SI7611405A8 - Process for obtaining rifamycin compounds - Google Patents

Description

The present invention relates to a process for the preparation of novel rifamycin compounds having strong antibiotic activity. Takva compounds izabraju su; with _b "hopes koju ranks of the compounds of the following formula:

wherein X is alkyl having less than 3 C atoms; Y is -H or -COCH ,; Z is selected from the group consisting of alkyl of less than 5 C atoms, alkoxyalkyl of less than 6 C atoms, hydroxyalkyl of less than 4 C atoms, carboxyalkyl of less than SC atoms, carboxyalkyl of less than 6 C atoms, halogen-alkyl of less of 4 C atoms, n, N-dialkylaminoalkyl, arylalkyl of less than 10 C atoms, cycloalkyl, and X and Z together with the C atom to which they are attached form a ring selected from the group containing a ring of less than 7 C atoms. ring with less than 7 C atoms substituted with at least one radical selected from the group consisting of alkyl with less than 4 C atoms, halogen and carboxy, heterocyclic ring with less than 7 elements containing N atom heterocyclic ring with less than 7 elements containing N atom and which is substituted by a radical selected from the group consisting of alkyl of less than 4 C atoms, arylalkyl of less than 9 C atoms, carboxy and acyl of less than 5 C atoms, and their 16, 17, 18, 19 -tetrahydro derivatives and 16, 17, 18, 19, 28, 29bexahydro derivatives te.

The rifamycin compounds of the present invention have a strong anti-bacterial activity, especially Mycobacterium tuberculosis: such compounds are in powder form pink to violet in color, soluble in many organic solvents and many insoluble in water

Such rifamycin compounds are prepared by a process in which the rifamycin compound is of the formula

where Υ-Η iii is -COCH ,; its 16, 17, 18, 19 tetrahydro derivatives and 16, 17, 18, 19, 28, 29 hexahydro derivatives, reacts with the ketone of the formula

CO - z ». '(HI)

X_ where X and Z are as defined above, both X and Z together with CO form a ring selected from the group consisting of a ring of less than 7 C atoms, a ring of less than 7 C atoms which is substituted by at least one radical selected from a group containing alkyl of less than 4 C atoms, halogen and carboxy, a heterocyclic ring of less than 7 elements containing one N atom and which is substituted by a radical selected from the group containing alkyl of less than 4 C atoms, arylalkyl with less of 9 C atoms, carboxy and acyl with less than SC atoms.

The compound of formula (II) and the processes for preparing the same are described in the already submitted Report of the Applicant.

It has been found that the reaction of a ketone of formula (III) with a compound of formula (II) is also easier to perform in improved yields when such a reaction is carried out in the presence of acetic acid and some reducing agent selected from the group that retains zinc and iron.

In order to make the present invention clearer, some non-limiting examples will be presented.

Example 1 g of 3-amino-4-deoxy-4-imino-rifamycin S was dissolved in 20 ml of cyclohexanone. To the solution was added 1 g of zinc, 20 ml of acetic acid and stirred for 60 minutes at room temperature. The unreacted zinc is filtered and 100 ml of dichloromethane is added to the reaction solution, washed with water, dried over sodium sulfate and evaporated to dryness. The residue was redissolved in 30 ml of dichloromethane, 200 ml of light petroleum was added to the solution, the resulting precipitate was filtered off, then concentrated to SO ml.

Crystallizes 4.8 g. products of formula (I), wherein YCOCH1 is X and Z, together with the C atom to which they are attached, form a cyclohexylidene radical. The physicochemical characteristics of the product are as follows:

- the electron absorption spectrum in methanol shows peaks at 495, 315 and 275 nm;

- IR spectrum in non-nucleus shows absorption bands in the region around 3250 and then at 1725, 1665, 1600, 1560, 1515, 1295, 1250, 1175-1155, 1060, 970, 920, 890, 765 and 725 cm ¹ ;

- nuclear magnetic resonance spectrum in deuterated-chloroform using tetramethylsilane as an internal standard shows the most significant peaks at: δ 0.60 (d); 0.83 (d); 1.05 (d); 3.10 (s); 4.81 (dd); 5.15 (dd); 8.23 (s); 9.20 (s) and 14.75 (s) p.p.m.

The last three peaks in the presence of deuterated water are also characteristic.

Example 2 g of 3-amino-4-deoxy-4-imino-rifamycin S

39768 is formed in 23 ml of methyl isobutyl ketone. To the solution was added 1 g of zinc, 30 ml of acetic acid and heated at 40 ° C for 30 minutes. The zinc screw was filtered, 100 ml of dichloromethane was added to the reaction solution and washed with water. After drying over sodium sulfate and concentrating on 20 ml, 100 ml of cyclohexane and 30 ml of light petroleum are added. The solution was filtered and the filtered solution was evaporated to dryness.

Yield: 4.4 g of the product of formula (I), where

Y-COCHj, X is methyl and Z is isobutyl, having the following physicochemical characteristics:

- the electron absorption spectrum in methanol shows peaks at 500, 310 and 270 nm;

- И.Р. spectrum in non-joules shows the most significant peaks at: 3400 (ex), 3250, 1725, 1620, 1600, 1560, 1510, 1415, 1290, 1250, 1155, 1060, 970, 945, 915, 890, 810 and 720 cm- ' .

Example 3 g of 3-amino-4-deoxy-4-imino-rifamycin S was mixed with 2.5 g of iron and dissolved in 15 ml of acetone and 15 ml of acetic acid. After stirring at 35 ° C for 15 minutes, excess iron was filtered and the solution was poured into 600 ml of water. The solution was filtered, washed with water, and the aqueous phase was extracted with toluene after adjusting the pH to 7 with disodium phosphate. The toluene was concentrated to 20 ml and then diluted with 80 ml of cyclohexane. After filtration, the mixture of the two solvents was evaporated to give 3.5 g of the product of the formula (D. where Υ-COCHj, Z and X are methyl, having the following physicochemical characteristics:

- the electron absorption spectrum in methanol shows peaks at 490, 350 (sh), 315 and 270 nm;

- И.Р. the spectrum in nonjugal shows the most significant peaks at: 3400 (pr), 3250, 1730, 1675, 1650 (pr), 1605, 1565, 1515, 1420, 1300, 1250, 1170, 1085, 1065, 975, 950, 930, 895. 815 and 690 cm- '.

Example 4 g of 3-amino-4-deoxy-4-imino-rifamycin S was dissolved in 25 ml of dioxane, 6 g of 1-methyl-4piperidone dissolved in S ml of dioxane was added and heated at 70 ° C for 10 minutes. The solution is poured into 400 ml of water containing 20 g of sodium chloride, the precipitate is filtered off, the filtrate is extracted with chloroform, the organic phase is dried over sodium sulfate and the solvent is evaporated. The resulting residue was dissolved in benzene and the solution was extracted with an aqueous solution of disodium phosphate. The benzene was washed with water, the solution was dried over sodium sulfate and then evaporated to dryness. Yield: 2.2 g of the product of formula (I), wherein YCOCH 1, and X and Z, together with the C atom to which they are attached, are formed by the 4- (1-methyl) piperidinylidene radical: The physicochemical characteristics of the product are as follows:

- Electron absorption spectrum in methanol shows peaks at 48S, 350 (pr), 310 and 270 nm;

- И.Р. spectrum in non-joules shows the most significant peaks at: 3400 (pr), 3250, 1730, 1670, 1650 (pr), 1605, 1565, 1515, 1420, 1300, 1255, 1180, 1160, 1065, 1015, 975, 95O (pt) , 920, 895, 815, 770 and 695 cm ';

- nuclear magnetic resonance spectrum in deuterated-chloroform using tetramethylsilane as the internal standard shows the most significant peaks at: J -0.16 (d); 0.60 (d); 0.86 (d); 1.04 (d); 1.77 (s); 2.02 (s); 2.06 (s); 2.32 (s); 2.49 (s); 3.10 (s); 4.82 (d); 5.14 (dd); 5.70-6.60 (m); 7.0-7.4 (m); 8.27 (s); 8.97 (s) and 14.67 (s) p.p.m.

The last three peaks in the presence of deuterated water are also characteristic. ftimer 5 g of 3-amino-4-deoxy-4-imino-rifamycin S is reacted with 1 g of zinc, 15 ml of tetrahydrofuran, 8.5 ml of 1-carboxy-4-piperidone and 25 ml of acetic acid at 50 ° C for 10 minutes . The reaction mixture was filtered and diluted with 200 ml of xylene, washed with phosphate buffer solution at pH 7.5, then with water and finally dried over sodium sulfate. The xylene is then evaporated to give 100 ml of solution, which is diluted with 150 ml of light petroleum. The resulting residue was re-treated by the addition of light petroleum, the filter and dried. Yield: 5 g of product of formula (1). where Y-COCH1 is X and Z, together with the C atom to which they are attached, form a 4- (1-caribethoxy) piperidinylidene radical.

The electron absorption spectrum in methanol shows peaks at 500, 360 (pr), 312 and 275 nm.

Example 6 g of 3-amino-4-dexo-4-imino-rifamycin S is reacted with 1 g of zinc, 10 ml of tetrahydrofuran, 12 ml of chloroacetone and 25 ml of acetic acid. After 5 minutes at 60 ° C, the reaction was terminated and after filtration of unreacted zinc, the solution was poured into 800 ml of buffered solution at pH 7.5 and containing 5 g of ascorbic acid. The resulting precipitate was filtered off, washed with water and dried in vacuo at 40 ° C. Finally, the residue is continuously extracted with light petroleum and evaporation of the solvent yields 3.6 g of the product of formula (I), wherein Y is CO-CH 2, X is methyl and Z is chloromethyl.

The electron absorption spectrum in methanol shows peaks at 495, 270, 238, and 210 nm.

Example 7 g of 3-amino-4-deoxy-4-imino-refamycin S is reacted with 1 g of zinc, 15 ml of tetrahydrofuran, 8 ml of 1-benzyl-4-piperidone and 30 ml of acetic acid. After stirring at 60 ° C for 15 min, the unreacted zinc was filtered, then 1 g of axorbic acid was added, diluted with 300 ml of xylene and washed with phosphorus buffer solution at pH 7.5 and then with water. After drying the solution over sodium sulfate, the solvent is evaporated to a dry residue, which is then continuously extracted with petroleum ether.

After evaporation of the solvent, 2.5 g of the product of formula (I) is formed, where Y-COCH, and X and Z together with the C atom to which they are attached form a 4- (1-benzyl) -piperidinylidene radical.

The electron absorption spectrum in methanol shows peaks at 500, 315, and 275 nm.

Example 8 g of 3-amino-4-deoxy-4-imino-16, 17, 18, 19 tetrahydrorifamkin S is reacted with 1 g of zinc, 15 ml of tetrahydrofuran, 6 ml of dctylaminoacetone and 30 ml of acetic acid. After stirring at room temp3

39768 boils for 15 minutes, the excess zinc is filtered off, 1 g of ascorbic acid is added and a solution is poured dropwise into 700 ml of water.

The resulting precipitate was filtered and dissolved again in a minimal volume of methyl alcohol. The methanolic solution was diluted with 250 ml of ethyl ether and then extracted with phosphate buffer solution at pH 7.5. The aqueous layer was acidified to pH 3 and then extracted with chloroform. The chloroform layer was washed with water, dried over sodium sulfate and evaporated to dryness. 0.8 g of 16, 17, 18, 19-tetrahydro derivatives of the product of formula (I) are thus obtained, where Υ-COCH 1, X is methyl and Z is diethylaminomethyl.

The electron absorption spectrum in methanol shows peaks at 455 and 320 nm.

Example 9 g of 3-amino-4-deoxy-4-imino-16, 17, 18, 19, 28, 29-hexahydro-25-desacetyl-rifamycin S is reacted with 1 g of zinc, 15 ml of tetrahydrofuran, 4.5 g of 1-acetyl -4- piperidone and 25 ml of acetic acid. After stirring at room temperature for 30 minutes, the unreacted zinc was filtered off, 1 g of ascorbic acid was added and diluted with 300 ml of ethyl ether. The ether solution was washed thoroughly with water and then dried over sodium sulfate. The residue was then diluted with 50 ml of light petroleum, filtered and evaporated to dryness. 1.7 g of 16, 17, 18, 19, 28, 29-hexahydro derivatives of the products of formula (I), obtain the way where Υ-Η and X and Z, together with the C atom to which they are attached, form 4- (1-acetyl) ) -piperidinylidene radical.

The electron absorption spectrum in methanol shows peaks at 495, 315, and 275 nm. and ¥ 10 g of 3-amino-4-deoxy-4-imino-rifamycin S react with 1 g of zinc, 15 ml of tetrahydrofuran, 2.5 g of methylcyclopropylketone and 25 ml of acetic acid. After 30 minutes at 50 ° C, the unreacted zinc was filtered, the solution was diluted with 100 ml of benzene and 300 ml of ethyl ether and then washed with phosphate buffer solution at pH 7.5 and finally with water. The organic layer was evaporated, the residue was reacted again with 30 ml. methyl alcohol and after addition of S ml of water containing 1 g of sodium mascorbate, the solution was poured dropwise into 300 ml of saturated aqueous sodium methylbisulphite solution. The resulting precipitate was filtered off, washed with water and dried. 2.2 g of the product of formula (I) are obtained. where Y is COCH1, X is methyl and Z is cyclopropyl.

The electron absorption spectrum in methanol shows peaks at 500 and 320 nm.

Example 11 g of 3-amino-4-deoxy-4-imino-rifamycin S was dissolved in 25 ml of tetrahydrofuran and a mixture containing 35 ml of acetic acid, 1 g of zinc and 5 g of 4-phenylbutan-2-one heated was added dropwise. at 60 ° C. After stirring at 60 ° C for 30 minutes, the unreacted zinc was filtered, the mixture was treated with the addition of 1 g of ascorbic acid and diluted with 250 ml of benzene. The mixture was then completely washed with water, dried over sodium sulfate and the benzene evaporated.

The resulting residue was dissolved in a minimal volume of methyl alcohol, treated with 5 ml of water containing 1 g of sodium mascorbate and then poured into 1000 ml of water. The resulting precipitate was filtered off, washed with water and dried. The product was redissolved in 4 ml of benzene, 80 ml of light petroleum was added, filtered and the solution was evaporated. The resulting violet residue was added water and filtrate. After drying, 2.8 g of the product of formula (1) are obtained, where YCOCH 1, X is methyl and Z is -phenethyl. The electron absorption spectrum in methanol shows peaks at 500 and 315 nm.

For the preparation of the compounds of formula I, the following methods of the invention are most advantageous.

g of 3-amino-4-deoxy-4-imino-rifamycin S was dissolved in 20 ml of cyclohexanone. To the solution was added 1 g of zinc, 20 ml of acetic acid and stirred for 60 minutes at room temperature. The unreacted zinc is filtered and 100 ml of dichloromethane is added to the reaction solution, washed with water, dried over sodium sulfate and evaporated to dryness. The residue was redissolved in 30 ml of dichloromethane, 200 ml of light petroleum was added to the solution, the resulting precipitate was filtered off and the residue was concentrated to 50 ml. Crystallizes 4.8 g of the product of formula (1) wherein Y is COCH _} and X and Z together with the C atom to which they are attached form a cyclohexylidene radical. The physicochemical characteristics of the product are as follows:

- the electron absorption spectrum in methanol shows peaks at 495, 315 and 275 nm;

- IR, spectrum in non-nucleus shows absorption bands in the region of about 3250 and then at 1725, 1665, 1600, 1560, 1515, 1295, 1250, 1175 - 1155, 1060, 970, 920, 890, 765 and 725 cm ^-1 ;

- nuclear magnetic resonance spectrum in deuterated chloroform using tetramethylselane as an internal standard shows the most significant peaks at O: 0.60 (d); 0.83 (d); 1.05 (d); 3.10 (s); 4.81 (dd), 5.15 (dd); 8.23 (s); 9.20 (s) and 14.75 (s) p.p.m.

The last three peaks in the presence of deuterated water are also characteristic.

g of 3-amino-4-deoxy-4-imino-rifamycin S was dissolved in 25 ml of methylisobutyl ketone. To the solution was added 1 g of zinc, 30 ml of acetic acid and heated to 40 ° C for 30 minutes. The excess zinc was filtered off, 100 ml of dichloromethane was added to the reaction solution and washed with water. After drying over sodium sulfate and concentrating on 20 ml, 100 ml of cyclohexane and 50 ml of light petroleum are added. The solution was filtered and the filtered solution was evaporated to dryness.

Yield: 4.4 g of a product of formula (I) wherein Y is COCH1, X is methyl and Z isobutyl, having the following physicochemical characteristics:

- the electron absorption spectrum in methanol shows peaks at 500, 310, and 275 nm;

- IR spectrum in non-joules shows the most significant peaks at 3400 (pr), 3250, 1725, 1620, 1600, 1560, 1510, 1415, 1290, 1250, 1155, 1060, 970, 945, 915, 890, 810, 720, cm ¹ .

g of 3-amino-4-deoxy-4-imino-rifamycin S was dissolved in 25 ml of dioxane, 6 g of 1-methyl 4-piperidone dissolved in 5 ml of dioxane was added and heated to 70 ° C for 10 minutes. The solution is poured into

400 ml of water containing 20 g of sodium chloride,

39768 The precipitate was filtered, the filtrate was extracted with chloroform, the organic phase was dried over sodium sulfate and the solvent was evaporated. The resulting residue was dissolved in benzene and the solution was extracted with aqueous disodium phosphate. The benzene was washed with water and the solution was dried over sodium sulfate and then evaporated to dryness. Yield is 2.2 g of the product of formula (I), where Y is COCH, and X and Z, together with the C atom to which they are attached, form a 4- (1-methyl) piperidinylidene radical. The physicochemical characteristics of the product are as follows:

the electron absorption spectrum in methanol shows peaks at 485, 35O (pr), 310 and 270 nm;

- IR spectrum in non-joules shows the most significant peaks at 3400 (pr), 3250, 1730, 1670, 1650 (pr), 1605, 1565, 1515, 1420, 1300, 1255, 1180, 1160, 1065, 1015, 975, 950 (pr ), 920, 895, 815, 770, 695 cm ¹ ;

- nuclear magnitude resonance spectrum in deuterated chloroform using tetramctylsilane as an internal standard shows the most significant peaks at O; -0.16 (d); 0.60 (d); 0.86 (d); 1.04 (d); 1.77 (s); 2.02 (s); 2.06 (s); 2.32 (s); 2.49 (s): 3.10 (s); 4.82 (d); 5.14 (49; 5.70-5.60 (m); 7.0-7.4 (m); 8.27 (s); 8.97 (s) and 14.67 (s) p.p.m.

The last three peaks in the presence of deuterated water are also characteristic.

COCH1 group, Z is C,. _4- alkyl, C _1-3 halogenoalkyl wherein halogen is primarily chlorine, N, N-di-C,. _4- alkylaminoC,. ₄ alkyl, phenylalkyl with 8 carbon atoms, cyclo-C,. ₄ alkyl, and X and Z attached to the C atom to which they are attached form a cyclohexyl or pyridine ring, which may be substituted by a C, alkyl, benzyl, carboxy or acetyl group, wherein the 3-amino-4-deoxy- 4-Imino-rifamycin S of Formula II

Claims (1)

PATENT APPLICATION A process for the preparation of rifamycin compounds of the formula wherein Y has the foregoing meanings, is reacted with a ketone of the formula lil wherein X and Z have the foregoing meanings, and X and Z together with CO form a cyclohexyl or pyridyl ring which may be substituted by C ,., alkyl, benzyl, caffeboxy or acetyl groups, at a temperature of 25 ° to 70 ° C in the presence of acetic acid and a metal selected from the group consisting of zinc and iron, and after 5 to 60 minutes the precipitate is filtered off and the solution is removed. isolates the desired compound of formula 1.