz), 5.46 (1H, d , J = 2 Hz), 5.25 (1H, d, J = 18 Hz), 5.17 (1H, d, J = 12 Hz), 4.57 (2H, d, J = 6 Hz), 4.25 (1H, dq, J = 6Hz, J = 5 Hz), 4.10 (1H, d, J = 19 Hz), 3.90 (1H, d, J = 19 Hz), 3.27 ( 1H, dd, J = 5 Hz, J = 2 Hz), 1.26 (3H, d, J = 6Hz), 0.84 (9H, s), 0.06 (3H, s), 0.04 ( 3H, s).

EXAMPLE 3 5R, 6S-2-OXO-6- (IR- (dimethyl-t-butylsilyloxy) ethyl) -penam-3-carboxylic acid allyl ester of formula (4)

The entire solution of the product of the above example was added to 133 ml (133 mmol) of 1.0 M lithium hexamethyl disilylamide (in THF) previously diluted with 1000 ml of THF and cooled to -78 ° C. The addition took 0.5 hours and the solution turned clear yellow. Acetic acid (38 ml, 664 mmol) was added and the reaction mixture was stirred for 10 minutes. Ca. half of the solvent was removed by concentration and the residue was diluted with diethyl ether to a volume of 2.7 liters. The ether solution was washed with saturated bicarbonate solution, saturated saline solution and then dried over sodium sulfate. The organic phase was concentrated and the residue was filtered through a pad of silica gel eluting with 15% ethyl acetate in hexane. 6.98 g (56%) of the present title product was obtained as a waxy solid; melting point 45-48 ° C, 1 H NMR (CDCl 3, 300 MHz) delta: 5.78-5.94 (1H, ddd, J - 18 Hz, J = 11 Hz, J = 7 Hz), δ, 51

(1H, d, J = 2 Hz), 5.32 (1H, d, J = 18 Hz), 5.25 (1H, d, J

= 11 Hz), 5.00 (1H, s), 4.65 (2H, d, J = 7 Hz), 4.32 (1H, 25 dt, J »7 Hz, J * 4 Hz), 3, 54 (1H, dd, J = 4 Hz, J = 2 Hz), 1.28 (3H, d, J = 7 Hz), 0.86 (9H, s), 0.07 (3H, s), 0 , 05 (3H, s); C13 NMR (CDCl3, 75, 43 MHz) delta: 199.0, 169.0, 163.4, 130, 4, 119.6, 71.7, 67.1, 66, 1, 64.6, 62 , 4, 25, 6, 22.5, 17, 9, -4.2, -5.1; m / e calcd for 30 C \HH _N05SSi (P-tBu): 328.0675, found: 328.0615.

EXAMPLE 4 5R, 6S-6- (IR- (dimethyl-t-butylsilyloxy) ethyl) -2- (trifluoromethanesulfonyloxy) penem-3-carboxylic acid allyl ester 5 of formula (5)

A solution of 100 mg (0.260 mmol) of the title product of the previous example in 5 ml of methylene chloride was treated with 0.180 ml (1.03 mmol) of diisopropylethylamine.

This clear solution was then cooled to -78 ° C in a bath of dry ice and acetone. Freshly distilled triflinic anhydride (0.045 ml, 0.270 mmol) was added and the clear solution was stirred for 1 hour at -78 ° C to give a cold solution of the present title product used directly in the next step. . A small portion of this solution was purified by chromatography on silica gel followed by low temperature crystallization (-78 ° C) from pentane; mp 40 ° C; 1 H NMR (CDCl 3, 300 MHz) delta: 5.84-5.98 (1H, ddd, J = 18 Hz, 20 J = 12 Hz, J = 6 Hz), 5.73 (1H, d, J = 2 Hz), 5.37 (1H, dd, J »18 Hz, J = 1 Hz), 5.25 (1H, dd, J = 12 Hz, J» 1

Hz), 4.73 (2H, dd, J = 6 Hz, J - 1 Hz), 4.25 (1H, dq, J = 6 Hz, J = 4 Hz), 3.86 (1H, dd, J = 4 Hz, J = 2 Hz), 1.24 (3H, d, J = 6 Hz), 0.87 (9H, s), 0.08 (6H, s); m / e calcd for C 14 H 17 NO 7 S 2 SiF 3 (P-tBu): 460.0168, found; 460.0246.

EXAMPLE 5 5R, 6S-2-OXO-6- (IR- (dimethyl-t-butylsilyloxy) ethyl) -penem-3-carboxylic acid 2- (trimethylsilyl) ethyl ester of formula (4)

By the methods of Examples 1 to 3 above, 2- (4R- (triphenylmethylthio) -3S- (1S- (dimethyl-t-butylsilyloxy) ethyl) -2-azetidinon-1-yl) acetic acid 2- (trimethylsilyl) ethyl ester converted to the above title product; 1 H-NMR (CDCl 3, 300 MHz) delta: 5.52 (1H, d, J = 3

Hz), 4.96 (1H, s), 4.35 (1H, q, J = 8 Hz, J = 5 Hz), 4.26 (2H, dt, J = 12 Hz), 3.56 ( IH, dd, J = 5 Hz, J = 3 Hz),

1.30 (3H, d, J = 8 Hz), 1.06 (2H, dt, J = 12 Hz), 0.89 (9H, s), 0.1 (3H, S), 0.08 ( 3H, s), 0.05 (9H, s); C13 NMR

10 (CDCl 3, 62, 89 MHz) delta: 199.3, 169.2, 163.9, 71, 8, 66, 4, 65.5, 64.7, 62.5, 25.7, 22.5 , 17.9, 17, 4, -1.5, -4.2, - 5.1; m / e calcd for C 15 H 26 NO 5 SSi 2 (P-t-Bu): 388.1179, found: 388.1125.

EXAMPLE 6 5R, 6S-2- (methoxymethoxy) methyl) -6- (IR- (dimethyl-t-butylsilyloxy) ethyl) penem-3-carboxylic acid allyl ester of formula (6 ')

The title product of Example 3 (49.8 mg, 0.129 mmol) was converted to a cold solution of the triflate title product of Example 4 by the procedure of Example 4. This solution was passed through a short plug of silica gel and then an equal large volume of 20% ethyl acetate in hexane used to elute the product from the silica gel. The resulting solution was evaporated under vacuum and then taken up in dry tetrahydrofuran. In a separate flask, 103 mg (0.284 mmol) of methoxy-methoxytri-n-butylstannane (Johnson et al., J. Org. Chem., 53, 4131 (1986)) was dissolved in 3 ml of dry tetrahydrofuran, the resulting solution was cooled to -78 ° C, and 0.185 ml (0.297 mmol) of 1.6 M n-butyllithium in hexane was added dropwise over 1 minute. The resulting solution was allowed to stir for 10 minutes. In a third flask, a clear, colorless solution of 29 mg (0.142 mmol) of copper (I) bromide dimethyl sulfide complex was prepared in 2 ml of 1: 1 tetrahydrofuran: diisopropyl sulfide (Hutchinson et al., J. Am.

Chem. Soc., 109, 4930 (1987)). To the solution of the copper (I) complex, cooled to -78 ° C, the solution of the lithium reagent was added over a few seconds via a cold steel cannula. To the resulting brown solution at -10 78 ° C, the above-mentioned solution of triflate was added with a syringe pump over 0.5 hour. After stirring for an additional 1 hour, the reaction mixture was quenched with 1 ml of pH 7 N + Cl / N + OH buffer, then diluted with ethyl acetate and allowed to warm to room temperature.

The organic phase was washed with brine, dried over sodium sulfate and evaporated under vacuum. The residue was chromatographed on silica gel (15% ethyl acetate in hexane) to give the above title product. 1 H NMR (CDCl 3, 300 MHz) delta: 5.9 (1H, ddd, J = 17 Hz, J = 12 Hz, J = 6 Hz), 5.58 (1H, d, J = 2 Hz) , 5.4 (1H, dd, J = 17)

Hz, J = 1 Hz), 5.25 (1H, dd, J = 12 Hz, J = 1 Hz), 4.88 (1H, d, J = 17 Hz), 4.7 (2H, s), 4.6-4.8 (2H, m), 4.23 (1H, dq, J = 6.8 Hz, J = 4.3 Hz), 3.7 (1H, dd, J = 4.3 Hz , J = 2 Hz), 3.4 (3H, s), 1.25 (3H, d, J = 6.8 Hz), 0.9 (9H, 25 s), 0.1 (6H, s) ; IR (CHCl 3) 1790, 1710 cm -1; UV (dioxane) lambda 321 nm, 250 nm. HRMS calcd for CigH24NOgSSi 386.1087 (P-tBu), found: 386.1058.

EXAMPLE 7 5R, 6S-2-methyl-6- (IR- (dimethyl-t-butylsilyloxy) ethyl) penem-3-carboxylic acid allyl ester of formula (6 ')

The title product of Example 3 (51.4 mg, 0.134 mmol) was converted to a solution of the triflate title product of Example 4 in tetrahydrofuran. Into a separate flask were placed 5 16 mg (0.179 mmol) of cuprocyanide and 1 ml of dry tetrahydrofuran. The suspension was cooled to 0 ° C and 0.336 ml (0.471 mmol) of 1.4 M methyl lithium in tetrahydrofuran was added dropwise over 10 minutes. The resulting clear solution was allowed to stir for 0.5 hour, then cooled to -78 ° C and the above-prepared triflate solution was added over 0.5 hour with a syringe pump. After stirring for an additional 1 hour, the cold reaction mixture was quenched with 1 ml of pH 7 NH 2 / Cl 3 / NH 2 OH buffer, then diluted with ethyl acetate and allowed to warm to room temperature. The organic phase was washed with brine, dried over sodium sulfate and evaporated under vacuum. The evaporation residue was chromatographed on silica gel (10% ethyl acetate in hexane) to give the above title product; 1 H NMR (CDCl 3, 300 MHz) delta: 5.91-5.79 (1H, ddd, J = 17 Hz, J = 11 Hz, J = 5.5 Hz), 5.47 (1H, d, J = 1.5 Hz), 5.33 (1H, dd, J = 17 Hz, J = 2 Hz), 5.16 (1H, dd, J = 11 Hz, J = 2 Hz), 4.71-4 , 53 (2H, m), 4.16 (1H, dq, J = 6 Hz, J = 5 Hz), 3.57 (1H, dd, J = 5 Hz, J - 1.5 Hz), 2, 28 (3H, s), 1.17 (2H, d, J = 6 Hz), 0.81 (9H, s), 0.01 (6H, s); IR (CHCl 3) 1785, 1710 cm -1; UV (dioxane) lambda 314 nm, 262 nm. (A) D 2 O = + 65.63 ° (c * 1.34); HRMS calcd for c18H29NO4si: 383.1586, found ; 383.1610.

Preparation 1 (R) -4-chlorobutane-1,3-diol 5 In a flame-dried glass container under nitrogen, (R) -4-chloro-3-hydroxybutyric acid methyl ester [1.00 g, 6.55 mmol) dissolved in 6.5 ml of dry tetrahydrofuran. The solution was cooled to 0 ° C and a solution of lithium borohydride (178 mg, 8.19 mmol) in 4.1 ml of dry tetrahydrofuran 10 with a syringe over a period of 30 minutes using 2 ml of tetrahydrofuran was added. rinsing. The ice bath was removed and the solution was stirred at 23 ° C for 6 h, then cooled to 0 ° C, guenched with 40 ml of methanol and acidified with 8 ml of saturated methanolic HCl. The mixture was stripped of solvent under vacuum and the residue was treated with methanol and the reaction mixture was distilled azeotropically (3 x 50 ml) to remove methyl borate and stripped to an oil * (1.55 g). The latter was flash chromatographed on a 8.5 cm deep silica gel pad of 8.5 cm diameter and was gradient eluted with CH 2 Cl 2 <1: 1 CH 2 Cl 2: ethyl acetate and ethyl acetate to give 0.67 g (82%) of the title product as an oil; (a) p = + 24.5 ° (c = 1.01, CH 3 OH).

25 PREPARATION 2

Methanesulfonic acid (R) -4-chloro-3- (methanesulfonyloxy) butyl ester In a 500 ml 3-neck flask under nitrogen, the title product of the above preparation (5.0 g, 0.040 mol) was dissolved in 150 ml of CH 2 Cl 2 · The solution was cooled to -20 ° c. Triethylamine (8.12 g, 11.2 ml, 0, 080 mol) and di-methylaminopyridine (0.489 g, 0.004 mol) were added followed by mesyl chloride (9.19 g, 6.21 ml, 0.080 mol) ). The solution was stirred at -20 to -15 ° C for 1 hour and then poured over 1 liter of crushed ice and stirred for 5 10 minutes. The separated aqueous layer was extracted with methylene chloride (1 x 300 ml). The combined organic layers were washed with 1 N HCl (1 x 500 ml), saturated NaHCO 3 (1 x 500 ml) and brine (1 x 500 ml), dried over MgSO 4 and stripped under vacuum to give 9.96 g 10 (88%) of the present title product; (a) p = + 32.74 ° (c = 1.06, CHCl 3).

PREPARATION 3 15 Methanesulfonic acid (R) -3-thiolanyl ester

The title product of the foregoing preparation (3.5 g, 0.0125 mol) was dissolved in 60 ml of 1: 6, H 2 O: CH 3 CN under N 2.

Sodium sulfide nonahydrate (3.90 g, 0.050 20 moles) was added. After heating at 50 ° C for 76 hours, the reaction mixture was diluted with 250 ml of CH 2 Cl 2 / washed with H 2 O x 100 ml) and then with brine (1 x 100 ml), dried over MgSO 4 and stripped under vacuum to give the above title product which was chromatographed on silica gel using CH 2 Cl 2 followed by 9: 1, CH 2 Cl 2: ethyl acetate as eluant to give 1.30 g (57%) of the above title product; (a) D = + 16.8 ° (c = 3.0, CHCl 3).

PREPARATION 4 3R- (methanesulfonyloxy) thiolane-1R oxide 26 GB 174361 B1

In the procedure of Example 3 of published international patent application WO 88/08845, the title product of the above example (1.17 g, 6.42 mmol) and potassium peroxymonosulfate (Oxon; 2.21 g, 3.6 mmol) in 15 ml acetone converted to 0.96 g (75%) of the above title product as a white solid; (α) ρ = + 2.04 ° (c = 2.94, CHCl 3) -

Claims (3)

1-N-v 30. nco2r wherein R and R1 are as defined above, DK 174361 B1 is reacted with a molar excess of AgNC> 3 in the presence of a molar excess of pyridine in a reaction inert solvent at a temperature in the range of from -25 to approx. 25 aC, followed by treatment with H 2 S to form an S compound of formula OR 1 in H AA / SH H 10 H; - (2) t-N-χO CO 2 R wherein R and R! is as defined above; (B) acylating the compound of formula (2) with substantially a molar equivalent of p-nitrophenyl chloroformate in the presence of substantially a molar equivalent of 4- (dimethylamino) pyridine in a reaction inert solvent at a temperature ranging from ca. -25 to approx. 25 ° C to form a solution of a compound of the formula OR H; --- (3) / -N-v 0 "" CO 2 R wherein R and R 1 are as defined above; (C) reacting the solution of the compound of formula (3) with a molar excess of lithium hexamethyldisilylamide at a temperature in the range of about -50 to approx. -100 ° C to form a compound of formula DK 174361 B1 ° r1 If // έχ \ 7_ _ / s \ 0 H ^ H - (4) INU O ^ CO-R 5 2 wherein R and R1 are as defined above ; (d) reacting the compound of formula (4) with substantially a molar equivalent of triflinic anhydride in the presence of substantially a molar excess of diisopropyl-ethylamine in a reaction-inert solvent at a temperature in the range of about 10 -40 to approx. -90 ° C to give a solution of a compound of formula 15 or 1 h oso2cf3 H I ^ il Η 'I; --- (5) iNk 20 (j CO 2 R wherein R and R1 are as defined above; and (e) reacting the solution of the compound of formula (5) with at least one molar equivalent (R5R6CH) 2Cu (CN) nLin + Wherein R 1 and R 6 are as defined above, and n is 0 or 1, at a temperature in the range of about -60 to about -100 ° C to form a compound of formula (6 ') B1 A process for the preparation of penem compounds of formula 5 OR1 I H _ / Sv- · CHR ^ R5 Η Γ for I H 1 --- (6 ') k-N-k 10. CO 2 R wherein R represents -CH 2 CX = CH 2, -CH 2 CH 2 S 1 (CH 3) 3, p-nitrobenzyl or a conventional radical forming an ester which is hydrolyzed under physiological conditions, X represents H or Cl, R a conventional protecting silyl group, and R 1 and R 6 are defined separately, wherein R 2 represents hydrogen or (C 1 -C 6) alkyl, R 2 represents hydrogen, methyl, (C 1 -C 6) alkoxy or OR 7, and R 7 is a conventional hydroxy protecting group, or and R® is defined together 20 and denotes - (CH2) mO (CH2) p-, where m and p are each 0 or an integer of from 1 to 5, provided that the sum of m and p is at least 3, characterized in that (a) that a compound of formula 25 OR1 1 H SC {C6K5) 3 HH --- (1) A method according to claim 1, characterized in that. that R 1 is dimethyl-t-butylsilyl and that when R is an ester hydrolyzable under physiological conditions, it is pivaloyloxymethyl or 1- (ethoxycarbonyl-oxy) ethyl. Process according to claim 1, characterized in that R 1 is dimethyl-t-butylsilyl, R is -CH 2 CH =: CH 2 / and R 2 and R 2 are defined separately and each is hydrogen or R 5 is hydrogen, R 6 is OR7 and R7 are methoxy-methyl.