FI83875C - ETT NYTT FOERFARANDE FOER FRAMSTAELLNING AV 4-DEOXIPYRIDO / 1'2 ': 1,2 / IMIDAZO / 5,4-C / RIFAMYCINER. - Google Patents

Description

1 83875

New process for the preparation of 4-deoxypyrido [1 ', 2': 1,2] imidazo [5,4-c] rifamycins

The invention relates to a new process for the preparation of 4-deoxypyrido [1 ', 2': 1,2] imidazo [5,4-c] rifamycin-SV of formula (I), CH CH CH 2 R 0 / JO. -L 3 10 i

OCH I OH OH

\> ^ ch3 \ / y CO CH, OH OH I 3 (I) 15 C H 3 • 4XKJ '20 o \ 4 = / CH | R 1 wherein R is hydrogen or acetyl, R 3 and R 2 independently represent hydrogen, (C 1-4) alkyl, or halogen, or R 1 and R 2 together with two adjacent carbon atoms of the pyridine ring form a benzene ring.

Part of formula I is known in the patent literature

30 compounds, in particular those in which R is hydrogen or acetyl and R 3 and R 2 are independently hydrogen, (C 1-1) alkyl, benzyloxy, mono- or di- (C 1-3) alkylamino- (C 1-4) -alkyl, (C 1-3) -alkoxy- (C 1-4) -alkyl, hydroxymethyl, hydroxy (C 2-4) -alkyl, nitro or R 3 and R 2 together with two adjacent carbon atoms 2 83875 of the pyridine ring form a benzene ring, optionally substituted with one or two methyl or ethyl groups; see, e.g., U.S. Patent 4,341,785, issued July 27, 1982.

IT Patent 1,164,453 describes other compounds of formula (I), in particular those in which R is hydrogen or acetyl and at least one of R 1 and R 2 is hydrogen, cyano, mercapto, (C 1-4 alkylthio, phenylthio, carbamoyl, mono- or di- (C 1-4) alkylcarbamoyl-10.

These two references also disclose a process for the preparation of compounds of formula (I).

Briefly, the known method was performed by administering one molar equivalent of the compound 3-halo-15 gene-rifamycin S of formula IV

CH C H C H

I 3 I 3 I 3 20 ° ^ Η3 0H 0H s.

I X

^ n n c-S ^ CK.

CH, ™, ° I 3 (IV)

25 T TT

ti halo ° -f-S 0 30 wherein R is hydrogen or acetyl and halogen is preferably bromine or iodine, react with about 2-8 molar equivalents of the appropriate 2-aminopyridine of formula III (discussed later).

3,83875

A compound of formula V CH CH CH was obtained

5

OCH3 OH OH

Xf ^ CH3 || ^ R <o ^ CH,, oh o ru 3 10 CH Y u 1, ώόζ 4AMJr 'ch3 r s 20 which was preferably isolated and characterized and then treated with ascorbic acid to give the final products of formula (I).

Despite the yields of the two mentioned steps, calculated from starting material IV, which are often quite good (between 45-75%), the process according to said US patent is severely limited by the fact that starting material IV is not a commercial product but must be once prepared from rifamycin S by appropriate, often complex halogenation. This results in the processes of both U.S. Patent No. 4,341,785 and iT Patent Publication No. 1,164,453 yielding significantly worse yields than those mentioned above, and thus the desired products are obtained in unsatisfactory yields from an industrial point of view.

35 4 83875

In the context of the invention, the term (C 1-4) -alkyl means straight or branched alkyl groups, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl and tert-butyl, while the term 5 (C 1-3) -alkoxy means mainly methoxy, ethoxy, propoxy or isopropoxy groups.

The compounds of formula (I) have significant antibacterial properties both in and out of the body. Because of their poor ab-10 sorption in animal organs and tissues when administered orally, they have been shown to be particularly useful in combating microbial infections in the gastrointestinal tract.

Compounds of formula (I) are prepared according to kek-15 according to the invention by administering one molar equivalent of Valentine's rifamycin B of formula (II) FH 3 C, "3 fH 3 20 C% CO 2 O 2 Y> Y O OH |

Xs "·. · 1 ^ OH OH CO CH3 (II)

° -1 - k 0 - CH-C00H

I N0 2 30 CH 3 to react with 1-9 molar equivalents of 2-aminopyridine of formula (III) 35 5 83875

5 W

»1 R 2 and about 1 to 4 molar equivalents of an oxidant selected from iodine, potassium ferricyanide, aqueous sodium hypochlorite and manganese dioxide in the presence of a solvent or solvent system and at a temperature between room temperature and the boiling point of the reaction mixture for 10 hours at a reaction time of The final reaction mixture is treated with a suitable reducing agent such as ascorbic acid.

The method according to the invention represents a significant improvement over the previous method. Rifamycin B, a commercial product, is used as the starting material for famycin (readily available by fermentation of Streptomyces mediterranes as described in Antibiotics Annual, 1959-1960, pp. 262-270, 1960e, DE Patent 1,113,288). and fermenting Streptomyces mediterrane ATCC 21,789 as described in BE-pa-25 Exam Publication 799,122).

Also according to FI patent publication 69 467, a pyridorifamycin of the formula (I) is prepared using a 2-aminopyridine derivative of the formula (III) and a 3-halofriphamycin derivative as a starting material.

The latter can be prepared from commercially available rifamycin S. (FI patent publication 65 254).

The process according to the present invention has the advantage over the process known from said FI patent publication 69 467 in that it uses as a starting material a primary fermentation product, rifamycin B, 6 83875, whereby the desired end product is obtained in a yield of about 80% in a very simple and inexpensive manner. .

According to the present invention, rifamycin B is reacted under mild conditions with a selected 2-amino-5 pyridine of formula III in the presence of a suitable oxidizing agent, in a suitable solvent or solvent system, from which the desired products are obtained by methods known to those skilled in the art. : and R 2 are as defined above and R is acetyl, with yields ranging from about 60% to 90% based on the rifamycin B used as starting material. The compound of formula (I) thus obtained can then be subjected to alkaline hydrolysis to give the corresponding compounds of formula (I) in which R is hydrogen.

The reaction between the compounds of formulas (II) and (III) in the presence of a suitable oxidizing agent takes place in only one step and is shown in the following scheme, which does not show the optional hydrolytic step R * C00H3 -> R = H.

7 83875

REACTION SCHEME I C H CH „CH

I 3 I 3 I 3

CH ^ COO

0CH3 I

0H 0H> 3 |) ^ OH OH? ° 'CH3 CH 3 1 A Je ill + _jl_ R oxidant ^ 0—1__ ° -CH2-C00H 2 ° R1 CH 1

3 III

11

CH CH CH

I 3 I 3 I 3 CH ^ COO 1 ^^ I.

OCH IN

J "3 \ OH OH / '' CH, I I CO 3 '" ytAJ · ”" 1 L / ~ v.

In practice, one molar equivalent of rifamycin B of formula (II) is reacted with 1 to 9 molar equivalents of a 2-aminopyridine of formula (III), preferably 2 to 4 molar equivalents of said aminopyridine, and about 1 molar equivalent. With 4 molar equivalents of a suitable oxidant.

The oxidant can be used either as a solution in a reaction medium or as a suspension or dissolved in a solvent which is immiscible with the reaction solvent. When a 10 molar excess of oxidizing agent is used compared to rifamycin B, the final product must be treated with a suitable reducing agent, usually an aqueous solution of ascorbic acid, to obtain the final product of formula (I).

The reaction is carried out in the presence of a solvent or solvent system, usually selected from those commonly used in rifamycin chemistry. For example, aromatic hydrocarbons such as benzene and toluene, lower halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane and analogs, lower alkanols such as methanol, ethanol, propanol, isopropanol or n-butanol can be used successfully. Lower alkyl esters of lower aliphatic acids, acetonitrile, dioxane and tetrahydrofuran may also be well used. These solvents can be used alone or as a mixture or also as a mixture with water in various volume ratios. The best solvents are benzene, toluene, lower halogenated hydrocarbons, lower alkanols alone or in admixture with water, acetonitrile, dioxane and tetrahydrofuran.

The reaction takes place at room temperature and over a wide range of temperatures, for example between room temperature and the boiling point of the reaction mixture. Usually, a temperature between room temperature and about 60 ° C gives satisfactory results.

9,83875

The reaction time depends on the nature of the aminopyridine substrate of formula (IIi) and the reaction conditions. It usually takes 10-100 hours to obtain the final products of formula (I) in the desired yields-5a.

The compounds of formula (I) thus obtained, in which R is an acetyl group, are recovered from the reaction medium by conventional methods. Thus, for example, an unreacted excess of aminopyridine of formula (III) is eliminated from the organic phase by means of an aqueous mineral acid solution. The organic phase is then separated and optionally dried over a suitable drying agent such as sodium sulphate and the final product obtained by evaporation of the solvent. Alternatively, the desired products 15 are obtained by crystallization from the reaction mixture at a temperature of about 0 ° -10 ° C when a solvent system containing water is used.

The compounds of formula (I) may be purified, if desired, by crystallization from suitable solvents or solvent systems.

The products of formula (I) in which R is acetyl can then be converted to the corresponding compounds in which R is hydrogen by mild alkaline hydrolysis. Alternatively, the same starting rifamycin B 25 can be converted to the corresponding deacetyl derivative, whereby the process of the invention can be used according to reaction formula I.

The invention is illustrated by the following examples, which, however, are not intended to limit the scope of the invention.

IR spectra were measured at KBr on a Perkin-Elmer 281-B spectrophotometer.

1 H-NMR and 13 C-NMR spectra were measured on a deuterochloroform 83875 in a Varian XL 100 spectrophotometer using tetramethylsilane as an internal standard. UV spectra were measured in absolute methanol on a Perkin-Elmer 552 spectrophotometer.

5 Example 1

4-Deoxy-4'-methyl-pyrido [1,2 ': 1,2,7-imidazo [5,4-c] rifamycin SV

7.5 g (0.01 mol) of rifamycin B, 4.3 g (0.04 mol) of 2-amino-4-methylpyridine and 2.5 g (0.01 mol) of iodine in 60 ml were dissolved. methylene chloride and the solution thus obtained were kept at room temperature for 15 hours. The reaction mixture was washed first with 40 ml of 2N aqueous hydrochloric acid and then with water and the organic phase was dried over sodium sulphate, the methylene chloride being removed by evaporation in vacuo.

A residue was obtained which was crystallized from ethanol / water 7: 3 (v / v). Yield 5.3 g (67% of theory). Melting point 200-205 ° C (decomposed).

UV spectrum: X maximum (mp) E1cm 232 489 20 260 339 292 295 320 216 370 119 450 159 25 IR spectrum: characteristic absorption lines were observed at the following frequencies (cm 1): 3440 (b), 2960 (s), 2920 (s), 2860 (s), 2820 (vw), 1705 (s), 1640 (s), 1580 (s), 1500 (s).

b = broad, s = strong, w = weak, vw = very weak.

1 H-NMR spectrum: characteristic resonance peaks were observed with the following (/ values (expressed in ppm)): -0.56 (d, 3H), 0.74 (d, 3H), 0.94 (d, 3H); 1.94 (s, 3H), 1.98 (s, 3H), 2.02 (s, 3H), 2.26 (s, 3H), 2.63 (s, 3H), 3.00 (s , 3H), 3.2-3.9 (m, 3H), 4.15-5.20 (m, 2H), -5.9-6.9 (m, 4H), 7.06 (dd, 1H), 7.38 (s, 1H), 8.39 (s, 1H), 8.43 (d, 1H), 11.0 (s, 1H), 13.12 (s, 1H).

35 s = singlet, d = doublet, m = multiple, dd = double doublet.

il 83875 1 3 C-NMR spectrum: characteristic resonance peaks were observed with subsequent O 2 values (expressed in ppm) 6.98; 8.06; 8.21; 10.76; 17.56; 20.43; 20.78; 21.44; 22.35; 32.91; 36.93; 37.78; 38.59; 56.99; 72.65; 73.91; 76.75; 77.86; 97.83; 5,103.86; 104.09; 108.97; 109.99; 112.03; 114.96; 115.52; 117.61; 119.26; 122.99; 125.35; 128.44; 128.96; 136.21; 138.87; 141.75; 142.10; 147.74; 155.10; 170.63; 171.89; 182.19; 188.84.

Example 2 1 0 4-Deoxyisoquinoline / '2 1, 1 1 r 1, 2-imidazo [5,4-c] rifamycin SV Mainly as described in the previous example, starting from 7.5 g (0.01 mol) ) rifamycin B and 4.3 g (0.03 mol) of 1-aminoisoquinoline and 2.5 g (0.01 mol) of iodine gave 5.8 g of the title product (71% 15 theoretical). Melting point 181-186 ° C (dec.).

UV spectrum: X maximum (mp) E1cm 253 532 288 363 300 346 20 320 290 382 120 430 129 IR spectrum: characteristic absorption lines were observed at the following frequencies (cm-2); 3440 (b), 3140 (b), 2910 (s), 25 2850 (w), 1700 (s), 1630 (b), 1610 (b), 1580 (w), 1555 (vw), 1535 (vw) .

b = wide; s = strong; w = weak; vw = very weak.

^ H-NMR spectrum; characteristic resonance peaks were observed with the following </ values (expressed in ppm): -0.65 (d, 3H); Δ 0.04 (d, 3 H); 0.7 (d. 3H); 0.88 (d. 3H); 1.55 (s. 3H); 1.92 (s. 3H); 2.02 (s. 3H); 2.27 (s. 3H); 2.77 (d, 1 H); 2.94 (s. 3H); 3.00 - 3.90 (m, 4H); 4.78 (d, 1 H); 4.93 (q, 1 H); 5.75-7.00 (m. 4H); 7.34 (d, 1H); 7.6-8.0 (m. 6H); 16.6 (m. 1H).

s = siglet, d = doublet; m = multiplet; q = quartet.

35 Example 3

31-Bromo-4-deoxypyrido [1,2-b] 1,2,2-imidazo [5,4-c] trifamycin IU

12 83875

By proceeding as described in Example 1 and starting from 7.5 g (0.01 mol) of rifamycin B, 3.5 g (0.02 mol) of 2-amino-5-bromopyridine and 2.5 g of (0.01 mol) of iodine, 6.4 g (75% of theory) of the title product were obtained.

UV spectrum: X maximum (mp) E1cm 225 481 238 502 298 345 330 185 10 378 107 450 133 IR spectrum; characteristic absorption lines were observed at the following frequencies (cm -1): 3440 (b); 3220 (w); 2960 (s); 2925 (m); 2870 (m); 1725 (w); 1715 (s); 1655 (w); 1635 (s); 15 1600 (vs).

b = wide; m = medium; w = weak; s = strong; vs = very powerful.

1 H-NMR spectrum: characteristic resonance peaks were observed with the following values of c 1 H (expressed in ppm): -0.56 (d, 3 H); Δ 0.13 (d, 3 H); 0.80 (d. 3H); 0.85 (d. 3H); 1.91 (s. 3H); 1.94 (s. 3H); 2.02 (s. 3H); 2.26 (s. 3H); 2.98 (s. 3H); 2.60-3.00 (m, 1H); 3.25 (d, 1 H); 3.56 (s, 1 H); 3.38-3-80 (m. 2H); 4.84 (d, 1H); 5.00 (q, 1 H); 6.02 (d, 1 H); 6.00 - 7.00 (m, 3 H); 7.60 (d, 1H); 7.87 (q, 1H); 8.39 (s, 1 H); 8.56 (d, 1 H); 16.80 (s. 1H).

25 s = siglet; d = doublets; q = quartet; m = multiplet.

13 C-NMR spectrum: characteristic resonance peaks were observed with the following O? Values (expressed in ppm): 7.13; 8.17; 10.86; 17.47; 20.41; 20.73; 21.28; 33.07; 37.12; 38.08; 38.77; 57.01; 72.94; 73.92; 76.80; 77.88; 98.48; 103.82; 30 105.11; 108.96; 109.28; 112.59; 112.81; 115.57; 116.33; 120.94; 123.38; 125.22; 129.06; 136.03; 136.80; 137.46; 141.96; 170.92; 171.59; 171.81; 182.62; 187.68.

Example 4

4-Deoxy-4'-methylpyrido [1,2,2 '; 1,2,7-indidazo [5,4-c] trifamy-35ine SV

To a solution of 7.5 g (0.01 mol) of rifamycin B i 83875 and 3.2 g (0.03 mol) of 2-amino-4-methylpyridine in 60 ml of methylene chloride was added 3.3 g ( 0.01 mol) of potassium ferricyanide and the reaction mixture were kept at room temperature for 24 hours with stirring. The reaction mixture was washed first with 40 ml of 1N aqueous hydrochloric acid and then with water until neutral. The organic layer was collected, dried over sodium sulfate, the solvent was evaporated in vacuo to give a residue which was crystallized from ethanol / water 7/3 (v / v). Yield 5.9 g (75% of theory).

The product obtained has the same chemical-physical properties as the product of Example 1.

Example 5

4-Deoxy-4 1-methylpyrido [-1,2 ': 1,2-imidazo [5,4-c] trifamycin SV

7.5 g (0.01 mol) of rifamycin B and 4.3 g (0.04 mol) of 2-amino-4-methylpyridine were dissolved in 75 ml of methylene chloride, and 10 ml of 1M aqueous sodium hypochlorite solution and the resulting reaction mixture were added thereto. stirred at room temperature for 15 hours. The aqueous layer was then separated and the organic layer was washed first with 50 ml of 2N aqueous 2N hydrochloric acid and then washed with water until neutral. After drying over sodium sulfate, the organic layer was evaporated in vacuo and the residue was crystallized from ethanol / water 7/3 (v / v) to give 5.2 g of product (66% of theory) having the same chemical-physical properties as the product of Example 1.

Example 6

4-Deoxy-4'-methylpyrido [N, 2 ': 1,2,7-imidazo [5,4-o] rifamycin SV

A mixture of 75 g (0.1 mol) of rifamycin B, 43 g (0.4 mol) of 2-amino-4-methylpyridine and 26 g (0.3 mol) of manganese dioxide in 250 ml of acetonitrile was kept at room temperature for 24 hours with stirring. The reaction mixture was filtered, diluted with 800 mL of methylene chloride and treated for 15 minutes with 100 mL of 25% (w / v) aqueous solution of 14,88875 ascorbic acid. The organic layer was then washed with 400 ml of 2N aqueous hydrochloric acid and then neutralized with water. After drying over sodium sulphate, the solvent was evaporated off and the residue was crystallized from ethanol / water 7/3 (v / v) to give, after drying, 61 g (78% of theory) of the product having the same chemical and physical properties as the product of Example 1. .

Claims (3)

A new process for the preparation of 4-deoxy-pyrido [1 ', 2': 1,2] imidazo [5,4-c] rifamycin-SV of formula (I), CH. CH CH 1 3 10 0CHo I OH OH I X / ^ CH / 1 r =. r »r CH> \ ^ NH / T v 15 1 o γ Y n—. r L _ / ^ r 2 H - \> —w CH 20 3 | R wherein R is hydrogen or acetyl, R 1 and R 2 independently represent hydrogen, (C 1-4) alkyl, or halogen, or R x and R 2 together with two adjacent carbon atoms of the pyridine ring form a benzene ring, characterized in that one molar equivalent of rifamycin B is administered. of formula (II) 30 35 ie 83375 fH3 73 7 3 c H c ° OCH I OH OH || react with 1 to 9 molar equivalents of 2-aminopyridine of formula (III) .alpha. With 1 to 4 molar equivalents of an oxidant selected from iodine, potassium ferricyanide, aqueous sodium hypochlorite and manganese dioxide in the presence of a solvent or solvent system and at a temperature between room temperature and the boiling point of the reaction mixture for 30 hours and a reaction time of 10 to 100 hours. treated with a suitable reducing agent such as ascorbic acid. Process according to Claim 1, characterized in that about 2 to 4 molar equivalents of 2-aminopyridine of the formula (III) are used for each molar equivalent of rifamycin B. i7 83875 Process according to Claim 1, characterized in that methylene chloride or acetonitrile is used as solvent. 18 83875