FI86429B - An improved method for production of S-oxide derivatives of pristinamycin IIB - Google Patents

Description

1 86429

An improved process for the preparation of S-oxide derivatives of pristinamycin IIB

The present invention relates to a new process for the preparation of pr-tinamycin IIB S-oxide derivatives.

EP Patent Application No. 191,662 discloses S-oxide derivatives of pristinamycin IIB of general formula (I *).

In 1 o o CH * (: 11) cws R-SO0 - ^ \ sS “-0

15 V

wherein R is either a nitrogen-containing heterocyclic radical containing 4 to 7 ring residues, optionally further optionally containing one or more other heteroatoms, which may be nitrogen, oxygen or sulfur in sulfoxide or sulfone form, and may be optionally substituted with an alkyl radical, or An alkyl chain of 2 to 4 carbon atoms substituted with one or two radicals which may be: phenyl, cycloalkylamino or N-alkyl-N-cycloalkylamino having 3 to 6 ring members, alkylamino, dialkylamino or dialkylcarbamoyloxy (the latter two). the alkyl moieties of said radical may optionally form a saturated or unsaturated 4-7 membered heterocycle, optionally also containing a second heteroatom, which may be nitrogen, oxygen or sulfur in sulfoxide or sulfone form, with the nitrogen atom to which they are bonded and may be optionally substituted by -: * · *: 35 and an alkyl radical), or substituent germinated with one or 2 86429 more nitrogen-containing 4- to 7-membered heterocycles optionally containing 1 or 2 other heteroatoms, which may be nitrogen, oxygen or sulfur in sulfoxide or sulfone form, and in addition may be optionally substituted by an alkyl radical , said heteroatoms being attached to the backbone via a carbon atom, at least one substituent group on the above alkyl group being a nitrogen group capable of forming salts, or a radical (1-methyl-2 (S) -pyrrolidinyl) methyl, said alkyl radicals being straight or branched, and including, unless otherwise stated, 1 to 10 carbon atoms, their isomeric forms or mixtures thereof, as well as their addition salts with acids, and the preparation thereof.

When R is a heterocycle, it may be selected, for example, from 3-azetidinyl, 3-pyrrolidinyl, 3- or 4-piperidyl or 3- or 4-azepinyl.

When R is heterocyclylalkyl, the heterocycle may be selected from, for example, the above or from 2-azetidinyl, 2-pyrrolidinyl, 2-piperidyl, 2-azepinyl, piperazinyl, 2-alkylpiperazinyl, quinolyl, isoquinolyl or imidazolyl.

When R is dialkylamino or dialkylcarbamoyl-oxy, the alkyl moieties of which form a heterocycle together with the nitrogen atom to which they are attached, this heterocycle may be selected from, for example, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-azepinyl, morpholino, thiomorpholino as sulfoxide or sulfone, 1-piperazinyl, 4-alkylpiperazin-1-yl, N-alkyl homopiperazin-1-yl, 1-imidazolyl.

FI patent application 873 015 relates to a process for the preparation of sulfones using the corresponding sulfoxides as starting material; said FI patent application does not relate to a process for the preparation of sulfoxides.

3 b 6 4 2 9

It has now been found that compounds of general formula (I) can be prepared by oxidizing pristinamycin IIB of general formula (II), a salt thereof or a protected derivative thereof with potassium monopersulphate.

The invention relates to an improved process for the preparation of pristinamycin IIB S-oxide derivatives of general formula (I), ο J o o CH> V0 so ^ S / R 0 (I)

i c H-C-CH-NC

10 l I \ r1r2 r4 where

R 1 and R 2 represent a hydrogen atom or a methyl or ethyl radical, R 3 represents a hydrogen atom or an alkyl radical containing 1 to 3 carbon atoms, R 4 represents an alkyl radical containing 1 to 4 carbon atoms, or a cyclohexyl radical, '25 or R 4 and R 2 together form their atoms , to which they are attached, a saturated 5-membered ring, or R 4 forms a saturated 5- or 6-membered ring with R 3, in its isomeric forms or mixtures thereof, and to prepare these acid addition salts by oxidizing a pristinamycin IIB derivative (or a salt thereof) ), whose general formula is (II) 35 4 oo <+ ά y I yR3 <“) hc-ch-n.

* '\ r1r2 R4 10 wherein R3, R2, R3 and R4 are as defined above, so that when R3 and R4 form a sulfur-containing heterocycle, the sulfur atom may be in sulphide, sulfoxide or sulfone form, optionally followed by separation of the resulting product. isomers, and optionally the product obtained is converted into a salt by means of an acid. The process is characterized in that the oxidation is carried out with potassium monopersulfate.

By potassium monopersulfate is meant a mixture containing both potassium sulfate and acid potassium sulfate, as disclosed in U.S. Patent No. 2,802,722, which is sold under the tradename Oxone®.

The reaction is carried out in water or a mixture of water and alcohol (e.g. water-methanol) or a mixture of water and a chlorine-containing solvent (e.g. water-dichloro-25-methane) at a temperature ranging from -60 ° to 25 ° C.

When the Pristina-mycin IIB derivative of the general formula (II) is used in its salt form, salts formed with organic or mineral acids are used, preferably salts of trifluoroacetic acid, tartaric acid, acetic acid, benzoic acid, hydrochloric acid or sulfuric acid.

Potassium monopersulfate is prepared according to the method disclosed in U.S. Patent 2,802,722.

The compounds of general formula (II) can be prepared according to the method described in EP Patent Application No. 191,662. 35 män. It is not absolutely necessary to isolate 5,8429 pristinamycin IIB derivatives of general formula (II) in order to carry out the process according to the invention.

The compounds of general formula (I) obtained by this method can be purified using known methods, for example by crystallization, chromatography or successive measurements in an acidic or basic environment. One skilled in the art, familiar with the sensitivity of synergists in a basic environment, will understand a "basic environment" to be an environment that is just necessary for the parent compound to be released from its acid addition salt, i. an environment whose pH does not exceed 8.

Isomers of the compounds of general formula (I) may be separated using all known methods. Chromatography or HPLC (high performance liquid chromatography) is preferably used.

The compounds of general formula (I) produced by the process of the invention have anti-bacterial activity against gram-positive bacteria (staphylococci, streptococci, pneumococci, enterococci) and 20 gram-negative bacteria (haemophilic bacteria, gonococci, meningococci). In addition, they have the advantage that they can be dissolved in water, usually in salt form, in therapeutically useful doses and that they synergistically increase the antibacterial effect of pristinamycin 25 Ix, virginiamycin S or the soluble derivatives disclosed in EP Patent Application No. 191,662.

In addition, the compounds of general formula (I) prepared by the process of the invention can be used for the preparation of pristinamycin IIB sulfonic derivatives of general formula (III): 6 06429 o

11 0 H

c o *. R.s-6/0 (o) 2 (III) wherein R is as defined above, which are active as antimicrobial agents and also have a synergistic effect on group I pristinamycins.

The preparation of pristinamycin IIB sulfone derivatives of general formula (III) is carried out by oxidizing the pristinamycin IIB derivative of general formula (I) under the conditions set out in EP Patent Application No. 191,662.

The process according to the invention has the advantage that it is easy to carry out and allows a purer product to be obtained, in the case of the corresponding sulfone compound the treatment in the last step is easier, or that the risk of degradation of the starting material is lower and especially in the preparation of compounds of general formula (I).

In particular, compounds according to the invention are prepared in which the group -CH-CH-N. is an alkyl group having 2 to 4 carbon atoms

R 1 R 2 is a radical substituted by one or two groups selected from the group consisting of phenyl-cycloalkylamino or N-alkyl-N-cycloalkylamino which is 5- or 6-membered, 1-4 alkylamino containing carbon atoms, dialkylamino (the alkyl moieties of which contain 1 to 3 carbon atoms or together with the nitrogen atom to which they are attached form a saturated 5-35 or 6-membered heterocycle, or is a 5- or 6-membered? 86429 nitrogen-containing heterocycle , which may be substituted with an alkyl group having 1 to 4 carbon atoms, wherein at least one of the substituents on the alkyl chain is a nitrogen-containing substituent which can form salts, and wherein at least one of the substituents on this chain is in the 1- or 2-position.

The compounds of general formula (I) thus obtained can be converted into salts.

Examples of pharmaceutically acceptable salts include, in particular, addition salts of mineral acids, such as hydrochlorides, hydrobromides, sulphates, nitrates, phosphates, or addition salts of organic acids, such as acetates, propionates, succinates, maleates, fumarates, fumarates, 15 Phonates, isothionates, citrates, tartrates or substituted derivatives of these compounds.

The following table shows the results of comparative experiments comparing the yields of the compounds of Examples 1 to 4 and 6 to 11 to the known compound of Example 3 of EP Application 191 662, the compound of Example 3 being the only example whose final product is comparable to that prepared according to the present invention. purity of the compounds. The results show that in almost all cases the yields of isomers and A2 as well as the yields of isomer A2 are higher and even considerably higher than the yield obtained by the process according to the EP patent. In the case of Example 5 of the present application, no comparison could be made because the method was carried out starting directly from pristinamycin IA without isolating the intermediate sulfide. It is therefore an advantage of the present invention to increase the yield of isomer Ax and A2 as well as the isomer A2 obtained alone. A further advantage of the new process is that the reaction proceeds to the formation of the isomer A2 and that purer end products are obtained, thus avoiding the subsequent purification operations by chromatography. The process of the present invention is all the less obvious when it would be apparent from the literature that the use of potassium monosulfate as an oxidant would not allow sulfides to be converted to sulfosides without altering the rest of the molecule.

li 9 86429

Vertailukoetulokset

Example Starting material Compound obtained Yield No. (g) (g)% 1 13 g 9.9 g 70.5% (isomer A) (isomer A2 85% (Ax + A2) isomer Aj 10%) 61.3% (A2) 2 3g 2.4 g 72.5% (isomer A) (isomer A2 88% (AL + A2) isomer A2 6%) 67.9% (A2) 3 3.2 g 2.2 g 61.7% ( A2) (isomer A) (isomer A2 80%) 4 2g 1.5 g 70.2% (isomer A) (isomer A2 90% (Ar + A2) isomer A: 10%) 66.5% (A2) 6 50 g 31 g 57.5% (isomer A2 85% (At + A2) isomer A2 10%) 51.5% (A2) 111 7 2 g 1.6 g 69.7%:: (isomer A) (isomer A2 90% ( A2 + A2) .. isomer A2 10%): V 61.9% (A2): V; 8 6 g 1.7 g 24.9% (A2) (isomer) (isomer A2 90%) 1 25.5 g 11.3 g 43.4% (A2) (isomer A2) 10 S6429

Example Starting material Compound obtained Yield No. (g) (g)% 5 10 9/1 9 3.4 g 35.7% (A2) (isomer A) (isomer A2) 11 g 9.7 g 63.4% (A () (isomer A) (isomer A2) 53.2 g 10.9 g S 32.2% (isomer A <75%) (isomer A2 60% (A: + A2) Example 3 isomer Ax 15 %) + 5 g 28.2% (isomer A2) (A2 as a whole)

The following non-limiting examples illustrate how the invention may be practiced. The NMR spectra described in the examples show the general characteristics common to all products of formula (I) as well as the specific properties of each product according to the groups of substituents. Only specific properties due to variable radicals are mentioned in the examples. All protons of the compounds of general formula (I) are numbered according to the following formula • -. In accordance with 25: o

· * 11 ^ 0H

*. 32 L 3 10 r w33 L · 5 O

CH. ^ A5 λ n CH3. ; CH, t-0 »·. * ^ R3

R - -SO-CH-CH-NK

i V I I \ ... 35 Rx R2 R4 11 86429

Unless otherwise stated, all spectra were measured at 250 MHz in deuterochloroform; chemical shifts are reported in ppm relative to the tetramethylsilane signal. Here are the abbreviations: 5 s = singlet d = doublet t = triplet mt = multiplet m massive 10 dd = doublet doublet dt = triple doublet ddd * doublet doublet doublet dddd * doublet doublet doublet

It is to be understood that the various isomers have been arbitrarily classified according to the chemical transfer observed in the NMR analysis.

Isomers A2 and A2 are those isomers of general formula (I) which have the following properties: about 1.7 (s, -CH3 at position 33); about 3.8 (s,> CH2 at position 17)? <5 (d, -H27) isomer A2 or> 5 (d, -H27) isomer Aj; about 5.50 (high d, -H13); about 6.20 (d, -Hu); about 6.6 (> NH at position 8); 28 (s, -H 2 O).

. The isomers Bx and B2 are called those of general formula (I). 25 isomers having the following characteristics:. about 1.5 (s, -CH 3 at position 33); about 3.7 and 3.9 (2d,> CH2 at position 17); about 4.8 (mt, -H13); <5 (d, -H27) isomer B2 or> 5 (d, -H27) isomer Bx; about 5.70 (at the limit AB; -Hn and -H10); about 7.7 (> NH at position 8); about 7.8 (s, 30 -H 2 O).

Isomer A is the isomer of general formula (II) whose NMR properties are identical to the above isomers of general formula (I) and A2 values when the value of H in position 27 is: 35 4.7 (d, J <1 Hz) .

i2 86429

Isomer B is the isomer of general formula (II) whose NMR properties are identical to the values of isomers Bx and B2 of general formula (I) given above, when the value of H in position 27 is: 4.6 (d, J> 2, 5 Hz).

Example 1

To a solution of 13 g of 26- (2-diethylaminoethyl) thiopristinamycin IIB (isomer A) as a suspension in 170 cm 3 of distilled water was added over 15 minutes at 10 ° C 40 cm 3 of an aqueous solution containing 8.1 g of Oxone ®.

The resulting mixture was stirred for 30 min at 0 ° C, after which 1.3 g of black NORIT SX ULTRA and a small amount of sodium thiosulfate were added. After stirring for 30 minutes at 20 [deg.] C., the suspension is filtered through Celite and rinsed with 50 cm <3> of distilled water. The pH of the solution was adjusted to 7 by the addition of solid sodium bicarbonate and washed 3 times with 100 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 20 [deg.] C. to give 9.9 g of a clear beige solid containing 85% of 26- (2-diethylaminoethyl) sulfinyl-pristinamycin IIB (isomer A2), 10% of isomer Aj and 5% of 26- (2-diethylaminoethyl) sulfonyl-pristinamycin IIB.

Crystalline 26- (2-diethylaminoethyl) sulfinyl-pristinamycin IIB can be produced as follows:

The solid obtained above (5 g) was taken up in 13 cm3 of acetonitrile. Dissolve with heating, then add 10 cm3 of ether and the crystals are scraped off. The crystals were filtered off, washed with ether and dried under reduced pressure (270 Pa) at 20 ° C. There were thus obtained 3.9 g of 26- (2-diethylaminoethyl) sulfinyl-pristinamycin IIB (isomer A2: 85%, isomer A 15%) as white crystals with a melting point of 116 ° C.

35 13 86429 NMR Spectrum (Isomer A2) 1.03 (t, -N (CH 2 CH 3) 2) 1.75 (s, -CH 3 at position 33) 2.05 and 2.55 (2 mt,> CH 2 at position 25) δ 2.45 δ 2.70 (mt, -N (CH 2 CH 3) 2) 2.70 ä 3.10 (mt, -SCH 2 -CH 2 -) 0 2.75 (mt, H en 4) 2.92 ä 3.10 (mt,> CH 2 at 15) 10 3.22 (mt, H at 26) 3.82 (p.> CH2 at 17) 4.81 (d, H at 27) 5.5 (d, H at 13) 6.19 (d, H at 11) ) Δ 6.50 (dd,> NH at position 8) 6.58 (dd, H at position 5) 8.12 (s, H at position 20) NMR spectrum (isomer Ax) δ 1.04 (t, -N ( CH2CH3) 2) 1.69 (s, -CH2 at position 33) 2 ä 2.3 (mt,> CH2 at position 25) 2.60 (mt,> N-CH2-CH3) 2.7 ä 2.95 (mt, -S ( O) -CH 2 -CH 2 -N) 2.7 (mt, H at position 4) 2.86 and 3.04 (2dd,> CH 2 at position 15) 3.28 (mt, H en 26) 3.78 (AB system,> CH2 at position 17) 5.25 (d, H at position 27) 30 5.4 (d, H at position 13) 6.15 (d, H at position 11) 6.60 (dd, H at position 5) 6.83 (dd ,> NH at 8) 8.08 (s, H at 20) 35 14 86429 26- (2-diethylaminoethyl) thiopristinamycin IIB can be prepared as described in U.S. Patent 4,590,004. Fig.

Example 2 To a solution of 3 g of 26- (2-diethylaminoethyl) thiopristinamycin IIB (isomer A) as a suspension in a mixture of 30 cm 3 of distilled water and 6 cm 3 of ethanol was added 10 cm 3 of an aqueous solution for 10 min at -5 ° C, which contained 1.9 g of Oxone®. The mixture obtained is stirred for 10 minutes, after which the reaction mixture is washed twice with 20 cm <3> of dichloromethane. The pH of the aqueous phase was adjusted to 7 by the addition of solid sodium bicarbonate, followed by extraction 4 times with 50 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. There was thus obtained 2.4 g of a white solid containing 26- (2-diethylaminoethyl) sulfinyl-pristinamycin IIB (isomer A2: 88%, isomer A ^ 6%) and 6% of 26- (2-diethylaminoethyl) sulfonylpristinamycin. HB. The NMR values of the product obtained are identical to those of the product of Example 1.

Example 3

To a solution of 3.2 g of 26- [1-diethylamino-2 (R) -propyl] thiopristinamycin IIB (isomer A: 87%, 25 B: 13%) dissolved in 48 cm 3 of methanol was carefully added at -30 ° C. in 32 cm 3 of distilled water containing 1.65 9 Oxone®. After 30 minutes at -30 ° C and 15 minutes at -40 ° C, 30 cm 3 of distilled water and 3 g of black NORIT SX ULTRA were added. The mixture is stirred for 30 min at 20 [deg.] C., filtered through Celite and rinsed with 50 cm <3> of distilled water. The aqueous phase is washed twice with 100 cm3 of ethyl acetate and then with 50 cm3 of ethyl ether before the pH is adjusted to 7 by adding solid sodium bicarbonate, followed by extraction twice with 250 cm @ 3 of 35 cm3 of dichloromethane. The organic phases are washed with 50 l of 8 6 429 cm3 of distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. 2.4 g of a very bright yellow meringue were thus obtained, which was shaken in 40 cm3 of a mixture of pentane-di-5 ethyl ether (50:50 by volume). After filtration, it was dried under reduced pressure (270 Pa) at 20 ° C to give 2.2 g of 26- [1-diethylamino-2 (R) -propyl] sulfinyl-pristinamycin IIB (isomer A2: 80%) as a white crack. as a solid with a melting point of 10,140 ° C.

NMR Spectrum 1.02 (t, -N (CH 2 -CH 3) 2)

S H

1.34 (d, / \ /) 15 0 C - CH2 - N (C2H5) ch3 1.72 (s, -CH3 at position 33) 2.01 and 2.55 (2mt,> CH2 at position 25) 2.45-2 , 70 (mt, 1H de -CH2-N (CH2-CH3) and 20 -N (CH2-CH3) 2) 2.90 (mt, 1H de -CH2-N (CH2CH3) 2) 2.76 (mt, H at 4) 2.88 and 3.08 (2dd,> CHX at 15) 3 (mt, -S-CH-) 25 and CH3 3.73 (mt, H at 26) 3.80 (s,> CH2 at 17) 4.92 (iso s, H at position 27) 5.42 (d, H at position 13) 30 6.15 (d, H at position 11) 6.55 (dd, H at position 5) 6.70 (dd, > NH at 8) 8.06 (s, H at 20) 26- [1-diethylamino-2 (R) -propyl] thiopristina-35 mycin IIB can be produced as follows: ie 86429 10.5 g of pristinamycin in methanol containing IIft as a suspension (200 cm 3) was added at -30 ° C under nitrogen 3.2 cm 3 of 1-diethylamino-2 (R) -thiolpropane. After stirring for 18 hours at -30 [deg.] C., 25 cm <3> of methyl acrylate are added and the mixture is stirred for 1 hour. 200 cm3 of distilled water, potassium acid sulphate were added until the pH was 4 to 10 ° C, after which 10 g of black NORIT SX ULTRA were added. Shake for 30 min at 0 [deg.] C., after which the mixture is filtered through Celite and washed with 150 cm <3> of distilled water. The aqueous phase is washed with 100 cm3 of ethyl acetate, 100 cm3 of ethyl ether, after which the pH is adjusted to 7 by adding solid sodium carbonate. Extract with 200 cm3 of dichloromethane, then wash the organic phase with 100 cm3 of water, dry over magnesium sulphate, filter and concentrate to dryness under reduced pressure (2.7 kPa) at 30 ° C. The solid obtained is triturated in 100 cm3 of ethyl ether, filtered through a sintered glass funnel and dried under reduced pressure (270 Pa) at 20 ° C. There was thus obtained 3.35 g of 26- [1-diethylamino-2 (R) -prop-20-yl] thiopristinamycin IIB (isomer A: 85%, isomer B: 15%) as a clear beige solid with a melting point of 130 ° C. .

NMR Spectrum (Isomer A) 1.03 (t, N (CH 2 CH 3) 2) 25 v

]-OF

1/32 (d, s

\ H

. 30 IN (CH 2 CH 3) 2 C-3 1.72 (s, -CH 3 at position 33) 1.88 and 2.10 (2 mt,> CH 2 at position 25) 35 2.55 (mt, -N (CH 2 CH 3) 2) 17 86429 2.45 and 2.60 (2mt, -CH2-N (CH2CH3) 2) 2.78 (mt, H at position 4) 2.92 and 3.10 (2dd,> CH2 at position 15) 3 (mt, -S- CH-) 5 CH3 3.52 (mt, H at position 26) 3.82 (s,> CH2 at position 17) 4.79 (iso s, H at position 27) 5.49 (d, H at position 13) 10 6.13 (d, H at position 11) 6.32 (m,> NH at position 8) 6.52 (dd, H at position 5) 8.13 (s, H at position 20) 15 (isomer B) 1 (t, -N (CH 2 CH 3) 2)

N-N

20 1'34 <d '\ -' j N (CH2CH3) 2 ch3 .. 25 1.50 (s, -CH3 at position 33) 2.05 and 2.5 (2mt,> CH2 at position 25) 2.5 (mt,> N -CH2-CH3) 2.44 and 2.55 (2mt, -CH2-N (CH2CH3) 2) 2.62 (mt, H at position 4) 2.74 and 3.10 (2dd,> CH2 at position 15) 3.01 (mt, -S-CH-). . CH 3 3.69 and 3.89 (2d,> CH 2 at position 17) 3.74 (mt, H at position 26): 35 4.01 (d, J = 2.5, H at position 27) is 86429 4.80 (AB system, H at position 13 and H at position 14) 5.65 (d, H at position 11) 6.60 (dd, H at position 5) 7.71 (mt,> NH at position 8) 5 7.80 (s, H in 20) 1-Diethylamino-2 (R) -thiolpropane can be prepared as follows:

To a suspension of 34.2 g of lithium and aluminum hydride in 1600 cm 3 of ethyl ether was added 137.5 g of (R) -N, N-diethyl-2-mercapto dropwise over 1 hour and 20 minutes. -propionamide dissolved in 500 cm3 of ethyl ether. The reaction mixture was then kept at about 0 ° C for 2 hours. 40 cm3 of distilled water were added so that the temperature of the mixture did not rise above 20 ° C, after which 29.4 cm3 of 5N soda and 133 cm3 of distilled water were added. The reaction mixture is filtered and the pH of the filtrate is adjusted to 8 by adding 70 cm3 of acetic acid. The mixture obtained is filtered again, rinsed 3 times with 300 cm3 of ethyl ether, then the filtrate is dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. A yellow oil is obtained which is purified by distillation under reduced pressure (1.3 kPa). There was thus obtained 101 g of 1-diethylamino-2 (R) -thiopropane as a colorless oil. jin (bp 13 kPa = 55-56 ° C; [α] 30 = -37.1 ° (c = 4.8, :: 25 ch3oh)).

(R) -N, N-Diethyl-2-mercaptopropionamide can be prepared as follows: To a 5N sodium hydroxide solution (517 cm 3) kept at 20 ° C was added 105 g of (R) -N, N -diethyl-2-30 thioacetylpropionamide in 600 cm3 of ethyl ether.

The reaction mixture was stirred for 2 hours 30 min at about 20 ° C. The aqueous phase was separated by decantation.

The pH of the aqueous phase was then adjusted to 5-6 by careful addition of 140 cm3 of acetic acid. The mixture obtained is extracted with 300 cm3 of dichloromethane, then with 200 cm3 of 9 8 6 429 dichloromethane, the combined organic phases are dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. There was thus obtained 78.6 g of (R) -N, N-diethyl-2-mercapto-propionamide as a purple oil ([α] 30 = -21.1 ° (c = 3.8; CH 3 OH)).

(R) -N, N-Diethyl-2-thioacetylpropionamide can be prepared as follows: To 300 cm3 of ethanol containing 72.6 g of the potassium salt of thioacetic acid was added 88.3 g of (S) -N, N-10 diethyl-2 -chloropropionamide soaked in 150 cm3 of ethanol. The reaction mixture was heated at about 60 ° C for 2 hours, filtered and concentrated to dryness under reduced pressure (130 Pa) at about 50 ° C. The residue obtained is taken up in 500 cm3 of dichloromethane, stirred and washed with 300 cm3 of distilled water, 300 cm3 of 10% potassium bicarbonate solution and 300 cm3 of distilled water. The organic phase is decanted, dried over sodium sulphate and 1 g of 3S-black, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. The residue obtained was distilled under reduced pressure (17 20 Pa). There was thus obtained 105.5 g of (R) -N, N-diethyl-2-thioacetylpropionamide as a pale yellow oil (b.p. 17 Pa = 105-107 ° C; [α] 30) + 156 ° (c = 18, 1; CHCl 3)).

(S) -N, N-Diethyl-2-chloropropionamide can be prepared as follows: To a solution of 175.2 g of (S) -2-chloropropionyl chloride in 900 cm3 of chloroform at 0 [deg.] C.: 480 cm3 of diethylamine was added over 1 hour. To the reaction mixture were added 400 cm3 of distilled water and 300 cm3 of dichloromethane. The organic phase is decanted, washed with 300 cm3 of 1 to 30 l of an aqueous solution containing 2N hydrochloric acid and 400 cm3 of 1 l of distilled water. The organic phase is dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. The residue obtained was distilled under reduced pressure (17 Pa). There was thus obtained 161.9 g of (S) -N, N-di-35-ethyl-2-chloropropionamide as a colorless oil (b.p. 17 Pa = 83-85 ° C; [α] 30 = + 39 ° (c = 10, 5; CHCl 3)).

20 6 6 2 2 (R) - and (S) -2-chloropropionyl chlorides can be prepared according to S-C.J. FU, S.M. BIRNBAUM and J.P. GREENSTEIN, J.Am.Chem.Soc., 76, 6054 (1954).

5 Example 4

To a solution of 2 g of 26- [1-diethyl-2 (S) -propyl] thiopristinamycin IIB (isomer A) in 30 cm 3 of methanol was added over 30 minutes at -60 ° C 20 cm 3 of 1.01 g of Oxonew. an aqueous solution. The resulting suspension was stirred for 30 min at -60 ° C and 16 h at -20 ° C. 0.2 g of Oxone® dissolved in 5 cm3 of water are then added and the mixture is stirred for 30 minutes at -20 ° C. The reaction mixture is diluted with 100 cm3 of water, 0.5 g of black NORIT SX ULTRA are added, stirred for 15 minutes, filtered through Celite 15 and rinsed 3 times with 5 cm3 of water. The aqueous phase is extracted 3 times with 50 cm3 of ethyl acetate, adjusted to pH 7 by adding solid sodium bicarbonate, saturated with sodium chloride and washed 3 times with 50 cm3 of dichloromethane.

The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. There was thus obtained a white ma-ring which was stirred in 20 cm3 of diethyl ether. The resulting solid was filtered, dried under reduced pressure (270 Pa) at 20 ° C to give 26- [1-diethylamino-2 (S) -propyl] sulfinyl-pristinamycin IIB as a white solid (Isomer A2: 90%, Isomer A : 5%), having a melting point of 130 ° C and having NMR values identical to those of Example 5 below.

26- [1-diethylamino-2 (S) -propyl] thiopristinamycin IIB (isomer A) can be obtained as follows: in 200 cm3 of a methylene chloride-methanol mixture (50:50 by volume) in which 10.5 g pristinamycin IIA, 3.2 g of 1-35 diethylamino-2 (S) -thiopropane were added at -20 ° C under nitrogen. After stirring for 70 hours at -20 [deg.] C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 21 [deg.] C. at 30 [deg.] C., after which it is taken up in 100 cm <3> of ethyl acetate. The solution obtained is washed with 100 cm3 of an aqueous solution containing 0.2N acidic potassium sulphate. The aqueous phase is decanted and washed 3 times with 100 cm3 of 5 ethyl acetate. The organic phase is washed with 50 cm3 of distilled water, after which the aqueous phases are combined, the pH is adjusted to 7 by adding 2 g of solid sodium bicarbonate and washed first with 100 cm3, then twice with 50 cm3 of dichloromethane. The final organic phases are combined, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The solid obtained is shaken in 150 cm3 of ethyl ether, filtered and rinsed 3 times in 10 cm3 of ether. There was thus obtained 9.2 g of a beige solid which was crystallized from 20 cm3 of acetonitrile. Filtered, dried at 20 ° C under reduced pressure (270 Pa) to give 2.3 g of 26- [1-diethylamino-2 (S) -propyl] thiopristinamycin IIB (isomer A) as white crystals with a melting point of 128 ° C.

NMR Spectrum 1.04 (t, -N (CH 2 CH 3) 2) δ

1.39 (d, S H

N (C2H5) 2 25 CH3 1.73 (s, -CH3 at position 33) 1.90 and 2.13 (2mt,> CH2 at position 25) 2.4-2.7 (mt, -CH2- N (CH 2 CH 3) 2) 2.78 (mt, H at position 4) 2.93 and 3.12 (2dd,> CH 2 at position 15) 3.02 (mt, -S-CH-) -1-CH 3 3.55 (mt, H at position 26) 35 3.84 (s,> CH2 at position 17) 4.81 (iso s, H at position 27) 22 86429 5.49 (d, H at position 13) 6.15 (d, H at position 13) 11) 6.30 (m,> NH at position 8) 6.53 (dd, H at position 5) 5 8.13 (s, H at position 20) 1-Diethylamino-2 (S) -thiolpropane can be prepared as follows:

To a suspension of 42.6 g of lithium and aluminum hydride in 1500 cm3 of ethyl ether was added dropwise 10 drops of 171 g of (S) -N, N-diethyl-2-mercaptopropionamide dissolved in 500 cm3 for 1 hour 20 minutes: ethyl ether. The reaction mixture was then refluxed for 2 hours 30 minutes and cooled to about 0 ° C. 49.8 cm3 of distilled water are then added so that the temperature of the mixture does not rise above 20 ° C, after which 36.6 cm3 of 5N soda and 166 cm3 of distilled water are added. The reaction mixture is filtered, the pH of the filtrate is adjusted to 8 by adding 70 cm3 of acetic acid. The mixture obtained is filtered again, the filtrate is dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. A yellow oil is obtained which is purified by distillation under reduced pressure (1.3 kPa). There was thus obtained 100 g of 1-diethylamino-2 (S) -thiolpropane as a colorless oil (kP-i.3kP <= 55-56 ° C; [α] 30 = + 39.6 ° (c = 5.6, CH 3 OH). )).

25 (S) -N, N-Diethyl-2-mercapto-propionamide can be prepared as follows: 1100 cm 3 of a 5N soda solution were kept at 20 ° C and 223 g of (S) -N, N-diethyl-2 -thio-acetyl-propionamide in 1000 cm3 of ethyl ether. The reaction mixture was stirred for 20 hours at about 20 ° C. The aqueous phase is separated by decantation, washed 3 times with 250 cm3 of ethyl ether. The pH of the aqueous phase was adjusted to 5 by adding 280 cm3 of acetic acid. The mixture obtained is extracted first with 500 cm3, then twice with 250 cm3 of dichloromethane, the combined organic phases are dried over sodium sulphate in the presence of carbon black, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. :in. There was thus obtained 171.7 g of (S) -N, N-diethyl-2-mercaptopropionamide as a violet oil ([α] D = 0 + 20.7 ° (c = 3, CH 3 OH)).

(S) -N, N-Diethyl-2-thioacetyl-propionamide can be prepared as follows:

To a suspension of 16 g of the potassium salt of thioacetic acid in 70 cm3 of ethanol was added 20 g of (R) -N, N-diethyl-2-chloropropionamide dissolved in 30 cm3 of ethanol. The reaction mixture was then heated at about 55 ° C for 2 hours and concentrated to dryness under reduced pressure (130 Pa) at about 60 ° C. The residue obtained is triturated with 300 cm3 of dichloromethane and washed with 200 cm3 of distilled water. The organic phase is decanted, dried over sodium sulphate and filtered off under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. The residue obtained was distilled under reduced pressure (17 Pa). There was thus obtained 22 g of (S) -N, N-diethyl-2-thioacetylpropionamide as a pale yellow oil (b.p. 17 Pa = 105-107 ° C; [α] 30 = -169 ° (c = 10, CHCl 3).

(R) -N, N-Diethyl-2-chloropropionamide can be prepared as follows:

To a solution of 87.7 g of 2-chloropropionyl (R) chloride in 600 cm 3 of chloroform at 20 ° C was added 153 g of diethylamine for 1 hour. The reaction mixture is washed with 500 cm3 of distilled water, 3 times with 500 cm3 of 1N hydrochloric acid and 500 cm3 of distilled water. The organic phase is dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. The residue obtained was distilled under reduced pressure (17 Pa). There was thus obtained 43 g of (R) -N, N-diethyl-2-chloropropionamide as a colorless oil (b.p. 17 Pa = 75-80 ° C; [α] 30 = -43.3 ° (c = 10 ; CHCl 3)).

Example 5

To a suspension of 63 g of pristinamycin IIA in 630 cm 3 of methanol was added 17.6 g of (S) -1-diethylamine-2-thiolpropane under nitrogen at -38 ° C over 30 minutes. After stirring for 20 minutes, 150 cm3 of distilled water were added at -38 [deg.] C., after which 410 cm @ 33.6 g of an aqueous solution containing Oxone were added over 30 minutes. The suspension obtained is stirred for 1 hour at -38 [deg.] C., 1.2 g of sodium thiosulphate are added, filtered at 20 [deg.] C. through a sintered glass 5 and washed 3 times with 200 cm <3> of distilled water. To the aqueous phase was added 20 g of black NORIT SX ULTRA, stirred for 30 min, filtered through Celite and the filtrate was washed 3 times with 200 cm 3 of distilled water. The pH of the solution was adjusted to 7 by adding 15 g of solid sodium bicarbonate, followed by washing 3 times with 500 cm3 of dichloromethane. The organic phases are combined, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. 55 g of a beige meringue are obtained, which is stirred in 500 cm3 of ethyl ether. Filter, wash 3 times with 50 cm3 of ethyl ether, dry under reduced pressure (270 Pa) at 20 [deg.] C. to give 46.6 g of a white solid which is dissolved in 150 cm <3> of a dichloromethane-methanol mixture (98: 2 by volume). ), followed by the addition of 4 cm 3 of acetic acid. This solution was purified by flash chromatography (eluent: dichloromethane-methanol 98: 2 by volume) and 100 cm3 fractions were collected. It is concentrated under reduced pressure (2.7 kPa) at 30 [deg.] C. to give 36 g of solid which is dissolved in 400 cm <3> of distilled water to which 6.5 g of acidic potassium sulphate have been added. The solution is washed 4 times with 500 cm3 of ethyl acetate, the pH is adjusted to 7 by adding 5 g of solid sodium bicarbonate, then extracted first with 200 cm3, then twice with 150 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 [deg.] C. to give 33.8 g of a beige meringue, which is stirred in 300 cm <3> of ethyl ether. 29.3 g of 26- [1-diethylamino-2-propyl] sulfinyl-pristinamycin IIB 35 (isomer A2) were filtered and isolated as a pale yellow powder with a melting point of 140 ° C.

86429 NMR Spectrum (Isomer A2) 1.05 (t, -N (CH2-CH3) 2) | CH 2 1.27 (d, OS 2) 1.74 (s, -CH 3 at position 33) 2.10 (mt, 1H in the group> CH 2 at position 25) 2.45-2.70 (mt, in the 1H group> CH 2 at position 25, 10 1H in the group> CH2-N (CH2CH3) 2, -N (CH2CH3) 2) 2.80 (mt, H in position 4) 2.88 (mt, 1H in the group> CH2-N (CH2CH3) 2) 2.90 and 3 , 15 (2dd,> CH2 at position 15) 3.06 (mt, -S-CH-)

ψ I

15 0 CH3 3.41 (mt, H at position 26) 3.83 (s,> CH2 at position 17) 4.77 (iso s, H at position 27) 5.50 (d, H at position 13) 20 6.20 ( d, H at 11) 6.55 (mt,> NH at 8) 6.63 (dd, H at 5) 8.11 (s, H at 20)

Example 6 To a solution of 50 g of 26- (2-diethylaminoethyl) thiopristinamycin IIB dissolved in 200 cm 3 of dichloromethane and 250 cm 3 of distilled water was added 30.7 g of Oxone at 0 ° C for 20 min. ® dissolved in 140 cm3 of distilled water. After stirring for 10 minutes, the decane-30 is fed with the organic phase, the aqueous phase is washed with 100 cm3 of dichloromethane and then the pH is adjusted to 7 by adding 120 cm3 of saturated sodium bicarbonate solution. The aqueous phase is washed 5 times with 100 cm3 of dichloromethane, adjusting the pH to 7, by adding sodium bicarbonate to each wash. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 26 [deg.] C. at 40 [deg.] C. There was thus obtained 31 g of 26- (2-diethylaminoethyl) sulfinyl-pristinamycin IIB (isomer A2: 85%, isomer Aa: 10%) as a clear beige powder having properties identical to those of the product of Example 1.

Example 7

To a solution of 2 g of 26- (1-diethylamino-2 (S) -propyl) thiopristinamycin IIB (isomer A) in 30 cm 3 of ethanol and 20 cm 3 of water was gradually added at 10 ° C 0.08 cm 3 concentrated sulfuric acid, followed by the addition of 0.9 g of Oxone® dissolved in 10 cm3 of distilled water. The resulting solution was stirred for 4 hours at 20 ° C. Solid sodium bicarbonate was then added to reach pH 4 and stirred for 2 days at 20 ° C. 15 Then 25 cm3 of distilled water, 2 g of black NORIT SX ULTRA were added. The mixture is filtered through Celite, rinsed with 20 cm3 of dichloromethane and then the pH is adjusted to 7 using solid sodium bicarbonate.

The aqueous phase is decanted and washed twice with 20 cm3 of dichloromethane. The organic phases are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

There was thus obtained 1.6 g of a beige solid containing 80% of 26- (1-diethylamino-2 (S) -propyl) -25 sulfinyl-pristinamycin IIB (isomer A2), 10% of isomer Ax and 10% of sulfur used as starting material. , and whose properties are identical to the compound shown in Example 4.

Example 8 To a solution of 6 g of 26- (1-diethylamino-2 (S) -propyl) thiopristinamycin IIB (isomer A) in 20 cm 3 of distilled water and 90 cm 3 of methanol at -30 ° C was added 0 , 25 cm 3 of concentrated sulfuric acid, after which 2.7 g of Oxone® dissolved in 10 cm 3 of 35 distilled water were carefully added. The resulting cloudy solution was stirred at -30 ° C for 1 h. The mixture was then filtered through Cel-

II

27 8 6 429 through the lite. The pH of the filtrate was adjusted to 7 by the addition of solid sodium bicarbonate and washed 3 times with 50 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C.

The solid obtained is mixed with a mixture of 20 cm3 of ethyl acetate and 70 cm3 of ethyl ether, filtered and washed with 50 cm3 of ethyl ether. 4.6 g of a clear beige solid are thus obtained, which is purified by flash chromatography (eluent: ethyl acetate-methanol, 90:10 by volume) and 15 cm3 of fractions are collected. Fractions 47-54 were concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C to give 1.7 g of 26- (1-diethylamino-2 (S) -propyl) sulfinyl-pristi-15 namycin IIB (isomer A2). , which contained 10% of sulfur used as starting material, the properties of which are identical to the product shown in Example 4.

Example 9

To a solution of 2.5 g of 26- (2-diethylamino-20 2 (S) -propyl) thiopristinamycin IIB in 350 cm 3 of ethanol was added 200 cm 3 of distilled water at -30 ° C, followed by the careful addition of 15. 1 g of Oxone® dissolved in 70 cm3 of distilled water. After stirring for 1 hour 30 minutes at -30 [deg.] C., 3.7 g of sodium thiosulphate-25 dissolved in 20 cm <3> of water are added. The reaction mixture is then poured into 400 cm3 of distilled water and 200 cm3 of dichloromethane, and the pH is adjusted to 7 by adding sodium bicarbonate. The organic phase is decanted and the aqueous phase is washed 3 times with 200 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. There was thus obtained 24 g of a bright yellow solid which was purified by flash chromatography (elution: chloroform-methanol, 90:10 by volume). Fractions 23 to 28 (volume 50 cm 3) were concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C, after which 28 8 6429 was obtained as a yellow meringue, which was stirred in 100 cm 3 of ethyl ether, filtered and dried under reduced pressure (90 Pa). ° C. There was thus obtained 11.3 g of 26- (2-diethylamino-2 (S) -propyl) sulfinylpristinamycin IIB (isomer A2) 5 as a bright yellow powder with a melting point of 128 ° C. Nuclear Magnetic Resonance Spectrum (0 N (CH 2 CH 3) 2 1.1 (mt, -CH 2 CH 3 and S-CH 2 -C 1 H 2) CH 2 O 3 1.77 (s, -CH 3 at position 33) 2 - at position 25) 2.30 ä 2.7 (mt, 1H de -CH2- at position 25, CH2-CH2 -N2, 1H de -SO-CH2-) 15 CH2-CH3 2.97 (mt, 1H du -SO-CH2-) 2.78 (mt,> CH- at position 4) 2.92 and 3.10 (2dd, -CH2- at position 15) 3.13 (mt,> CH- at position 26) 20 3.50 (mt,> N-CH-) 3.81 (s, -CH2- at position 17) 4.77 (d,> CH- at position 27) 5.52 (d, = CH- at position 13) 6.18 (d , = CH- at position 11) 25 6.48 (mt, -NH- at position 8) 6.57 (dd, = CH- at position 5) 8.12 (s, = CH- at position 20) 26- (2-diethylamino -2 (S) -propyl) thiopristinamycin IIB (isomer A) can be prepared as follows: To a solution of nitrogen containing 31.5 g of pristinamycin II in 230 cm 3 of methanol and 70 cm 3 of chloroform was added -40 10 g of 2-diethylamino- (S) -propanethiol dissolved in 50 cm3 of chloroform at -40 [deg.] C. The mixture is stirred for 4 days at -40 [deg.] C., after which the mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 35 [deg.] C. :in, after which the solid obtained is stirred in 500 cm3 of li 29 66429 ethyl ether, filtered and stirred again in 300 cm3 of diethyl ether. After filtration, the solid was dried (90 Pa) at 20 ° C and purified by flash chromatography (eluent: chloroform-methanol-90:10 by volume) and 100 cm 3 fractions were collected. Fractions 18-30 were concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C to give 26.6 g of 26- (2-diethylamino-2 (S) -propyl) thiopristinamycin II as a bright yellow solid with a melting point was 10 110 ° C.

Nuclear Magnetic Resonance Spectrum: HN (CH 2 CH 3) δ 1.05 (mt, CH 3 -CH 2 - and -S-CH 2 -C 2) δ CH 2 1.72 (s, -CH 3 at position 33) 1.95 δ 2.10 ( mt, -CH2- at position 25) CH2-CH2 2.50 (mt, -N2) ^ CH2-CH3 2.60, 2.87 and 3.04 (mt, -S-CH2-CH <) 2, 77 (mt,> CH- at position 4) 2.9 and 3.10 (2dd, -CH2- at position 15) 3.35 (mt,> CH- at position 26) 3.82 (s, -CH2- at position 17) 25 4.7 (d, = CH- at position 27) 5.47 (d, = CH- at position 13) 6.15 (d, = CH- at position 11) 6.46 (m, -NH- at position 8) 6 .54 (dd, = CH at position 5) 30 (2-diethylamino- (S) -propanethiol can be prepared as follows:

To a solution of 39 g of 2-diethylamino- (S) -isothiouronium propyl dihydrochloride in 140 cm 3 of ethyl ether was added 59.4 cm 3 of 5N sodium hydroxide solution. Stir for 35 minutes under nitrogen, decant the aqueous phase and wash 3 times with 150 cm3 of ethyl ether. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The resulting liquid was distilled at 78 ° C under a pressure of 2.7 kPa to give 10.6 g of 2-diethylamino- (S) -propanethiol as a colorless liquid (containing 6% of 1-diethylaminopropanethiol) [α] £ 0 = +32 ± 0.6 (c = 0.943; ethanol).

2-Diethylamino- (S) -isothiouronium propyl dihydrochloride can be prepared as follows:

To a solution of 18.2 g of thiourea in 80 cm3 of 10 N, N-dimethylformamide was added at 130 ° C 45 g of 2-diethylamino-1-chloro- (S) -propane hydrochloride dissolved in 150 cm3. n, n-dimethylformamide. After 5 min at 130 ° C, the solution was cooled. The obtained crystals were filtered, washed with ethyl ether and dried under reduced pressure (90 Pa) at 20 ° C. There was thus obtained 39 g of 2-diethylamino-isothiouronium (S) -propyl dihydrochloride as white crystals, m.p. 209 DEG C. [.alpha.] D @ 20 = -2.6 (c = 1; ethanol).

2-Diethylamino-1-chloro- (S) -propane hydrochloride 20 can be prepared as follows: To 110 cm 3 of thionyl chloride at 2 ° C was added 50 g of 2-diethylamino- (S) -propanol hydrochloride in small portions. The resulting solution was heated at 60 ° C for 4 hours. Excess thionyl chloride was removed by distillation under reduced pressure (90 Pa), after which 250 cm3 of ethyl ether were added to the residue obtained. The solid obtained is filtered off, rinsed with 300 cm3 of ethyl ether and recrystallized from 150 cm3 of methyl isobutyl ketone. Filtered, washed with ethyl ether to give 45.6 g of 2-diethyl-30-amino-1-chloro- (S) -propane hydrochloride as white crystals, m.p. 103 DEG C. [.alpha.] D @ 20 = c = 0, 7; ethanol).

2-Diethylamino- (S) -propanol hydrochloride can be prepared as follows: To a suspension of 18.23 g of lithium hydride and aluminum in 2000 cm 3 of tetrahydrofuran was added 48.66 g of N-acetyl-N- ethyl 2-amino- (S) -propanol dissolved in 300 cm3 of tetrahydrofuran. The reaction mixture was then refluxed for 4 hours, after which it was cooled to 0 ° C. Then 22 cm3 of distilled water, 16 cm3 of 5N soda and 72 cm3 of distilled water were carefully added. After stirring for 1 hour at 20 ° C, the mixture was filtered through Celite. The filtrate was concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C, taken up in 300 cm 3 of dichloromethane, dried over magnesium sulphate-10, filtered, concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C to give 42.45 g of a bright yellow solution which was distilled under reduced pressure. There was thus obtained 26.56 g of 2-diethylamino- (S) -propanol as a colorless solution. (Bp x kPa = 55.5 ° C).

31.41 g of 2-diethylamino- (S) -propanol hydrochloride are obtained in the form of a white solid with a melting point of 98 [deg.] C. by adding 40.5 cm <3> of 4.9 N hydrochloric acid in 136 cm <3> of acetone dissolved in ethyl ether. product and the crystals obtained by filtration.

[Α] D 20 * +20.7 (c * 1; ethanol).

N-acetyl-N-ethyl-2-amino- (S) -propanol can be prepared as follows:

To a solution of 9.15 g of N-ethyl-2-amino- (S) -propanol in 100 cm3 of dichloromethane was added 13.7 cm3 of triethylamine at 0 [deg.] C., followed by the addition of 7.1 cm3 over 45 minutes. acetyl chloride. After the addition was complete, the temperature was allowed to rise to 20 ° C. The reaction mixture is diluted with 100 cm3 of water, the pH is adjusted to 9 by adding sodium carbonate and then washed twice with 200 cm <3> of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C to give 9.54 g of a yellow solution which is distilled at 108 ± 2 ° C under reduced pressure (26.3 Pa). ). There was thus obtained 6 g of a colorless solution containing about 80% of N-acetyl-N-ethyl-2-amine-32-6429 no- (S) -propanol and 20% of the corresponding diacetyl derivative (used as such in the further synthesis).

N-ethyl-2-amino- (S) -propanol can be prepared as follows: To a suspension of 81 g of lithium and aluminum hydride in 4000 cm 3 of tetrahydrofuran was added at 0 ° C 227 g of 2-acetylamino ( S) -ethyl propionate dissolved in 800 cm3 of tetrahydrofuran over 45 minutes. After the addition was complete, the temperature was allowed to rise to 20 ° C, after which the mixture was heated to reflux for 5 hours. After cooling to 0 [deg.] C., 97 cm <3> of distilled water, 72 cm <3> of 5N sodium hydroxide solution and finally 320 cm <3> of distilled water are carefully added. The mixture was filtered at 20 ° C through Celite. The filtrate was concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C, taken up in 500 cm 3 of dichloromethane, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C to give 143 g of a yellow solution. . Distillation under reduced pressure (460 Pa) at 57 ° C gave 90.8 g of N-ethyl-2-amino-20- (S) -propanol as a colorless solution, [α] 30 = +45.4 (c = 1.48; ethanol).

2-Acetylamine ethyl propionate can be prepared using the method of J.P. Wolfff III et al., Biochemistry 2, 493 (1963).

25 Example 10

The procedure was as in Example 9, except that 9.1 g of 26- [N-methyl-N-cyclohexyl-1-amino-2 (S) -propyl] thiopristinamycin IIB (isomer A) and 5.1 g of Oxone® were used as starting materials, whereby 8.3 g of a beige solid are obtained, which is purified by flash chromatography (eluent: ethyl acetate-methanol 90:10 by volume) to collect 20 cm3 of fractions. After evaporating to dryness under reduced pressure (2.7 kPa) at 30 [deg.] C. fractions 32-70 and shaking the solid obtained in ethyl ether, 3.4 g of 26-3386429 [N-methyl-N- cyclohexyl-1-amino-2 (S) -propyl] sulfinylpristinamycin IIB (isomer A2) as a pale yellow solid, m.p. about 140 ° C.

Nuclear Magnetic Resonance Spectrum (400 MHz) δ 1-1.3 and 1.5 δ 1.85 (2 mt, CH 2 cyclohexyl) 1.27 (d, y) tS-I 2 -o ch 3 ch 3 1.76 -CH3 at position 33) 2.09 and 2.55 (2mt,> CH2 at position 25) 2.31 (s,> N-CH3) 2.37 (mt, CH cyclohexyl) 2.55 and 2.90 (2dd ,> N-CH2-) 2.78 (mt, H at position 4) 2.92 and 3.16 (2dd, CH2 at position 15) 3 (mt, -S-CH <) t 3.41 (d broad, H at 26) 3.83 (s,> CH2 at 17) 20 4.78 (s, H at 27) 5.48 (d, H at 13) 6.18 (d, H at 11) 6.53 ( dd, NH at position 8) 6.60 (dd, H at position 5) 25.10 (s, H at position 20) 26- [N-methyl-N-cyclohexyl-1-amino-2 (S) -propyl ] pristinamycin IIB (isomer A) can be prepared as follows:

Proceed as in Example 4 to prepare 26-30 [N-diethylamino-2 (S) -propyl] thiopristinamycin IIB

(Isomer A), except that the mixture used was methanol-chloroform in a volume ratio of 70:30 and that the starting materials were 5.9 g of N-methyl-N-cyclohexyl-1-amino-2 (S) -propanethiol to give 48 hours. after 35-30 ° C 10.6 g of 26- [N-methyl-N-cyclohexyl] amino-2 (S) -propro] 348 6 429 pyl] thiopristinamycin IIB (isomer A) as a beige solid, m.p. . about 160 ° C.

NMR Spectrum: 1-1.35 (mt,> CH 2 cyclohexyl) δ 1.55-1.8 (mt,> CH 3 cyclohexyl) 1.36 (d, -S-CH-Nc) CH 3 1.72 (s , -CH 3 at position 33) 1.90 and 2.10 (2mt,> CH 3 at position 25) δ 2.31 (s,> N-CH 3) 2.40 (mt, - * CH cyclohexyl) 2.5-2, Δ (2dd,> N-CH 2 -) 2.77 (mt, -H at position 4) 2.95 and 3.13 (2dd,> CH 2 at position 15) 3.05 (mt, -SCH-) 3.56 (mt, -H at position 26) 3.82 (s,> CH2 at position 17) 4.82 (s, broad, -H at position 27) 5.48 (d, -H at position 13) 20 6.17 (d, -H at position 11) 6.48 (mt,> NH at position 8) 6.54 (dd, -H at position 5) 8.13 (s, -H at position 20) N-methyl-N-cyclohexyl-1-amino-2 (S) -propane-25 thiol can be prepared as follows:

To a suspension of 15.7 g of lithium aluminum hydride in 850 cm3 of ethyl ether was added dropwise over 1 hour 30 minutes 79.34 g of N-methyl-N-cyclohexyl-2-mercapto- (S) -propionamide dissolved in 200 cm3. to ethyl ethers-30 blades. The reaction mixture was refluxed for 2 h and then cooled to about 0 ° C. Then 45 cm 3 of distilled water were added so that the temperature did not exceed 20 ° C; then 45 cm3 of 5N sodium hydroxide and 150 cm3 of distilled water were added. The pH of the reaction mixture is adjusted to 8 by adding 40 cm3 of acetic acid. The resulting mixture was filtered, the filtrate was decanted and the aqueous phase was washed 4 times with 400 cm3 of ethyl ether. The ether phases are combined, dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. A yellow oil was obtained which was purified by distillation under reduced pressure (1.3 kPa). This gave 37 g of N-methyl-N-cyclohexyl-1-amino-2 (S) -propanethiol as a colorless oil, b.p. 0 2 kPa = 110-113 ° C; [α] 30 = + 27.2 ° (c - 2.4 CHCl 3).

N-methyl-N-cyclohexyl-2-mercapto- (S) -propionamide can be prepared as follows:

To a solution of 89.76 g of N-methyl-N-cyclohexyl-2-acetylthio- (S) -propionamide in 85 cm3 of methanol was added at 13 ° C under a nitrogen atmosphere 80 cm3 of 10N aqueous sodium hydroxide solution. The reaction mixture is stirred for 3 h at 40 [deg.] C., the reaction mixture is evaporated to dryness under reduced pressure (2.7 kPa), the residue is dissolved in 200 cm <3> of distilled water and washed twice with 200 cm <3> of ethyl ether. It is then decanted and the pH of the aqueous phase is adjusted to 5 by slow addition of 30 cm3 of acetic acid. The mixture obtained is extracted 3 times with 100 cm3 of chloroform. The organic phases are combined, dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. There was thus obtained 80.54 g of N-methyl-4-cyclohexyl-2-mercapto- (S) -propionamide as an oil, [α] D 20 = + 24.5 (c = 1.1 CH 3 Cl 3).

N-methyl-N-cyclohexyl-2-acetylthio- (S) -propionamide can be prepared as follows:

To a suspension of 56.2 g of the potassium salt of mercaptoacetic acid-30 in 200 cm3 of ethanol was added 80 g of N-methyl-N-cyclohexyl-2-chloro- (R) -propionamide dissolved in 60 cm3 of ethanol. The reaction mixture was heated at about 69 ° C for 2 h 45 min and then evaporated to dryness under reduced pressure (130 Pa) at 40 ° C. The residue tri-35 is triturated with 300 cm3 of dichloromethane, filtered off with 36 86429 and washed twice with 300 cm3 of distilled water, then with 300 cm3 of 10% aqueous KHCO3 solution and then with a further 300 cm3 of distilled water. . The organic phase is decanted, dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. This gave 90.6 g of N-methyl-N-cyclohexyl-2-acetylthio- (S) -propionamide as a yellowish-orange oil, [α] 30 = -97.8 ° (c = 1 CHCl 3).

N-methyl-N-cyclohexyl-2-chloro- (R) -propionamide-10 di can be prepared as follows:

To a solution of 70.7 g of 2-chloro- (R) -propionyl chloride in 320 cm3 of chloroform was added to a solution kept between -4 ° C and + 2 ° C. N-cyclohexylamine over 1 h. The reaction mixture is washed with 250 cm3 of distilled water, 3 times with 250 cm3 of 1N aqueous hydrochloric acid, then 4 times with 250 cm3 of distilled water. The organic phase is dried over sodium sulphate and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. The residue was distilled under reduced pressure (135 Pa). There was thus obtained 80.45 g of N-methyl-N-cyclohexyl-2-chloro- (R) -propionamide as a colorless oil, b.p. 13 kPa = 125 ° C; [α] 30 = -34 ° (without solvent).

Example 11

The procedure was as in Example 9, except that 14.4 g of 26- [1-diisopropylamino-2 (S) -propyl] pristinamycin IIB (isomer A) and 8.2 g of O

Oxone to give 14.1 g of a beige solid which was purified by flash chromatography (eluent: ethyl acetate-methanol 90:10 by volume) collecting 20 cm 3 fractions, fractions 62-81 were evaporated to dryness under reduced pressure (2.7 kPa). ) At 30 ° C to give a yellow solid which was shaken in ethyl ether, then filtered and dried at 20 ° C under reduced pressure (270 kPa) to give 9.7 g of 26- [1-di- isopropylamino-2 (S) -propyl-37 8 6 4 2 9 li] sulfinylpristinamycin IIB (isomer A2) as a yellow solid, mp about 120 ° C.

NMR spectrum 1 (mt, -CH 3 isopropyl) δ 1.24 (d, XS- | H-CH 2 -N <) 0 * CH 3 1.74 (s, -CH 3 at position 33) 2 and 2.53 (2 mt, > CH2 at position 25) 2.67 and 2.84 (2mt,> N-CH2-) δ 2.77 (mt, -H at position 4) 2.87 (mt, -S-CH <) £ 2.85- 3.05 (mt, -N (-CH <) 2 0 1H> CH2 at position 15) 3.15 (dd, 1H> CH2 at position 15) 15 3.37 (d broad, -H at position 26) 3.81 ( s,> CH2 at position 17) 4.65 (s, broad, -H at position 27) 5.51 (d, -H at position 13) 6.20 ((d, -H at position 11) 20 6.64 (dd + mt, -H at position 5 and> NH at position 8) 8.11 (s, -H at position 20) 26- [1-diisopropylamino-2 (S) -propyl] thiopristin-amycin IIB (isomer A) can be prepared by the following The procedure was as in Example 4 for the preparation of 26- [1-diethylamino-2 (S) -propyl] thiopristinamycin IIB (isomer A) except that a 80:20 v / v mixture of methanol and chloroform was used as the solvent mixture and 20 g of pristinamycin IIA and 8 , 88 g of 1-diisopropyl-30-amino-2 (S) -propanethiol, which was obtained after maintaining the temperature at -30 ° C for 48 h, a light beige solid which was shaken in 150 cm 3 of a mixture of ethyl ether and pentane (50-50 by volume), then filtered and dried at 20 ° C under reduced pressure (270 Pa). There was thus obtained 16.8 g of 26- [1-diiso- 38 8 6 429 propylamino-2 (S) -propyl] thiopristinamycin IIB (isomer A) as a pale beige solid, m.p. about 140 ° C.

Nuclear Magnetic Resonance Spectrum (400 MHz) δ (mt, -CH 3 isopropyl) 1.39 (d, -S-CH-CH 2 -N 2 O 3 N 5)

CH3 Y

1.75 (s, -CH 3 at position 33) 1.93 and 2.15 (2mt,> CH 2 at position 25) δ 2.41 and 2.68 (2dd,> N-CH 2 -) 2.82 (mt, - H at 4) 2.96 (mt, -S-CH <) 3 and 3.15 (2dd,> CH2 at 15) 3.05 (mt, -N (-CH <) 2) 15 3.57 (mt , -H at position 26) 3.88 (s,> CH2 at position 17) 4.88 (s broad, -H at position 27) 5.57 (d, -H at position 13) 6.17 (d, -H at position 11) 20 6, 35 (mt,> NH at position 8) 6.65 (dd, -H at position 5) 8.15 (s, -H at position 20) 1-Diisopropylamino-2 (S) -propanethiol can be prepared as follows: as in Example 10 for the preparation of N-methyl-N-cyclohexyl-1-amino-2 (S) -propanethiol, except that 48 g of N, N-diisopropyl-2-mercapto- (S) -propionamide and 10.16 g were used as starting materials. g of lithium aluminum hydride. The reaction mixture was distilled under reduced pressure (225 Pa) to give 24.1 g of 1-diisopropylamino-2 (S) -propanethiol as a colorless oil, b.p. 235 Pa = 69 ° C; [α] D = -24.2 ° (c = 1.3 CHCl 3).

N, N-Diisopropyl-2-mercapto- (S) -propionamide can be prepared as follows: 35 The procedure was as in Example 10 for the preparation of N-methyl-N-cyclohexyl- (S) -propionamide, except that

II

61.62 g of N, N-diisopropyl-2-acetylthio- (S) -propionamide and 55 cm3 of 10N aqueous sodium hydroxide solution were used as starting materials. This gave 48 g of N, N-diisopropyl-2-mercapto- (S) -propionamide as a red oil, [α] D 20 = + 5.6 ° 5 (c = 1, CHCl 3). This was used as such in the next reaction.

N, N-Diisopropyl-2-acetylthio- (S) -propionamide can be prepared as follows:

The procedure was as in Example 10 for the preparation of N-10 methyl-N-cyclohexyl-2-acetylthio- (S) -propionamide, except that 46.8 g of the potassium salt of mercaptoacetic acid and 65.01 g of N, N-diisopropyl-2 chloro (R) -propionamide. This gave 70.53 g of N, N-diisopropyl-2-acetylthio- (S) -propionamide as a yellow oil, [α] 30 D = -91.7 ° (c = 2, CHCl 3).

N, N-diisopropyl-2-chloro- (R) -propionamide can be prepared as follows:

The procedure was as in Example 10 for the preparation of N-methyl-N-cyclohexyl-2-chloro- (R) -propionyl, except that 73.6 g of 2-chloro- (R) -propionyl chloride in 350 cm3 of chloroform and 166 cm3 of diisopropylamine. This gave 64.5 g of N, N-diisopropyl-2-chloro- (R) -propionamide as a colorless liquid, b.p. 18 Pa = 71 ° C; [α] ο ° = 73 ° (without solvent).

25

Claims (3)

40 86429 Improved process for the preparation of S-oxide derivatives of pristinamycin IIB of general formula (I) 5 0 V o o CH 'V ° 10 CH' R 0 (I) H-C-CH-N Z 1 R 1 R 2 R 4 wherein R 1 and R 2 represent a hydrogen atom or a methyl or ethyl radical, R 3 represents a hydrogen atom or an alkyl radical containing 1 to 3 carbon atoms, R4 represents an alkyl radical containing 1 to 4 carbon atoms or a cyclohexyl radical, or R4 and R2 together with the atoms to which they are attached form a saturated 5-membered ring, or R4 forms a saturated 5- or 5-membered ring with R3. 6-membered ring, in its isomeric forms or in mixtures thereof, and for the preparation of these acid addition salts by oxidation of a pristinamycin IIB derivative (or a salt thereof) of the general formula (II) 35 41 86429 V '^' AU, * 3 (II> hc-ch- where R 1, R 2, R 3 and R 4 are as defined above, so that when R 3 and R 4 form a sulfur-containing heterocycle, the sulfur atom may be in sulfide, sulfoxide or sulfone form, optionally followed by separation of the isomers of the resulting product. , and optionally the product obtained is converted into a salt by means of an acid 15, characterized in that the oxidation is carried out with potassium monopersulphate 42 86429 That is to be determined The S-oxide derivative of pristinamycin IIB in the form of 5 (I) 0 JK. _CH ^ ΝΙ-Γ CH, J CH, L .0 1. oo 3 ^ 10 ch .1 JL I * J VTT CH, SO-A ^ '° (I, HC-CH-N CII \ r1r2 r4 15 där Rx and R2 is a substituent or a methyl or ethyl radical, R3 is a substituent or an alkyl radical having 1-3 cholatomers, R4 is a radical of an alkyl radical having 1-4 cholaters or a cyclohexyl radical, or R4 and R2 are a radical of an atom, with a single ring, a ring of 5 or more rings, 25 or R4 of the same ring and a ring of 5 or 6 rings, the form of an isomer or a ring of a ring, the same as the compound of the ring, the genome of which is derived from the ring pristinamycin 30 IIB med denmänna formuleln II (eller et sait därav) 35 li 43 864 29 5 'ν' 0 0 CH> V ° CH I JL ». T Ύ 0 n'TT CH, 1J 1-0 • I R3 HD hc-ch-n ^ RiR? r. 10 1 2 4 of Rx, R2, R3 and R4 are selected from the group consisting of sulfides, sulfoxides, sulfoxides and sulfoxides. or a sulfone The form may be separated from the isomeric form of the product and the product is optionally separated from the salt product in the form of a mixture of potassium monopersulfate.