FI78077C - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA 3- (P-ALKYNSULFONYLFENYL) -OXAZOLINDINONDERIVAT. - Google Patents

Description

1 78077

The invention relates to a process for the preparation of therapeutically useful 3- (p-alkylsulfonylphenylphenyl) oxazolidinone derivatives of the formula I, their optical isomers and their pharmaceutically acceptable derivatives. 0 h ~ St0) n- (O ^ ^ / O ^ V_ X <I »15 wherein R 1 is CH 2, CF 2, CF 2 H or CF 2 CF 2 H, X is Cl or O 2 R 2 is H, -CR 1 - C (CH 2) CO H or -C-CH-R 1 O 0 0 n nh 2 R 3 is lower alkyl, m is 2 or 3 and n is 1 or 2, provided that when R 1 is CH 3, then X is 0R2 · These compounds have anti-bacterial activity.

U.S. Patent 4,128,654 to Fugitt et al. Describes compounds of formula 0 wherein A = R 5 (O) n, X = Cl, Br or F, R = C 1 -C 4 alkyl and n = 0 , 1 or 2. The compounds are said to be useful in controlling fungal and bacterial diseases of plants.

35 GB Patent 2003-151 (Delande) discloses a compound having the formula 2,78077 o / l

CH-S - / Γ) \ _JN O

3 \ ry w 5 ^

Neither the foregoing reference nor any known reference mentions the novel compounds of formula-10 described herein or their antibacterial activity in mammals.

Preferred compounds of formula I are those wherein X is OR 2, R 2 is H or -COR 3 and n is 2.

Compounds of formula I, their optical isomers and pharmaceutically acceptable acid and base salts thereof may be prepared by reacting a compound of formula

/ NVA

20 RXS— (oy \ P

wherein R 1 is as defined above and is OH or Cl # 25 is oxidized with peracid to give a compound of formula I wherein X is OH or Cl? and, if desired, reacting the resulting compound of formula I wherein X is OH with (i) an acid chloride of the formula R 1 COCl having the same meaning as above or an anhydride of the formula (R 3 CO) 20 wherein R 3 represents the same as above to give a compound of formula I wherein X is -OCOR 3, or (ii) with an N-protected amino acid of formula 3,78077 h

H02C-CH

NH-COO-t-Bu 5 wherein is as defined above, in the presence of a condensing agent to give a compound of formula I wherein X is -OCOCH-R 2, or nh 2 (iii) with an anhydride of formula 10

O

IV

(CH „) O

Wherein m is as defined above to give a compound of formula I wherein X is OC (CH-) COH.

n * m "

O O

20

The preparation of compounds of formula I wherein X is Cl can be illustrated by the following reaction scheme:

Reaction Scheme A

25 _ 5 ^ R1S - ^ o ^ -N = c = 0 Ris -φ} - »0

IV + _ ^ II ^ —X

30 x-ch2-ch-ch2 I

X = Cl V

Ηι5 (0> η - <^ θ) -Λ, 0 35 111 x 4 78077

The oxazolidinone methyl chloride of formula II can be prepared by the reaction of a suitable isocyanate and epichlorohydrin, as disclosed in U.S. Patent 4,128,654.

It has been found that better yields and easier isolation of the product are obtained when xylene is used as the solvent and the lithium bromide-tri-n-butylphosphine oxide complex as the catalyst. The reaction is carried out at a temperature in the range of about 100-145 ° C, preferably about 140-145 ° C

The oxazolidinone methyl chloride of formula II can be oxidized to the corresponding sulfoxide of formula III (n = 1) or sulfone (n = 2) with peracid, for example m-chloroperbenzoic acid or peracetic acid. The reaction is best carried out at a temperature in the range of about 10 to 60 ° C, preferably in the range of 20 to 30 ° C in a solvent such as methylene chloride or chloroform. The product can be isolated by triturating the reaction mixture with ether and separating the solid product by filtration. If necessary, it can be further purified by recrystallization from a suitable solvent.

The isocyanate IV of Reaction Scheme A, where R 1 = CH 2, is a commercially available product. Other isocyanates can be prepared as shown in Reaction Scheme B.

5 1.

78077

Reaction Scheme B

/ 7Λ H »hv / 7Λ H? HS— {Q V-N-C-CH3 + CF3I - = * ► CF3S- ^ CJ Vn-C-CH3

5 v lVI

CF3S- (5) -N = C = Q <-CF3S ^ NH2

IV-a (R 1 = CF 3) VII

io 1 -3 2. 0

Hs ~ (oy ”-c-ch3 0 o VIII -3 * HCP, s / oV" -C-CH3

15 "+ Z \ / IX

ClF2C-C-ONa '-Ί.

HCF2S- (0 ^ ^ 0 <r - HCF2 ^ Ö> —NH2

IV-b (R1 = HCF2) X

20 3. o HS - \ OV n-2-ch3 + cf2 = cf2 -> h o VIII HCF2CF2S_ / Q Vn-C-CH3

XI

> * HCF2CF2S - / q "\ _ N = C = O -HCF2CF2S- ^ 0 ^ ~ NH2 30

IV-c (R1 = -CF2CF2H) XII

6 78077

In Reaction 1, p-acetamidothiophenol V is reacted with trifluoromethyl iodide in liquid ammonia under UV light at -33 ° C. After completion of the reaction, the ammonia is removed and 5 water is added to the residue. The solid product VI is isolated by filtration and converted to the aniline VII by hydrolysis in an alcoholic (ethanol or methanol) potassium or sodium hydroxide solution at a temperature of about 60-80 ° C. The product is isolated by diluting the reaction mixture with water and extracting with a suitable solvent such as ether or ethyl acetate. The aniline VII is then reacted with phosgene in a suitable solvent such as toluene or xylene at an initial temperature of about 40-70 ° C, after which the temperature is raised to 100-110 ° C. The product, isocyanate IV-a (R 2 = CF 3) is isolated and purified by distillation.

In Reaction 2, p-acetamidothiophenol VIII is contacted with an alkali salt of chlorodifluoroacetic acid (Na or Li) using 2-methoxyethyl-20 ether as a solvent at a temperature of about 130-165 ° C, preferably 155-165 ° C. The difluoromethyl by-product IX formed is converted to the isocyanate IV-b (R = HCF2) in reaction X in two steps according to the procedure described above.

In reaction 3, p-acetamidothiophenol VIII is reacted with tetrafluoroethylene with an organic base, for example diisopropylamine. The reaction is carried out in a bomb in dimethylformamide or dimethyl sulfoxide in the range of about 0 to 50 ° C, preferably between 20 and 30 ° C. The product is isolated by pouring the reaction mixture into water and extracting with ether.

The obtained tetrafluoro derivative XI is converted to the IV-c compound (R 1 = -CF 2 -CF 2 H) via step XII in two steps according to the procedure described above.

35 7 78077

The preparation of compounds of formula I wherein X is OR2 can be illustrated by the following reaction scheme:

Reaction Scheme C

5 O

II \ - X

10 II V

a. / c. \ i / b · 15 o 0 / —v h ohoh / - \ / ΤΛ

RlS ~ yO y ~~ ^ \ P / \ _? ^ n \ 0 / ~ ^ ° \ / ^ \ XIV XV / ^ O-CCH ^ 20 /

O

/ - \ / -y H ° H? H

25 RISYOy-P? Rls (0) n_ / QV_NCH2CT-IH2

XVI 0H XVIII

30 \ ris, o)

XVII \ - OH

35 8 78077

Reaction a involves hydrolysis of compound II to aminodiol XIV under basic conditions. The hydrolysis is best performed in a water / alcohol mixture of sodium or potassium hydroxide (ethanol or methanol) in the range of about 40-80 ° C, preferably at a temperature between 70-80 ° C. The product can be isolated by diluting the reaction mixture with water and extracting with methylene chloride.

The resulting aminodiol XIV is then cyclized to compound XVI by reaction with diethyl or dimethyl carbonate 10 in ethanol or 1,2-dimethoxyethane as a solvent in the presence of a basic catalyst, for example, sodium ethoxide or methoxide. The product, which usually separates as a solid upon cooling the reaction mixture, is isolated by filtration.

Reaction b involves the replacement of group X in compound II with a carboxylate to give compound XV. This reaction is carried out with potassium acetate in dimethylformamide or dimethyl sulfoxide in the range of about 80 to 140 ° C, preferably at a temperature of 120 to 130 ° C. A catalyst such as 18-crown-6 can be used to improve the reaction rate. The product is isolated by diluting the reaction mixture with water and extracting as a suitable solvent, for example ether. The resulting ester XV is then converted to methanol XVI under basic hydrolysis conditions. This reaction is carried out in an alcoholic solution of potassium or sodium hydroxide (ethanol or methanol) in the range of about 0 to 60 ° C, preferably between 25 and 30 ° C. The product, which usually separates as a solid when the reaction is complete, is isolated by filtration.

The process for oxidizing sulfide XVI to sulfoxy-I XVII (n = 1) or sulfone XVII (n = 2) is the same as that shown in Reaction Scheme A for the oxidation of II to III.

Product XVII can also be prepared as compound III via compound XVIII according to the same method as described for the preparation of intermediate XVI from compound II via compound XIV.

The preparation of the amidodiol intermediate XIV shown in Reaction Scheme C can be carried out according to two alternative methods shown in Reaction Scheme D.

Scheme D

a.

10 ris <5V NH2 + ch ^ Q ^) ~ SQ2C1 "^ RlS ~ ^ 0 ^ ~ NH ~ SQ2 ^ 0yCH3

'- / XX O

XIX / \ HO-CH2-CH-CH2 s1 b R1S N-SO2 (g) -CH3 CH "CH-CH, 'I -

OH OH O

20 RlS ^ Oy-> ™ 2 + HO-CH2-M-OH2 sj. xxl

XIX N ^ J, -v H ° H ° H

R1S Λ O Vn-CH2-CH-CH2

XIV

In reaction a, aniline XIX is reacted with p-toluenesulfonyl chloride in a solvent such as tetrahydrofuran, 1,2-dimethoxyethane or acetonitrile in the presence of an aqueous solution of pyridine or sodium hydroxide. The reaction is carried out at a temperature in the range of 0 to 50 ° C, preferably in the range of about 20 to 25 ° C. The sulfonamide XX is then reacted with a glycidol in the presence of a base, for example 1,4-diazabicyclo (2,2,2) -octane or triethylamine. Suitable solvents include dimethylformamide or dimethyl sulfoxide.

The reaction is best carried out at a temperature in the range of about 80 to 120 ° C, preferably 90 to 100 ° C. Removal of the sulfonyl group of compound XXI is accomplished by reacting compound XXI with sodium naphthalene at a temperature in the range of about 10-40 ° C, preferably between 25-30 ° C. Suitable solvents include 1,2-dimethoxyethane-5 and tetrahydrofuran.

Alternatively, compound XIV can be obtained directly from aniline XIX and glycol in a boiling methanol solution, as shown in reaction b. The product is isolated by diluting the reaction mixture with water and extracting with methylene chloride.

Various simple esters of compounds XVI and XVII can be prepared according to Reaction Scheme E by reacting the compounds with a suitable acid chloride or anhydride in an inert solvent, for example methylene chloride, dimethylformamide or 1,2-dimethoxyethane. The reaction is preferably carried out at a temperature in the range of about 0 to 60 ° C, if desired in the presence of a base, for example pyridine or triethylamine. If the reactive anhydride is cyclic, such as succinic anhydride, the product is succinic acid monoester XIII-a (R3 = -CH2-CH2-CC> 2H).

Reaction Scheme E

° 0 / -V. 2 / -v 25 RlS (0) n <^ Oy- ^ * »3 - = - C1 ¥ IOIl (OV / ° XVI OH Ο *" ~ ^ \ -o (or XVII) (R.-CKO XIII-a '_ 3 2 C = 0

R

30 J

Barrier compounds of compounds XVI or XVII and amino acids are prepared as described in Reaction Scheme Part F by condensing ιχ 78077 with N-protected amino acids XXII in the presence of a condensing agent, e.g., Ν, Ν-dicyclohexylcarbodiimide. Inert solvents such as methylene chloride or dimethylformamide are used and the temperature is in the range of about 0-50 ° C, preferably in the range of about 25-40 ° C.

Reaction Scheme F

O

A A3

10 R, S (O) -cOVN 0 + HO-C-CH S

1 \ __ / \ / ^ NH-C-O-t-Bu

OH

I XXII

XVI

(or XVII)

as

Rls (0 »n <0) - ·; , ° W W ° / R3

> - O-C-CH O

\ "N-C-O-tBu

25 XXIII H

V

O

/ —V A.

30 /

w A. 2 A

° -C-CA „3 © x © 35 XIII-b ,, 78077 12

Product XXIII is isolated from the reaction mixture by removing the precipitated urea by filtration and concentrating the filtrate. The N-protecting group is then removed from XXIII by treatment with trifluoroacetic acid in the range of about 0-50 ° C, preferably between 5-25 ° C. Product XIII-b is isolated by diluting the reaction mixture with ether and filtering the solid product.

The product XVII (n = 2) obtained by the above method is a racemic mixture, i. 50:50 mixture of (+) and (-) - 10 enantiomers. The synthesis of the optically active compound XVII (R 2 = CH 2, n = 2) can be carried out by resolution of intermediate XIV utilizing its basic nitrogen. Conventional resolving acids can be used, for example d- or 1-mandelic acid. In this case, compound XIV (R 2 = CH 2) is reacted with 1-mandelic acid in aqueous ethanol. The resulting salt is then repeatedly recrystallized from acetonitrile until a constant melting point is reached. The salt is then basified by treatment with ammonium hydroxide to give the optically active (+) - compound XIV (R 2 * CH 2). The (-) compound XIV is then converted to the optically active (-) compound XVII (R 2 = CH 2) as described above. Compound (+) - XVII (R 1 = CH 2, n = 2) can be prepared using d-mandelic acid.

The compounds of formula I are effective in vitro against a variety of bacterial organisms, including gram-negative Enterobacteriaceae species; beta-lactase-forming Staphylococci and anaerobic bacteria. These microorganisms are of medical importance to humans and animals because they are considered active ingredients in infections involving the blood, central nervous system, respiratory system, digestive system, genitourinary system, tissue fluids, soft tissues, and bone.

The compounds of formula I have been tested in vivo in i3 78077 and in vitro experiments for their antibacterial efficacy. The 24-hour minimum in vitro concentration (MIC) of the compounds against the test species Staphylococcus epidermis was measured using the standard micro-dilution method 5 in Mueller-Hinton broth. This method is described by Conrath, Theodore B. in "Handbook of Microtiter Procedures", Dynatech Corporation, Cambridge, Massachusetts, which is incorporated herein by reference.

The in vivo antibacterial activity of the compounds was determined as follows.

Cultures of Staphylococcus aureus and Escherichia coli were grown from stored frozen aliquots in trypticase-soy broth (BBL), a standard bacteriological culture medium, with shaking until an optical density turbidity (650 μl) of 0.4-0.5 was reached. These cultures were centrifuged and resuspended in either 50% porcine gastromusin for Staphylococcus aureus or saline for Escherichia coli. These suspensions were injected intraperitoneally as dilutions calculated to cause 90-100% internal mortality within 7 days in control mice.

Compounds were suspended or dissolved in 0.25% "Methocel" at 15 CPS, at various concentrations.

Mice were dosed by oral intubation at the time of infection and again after 4 hours. The estimated dose 50 (ED 2 q) was calculated by the Reed-Muench method of Reed, L.J. and Muench, H., in the American Journal of Hygiene, 27, 493-497 (1938).

30 The results are shown in the following table.

i4 78077

Table 1 Antibacterial effect of 2-oxazolidinone derivatives

Compound In vitro ^ In vivo ED [-0; mg / kg 5 MIC: .mu.g / E. aureus E. coli 7 ml of 5-chloromethyl-3- (4-methylsulfinyl) phenyl-2-oxazolidinone 5-chloromethyl-3- (4-methylsulfonyl) phenyl) phenyl-2-oxazolidinone 5 29 63 5-fluoromethyl-3- (4-methylsulfonyl) phenyl-2-oxazolidinone 20 35 5-branmethyl-3- (4-methylsulfon-15-yl) phenyl-2-oxazolidinone 5 5-Hydroxymethyl-3- (4-methylsulfonyl) phenyl-2-oxazolidinone 50 27 5-Hydroxymethyl-3- (4-methethylsulfonyl) phenyl-2-oxazolidinone 12.5 18 40 (1) -5-Hydroxymethyl-3- (4-methylsulfonyl) phenyl-2-oxazolidinone 12,5,925 5-Acetoxymethyl-3- (4-methyl-sulfonyl) phenyl-2-50 100 oxazolidinone (dl) -mono {3- (4-Methylsulfonyl) -phenyl] -2-oxo-oxazolidin-5-ylmethyl-O-butanedioic acid ester, monosodium salt 50 26 40 (1) -meno- {3- [4- (methylsulfonyl) li) Phenyl-2-oxo-oxazolidin-5-ylmethyl} -butanedioic acid ester, monosodium salt - 5- (L) -alanyloxymethyl- (1) -3- (4-methylsulfonyl) phenyl-2-oxazo trifluoroacetic acid salt of lidinone 15 78077

Table 1 (continued) Antibacterial activity of 2-oxazolidinone derivatives

Compound In vitro'1 'In vivo ED5Q; mg / kg ^ MIC: / Ug / E. aureus E. coli / πα - 5-chloromethyl-3- (4-ethylsulfonyl) phenyl-2-oxazolidinone 50 10 5-chloromethyl-3- (4-difluoro- methylsulfanyl) phenyl-2-oxazolidinone 2,5 20 3- (4-Difluoromethylsulfanyl) -phenyl-5-hydroxymethyl-2-oxazolidinone 3.13 27 5-Chloromethyl-3- (4-trifluoromethylsulfanyl) phenyl-2 - oxazolidinone 4,7 105 5-hydroxymethyl-3- (4-trifluoro-20-methylsulfonyl) phenyl-2-oxazolidinone 12,5 20 5-chloromethyl-3- (4- (1,1,2,2-tetrafluoroethylsulfonyl) ) -phenyl-2-oxazolidinium 10 92 25 5-hydroxymethyl-3- (4- (1,1,2,2-tetrafluoroethylsulfonyl) -phenyl-2-oxazolidinyl 12.5 108 1 = minimum 24-hour minimum concentration determined by the micro-dilution method using S. epidermidis 30 as a test organism.

16 78077

Table 2 shows the in vitro antibacterial activity spectrum of (1) -5-hydroxymethyl-3- (4-methylsulfonyl) -phenyl-2-oxazolidinone as determined by the agar dilution procedure. This procedure is known in the art and can be illustrated as follows. Petri dishes were prepared containing twice the concentration of compound in the range of 1.0 ug / ml to 128 ug / ml added to Mueller-Hinton agar. Agar plates were inoculated using 0.001 ml of calibrated looped bacterial inoculum diluted to contain 5 x 10b culture forming unit (CFU) per milliliter. The MIC value was determined as the lowest concentration of compound that inhibited macroscopic bacterial growth during the 24 hour incubation period at 35 ° C. The test organisms comprised clinical bacterial isolates corresponding to two gram-positive and nine gram-negative species.

i7 78077

Table 2

In vitro susceptibility of clinical bacterial isolates to (1) -5-hydroxymethyl-3- (4-methylsulfonyl) -phenyl-2-oxazolidinone_ 5 Test organism No- Mean isolates MIC value ___ yug / ml

Serratia sp. 44 108.4

Enterobacter sp. 41 37.9 10 E.coli 86 21.7

Proteus sp. 88 21.7

Pseudomonas sp. 78 128.0

Salmonella sp. 6 16.0

Shigella sp. 9 11.6 15 Staphylococci sp. 37 3.8

Klebsiella sp. 68 37.5

Providencia sp. 12 26.7

Streptococci sp. 12 3.7

Neisseria sp. 42 10.5 20 Hemophilus influenzae 4 16 Determined from 5-chloromethyl-3- (4-difluoromethylsulfonyl) -phenyl-2-oxazolidinone and (1) -5-hydroxymethyl-3- (4-methylsulfonyl) phenyl-2 -oxazole-dinone inhibitory activity against anaerobic bacteria using the agar dilution method presented by Barry, Arthur L., "Antimicrobic Susceptibility Test: Principles and Practices", 1976 Lea & Febiger, Philadelphia. The minimum inhibitory concentrations shown in Table 3 indicate that these compounds are effective in inhibiting the growth of anaerobic bacteria.

ie 8077

Table 3

In vitro susceptibility of anaerobic clinical bacterial isolates to 5-chloromethyl-3- (1) -5-hydroxymethyl-5- (4-difluoromethyl-ethyl-3- (4-methylsulfonyl) phenylsulfonyl) -phenyl-2-oxazolidinone 2-oxazolidinone

Test organism Isolates Avg. Insulation Central.MIC

tested, MIC1 tested,, ug / ml No, ug / ml No '10 - L- - -

Clostridium sp. 4 1.0 4 7.0

Fusobacterium sp. 4 0.06 4 0.3

Bacteroides sp. 32 1.8 28 3.4

Gram-positive cocci 7 0.7 7 1.0 15 1 = 48-hour mini-cut concentration measured by agar dilution.

The following examples illustrate the invention.

Example 1 5-Chloromethyl-3- (4-methylthiophenyl) -2-oxazolidinone (II, = CH 2) · - In a hot (130 ° C) solution containing 105 g (0.64 mol) of 4-methylthiophenyl isocyanate and 93 g (1 mol) of epichlorohydrin in 600 ml of xylene, 200 ml of tri-n-butyl-phosphine oxide lithium broride complex were added. (The complex was prepared by refluxing a mixture of 45 g of tri-n-butylphosphine oxide, 12.7 g of lithium bromide and 550 ml of xylene until a clear solution formed on removal of water). An exothermic reaction occurred. After all the catalyst was added, the mixture was refluxed for 1 hour and then cooled. The solution was decanted into a flask and concentrated to half its volume. An equal volume of petroleum ether was added to the residue. The solid formed was taken up in filtration and recrystallized from acetonitrile to give 102 g (62% yield) of the title compound; mp. = 106.5-107.5 ° C.

Examples 2-4 Following the procedure described in Example 1, the following compounds were prepared:

Example Starting Materials (IV) Products (II) 2,4-Trifluoromethylthio-5-chloromethyl-3- (4-phenylisocyanate trifluoromethylthiophenyl) -2-oxazolidinone, m.p. 83-85 ° C; 3 4-Difluoromethylthio-5-chloromethyl-3- (4-diphenyl isocyanate fluoromethylthiophenyl) -2-oxazolidinone; 15 colors 88-90 ° C; 4- (1,1,2,2-tetrafluoro-5-chloromethyl-3- (4-ethylthio) phenyl (1,1,2,2-tetrafluoroethylthio) phenyl) -2-oxazolidinone m.p. 66-20 ° C.

Example 5 5-Chloromethyl-3- (4-trifluoromethylsulfonyl-phenyl) -2-oxazolidinone (III, = CF 3, X = Cl, n = 2).

4.5 g (0.022 mol) of 85% m-chlorobenzoic acid were added to a mixture of 2.9 g (0.01 mol) of 5-chloromethyl-3- (4-trifluoromethylthiophenyl) -2-oxazolidinone (II , R 2 = CF 2, X = Cl) and 50 ml of methylene chloride. The mixture was refluxed for 5 hours and then the solvent was evaporated off to concentrate the mixture and the solid residue was triturated with ether and filtered to give 2.3 g of the title product; mp. = 121-123 ° C.

Analysis: Calculated for C 12 H 12 Cl 2 N 2 O 2 S: 35 C 38.32, H 2.92, N 4.06, 20,78077 Found C 38.47, H 2.72, N 3.84.

Examples 6-8

Following the procedure described in Example 5, the following compounds were prepared:

5 Example Starting material II Product III

6 5-Chloromethyl-3- (4-difluoro-5-chloromethyl-3-methylthiophenyl) -2-oxazole- (4-difluoromethyldinone sulfonylphenyl) -3-oxazolidinone;

10 sp. 127-129UC

Analysis for C 12 H 12 Cl 2 F 2 NO 2 S: Calculated C 40.56, H 3-09, N 4.30; found C 40.61, H 3.23, N 4.17.

7 5-Chloromethyl-3- (4- (1,1,2,2-5-chloromethyl-3-tetrafluoroethylthio) phenyl) - (4- (1,1,2,2-tetra-2-oxazolidinone fluoroethylsulfo-

nyl) phenyl) -2-oxazolidinone; tr. 123-125 ° C

Analysis calculated for C 12 H 20 Cl 2 F 4 NO 4 S: Calculated C 38.36, H 2.68, N 3.37; found C 38.39, H 2.79, N 3.56.

8 5-Chloromethyl-3- (4-methyl-5-chloromethyl-3-thiophenyl) -2-oxazolidinone (4-methylsulfon-phenylphenyl) -2-oxazolidinone; mp. 172-173 ° C.

Example 9 3- (4-methylthioanilino) -1,2-propanediol 30 (XIV, R = CH 3)

Method A - A mixture of 12 g of 4-methylthioaniline and 6.5 g of glycidol in 40 ml of methanol was refluxed for 2 1/2 hours. An additional 3 g of glycidol was added and cooking was continued for another 35 hours. To the cooled solution was added a mixture of 10 g of oxalic acid dissolved in 40-50 ml of warm methanol. The resulting solution was kept at room temperature, whereupon the solid product slowly precipitated. After cooling, the solid was collected by filtration in an ice bath. The oxalic acid salt was suspended in cold water and basified by the addition of 50% sodium hydroxide solution. The separated product was extracted with methylene chloride. The extract was dried over anhydrous potassium carbonate, filtered and concentrated to give an oily product which slowly solidified on standing. The solid was triturated with 1-chlorobutane, isolated by filtration and dried at room temperature under reduced pressure to give 8.5 g of the title compound; mp. 45-46 ° C.

Method B - A mixture of 99 g of 5-chloromethyl-3- (4-methylthiophenyl) -2-oxazolidinone, 34 g of sodium hydroxide, 300 ml of ethanol and 300 ml of water was refluxed for 5 hours. The mixture was concentrated to remove ethanol-20 and the aqueous mixture was carefully acidified by the addition of dilute hydrochloric acid. Slightly insoluble material was removed by filtration. The clear aqueous solution was then basified by the addition of concentrated ammonium hydroxide solution. The organic material was extracted into methylene chloride, and the methylene chloride extract was dried over anhydrous potassium carbonate and concentrated. the oily residue was treated with oxalic acid as in Method A to give the title compound; mp. 45-46 ° C.

Method C - A solution of 88 g (0.63 mol) of 4-methylthioaniline in 200 ml of 1,2-dimethoxyethane and 200 ml of water was stirred while adding a solution of 96 g of p-toluenesulfonyl chloride. dissolved in 100 ml of 1,2-dimethoxyethane-35. During the addition, the solution was kept alkaline by the addition of 25% sodium hydroxide solution. The mixture was stirred vigorously and base was added until the pH remained between 10-11. The mixture was acidified with concentrated hydrochloric acid and the 1,2-dimethoxyethane was removed by evaporation under a stream of nitrogen. The solid was filtered off and washed with water; yield 136.3 g; tr. 103-108 ° C. This product was recrystallized from 100 ml of acetonitrile to give 108.3 g; mp. 108-120 ° C. The product was further purified to convert to 10 ml of sodium salt in 400 ml of 1,2-dimethoxyethane using 26 g of 50% aqueous sodium hydroxide solution. The salt was filtered off and washed with 1,2-dimethoxyethane. The solid was resuspended in 500 mL of 1,2-dimethoxyethane and over-15 acetic acid, stirred, filtered and concentrated to give 76.4 g of compound XX = CH 3); mp. 110-112 ° C.

A solution of 87.9 g (0.3 mol) of this sulfonamide in 300 ml of dry DMF containing 5 g of 1,4-diazabicyclo (2.2.2) octane (DAMCO) was heated at 100 ° C. under nitrogen. 22 g of glycidol (freshly distilled to remove polymer) in 25 ml of DMF were added over the course of one hour. Heating was continued for 3 hours and an additional 11 g of Gly-25 zidol in 25 mL of DMF was added. After 1 hour, the reaction mixture was poured into 2 liters of water and allowed to stand overnight. The product had crystallized and was filtered off and washed with water. The yield was 96 g; mp. 97-100 ° C.

The product was recrystallized from 150 ml of toluene to give 86.5 g of compound XXI (Rf = CH3); mp. 112-113 ° C.

A solution of 450 g of naphthalene and 2 liters of 1,2-dimethoxyethane was stirred under a nitrogen atmosphere, adding 180 g of 40% sodium dispersed in mineral oil. The temperature was maintained at 25-30 ° C with cooling if necessary. After all the sodium had been added, stirring was continued for 15 minutes. The solution (dark green to black) was stirred with the addition of 213 g of the above tosylamide. The mixture was then stirred for 45 5 minutes. It remained black during this time, indicating an excess of the sodium naphthalene radical anion. Water was added until the color had faded to yellow. Concentrated hydrochloric acid was then added until the pH of the mixture was 2-3. 1,2-Methoxyethane was removed by concentration in vacuo. The aqueous solution was extracted several times with hexane and then toluene. Nitrogen was blown through the solution to remove organic solvents and then made alkaline saturated with a base (ammonium hydroxide) salt and extracted 10 times with dichloromethane (or until no more organic base was detected in the extract). The combined extracts were dried over anhydrous potassium carbonate, filtered and concentrated to give 131.4 g of the title compound as an oil which crystallized on standing; 20 sp. 45-46 ° C.

Example 10 Using Method B of Example 9, 3- (4-difluoromethylthioanilino) -1,2-propanediol (III, R f = CF 2 H) (m.p. 82-84 ° C) 5-chloro-25-methyl-3- (4-difluoromethylthiophenyl) -2-oxazolidinone.

Example 11 5-Hydroxymethyl-3- (4-methylthiophenyl) -2-oxazolidinone (XVI, R 2 CH 2).

Method A - A mixture of 50 g (0.235 moles) of 3- (4-methylthioanilino) -1,2-propanediol (XIV, R 2 -CH 2), 28 g (0.0237 moles) of diethyl carbonate and 0, 5 g of potassium t-butoxide in 200 ml of ethanol, boiled under reflux for 15 hours. An additional 7 g of diethyl carbonate and 0.7 g of potassium t-butoxide were added and refluxing was continued for 3 hours. On cooling, the solution precipitated as a solid which was collected by filtration and dried to give 50 g (89% yield) of the title compound; mp. 135-137 ° C.

Method B - A mixture of 15 g of compound II (R 2 = CH 2, X = Cl), 50 g of potassium acetate, a catalytic amount of 18-crown-6 catalyst and 60 ml of dimethylformamide was heated at 130 ° under a nitrogen atmosphere. C at 5 hours. The mixture was poured into ice water and the solid precipitate was collected by filtration. Solid 10 was recrystallized from 1-chlorobutane to give 11 g of 5-acetoxymethyl-3- (4-methylthiophenyl) -2-oxazolidinone (XV, R 2 = CH 2).

To a solution of 2.1 g of potassium hydroxide in 70 ml of methanol was added 10.4 g (0.037 mol) of the above compound XV (R 2 CH 2). The resulting solution was stirred at room temperature for 3 hours. An additional 0.2 g of potassium hydroxide was added and stirring was continued for one hour. Upon cooling, the solution precipitated a solid. This solid was collected by filtration and washed with very cold methanol to give 7.7 g (87% yield) of the title compound; mp. 135-137 ° C.

Example 12

Following the procedure of Example 11, the following compound was prepared: Example Example Starting material (XIV) Product (XVI) 12 3- (4-Difluoromethylthio-5-hydroxymethyl-3- (4-anilino) -1,1-propane-difluoromethylthiophenyl diol) ) -2-oxazolidinone; mp. 120-122 ° C.

30 Examples 13-14

Following Method B of Example 11, the following compounds were prepared: 25 7 8 0 7 7

Example Starting material (II) Product (XVI) 13 5-Chloromethyl-3- (4-fluoro-5-hydroxymethyl-3-methylmethylthiophenyl) -2- (4-trifluoroethyloxazolidinone thiophenyl) -2-oxazole

5 lidinones; mp. 142-143 ° C

14 5-Chloromethyl-3- (4- 5-hydroxymethyl-3- (1 / 1,2,3-tetrafluoro- (4- (1,1,2,2-tetrafluoroethylthio) phenyl) -2-diethylthio) phenyl) oxazolidinone 2-oxazolidinone;

10 sp. 134-136 ° C

Example 15 5-Hydroxymethyl-3- (4-methylsulfonylphenyl) -2-oxazolidinone (XVII, R 2 CH 2 N, n = 2). To a solution of 50 g (0.21 mol) of 5-hydroxymethyl-3- (4-methylthiophenyl) -2-oxazolidinone (XVI, = CH.j) in 500 ml of methylene chloride was added 93 g (0, 46 moles) of 85% m-chloroperbenzoic acid portionwise and with cooling. The mixture was then stirred at room temperature for 15 hours to 20 hours. The resulting mixture was concentrated to remove methylene chloride and the solid residue was triturated with ether. The solid was collected by filtration and recrystallized from acetonitrile to give 48 g (85% yield) of the title compound; mp. 177-180 ° C. 25 Examples 16-18

Following the procedures of Example 15, the following compounds were prepared: 26 7 8 0 7 7

Example Starting material (XVI) Product (XVII) 16 5-hydroxymethyl-3- (4-tri-5-hydroxymethyl-3- (4-trifluoromethylthiophenyl) fluoromethylsulfonylphen-2-oxazolidinonyl) -2-oxazolidinone; 5 sp. 133-135 ° C.

Analysis for: Calculated: C 40.62, H 3.10, N 4.31 Found: C 40.97, H 3.30, N 4.04.

17 5-hydroxymethyl-3- (4-di- 5-hydroxymethyl-3- (4-difluoromethylthiophenyl) fluoromethylsulfonylphen-2-oxazolidinonyl) -2-dexazolidino;

mp. 126-129 ° C

Analysis for C 1 H 2 N 2 O 3 S; calculated: C 42.99, H 3.61, N 4.56; Found: C 43.16, H 3.70, N 4.91.

18 5-hydroxymethyl-3- (4-1,1,5-hydroxymethyl-3- (4- 2,2-tetrafluoroethylthiophene (1,1,2,2-tetrafluoroethynyl) -2-oxazolidinanesulfonyl) phenyl ) -2-oxazolidinone; 20 sp. 130-132 ° C.

Analysis for the formula: C 12 H 19 F 4 N 2 S requires C 40.34, H 3.10, N 3.92; found C 40.50, H 3.18, N 3.91.

Example 19 5-Hydroxymethyl-3- (4-methylsulfinylphenyl) -2-oxazolidinone (XVII, = CH 2, n = 1)

A mixture of 23.9 g (0.1 mol) of 5-hydroxymethyl-3- (4-methylthiophenyl) -2-oxazolidinone in 200 ml of dichloromethane was boiled under reflux and stirred while 21.6 g of 80- 90% m-chloroperoxybenzoic acid.

. . The recovery soup was continued for an hour. A thin layer indicated that some starting material was left and therefore an additional 5.3 g of 80-90% m-chloro-35 riperoxybenzoic acid was added and refluxing was continued for eight hours. The resulting mixture was concentrated, stirred with ether, filtered and washed well with ether. The product was dissolved in water, potassium bicarbonate was added and the water was extracted with tetrahydrofuran. The extract was concentrated in a yield of 6.8 g.

This product was passed through two silica gel columns (Water's Prep 500) using a mixture of 70% dichloromethane and 30% acetonitrile. A broad peak was observed, but the resolution of the two diastereoisomers was poor. Six fractions were concentrated and had melting points in the range of 143-153 ° C. The antibacterial effect of all and who proved to be the same.

The product is a mixture of diastereoisomers of the title compound.

Example 20 (4S) -3- (4-Methylsulfonylphenyl) -2-hydroxymethyl-2-oxazolidinone (XVII, R = CH 3, n = 2). A mixture of 60 g (0.207 mol) of 5-chloromethyl-3- (4-methylsulfonylphenyl) -2-oxazole-20-dinone, 30 g of potassium hydroxide, 250 ml of water and 250 ml of ethanol was refluxed for 2 hours. All solids dissolved. The solution was concentrated to remove ethanol and then acidified with hydrochloric acid. It was then basified with ammonium hydroxide and evaporated to dryness. The solid was refluxed with tetrahydrofuran and filtered and then washed four times with tetrahydrofuran. The tetrahydrofuran extracts were combined and dried over anhydrous potassium carbonate and concentrated. Residue 30 was dissolved in 133 ml of hot, absolute ethanol. The product crystallized to give 39.3 g of compound XVIII (R 1 = CH 3, n = 2); mp. 113 to 114.5 ° C.

A mixture of 2.45 g (0.010 mol) of (dl) -3- (4-methylsulfonylanilino) -1,2-propanedio-35 in 20 ml of 1,2-dimethoxyethane and 1.3 ml of 28 7 8 0 7 In 7 liters of diethyl carbonate, boiled under reflux and 30 mg of sodium methoxide were added. The reaction mixture was refluxed for 2 hours. The mixture was cooled to room temperature and the solid was filtered off and washed with ether and then water. This gave 2.4 g of the title compound; mp. 176-177 ° C.

Example 21 4-Trifluoromethylthiophenyl isocyanate (IV, Rx = CF 3) To 10 250 ml of liquid ammonia was added 33 g (0.198 moles) of 4-acetamidothiophenol followed by 42 g (0.214 moles) of trifluoromethyl iodide. The resulting mixture was stirred for 1 hour at -33 ° C under a UV-sun bulb. Excess ammonia was removed by evaporation. Ice water was added to the solid residue, after which the solid product was isolated by filtration. The product (VI), p-trifluoromethylthioacetanilide, was purified by recrystallization from acetonitrile; yield 44.3 g (96% yield); mp. 186-187 ° C.

A mixture of 2.9 g of compound VI, 15 ml of ethanol and 2 g of potassium hydroxide was refluxed for 4 hours. The mixture was then concentrated to remove ethanol and the residue was extracted with ether. The ether extract was dried over anhydrous calcium carbonate, filtered and concentrated to give the oily product VII, 4-trifluoromethylthioaniline. To a solution of 35 g of compound VII in 400 ml of toluene was rapidly added 25 ml of phosgene. The mixture was then stirred and slowly warmed to 70-80 ° C. After a homogeneous solution formed, the temperature was raised to 110 ° C and maintained at this temperature for 1 hour. The solution was cooled and concentrated to give an oily product which was distilled to give 29 g (73% yield) of the title compound, 4-trifluoro-35-rithiophenyl isocyanate; bp, 39-40 ° C / 0.75 mm; IR. = 2300 cm-1, max 29 7 8 0 7 7

Example 22 4- (1,1,2,2-Tetrafluoroethylthio) phenyl isocyanate (IV, = -CF 2 -CF 2 H)

A mixture of 25 g (0.15 moles) of 4-acetam-5-dothiophenol and 15 g (0.15 g) of diisopropylamine in 80 ml of dimethylformamide was treated with 15 grams (0.15 moles) of tetrafluoromethylene in a bomb.

The temperature was slowly raised from -44 ° C to 25 ° C. The reaction mixture was then poured into water and the solid product was isolated by filtration. The solid was dissolved in ethyl acetate, and the resulting solution was dried over anhydrous magnesium sulfate, filtered and concentrated. The solid residue was triturated with petroleum ether and filtered to give 35 g (87.5% yield) of p- (1,1,2,2-tetrafluoroethylthio) acetanilide (XI); mp. 133.5-135 ° C.

A mixture of 5 g of compound XI and 40 ml of 6N hydrochloric acid was refluxed for 4 hours. The mixture was diluted with 200 mL of water and filtered.

The filtrate was concentrated to dryness and the solid residue was triturated with ether and filtered to give 4- (1,1,2,2-tetrafluoroethylthio) aniline (XII) as the hydrochloride salt.

Compound XII was reacted with phosgene 25 as in Example 21 to give the title compound, 4- (1,1,2,2-tetrafluoroethylthio) phenyl isocyanate; mp. 73 ° C / 25 mm; IRmax = 2270 cm

Example 23 4-Difluoromethylthiophenyl isocyanate 30 (IV, R1 = HCF2)

Over one hour, 5.5 g (0.04 mol) of lithium chlorodifluoroacetate dissolved in 20 ml of 2-methoxyethyl ether were added to a stirred mixture of 3.4 g (0.02 mol) of 4-acetamidothiophenol and 0.2 g of potassium. -butoxide in 30 ml of 2-methoxy-30? SO 7 ethyl ether, at 140 ° C. The resulting mixture was then heated at 140 ° C for 10 minutes and poured into ice water. The cold mixture was basified with dilute sodium hydroxide solution and filtered.

The solid was dissolved in ethyl acetate. The ethyl acetate solution was washed with dilute sodium hydroxide solution and saturated sodium chloride solution, dried, filtered and concentrated to give 3.5 g of product, p-difluoromethylthioacetanilide (IX); mp. 141-10 143 ° C.

A mixture of 71 g (0.33 mol) of compound IX, 45 g of potassium hydroxide and 300 ml of methanol was refluxed for 15 hours. The mixture was concentrated to remove methanol and the residue was diluted with water. The organic material was extracted with ether, and the ether extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The liquid residue was distilled to give pure 4-difluoromethylthioaniline (X); tr. 70-75 ° C / 0.15 mm.

Compound X (5 g) was reacted with 30 ml of phosgene as in Example 21 to give 4.4 g (77% yield) of the title compound, 4-difluoromethylthiophenyl isocyanate; tr. 75-79 ° C / 0.25 mm * IRmax = 2250 cm-1 · 25 Example 24 (dl) -3- (4-Methylsulfonyl-phenyl) -2-oxo-oxazolidin-5-ylmethyl-1,4-butanedioic acid monoester , monosodium salt A solution of 22 g (0.081 mol) of 3- (4-30 methylsulfonylphenyl) -5-hydroxymethyl-2-oxazolidinone in 110 ml of pyridine was stirred while adding 8.5 g of succinic anhydride. The solution was kept at 50 ° C for 2 hours. While standing, crystals formed. The mixture was poured into water and hydrochloric acid was added until the pH was 1 or less. The product was filtered and washed with water. The yield was 24.2 g; 31 78077 sp. 159-162 ° C. It was recrystallized from nitromethane to give 22.6 g; mp. 167-168 ° C.

A suspension of 22.3 g of this acid in 250 ml of distilled water was stirred and solid sodium bicarbonate was added until the solid acid was completely dissolved and the pH was 8.3. The solution was filtered through "Celite Analytical Filter Aid" material. The solution was concentrated in vacuo and ethyl alcohol was added and removed in vacuo. Xylene was added and removed under reduced pressure. The solid was slurried in xylene, filtered and washed with ether to give 32 g of the title product as a monohydrate.

Example 25 5-L-Alanyloxymethyl-3- (4-methylsulfonyl) -phenyl-2-oxazolidinone trifluoroacetic acid salt (XIII-b, R 1 CH 2 O 3 n = 2, R 4 = CH 3)

A solution of 4.5 g (0.02 moles) of Ν, Ν'-di-20-cyclohexylcarbodiimide in methylene chloride was added to a solution of 5.4 g (0.02 moles) of 5-hydroxymethyl-3- (4 -methylsulfonylphenyl) -2-oxazolidinone, 3.8 g (0.02 moles) of Nt-butyloxycarbonyl-L-alanine, 1.2 g of pyridine and 100 ml of methylene chloride. The resulting mixture was stirred at room temperature for 18 hours, after which the solid precipitate was removed by filtration. The filtrate was washed successively with 1M potassium bisulfate solution, water and dilute sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated.

The solid residue was recrystallized from ethyl acetate to give compound XXIII (R 2 = CH 3, n = 2, R 2 = CH 3).

2.2 g of compound XXIII were added to 15 ml of cold (0 ° C) trifluoroacetic acid. Stirred at 0 ° C for 15 minutes and the solution was poured into 32,78077 ether. The solid precipitate was collected by filtration and dried to give the title compound.

Example 26 1-3- (4-Methylsulfonylphenyl) -2-oxoazol-5-yn-5-ylmethyl-n-heptanoic acid ester in a solution containing 1.3 g of the 1-isomer of compound XVII (R 2 = CH 2, n = 2) (from Example 27) and 0.6 g of triethylamine in 20 ml of 1,2-dimethoxyethane, a solution of 0.8 d of 10 n-heptanoyl chloride in 10 ml of 1,2-dimethoxyethane was added at 0 ° C. After stirring for 1 hour, an additional 0.3 g of n-heptanoyl chloride was added. After stirring for 1 hour at room temperature, the mixture was poured into water and the solid product was isolated by filtration. The solid was recrystallized from ethanol to give 1.6 g of the title compound; mp. 138-140 ° C.

Analysis for C 18 H 18 N 2 O 2 S; calculated C 56.4, H 6.6, N 3.7 found C 57.0, H 6.8, N 3.7.

Example 27 R - (-) - 3- (4-Methylsulfonylphenyl) -5-hydroxymethyl-2-oxazolidinone

A mixture of 148.5 g of (dl) -3- (4-methylthioanilino) -1,2-propanediol, 570 ml of a mixture containing 20% ethanol and 80% water and 110 g of 1-almond acid, stirred and heated until all solids had dissolved. On standing and cooling, crystals separated. These were removed by filtration and washed with 20% ethanol and water and dried; yield 83 g; mp. 99.5 to 100.5 ° C. The product was recrystallized from 350 ml of acetonitrile to give a yield of 76 g; mp. 101 to 101.6 ° C. Recrystallization of this product from 320 ml of acetonitrile containing 3 g of 1-mandelic acid gave 66.0 g of 35 product; mp. 101 to 102.0 ° C.

33 7 8 0 7 7 63.4 grams of the above-mentioned 1-mandelic acid salt were suspended in 100 ml of water, 100 ml of chloroform and ammonia were added until the mixture was strongly basic. The amine was extracted into a chloroform-5 layer which was separated. The aqueous layer was extracted four times with 25 ml portions of chloroform. The combined chloroform extracts were dried over anhydrous potassium carbonate, filtered and concentrated to give 41.3 g of an oil, the oil was dissolved in 50 ml of dichloromethane and allowed to stand overnight.

The product crystallized; it was separated by filtration and washed with dichloromethane; yield 35.4 g; mp. 68-69 ° C. (A sample taken at this point had a melting point of 76.5-78 ° C). This product is

15 / T \ H? H

ch3 ~ s— / Q \ -n-ch2-ch-ch2oh & JO = 21.2 + 0.5 ° (c = 1 in ethanol).

A solution of 35.4 g (0.166 mol) of (d) -3- (4-methylthio) -anilino-1,2-propanediol in 140 ml of 1,2-dimethoxyethane and 21 ml of diethyl carbonate was boiled under reflux. and stirred while adding 0.1 g of sodium methoxide. The mixture was refluxed for 2 hours and then cooled to room temperature. The product crystallized. The suspension was stirred and acetic acid (a few drops) was added until the sample diluted with water was no longer basic. The product was isolated by filtration and washed with 1-propanol, then dried to give 29.8 g of product; mp. 138-139 ° C. The product was recrystallized from acetonitrile, filtered hot to give 26.4 g of product; mp. 139-140 ° C. The product obtained in this reaction is: 34 78077

O

c * 3-s - (& \ _ y * ~ 0Η 5 PJO = -66.5 * 0.5 ° (c = 0.9 in acetonitrile)

A solution of 26.1 g (0.109 mol) of 3- (4-methylthiophenyl) -5-hydroxymethyl-2-oxazolidin-10 in 600 ml of dichloromethane was refluxed. The heater was then removed and 55 g of m-chloroperoxybenzoic acid was added at a rate that allowed a smooth reflux. At the end of the addition, the mixture was refluxed for half an hour. Excess peracid 15 was destroyed by the slow addition of 7 mL of methyl sulfide and refluxing for 10 minutes. At this point, the peracid assay was negative. The resulting mixture was concentrated under reduced pressure and the solid was stirred with 500 mL of ether for 2 hours, then filtered and washed five times with 100 mL portions of ether. The dried yield was 29.1 g; mp. 183-184 ° C. This was recrystallized from 275 milliliters of acetonitrile to give a yield of 22.6 g; mp. 183-184 ° C. In the final recrystallization from 250 ml of acetonitrile under hot filtration, the yield was 17.6 g; mp. 188-189 ° C to give a second crop of 3.3 g and a melting point of 187.5-188 ° C. The two batches were mixed together to give 20.8 g of product; mp. 188.5 to 190 ° C. The product was: 35 780 7 7 o c »4

5 '-OH

09 Ώ = -6i, 9 1 0.1 ° (c = 0.884 in acetonitrile).

Analysis for C 12 H 12 NO 2 S: Calculated C 48.70, H 4.83, N 5.16 Found C 48.74, 48.71; H 4.93, 4.83; N 5.19, 5.07.

Example 28 1-3- (4-Methylsulfonylphenyl) -2-oxoazolidin-5-ylmethyl 1,4-butanedioic acid monoester, monosodium salt

A mixture of 5.0 g (0.0184 mol) of 1,3- (4-methylsulfonylphenyl) -5-hydroxymethyl-2-oxazolidinone in 110 ml of pyridine was stirred and 2.1 g of succinic anhydride was added. The solution was kept at 50 ° C for 4 hours, cooled and poured into 300 ml of water and acidified with concentrated hydrochloric acid. The product was isolated by filtration, washed with water and dried; the yield was 4.32 g; mp. 155-160 ° C. This was recrystallized from 20 ml of 25 N nitromethane to give 3.48 g of product; mp. 163 to 164.2 ° C.

A 3.042 gram portion was suspended in 50 mL of water, a small amount of ethanol was added to facilitate wetting, and 1N sodium hydroxide-30 dia was added until the pH was 7.5. The aqueous solution was concentrated to give a white solid: 36 7 8 0 7 7

o ATX A

o 5 \ 0-C-CH2CH2-CO2-Na +. H 2 O [α] D = -51.6 ± 0.5 ° (c = 1.0 in water).

Claims (2)

00. NH2 R3 is alkyl, m is 2 or 3 or 1 is 1 or 2, for which CH3 is X3R2, 20 turns of which are O / - \ nerw i 25 '- x is R ^ betecknar samma som ovan och är OH or Cl, oxideras med en persyra, varvid erhälls en förening med formuleln I, där X är OH or Cl; och, om sk önskas, omsätts 30 en erhällen förening med formula I I (i) en syrachlorid med formulaeln R3C0C1, rär R3 betecnar samma som ovan, eller en anhydride med formuleln (R3C0) 20, rär R3 betecknar samma som ovan, varvid erhälls in the form of formula I, wherein X is -0C0R3, or 35 (ii) in the N-amino acid form of formula A process for the preparation of therapeutically useful 3- (p-alkylsulfonylphenyl) -oxazolidinone-5 derivatives of the formula I, their optical isomers and their pharmaceutically acceptable acid and base salts, R1 ~ S (O) n - <rO / -NO2 - x (i) wherein R ± is CH3, CF3, CF2H or CF2CF2H, X is Cl or OR2, R ~ is H, -CRo, -C (CH9) COH. or -C-CH-R 1, Δ II J H Z m, | H | O 0 0 0 O NH 2 R 3 is lower alkyl, m is 2 or 3 and n is 1 or 2, provided that when R 1 is CH 3, then X is OR 2, characterized in that the compound of formula a wherein R 1 is as defined above and X 1 is OH or Cl, is oxidized with peracid to give a compound of formula I wherein X is OH or Cl; and optionally reacting the resulting compound of formula I wherein X is OH with (i) an acid chloride of formula R 3 CO 1 wherein R 3 is as defined above or an anhydride of formula (R 3 CO) 20 wherein R 3 means the same as above to give a compound of formula I wherein X is -OCOR 3, or (ii) with an N-protected amino acid of formula 38 780 7 7 f3 HO-C-CH 1 1 NH-COO- tB u 5 wherein is as defined above, in the presence of a condensing agent, to give a compound of formula I wherein X is -OCOCH-R-, or i 3 NH 2 (iii) with an anhydride of formula 10 ί <θ £ Β X0 V /% 15 wherein m is as defined above to give a compound of formula I wherein X is OC (CH-) COH. li Ί oo 39 78077 For the preparation of therapeutically active 3- (p-alkylsulfonylphenyl) -oxazolidinone derivatives with the formula 5 I, optical isomers and pharmaceuticals with a mixture of syrup and basalt, 0 Rrs (°) n-ID “w and the formula is CH3, CF3, CF2H or CF2CF2H, X is Cl, or 0R2, 15 R- is H, -CR-, -C (CH-) COH or -C-CH-R-, 2 tl 3 n 2 Iti n i J