Method of preparing pristinamycine or its isomers

专利摘要:
There is described a process for the preparation of therapeutically useful pristinamycin IIB sulphone derivatives, of the general formula (I) hereinafter depicted, and their acid addition salts, in which R denotes: either a nitrogen-containing 4 to 7-membered heterocyclic ring radical, which may contain 1 or more other hetero atoms chosen from nitrogen, oxygen and sulphur in the form of sulphoxide or sulphone, and unsubstituted or substituted by alkyl; or alkyl of 2 to 4 carbon atoms substituted by 1 or 2 radicals chosen from phenyl, cycloalkylamino of 3 to 6 ring atoms, N-alkyl-N-cycloalkylamino of 3 to 6 ring atoms, alkylamino, dialkylamino and dialkylcarbamoyloxy, the alkyl parts of these 2 latter radicals being unjoined or joined to form, with the nitrogen atom to which they are attached, a saturated or unsaturated 4 to 7-membered heterocyclic ring which may contain another hetero atom chosen from nitrogen, oxygen and sulphur in the form of sulphoxide or sulphone, and unsubstituted or substituted by alkyl, or alkyl of 2 to 4 carbon atoms substituted by one or more nitrogen-containing, 4 to 7-membered hetercyclic rings which may contain 1 or 2 other hetero atoms chosen from nitrogen, oxygen and sulphur in the form of sulphoxide or sulphone, and unsubstituted or substituted by alkyl, these heterocyclic rings being linked to the alkyl by a carbon atom of the ring, at least one of the substituents carried by the said alkyl chain being a nitrogen-containing substituent capable of forming salts, or the [(S)-1-methyl-2-pyrrolidinyl]methyl group, and n is 2, and their isomers and their mixtures which comprises oxidising a compound of formula (I) as as hereinbefore defined in which n is 1 or a compound of formula (II) in which R is as hereinbefore defined, with a periodic acid salt and a catalytic amount of ruthenium (VIII) compound, which may optionally be prepared in situ by oxidation of a ruthenium compound of a lower oxidation state. Also disclosed are compounds of general formula (I) in which n is equal to 2 in the form of their B isomers, and certain novel compounds of general formula (I) in which n is equal to 2.
公开号:SU1639429A3
申请号:SU874202981
申请日:1987-07-07
公开日:1991-03-30
发明作者:Чэттерджи Девнандан；Виктор Хэррис Нил；Паркер Тревор；Смит Кристофер；Джеймс Варрен Питер
申请人:Мэй Энд Бейкер Лимитед (Фирма)；
IPC主号:

专利说明:

The invention relates to a method for producing biologically active sulphone derivatives of pristinamycin PA.
general formula
ABOUT
(I)
where k
alkylaminoalkyl selected from 2-diethyllaminoethyl, 2-di-isopropylaminoethyl, 2-dibutylaminoethyl, 2-dipropylaminoethyl, M-ethyl-H-isopropyl-2-aminoethyl, 2- (1-pyrrolidinyl) - ethyl, 2-morpholinoethyl, 2-di-methylaminoethyl, N-butyl-N-methyl-2-aminoethyl, 2-piperidinoethyl.
The purpose of the invention is to provide a conveniently preparative method for the preparation of sulphonus derivatives, Pristina P &, with high bacteriostatic activity.
The invention is illustrated by the following examples.
All NMR spectra are recorded at 250 MHz and deuterium chloroform; chemical shifts are expressed in the rrH, relative to the signal of tetramethylsilane. The following abbreviations are used in the text: c sinlet, doublet, t triplet, mt multiplet, m unresolved stripes, dd double doublet, dt doublet of triplets, ddd triple doublet, dddd fourth quartert.
For the compound of general formula (I), all protons are designated according to the numbering indicated in the following formula
32
CH3
9 11 „13
No. &
SNS J3 D27 g Y gg%
30 V290% Ne17 CH32R 24f0L0l9
.41ZD
I Various isomers classified
arbitrarily according to the chemical shifts observed in NMR.
0
0
five
about
.
0
five
50
five
The isomer AJ and isomer A of the compounds of general formula (I),, are given to isomers with the following characteristics: approximately 1.7 (s, -CHj at 33); approximately 3.8 (s, CH2 at 17); 5 (d, -Ngt) itomer A or 5 (d, -Hg7) isomer A ,; approximately 5.50 (hair.d, -H0); approximately 6.20 (d, -H (); approximately 6.6 SS at 8); Ј8 (with, -go). The names of B isomers (and Be isomers of compounds of general formula (I),, are given to isomers with the following characteristics: approximately 1.5 (s, -CH at 33); approximately 3.7 and 3.9 (2d, CHg at 17); about 4.8 (mt, -H &); 5 (d, -H27) isomer B or 5 (d, H27) isomer B ;; about 5.70 (line AB, -Ni and -H); approximately 7.7 (NH at 8); approximately 7.8 (s, -HDA.
The name Isomer A of the compound of general formula (II) is given by the isomer, the NMR characteristics are identical for the isomers Af and AV of the compounds of general formula (I), provided that H at 27 is characterized by the following: 4.7 (d, Hz).
The isomer B of the compound of general formula (II) is given an isomer with NMR characteristics identical for isomers B and B of the compounds / formula (I), provided that H at 27 is characterized by the following: 4.6 (d, 5 Hz),
In the following examples, the term flash chromatography is given to a purification technique that uses a short chromatographic column operating at medium pressure (50 kPa) using silica with a specific fractional composition of 40-53 microns.
In these examples, all compounds can be dissolved in 2% hydrochloride.
Example 1. To a stirred solution of 26- (2-diisopropylaminoethyl) -sulfinylprythinamine Ilg (AZ isomer) (10 g) in dichloromethane (300 cm3) was added a solution of sodium metaperiodate (8.5 g) in distilled water (75 cm3), pH the aqueous phase is adjusted from 6 to 7 by adding portions of solid sodium bicarbonate with rapid stirring of the mixture. The mixed two-phase system is cooled to
516
after which ruthenium dioxide dihydrate (10 mg) is added. After stirring at 10 ° C for 4 hours, the temperature of the reaction mixture is brought to room temperature and the organic phase is separated, the aqueous phase is adjusted to pH 7.5 by adding solid sodium bicarbonate, then extracted twice with dichloromethane (70 cm3). The combined organic phases are dried in the presence of anhydrous sodium sulfate,
evaporated other dryness under reduced pressure at 40-45 C and left

the exact tan solid (10 g) is dissolved in ethyl acetate (300 cm3). The solution is washed repeatedly with a buffer solution of citrate at pH 4 (10x60 cm3) until there is a minor product left in the ethyl acetate solution (controlled by thin layer chromatography and high performance liquid chromatography). The wash water of the citrate buffer was adjusted to pH 7.5 by adding portions of solid sodium bicarbonate with stirring, and the solution was extracted with dichloromethane (100 cm 3, then four batches of 500 cm 3). The combined extracts of sugaat in the presence of anhydrous sodium sulphate and evaporated under reduced pressure at 40-45 ° C to obtain a yellow solid (6.8 g), which is purified by flash chromatography (eluant: (ethyl acetate-methanol 92: 8 by volume) , collecting 30 cm3 fractions. Fractions 14-30 are combined with a concentrate solution, pH 4 (2 x 50 cm3). The combined buffer solutions are backwashed with ethyl acetate (3 × x 25 cm3), saturated with solid sodium carbonate and extracted with dryness under reduced pressure at 40-45 Cj, getting white solid; Anoma (.100 cm3, then 2x50 cm3), the whole body (3.99 g). Further purification
2.56 g of this substance is carried out by flash chromatography (eluent: chloroform-methanol 95: 5 by volume), collecting 14 cm3 fraction. Fractions 32-50 are combined and concentrated to dryness under reduced pressure to give a white solid (2.24 g), which is dissolved in ethyl acetate (10 cm3). The solution is slowly added to petroleum ether (boiling range 40-60 ° C) (100 cm3) and the precipitate is separated by filtration to obtain 26- (2-diisopropylaminoethyl) sulfonyl-acridinamine P g, (isomer A) as 55 white powder (2.1 g), melting slowly with decomposition above 110 ° C.
Found,%: C 60.3; H 7.5; N 7.6.
C36-H N40, S.
50
The combined organic extracts were dried over anhydrous magnesium sulphate and evaporated to give a light yellow powder (4.3 g). This powder was dissolved in ethyl acetate (40 cm3), filtered to remove insoluble soluble material and evaporated to give 26- (2-diethylaminoethyl) sulfonylprythinamycin Pv (isomer A) as a light yellow powder (3.7 g), melting slowly with decomposition of more than 105 C.
Found,%: C 54.1; And 7.5; N 7.9; S 4,6. C 4HSON40, S.
| Calculated,%: C 59.1; H 7.3; N 8.1i; S 4,6.
The NMR data confirm the structure of this compound.
N
0
Calculated,%: C 50.1; H 7.57; 7.79.
NMR data exposes the structure of this sulfonyl derivative. The characteristics of the NMR spectra for all the compounds obtained are presented in the table.
Example 2. To a vigorously stirred mixture of a buffer solution of pH 8 (350 cm3) and dichloromethane (350 cm3), sodium metaperiodate (9.1 g) was added in one portion at ambient temperature, followed by immediate addition of 26- (2- diethlamino-ethyl) -sulfoniclpristinamycin Pe (Ag isomer) (8.5 g). After 1 minute, ruthenium dioxide dihydrate (50 mg) was also added in one portion. After
After vigorous stirring for 10 minutes, the mixture is scanned into a separatory funnel, washing the reaction flask with fresh dichloromethane (175 cm3). The layers are separated by yut1 and the organic phase.
5 is washed with water (200 cm3), dried over anhydrous magnesium sulphate and evaporated to give a light brown powder (5.6 g). This powder is shaken with a mixture of ethyl alcohol.
0 acetate (150 cm3) and buffer solution with pH 4 (100 cm3). After decanting from a small amount of insoluble tar, the layers are separated and the organic phase is re-extracted with bu
ferric solution, pH 4 (2x50 cm3). The combined buffer solutions are backwashed with ethyl acetate (3 × x 25 cm 3), saturated with solid acid sodium carbonate, and extracted with hydrogen chloride (. 100 cm 3, then 2 × 50 cm 3),
hpormetanom (.100 cm3, then 2x50 cm3)

The combined organic extracts were dried over anhydrous magnesium sulphate and evaporated to give a light yellow powder (4.3 g). This powder was dissolved in ethyl acetate (40 cm3), filtered to remove insoluble soluble material and evaporated to give 26- (2-diethylaminoethyl) sulfonylprythinamycin Pv (isomer A) as a light yellow powder (3.7 g), melting slowly with decomposition of more than 105 C.
Found,%: C 54.1; And 7.5; N 7.9; S 4,6. C 4HSON40, S.
| Calculated,%: C 59.1; H 7.3; N 8.1i; S 4,6.
The NMR data confirm the structure of this compound.
Example 3. Solution metaperiol; date of sodium (16.2 g) in water (500 cm); rapidly added in one portion to a vigorously stirred solution of 26- (2-idiethylaminoethyl) -thiopristinAG Icin Hfc, (isomer A) (10.0 g) in acetone (500 cm3) at room temperature, followed by 15 with the addition of hydrate ruthenium dioxide (50 mg) is also in one portion. After stirring at room temperature for 10 minutes, during which time a white precipitate formed, solid sodium carbonate (20 g) was added. After J stirring for 1 min, the mixture was filtered through diatomaceous earth, washing the filter pad with dichloromethane (750 cm 3). The filtrate is thoroughly mixed, the layers and water2 are separated, the layer is re-extracted with fresh dichloromethane (250 cm3), the addition of solid sodium chloride at this point promotes the separation of the two layers. The combined dichloromethane 2 extracts were dried in the presence of anhydrous magnesium sulphate and evaporated to give 7.8 g of a light brown powder. This product was shaken thoroughly with ethyl acetate (150 cm3) for 5 minutes, filtered to remove insoluble material, and the filter pad was washed with fresh ethyl acetate (50 cm3). Evaporation of the combined filtrates allows to obtain 26- (2-diethylamine ethyl) -superphonyl pristinamycin Ig (isomer A) as a light yellow powder (6.1 g), melting slowly with decomposition at a temperature higher than 105 ° C.
Similarly, but replacing 26- (2-diethylaminoethyl) -thiopristinamine of cin II in (isomer A) with 26- (2-diisopropylaminoethyl) -hyopristinamycin Pv (isomer A), (1 g), 26- (2- di-isopropylaminoethyl) -sulfonylpristine-amicum “on P (isomer A) 0.53 g, so pl. 110 ° C (decomposition).
Similarly, but replacing 26- (2-diethylaminoethyl) -hyopristinamine Hg (isomer A) with 26- (2-diethyl-aminoethyl) -thiophothristinamine Tig (isomer B) (3.95 g) and carried out the reaction at give 26- (2-diethylamino-, ethyl) -sulfonylpristinamycin Pv (isomer B) as a yellow amorphous powder (3.47 g). Purification of this material is carried out by flash chromatography (eluent: chloroform-methanol 95: 5
five
P
.
0
by volume), collecting 30 cm3 fraction. Fractions 21-23 are combined and concentrated to dryness under reduced pressure to give 1.16 g of 26- (2-diethyl-aminoethyl) -sulfonylpristinamycin IL (isomer B) as a white powder, melting slowly from 93 ° s Found,%: C 56.2; H 7.0; N 7.3; S 4.55. „
  2IN0. Calculated,%: C 56.2; H 7.49; N 7.71; S 4.41.
Similarly, however, replacing 2b (2-diethylaminoethyl) -thiopristin-amycin Pv (isomer A) with 26- (2-diethylaminostil) -sulfonylpristinamine P 38 38.5 g) (isomer A) and using 2.8 equivalent of sodium metaperiodate, 2b- (2-diethylamino-ethyl) -sulfonylpristinamine Lev (isomer A), 3.7 g, slowly melting from 105 ° C with decomposition, are obtained.
Similarly, but replacing 26- (2-diethylaminoethyl) thiopristinamycin L8 (isomer A) with 2b- (2-diethylaminoethyl) - sulfonylpristinamycin P & (isomer) (10.12 g) and using 2.8 equivalents of sodium metaperiodate, 26- (2-diethylaminoethyl) sulfoiyl-pristinamycin P (isomer A), 5 G, slowly melting with decomposition of 105 ° C, is obtained.
Similarly, but replacing 26- (2-diethylaminoethyl) -thiopristinamycin Pv (isomer A) with 26- (2 diisopropylaminoethyl) -sulfonylpristchkamcin And- (isomer.) (S500 g) and using 2.8 equivalents of sodium metaperiodate, 26- (2 diisopropylaminoethyl) -sulfonylpyretinamycin P & (isomer A), 6.5 g, slowly melting with decomposition from 110 ° C.
Similarly, but replacing 26- (2-diethylaminoethyl) thiopristinamycin ng f (isomer A) and aa 26- (K-ethyl-H-isopropyl-2-aminoethyl) -t opristinamycin P- (isomer A), (3,36 d) by pre-cooling a solution of sodium metaperiodate in water to 12 ° C and carrying out the reaction at 6 ° C, 26- (N-ethyl-L-isopropyl-2-aminoethyl) -sulfonylprystintyl acetate & (isomer A) (2.3 g) as a pale yellow powder. This material was purified by flash chromatography (eluant: chloroform-methanol 95; 5 by volume), collecting 25 cm3 of fraction. Fractions 10-13 are combined and concentrated to dryness; the residue is 1639429
thrown in ethyl acetate followed by evaporation to remove residual traces of chloroform, which allows to obtain 26- (y-ethyl-n-isopropyl-2-amino-ethyl) -sulfonylpristinamycin Pb (isomer A) (1.54 g) pale yellow powder, melting slowly at 103-1100 ° C,
Found,%: C 7.6; S 4.4. ,five
58.7; And 7.4;
sn3gsognsne.
N
Calculated,%: C 59.3; H 7.54; 7.48; S 4.28.
Similarly, but replacing 26- (2-diethylaminoethyl) -thiopristinamycin Pv (isomer A) by 26 -. (- 1-pyrrolidinyl) is pl-thiopristinamine P. (isomer A) (3.28 g), pre-cooled solution of metaperiodate sodium in water to 12 and carried out the reaction while receiving 26-2G- (1-pyrrolidinyl) ethyl-sulfonylpristinamycin II. (isomer A) (0.56 g) as a pale yellow powder. This material was purified by flash chromatography (eluant: chloroform-methanol 95: 5 by volume), collecting fractions of 25 cm 3. & 23-32 are combined and concentrated to dryness, the residue is dissolved in ethyl acetate, followed by evaporation to remove residual traces of chloroform, which allows to obtain (1-pyrrolidinyl) ethyl sulfonistristine P. (isomer A) in as a pale yellow powder, melted honey

Lenno at a temperature of 110 to 117 C
Found,%: C 59.6; H 7.2; N 7.7; S 4,6.
C34H48N4- ° 4S CH3C02 CHtCH3.
Calculated,%: C 59.0; And 7.10; N 7.65; S 4.38.
Similarly, but replacing 26- (2-diethylaminoethyl) -thiopristinamycin Pv (isomer A) with 26- (2-morpholinoethyl) - t-iopristinamine Ho (isomer A)
LC
(3.36 g), after cooling the solution of sodium metaperiodate in water to 12 ° C and performing the reaction at 6 ° C., 26- (2-morpholinoethyl) -sulfonylpristinamycin Pv (isomer A) is a pale yellow powder. Purification of this substance was performed by flash chromatography (eluent: chloroform-methanol 85: 5 by volume), collecting fractions of 25 cm3. Fractions 17-21 are combined and concentrated to dryness, the residue is dissolved in ethyl acetate, followed by evaporation to remove the residue.
YU

five

Traces of chloroform, which allows to obtain 26- (2-morpholinoethnl) -sulfononpristinamycin P8 (isomer A) 0.74 g as a white powder, melting slowly at a temperature above 108 ° C.
Found,%: with 57.7; H 7.0; N 7.6; S 4,2.
C34H4eN 4 ° tos ° 5 CH, CO CHZCH3.
Calculated,%: C 57.7; H 7.0; N 7.48; S 4.23.
II p. Example 4. A solution of sodium metaperiodate (7.3 g) in water (90 cm3) is added in one portion as quickly as possible to a vigorously stirred solution of 26- (2-dimethylaminoethyl) -thioistinamycin P6 (isomer A ) (4.66 g) in acetate (90 cm3) at 15 ° C, followed by the addition of ruthenium dioxide dihydrate (50 mg) after 1 min, also in one portion. After stirring at room temperature for 15 minutes, during which time a white precipitate forms, acid sodium carbonate is added in the solid state (4.6 g). After stirring for 1 min, the mixture is filtered, the filtered pad is washed with dichloromethane (300 cm3), then the filtrate is thoroughly mixed, the layers are allowed to separate, and the aqueous layer is re-extracted with fresh dichloromethane (2x100 cm3). The combined dichloromethane extracts are dried in the presence of anhydrous magnesium sulphate and evaporated to give 3.6 g of a light brown powder, which is purified by phlega (eluant: chloroform-methanol 95: 5 by volume), collecting fractions of 20 cm3, fractions 23-45 are combined and concentrated to dryness under reduced pressure to obtain a white solid (1.3 g), which is dissolved in ethyl acetate (10 cm3). The solution is slowly added to petroleum ether (boiling range 40-60 ° C, 300 cm3) and the precipitate is separated by filtration, which allows to obtain 26- (2-dimethylaminoethyl) -sulfonylpristinamncin P6 monohydrate (isomer A) as a white powder (0.7 g), m.p. 120-122 ° C.
Found,%: C 56.9; H 6.96; N 8.0; S 4.61.
SYN46 098.H20.
Calculated,%: C 56.5; H 7.10; N 8.23; S 4.70.
1 16
Similarly, but replacing 26- (2-di
ngo.
methylaminoethyl) - thiopristinamycin P, (isomer A) on 26- (H-butyl-L-methyl-3-aminoethyl) -thiopristinamine GT (isomer A) (10 g), receive monohydrate 26 (M-butyl K - methyl-2-aminoethyl) sulfonylpristinamycin C. (isomer, 1 g as a cream-colored solid, mp. 118-121 ° C. Found: C 58.7; H 7.20; 7.70; S 4.50. C35H5jN4OfS
Calculated, Y: C 58.2; H 7.53; 7.75; S 4.43. Similarly, but however (2-dimethylaminoethyl) -thiopristinamine H & (isomer A) 26- (2-piperidinoethyl) -thiopristinamycin II & (isomer A) 8.1 g, get 26- (2-piperidinoethyl) sulfonylprinthymnine Pe hemihydrate (isomer A) 1.4 g as a white powder, m.p. 125-127 C.
Found,%: C 59.2; H 7.20; 7.80; S 4,6.
N
N
replacements 26
N
C35HFON4 ° S
“5HgO.
Calculated,%: C 59.0; H 7.15; N 7.86; S 4,5.
Similarly, but replacing 26- (2-di-methylaminoethyl) -thiopristinamine P0 (isomer A) with 26- (2-di-n-butylamino-ethyl) -thiopristinamycin P (isomer A), 10 g, get 26- (2 -di-1; -butylamino-ethyl) -sulfonylpristinamycin (isomer A) 4.4 g in the form of a light yellow powder, so pl. over 90 C.
Found,%: C 60.9; H 7.9; N 7.0; S 4,2.
 Hgg S.
Calculated,%: C 61, t; H 7.8;
N 7.5; S 4.3.
PRI me R 5. A solution of 26- (propylaminoethyl) -thiopristinamine, IIg (isomer A) (20.6 g) in acetone (1030 cm3) and water (1030 cm3) is cooled to 0 ° C (internal temperature ) with mixing. Ruthenium dioxide dihydrate (0.103 g) is added, followed by the addition of sodium metaperiodate (38.72). After stirring at from (0) to (-5) ° C for 1 h, solid sodium bicarbonate (20.6 g) is added, the mixture is filtered, the residue is washed with dichloromethane (1000 cm3)
The filtrate and washings are carefully smoked, the organic phase is separated and the iodine phase is extracted with dichloromethane (3x200 cm 3). The combined organic phases are dried in the presence of
12
0
five
0
five
0
five
d
5 o
anhydrous magnesium sulphate and evaporated under reduced pressure at 40-45 ° C, which allows to obtain a cream-colored solid (16.9). 11.2 g of this material is heated with ethyl acetate (175 cm3) and the mixture is filtered to remove insoluble material (1.2 g), then cooled to (0) (-5) ° C overnight and filtered again. The filter cake is concentrated to a volume of 70 cm3 and the solution is slowly added to petroleum ether (boiling range 40-60 ° C) (700 cm3). The precipitate was separated by filtration to give (26- (2-di-n-propylamino-ethyl) -sulfonylpristinamine Lev (isomer A) as a cream-colored solid (7.8 g), mp 129-131 ° C with decomposition.
Found,%: C 58.4; H 7.5; N 7.4.
C36H N4 ° 9S Ha °
Calculated,%: C 58.7; H 7.65;
N 7.6.
Example Water (300 cm3) is added to the stirred suspension of 26- (2-diethylaminoethyl) -thioostinamine P6 (isomer A) (10 g) in acetonitrile (300 cm3). Almost all of the solid is dissolved and the mixture is cooled to 2 ° C with the addition of ruthenium trichloride trihydrate (30 mg) in one portion, followed by the addition, after one minute, sodium metaperiodate (16.2 g), as well as in one portion. Stirring is continued at from 0 to 2 ° C for 5 minutes, after which the mixture is filtered and the filter pad is washed with acetonitrile (50 cm3). Sodium bicarbonate is added to the combined filtrate and washings in a solid state (6 g), followed by the addition of dichloromethane (150 cm3) and then sodium chloride (10.6 g) with stirring. The precipitated solid is filtered and the filter pad is rinsed with dichloromethane (50 cm 3). The filtrate is thoroughly mixed and the upper organic phase is separated. The lower aqueous phase is extracted with the washings of dichloromethane used above. The combined organic phases are washed with saturated brine (50 cm3), dried in the presence of anhydrous magnesium sulphate and filtered, washing the filter pad with dichloromethane (50 cm3). The solution (460 cm3) obtained in this way is treated, by stirring, with a solution of citric acid in acetone (0.2 m) (68 cm3) and the resulting milky solution is decanted from the precipitated brown gum (2.2 g), then filtered through di- 5 atomic ground to obtain a clear pale yellow filtrate. Evaporation under reduced pressure affords a light yellow solid (9.84 g), which is washed with ethyl acetate-JQ tatom (100 cm3) to give 26- (2-diethyl-amino-ethyl-N) -sulfonylpristinamycin P nitrate (isomer A) as a light yellow solid (9.6 g) melts slowly from 130 ° C with decomposition. This substance is analyzed for (85%) 26- (2-diethylaminoethyl) -sulfonylpristinamycin pv (isomer A) with the help of high-resolution analytical liquid chromatography chromatography on reversed-phase silica.
The light yellow solid (9.5 g) was dissolved in water (100 cm3) and the resulting yellow solution was washed with 1.1, 2.2 g of tetrachloroethane (3x10 cm3), then 25 dichloromethane (2x10 cm3). The aqueous phase is practically colorless, sodium chloride (1 g) is added and the mixture is extracted six times with dichloromethane (50 cm3). The combined extracts are dried in the presence of anhydrous magnesium sulfate, concentrated to a volume of 50 cm3 and petroleum ether (limits boiling 40-60 ° C) (100 cm3). The precipitate obtained is filtered, which allows to obtain 26- (2-diethylaminoethyl) -sulfonyl-pristinamycin Pv hemi-citrate (isomer A) as a white powder (3.5 g), melting slowly with decomposition from 120 ° C . before
This substance is analyzed for (97.3%) 26- (2-diethylaminoethyl) -sulfonylpristinamycin Pv (isomer A) by means of high performance liquid chromatography with reversed phase 45.
Zoya
Similarly, citrate 26-3-diethylaminoethyl) sulfonylpristinamine P6 (isomer A) (ft, O g) is obtained in the form of a light yellow solid, which is, eg, dissolved in water (160 cm3). / (the yellow solution is washed with dichloromethane (3x40 cm3), sodium citrate in an amount of 10.6 g is added to the aqueous phase, which is then extracted with dichloromethane (6x70 cm3). The combined dichloromethane extracts are washed with a saturated aqueous solution of brine, dried in the presence of anhydrous magnesium sulfate and concentrated to dryness to give 26- (2-diethylaminoethyl) sulfonylpristinamycin Pr (isomer A) as a pale yellow solid (3.27 g), melting slowly with decomposition from 105 ° C.
Found: C 59.2; H 7.3; N 8.2; S 4,6.
C 4ltfoN409S.
Calculated,%: C 59.1; H 7.29; N 8.11; S 4.64.
Example 7. A solution of 26- (2-diethylaminoethyl) -thiopristinamycin Pv (isomer A) (5.0 g) in acetone (150 cm3) and water (150 cm3) is cooled to (internal temperature), vigorously stirred. Solid ruthenium trichloride trihydrate (25 mg) is added, followed by the immediate addition of solid sodium metaperiodate (8.1 g). After stirring at 0 ° C for 1 h, solid sodium hydrogen carbonate (5.0 g) was added. After 1 min, the mixture is filtered through diatomaceous earth and the filter pad is washed with dvichloromethane (200 cm3). The filtrate is thoroughly mixed and the layers are separated. Water. the layer is re-extracted with fresh dichloromethane (100 cm3, then 50 cm3) and the combined extracts of sugaat in the presence of anhydrous magnesium sulphate and evaporated to give 26- (2-diethylaminoethl) -sulfonylpristin-amycin II g (isomer A) as a sand powder (4, 1 g), slowly melts with decomposition from 105 ° C.
ExampleB A solution of 26- (2-diethylaminoethyl) -thiopristinamicin Hg (isomer A) (5.0 g) in acetone (150 cm3) and water (150 cm3) is cooled to 0 ° C (internal temperature), vigorously stirring. A solution of tris (triphenylphosphine) ruthenium (II) chloride (100 mg) in acetonitrile (10 cm3) is added, followed by the immediate addition of solid sodium metaperiodate (8.1 g). After stirring at 0 ° C for 1 h, solid sodium hydrogen carbonate (5.0 g) was added. After stirring for another minute, the mixture was filtered through diatomaceous earth, filter pad, washed with dichloromethane (200 cm 3). The filtrate is thoroughly mixed, the layers are separated and the aqueous layer is re-extracted with fresh dichloromethane (100 cm 3, then 50 cm 3). The combined extracts are dried
15
in the presence of anhydrous magnesium sulphate and evaporated to give 26- (2-type amine oe-thyl) -c ul phonylpristinamine P (isomer A) as a light brown powder (3.9 g), melting slowly with decomposition from 105 WITH."
Example9. To a solution of 26- (2-diethylaminoethyl) -sulfonylphosphate 0 ° C, after which a solution of sodium metaperiodate (0.317 g) in water (3 cm3) is added dropwise. After 4 minutes, another portion of sodium metaperiodate (0.317 g) in water (3 cm3) was added dropwise, and after 11 minutes ruthenium trichloride trichloride (0.5 mg) was added in one portion. Through
amycin JIj (isomer) (1 g) in di-JQ 6 minutes, stirring is stopped, and chloromethane (40 cm3) is added water (20 cm3). The mixture was stirred rapidly, cooled to 0 ° C, after which a solution of ruthenium trichloride trihydrate (2 mg) in water 15 (1 cm3) was added to it, followed by the addition of a solution of sodium metaperiodate (0.634 g) in water (6 cm3) in the absence of light . After 25 minutes, ruthenium trichloride trihydrate (1 mg) and sodium meta-20 periods (0.168 g) are added and stirring is continued for another
The mixture is decanted and a saturated aqueous solution of sodium thiosulfate is added until all the excess sodium metaperiodate is decomposed. The organic phase is separated and the aqueous phase is extracted with dichloromethane (10 cm3), then again 10 cm3 after saturation of the aqueous phase with acidic sodium carbonate and sodium chloride). The combined organic phases are washed with aqueous sodium hydrogen carbonate (10 cm3, pI 7), dried in the presence of anhydrous magnesium sulphate
2
3
four
10 minutes, the pH of the reaction mixture is adjusted to 7 by adding saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (2 x 10 cm 3). The combined extracts are washed with water (10 cm 3), then extracted into dilute hydrochloric acid (0.01 N) (10 ml), 3 plus water (20 ml). The organic layer, which is slowly separated, is further extracted with dilute hydrochloric acid (0.1 N) (1 cm 3). The combined acid extracts are treated with ethyl acetate (40 cm3) followed by the addition of a saturated aqueous solution of sodium bicarbonate in order to adjust the pH to 7. The organic layer is separated and the aqueous phase is extracted with ethyl acetate (30 cm3). The combined organic extracts of sumat in the presence of anhydrous magnesium sulphate and evaporated under reduced pressure, drying the residue in vacuo, which allows to obtain 26- (2-diethylaminoethyl) -sulfonylstistinamycin II in (isomer A) in the form of pale yellow solid (0.252 g), melts slowly with decomposition from 105 ° C.
Example 10. To a solution of 26- (2-diethylaminoethyl) .- sulfonylprystinamine-H 8 (isomer Aj + Ag) (1 g) in dichloromethane (40 cm3) is added water5
(20 cm3) followed by the addition of a solution of ruthenium trichloride trihydrate (2 mg) in water (1 cm3). The mixture is changed and cooled to a tempera
42916
0 ° C, after which a solution of sodium metaperiodate (0.317 g) in water (3 cm3) is added dropwise. After 4 minutes, another portion of sodium metaperiodate (0.317 g) in water (3 cm3) was added dropwise, and after 11 minutes ruthenium trichloride trichloride (0.5 mg) was added in one portion. Through
6 min. Stirring is stopped, 0
five
five
0
0 5 0
five
The mixture is decanted and a saturated aqueous solution of sodium thiosulfate is added until all the excess sodium metaperiodate is decomposed. The organic phase is separated and the aqueous phase is extracted with dichloromethane (10 cm3), then again 10 cm3 after saturation of the aqueous phase with acidic sodium carbonate and sodium chloride). The combined organic phases are washed with aqueous sodium hydrogen carbonate (10 cm3, pI 7), dried in the presence of anhydrous magnesium sulphate
and filtered. To mixed filter
diatomaceous earth is added
, (0.2 g) followed by the dropwise addition of a solution of citric acid (0.311 g) in acetone (2 cm3). Receive- The mixture is filtered and the filter pad is washed with a small amount of dichloromethane. Water (50 cm3) is added to the filtrate, then dilute hydrochloric acid (0.1 N) is added to obtain an aqueous phase with a pH of 2-3, which is separated. The organic phase is extracted with water (10 cm3) and diluted hydrochloric acid (0.1 N) to obtain an aqueous phase with a pH of 2-3, which is separated. The organic phase is extracted with water (10 cm 3) and diluted hydrochloric acid (0.1 N) (1 cm 3). The combined acid extracts are washed with dichloromethane (Ucm3), treated with carbon black and filtered through diatomaceous earth. The filtrate is treated with dichloromethane (20 cm3) and saturated aqueous sodium hydrogen carbonate to obtain an aqueous phase with pI 7. The organic phase is separated and the aqueous phase is extracted with dichloromethane (2 x 20 cm3). The combined organic extracts are dried in the presence of anhydrous magnesium sulphate, concentrated to dryness and the residue is dried in vacuo to give 26- (2-diethylaminoethyl) sulfonylpristin amycin II (isomer A) as a pale yellow solid (0.24 g) , pla17
1639429
In the face slowly with decomposition from 105 C.
Example 11. A solution of 26- (2-diethylaminoethyl) -suphenylprythinamine P6 (isomer) (882 g) in dichloromethane (15 l) is added to water (44l). The mixture is stirred and cooled to 1-2 ° C, after which ruthenium trichloride trihydrate (0.88 g) in jg water (0.38 l) is added, followed by the addition of a solution of sodium metaperiodate (447 g) in water (4, 4 l), which is added dropwise. Ruthenium trichloride trihydrate (0.88 g) in water 15 (0.88 l) is again added to the mixture with the simultaneous addition of half of the sodium metaperiodate solution.
Similarly, to isolate the final product, but forming 2, 2, 26- (2-diethylaminoethyl) -sulfonylpristinamycin Pe (isomer A) (510 g) melting slowly with decomposition from 105 ° C is obtained.
PRI me 12; K 3.7 g 26 - {(5) -1- / diisopropylamino-2-propth sulfinsh-G | - pristinamycin Lv (A, and A isomers) in a solution containing 100 cm of chloroform, 200 cm3 of distilled water, add 3.9 mg of ruthenium trihydrochloride trihydrate. The mixture is cooled to 0 ° C and after 5 minutes, 1.6 g of sodium metaperiodate is added. After stirring for 10 minutes, 3.9 mg of ruthenium trichloride trihydrate was added, followed by the addition of 0.6 g of sodium metaperiodate. The mixture is stirred for 2 hours at 0 ° C. and then filtered through Celite1 and washed with 5 cm 3 of dichloromethane. The aqueous phase is decanted, and the organic phase is washed first with 50 cm 3 of aqueous sodium bicarbonate solution and a second time with 50 cm 3 of distilled water. The organic phase is dried under reduced pressure (2.7 kPa) at 30CC. 1.8 g of the obtained beige solid phase is purified by phlega chromatography (elution solution: ethyl acetate - methanol of 90:10 volume). Fractions 265 to 36 are concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C and the resulting bright yellow solid is triturated in 20 cm3 of ethyl ether. As a result of the subsequent filtration and drying under reduced pressure, 0.7 g of 26- | (S) -1 diisopropylamino-2-propylD is obtained.
four


50
five
18
Sulfonyl pristinamycin P & (isomer A) in the form of a white solid phase, which melts at 112 ° C.
The biological activity of the isomers of the pristinamycin Pv derivatives is known. The following comparative test data show that the isomers A and B of the pristinamycin Pv derivatives, in particular, the derivative of 2-d-ethylaminoethyl, have similar activity.
Bacteriostatic activity in vitro. To a series of plates containing a known volume (20 cm3) corresponding to the culture medium (Muller – Hinton agar), 1/10 of this volume was added from a series of dilutions growing exponentially (ratio 2) of the test product. Plates were inoculated with a multi-point inoculum, which applied a spot containing 10 units of microorganisms forming a colony, inoculated in soy broth with trypsin for 18 hours at 37 ° C and - diluted with the same medium in a ratio of 1 to 100.
After the inoculum, the ears were incubated for 24 hours at 37 ° C.
The lowest inhibitory concentration is assumed to be the lowest concentration at which the development of microorganisms is inhibited.
Activity against intraperitoneal infections of mice. Mice were injected into the utry-peritoneal 0.5 cm3 of the appropriate agitated 18-hour culture of the tested microorganisms in Brain Heart Infusion Medium (Difco), respectively, diluted with 5% pork mucin. This inoculation causes the death of control animals within 24–48 h. The test compound was administered subcutaneously twice a day of inoculation at an interval of 5 h, the first dose was administered 1 h after inoculation with microorganisms. The total doses used were contained in a volume of 50 cm3 / kg.
The 50% therapeutic dose (CD50) is the dose of the test compound that, with each administration, causes half of the treated animals to survive during the test period (8 days).
The following results were obtained.
and
In vitro activity
SG11 S.aureus smith, mg / mp
One with 27,404 RP
Isomer A 8 0.5
163942920
In vitro activity
CD jo S.aureus smith, mg / kg s:
One with 27,404 RP
1208.5
Isomer B
0.25 Formula of the invention

权利要求:
Claims (7)
[1]
1. The method of obtaining derivatives of pristinamycin L in the general formula (1)
  he
/ with
n3s. Г ™ pr, k, o
H VoV YV
k & h
(0)
R is alkylaminoalkyl selected from the group containing 2-diethylaminoethyl, 2-diisopropyl-aminoethyl, 2 dibutylaminoethyl, 25 2-dipropylaminoethyl, N-ethyl-E-isopropyl-2-aminoethyl, i 2- (1 pyrrolidinyl) -ethyl 2- -morpholinoethyl 2-dimethylaminoethyl, M-butyl-N-methyl-2-amino-30-ethyl, 2-piperidinoethyl, (S) -1-diisopropylamino-2-pro nl,
their isomers and mixtures of isomers or acid additive salts, of which it is 35% that the compound of Formula (II)
ABOUT
.HE
40
ABOUT
where or 1,
R has the indicated meanings, is oxidized with a salt of a periodic acid, and
60
20
a catalytic amount of an octavalent ruthenium compound formed during the oxidation of a lower degree of valence ruthenium compound, with a molar ratio of a periodic salt salt: a compound of eight-valent ruthenium 100-1000: 1 in a solvent.
[2]
2. The method according to claim 1, differing from that with the use of ruthenium (VIII) obtained in situ by the oxidation of ruthenium trichloride trihydrate.
[3]
3. The method according to claim 1, characterized by the fact that the compound of the general formula (II), where, is oxidized with a salt of a periodic acid and a catalytic amount of ruthenium trichloride trihydrate in acetonitrile.
[4]
4. A method according to claim 1, characterized in that the compound of the general formula (II), wherein, is oxidized with periodic acid and a catalytic amount of ruthenium trichloride trihydrate in dichloromethane and water.
[5]
5. Method pop. 1 and 2, characterized in that the oxidation is carried out in an aqueous medium in the presence of an organic solvent at a temperature of from 0 ° C to ambient temperature.
[6]
 6. The method according to paragraphs. 1 and 2, about tl, which is due to the fact that the oxidation of a compound of the general formula (II), where the molar annealing of the periodate to the starting product is from 1.6: 1 to 5: 1.
[7]
7. The method according to PP and 2, about that by that, during oxidation, the compound of the general formula (II), where the molar ratio of periodate to the initial product is from 5: 1 to 7: 1.
Example connection
R-substitute
1.2-Diisopropylaminoethyl
2.2-Diethylaminoethyl (isomer A)
R-Deputy
3.2-Liethylaminoethyl (isomer B)
3.2-N-Ethyl-M-isopropyl-aminoethyl
Table 1
NMR spectrum
I
1.06 (d, isopropyl-CH 1.75 (with SNE at 33) 2.79 (mt, -N
2.92 and 3.10 (2 dd C at 15
2.7 at 3.30 (mt, -D-
rN (COt)
3.52 (wide d-Ng6)
3.82 (s, CH2 at 17)
5.27 (narrow d -H27) 5.47 (d, -H13) 6.17 (d, -Htl)
6.42 (d, W at 8) 8,12 (s -H)
0.97 (d -CH3 at 30.3
ethyl-CH3)
1.75 (s, -S1C at 33)
CH2-2,62 (q, -A)
CISG00 to 3.4, (MT,
-S02.CH rO1g-NO
3.82 (s, CHe at 17)
5.34 (d, -H, 3)
5.43 (d, -N0) 6.16 (d-, Hn)
6.54 (dd, W at 8) 8.10 (s, -Hgo)
1.07 (t - (С113СН,) 2.) 1.56 (s, -CH3 at 33) 2.4-2.8 (mt, -802. СНгСНгК (СП2СН,) g.) 3.14 (mt , -SOACH4-) 4.07 (wr, -H2e) 4.87 (d,)
5.28 (d, -Hg) 5.68 (d - N)
7.71 (t, broad - Hg) 7.89 (s, -H)
0.9-1.1 (dt, -CH3 at -C% at (CH3), SNgCH3)
1.73 (s, -СНз at 33) 2.54 (q, NCHjCH ,,) 2.98 (t, -80-СНгСНгЫС) 3.23 (t, -80 g СН2 СНгКСГ)
R-Deputy
3.2- (1-Pyrrolidinyl) ethyl
3.2-morpholinoethyl
R-Deputy
4. Dimethylaminoethyl
4. 2-N-Butyl-No.-methylamino-ethyl
Table continuation
5.32 (d, -Y1) 5.44 (d, -H19) 6.16 (d, -H ,,,)
6.58 (t wide -Hg)
8.03 (s, -n,)
1.73 (s, -CH, at 33
7.82 (mt wide,
2.60 (mt wide, t.
CIS-CH2
CH3 CH2
With t
z.bo (t, -8ogs ± sngns) CH2-CH2
3.33 (t, -80 CH2SNgMG)
5.38 (d, -Igg)
5.45 (d, -H, e)
6.16 (d, -Ni)
6.58 (t wide, -Hg)
8.08 (s, -bad)
1.77 (s, -CH3 at 33)
 v / °)
2.57 (m,
Assembly, 97 (t, -SCy CIkNc :) 3.37 (t, -802СНгСНгМС)
-U
CH x
ABOUT)
-H27)
-N, 9 -Hjf)
IROKY -ND)
-Ngo) mt „
NgSNg-Yu-Ng7)
-N13) -N, ()
wide, -%)
)
, H (Sig) zSN3)
(SNg) gOThSN3)
NCH2CHZCHZCH3) -CH3 at 33) W1)
SNG (SNG) HSSC) -SO CILjC NC)
-SQ CHzCH O
Table continuation
R-Deputy
4. 2-Piperidinoethyl
4. 2-Di-n-butylaminoethyl
R-Deputy
5. 2-Di-n-propylamino-ethyl
12. 1-Diisopropylamino-2-propyl
: g
-H)
Qh-i.
-)
-G2
n s
-2 CHF 1
(s, -СН Зпри 33) (mt, / С-
-N CHF
B0)
H2
2.94 (t, -S02CH2CH2NO
3.34 (t, -502СНгСН2ЛС)
5.35 (d, -P17) 5.44 (d,) 6.17 (d, -H ,,)
6.60 (t wide, Hg)
8.10 (s, -go)
0.96 (t, -N (CHz) CH,) J
1.2-1.6 (mt, -NfCHtCJiC
1.76 (s, -SP at 33)
2.48 (t, -NfCH2. (CH2) CH,
3.08 (mt, -SO CH2CTleNO
3.14 (mt, -50gSNg SNGNS)
5.31 (dh, -11r7)
6.16 (d,)
6.47 (dd wide, -H8)
8.10 (s, -H)
1.50 (sixth, NCHaCHЈ 1.75 (s, -CH3t ri 33)
2.46 (t,: NCJ1ZCHZCII3)
3.07 (mt, -S02.CHZCHZNC) 3.27 (t, -SOj.CHzCHjjNO 3.57 (mt, -N,)
5.31 (d, -yyyy)
5.47 (d, -N „) 6.16 (d, -N„)
6.47 (t wide, -Nd) 8.12 (s, -H)
1.04; 1.05 (2d, -CH isopropyl) 1.47 (l, -80g-9P-) SCh C
1.75 (s, -CH3 at 33) 2.13; 2.55 (2.
2.8 (mt, -N at 4)
2.63; 3.16 (2 dd, M-CH
27163942928
Table continuation
2.95; 3.10 (2 dd, 15) 3 (mt, BOCx2) 3.32 (mt
- Deputy 3.75 (mt, -M at 26)
3.82 (s, C% at 17) 5.3 (s, -H at 27) 5.46 (d, -H at 13) 6.16 (d, -H at 11) 6.41 GvONH at 8) 6.6 (dd, N at 5) 8.12 (s, H at 20)
Note: doublet, doubled doublet,
c - singlet, mt-multiplet.

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FR2576022B1|1985-01-11|1987-09-11|Rhone Poulenc Sante|NOVEL DERIVATIVES OF PRISTINAMYCIN II B, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|DE3778359D1|1987-07-07|1992-05-21|Rhone Poulenc Sante|METHOD FOR PRODUCING DERIVATIVES OF PRISTINAMYCIN IIB.|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB868616768A|GB8616768D0|1986-07-09|1986-07-09|Process|

---