DK160829B - Process for preparing pyridoimidazorifamycins - Google Patents

Description

in

DK 160829 B

The present invention relates to a particular process for the preparation of pyrido-imidazo-rifamycins of the formula (I) of claim 1.

Some of the compounds of formula (I) 5

O ... CH "CH" CH

il I O I ό I o

0CH3 OH OH II

io CHs il 1 J OH OH CO CH3

In ch, in l / NH

15 0- ^ If ^ -n R.

20 more precisely such compounds wherein R 1 and R 9 are independently (C 14) -alkyl, or R 2 and R 2 together with two consecutive carbon atoms in the pyridine nucleus form a benzene ring known from the literature, see US Patent No. 4341785.

Other compounds of formula (I), more precisely those wherein at least one of R 1 and R 2 is halogen, are disclosed in Italian Patent Application No. 3626 A / 82, which is now publicly available.

In these two documents, a process for preparing the compounds of formula (I) is also described.

Briefly, the known process relates to the reaction of a molar amount of 3-halo-rifamycin S of formula 35

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2 o CH3 CH3 CH3

^ yVVS

AND, OH OH I

5 γ'vis S * 3 halogen O-i-i 0 '0 CH3 15 wherein halogen preferably represents bromine or odor, with approx. 2 to approx. 8 molar equivalents of a suitable 2-aminopyridine of the formula

H, N N

V

R 2 R 2 wherein R 2 and R 9 have the meanings given above, or a salt thereof, to form a compound of the formula

25 ° CH - ch CH

ch3-c-o i- Ij 1 “and3 C 'oh oh il Π

3 µl V

OH 0 CH3 30 οΛΛΑν 0 - X0 CH> == / 35 R 1 wherein R 1 and R 5 have the meanings set forth above, which compound is preferably isolated and characterized and then treated with ascorbic acid.

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3 formic acid to form the si compounds of formula (I).

The yields of said steps calculated from the starting compound (IV) are sometimes quite good (ranging from about 45% to about 75%), but the process described in U.S. Patent No. 4,341,785 is severely hampered by the fact that the starting compound (IV) is not commercially available. It must be prepared from rifamycin S by suitable, often cumbersome halogen ring processes, which yield a yield of approx. 90-95% crude 3-halo-rifamycin S and ca. 85% pure 3-halo-rifamycin S, so that the final yields are between approx. 40% and approx. 64%. For this reason, the processes for preparing the compounds of formula (I) disclosed either in U.S. Patent No. 4,344,1785 or in Italian Patent Application No. 3626 A / 82 yield overall yields lower than those obtained by the process of the invention, and does not allow the desired compounds of formula (I) to be obtained with satisfactory yield from an industrial point of view.

The present invention relates to a particular process for the preparation of rifamycins of the general formula

n CH, CH 2 CH

Oh. 3. 0 I

CH3-C-O

AND, I OH OH

'ΓΧ. 1 i (P CH O «OH CO 3 CH 3 i i NH 1

XxX

· 4Τκ3τ ''

ch3 W

R1 wherein R2 and R2 are independently (C1-6) alkyl or halogen, or R1 and R2 together with two consecutive carbon atoms in the pyridine nucleus form a benzene ring which is characterized by the characterizing part of claim 1.

The term (C1-4) alkyl means straight or branched chain alkyl groups such as e.g. methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, isobutyl and tert-butyl.

The compounds of formula (I) have excellent antibacterial

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4 properties in vitro as well as in vivo. In particular, they have been found to be very valuable in combating gastrointestinal microbial infections by virtue of their sparse absorption into the tissues and organs of animals by oral administration.

The process of the invention represents a remarkable improvement over the method of the prior art, with rifamycin S having the formula CH CH CH CH 2 COO J. 60 CH 3 OH OH (I ["CH 3> j T", co c «3 15 ch 3 0 1

CH3 O

used as a starting compound is a commercial product which can be readily obtained either by chemical conversion of rifamycin B as described in French Patent FM 739 or by acid hydrolysis of rifamycin 0 as described in Belgian Patent No. 820517 or by the oxidation of halogen mycin A, B and D by nitric acid as described in U.S. Patent No. 3880839 or by fermentation of Micromonospora Chalcea strains as described in U.S. Patent No. 3884763.

Rifamycin S is reacted by the process of the invention with a 30 molar excess of a 2-amino-pyridine of the formula H2N \ 'N.

I i i i i

S>! wherein R 1 and R 2 have the above meanings, in the presence of od or a suitable iodide together with an iodide oxidizer, optionally in

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In the presence of an organic or inorganic acidic agent, at a temperature between room temperature and the boiling point of the reaction mixture, in a suitable solvent or solvent system, after which the reaction mixture is treated with a reducing agent selected from ascorbic acid, iso-ascorbic acid and dihydroxyacetone, and the desired compounds of the form ( I), wherein R 1 and R 2 have the meanings set forth above, are recovered by techniques known to those skilled in the art in yields of ca. 65% to approx. 80% calculated from the starting material rifamycin S.

Therefore, the reaction of the compounds of formula (II) with the compounds of formula (III) takes place in just one step and is elucidated by the following reaction scheme.

15 20 25 30 35 6

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diagram in GH CH CH „5 0CH3 r X TH I Vy.

γ ch3 1 + T i f ch3 «*« ty 10 Rx R2

I I

o you)

CH o CD

15 -> Λ, CH3 ™ 3 Ψ3 20 ®3 “0γ ^ γΝΑ

0CH3 1 OH OH I

1 0.1 I

Λ, r 7 = r “3 25 Yfll -—I — ζ κ3"! 30 CH3 R1

Rj and Rg have the meanings given above.

In practice, a molar amount of rifamycin S of formula (II) is reacted with from 1 to 8 molar equivalents of a 2-aminopyridine of formula (III) and preferably with from 3 to 6 molar equivalents of the aminopyridine of form

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7 (III), optionally in the presence of an organic or inorganic acidic agent such as iodic hydrochloric acid or acetic acid, in the presence of iodine or an iodide together with an iodide oxidizing agent, wherein the iodide e.g. may be the iodide of an alkali or an alkaline earth metal or the iodide hydrate of the starting 2-aminopyridine of formula (III) and the oxidizing agent a compound such as e.g. manganese dioxide, potassium iodate, sodium iodate or potassium umferri cyanide capable of oxidizing the iodide ion to release iodine in the reaction medium under the reaction conditions used.

The iodine or iodide together with the iodide oxidant may, respectively, be present in the reaction medium in amounts ranging from 0.1 to 4 molar equivalents of iodine for each mole of starting rifamycin S, or in quantities capable of releasing from 0 , 1 to 4 molar equivalents of enter iodine per day. The reaction is carried out in a solvent or solvent system selected from the commonly used in the field of rifamycin chemistry. Eg. lower halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, and thus analogous or lower al channels such as e.g. methanol, ethanol, propanol, isopropanol or 4-butanol. Also lower alkyl esters of lower aliphatic acids, acetonitrile, dimethoxyethane, dioxane, tetrahydrofuran and aromatic hydrocarbons have been found to be good reaction solvents. All of these solvents can be used alone or in admixture or in admixture with water in various conditions. The best results are obtained with solvents such as lower halogenated hydrocarbons, lower alkanols, alone or in admixture with water in various ratios, acetonitrile, dimethoxyethane, dioxane and tetrahydrofuran.

The reaction is carried out at a temperature in the interval between room temperature and the boiling point of the reaction mixture; in general, a temperature between room temperature and 60 ° C is sufficient to obtain the most satisfactory results.

The reaction is completed within a period which is essentially dependent on the nature of the pyridine of formula (III), the reactant ratios and the reaction temperature. Generally, from 1 to 120 hours is required to obtain the final products of formula (I) in the desired yields.

The reaction solution should then be treated with a suitable reducing agent such as e.g. ascorbic acid, isoascorbic acid or dihydroxyaceous tone. All of the above operations take place without isolating the intermediates so as to preserve the character of the "one-step reaction" typical of the present invention. The compounds thus obtained of formula (I) are recovered from the reaction medium according to known techniques.

Thus, e.g. the excess unreacted aminopyridine of formula (III) from the organic phase by treatment with an aqueous solution of a mineral acid. The organic phase is then separated, optionally dried over a suitable agent, e.g. anhydrous sodium sulfate, and the final product of formula (I) is obtained by evaporation of the solvent. Alternatively, the desired compounds of formula (I) are obtained by crystallizing the reaction medium at a temperature of about 0 ° C to approx. 10 ° C when 10 solvent systems are used which contain water.

If necessary, the compounds of formula (I) can be purified by crystallization from suitable solvent or solvent systems.

The present invention is further illustrated by the following examples.

The UV spectra were performed in absolute methanol with a "Perkin-Elmer 552" spectrophotometer, the IR spectra were performed in KBr. with a "PerkinElmer 281-B" spectrophotometer, while the nuclear magnetic resonance spectra 1 H-NMR and 13C-NMR were performed. deuterochloroform using tetramethylsilane as a reference standard with a "Varian XI 100" spectrophotometer.

20

Example 1

4-deoxy-47-methyl-pyridoTl7,2 ': 1,2] imidazoro5,4-clrifamycin SV

4.9 g (0.007 mol) of rifamycin S, 2.27 g (0.021 mol) of 2-amino-4-methyl-pyridine and 0.89 g (0.0035 mol) of od are dissolved in 30 ml of methylene chloride, and The resulting reaction mixture is stirred at room temperature for 30 hours. Then, the reaction mixture is added 5 ml of a 20% (w / v) aqueous solution of ascorbic acid, and after stirring for 30 minutes, the organic phase is separated and washed first with 0.5 N aqueous hydrochloric acid and then with water to neutrality. Then, solvent 30 is evaporated in vacuo and the residue is crystallized from a 7/3 (v / v) ethanol / water mixture. After filtration and drying, 4.2 g of the product is obtained in a yield of 76% of theory. The product has the following physicochemical characteristics: 35 1% 9

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UV spectrum: λ max (m / j) Ejcm 232 489 260 339 5 292 295 320 216 370 119 450 159 10 IR spectrum: characteristic absorption bands were observed at the following frequencies (in cm ”1): 3440 (b), 2960 (s) , 2920 (s), 2860 (w), 2820 (vw), 1705 (s), 1640 (s), 1580 (s), 1500 (s).

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

H-NMR spectrum: characteristic resonance peaks were observed at the following S (expressed as ppm): -0.56 (d, 3H); 0.14 (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).

s = singlet; d - doubled; m = multiplied; dd = double doubled.

13 C-NMR spectrum: characteristic resonance peaks were observed at the following S (expressed as 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; 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; 301.75; 142.10; 147.74; 155.10; 170.63; 171.89; 182.19; 188.84.

Example 2

4-Deoxy-4'-methyl-pyridoTl / 2 ': 1,21imidazoro5,4-clrifamycin SV

6.95 g (0.01 mole) of rifamycin S and 3.24 g (0.03 mole) of 2-amino-4-methyl-pyridine are dissolved in 20 ml of methylene chloride and the reaction mixture is added to a solution of 3.8 g (0.015 mole) of iodine in 100 ml of methyl chloride in one hour with vigorous stirring. The reaction mixture is stirred for an additional 4 hours at room temperature and then 20 ml of a 20% is added.

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ίο (w / v) aqueous solution of ascorbic acid. Stirring is continued for another 30 minutes, then the phases are separated and the organic layer is washed first with a 0.5 N aqueous solution of hydrochloric acid and then with water for neutrality. After evaporation of the methylene chloride in vacuo, a residue is obtained which is crystallized from a 7: 3 (v / v) ethanol / water mixture to give 6.1 g of the product having the same physicochemical characteristics as described for the compound of Example 1. The yield is 78% of theory.

Example 3 3'-Chloro-4-deoxy-pyri do Γ1 ', 2': 1,2] in mi dazo [5,4-c] rifamycin SV By proceeding essentially as described in Example 1, starting with 3.47 g (0.005 mole) of rifamycin S, 1.54 g (0.012 mole) of 2-amino-5-chloro-pyridine and 0.63 g (0.0025 mole) of iodine in 20 ml of methylene chloride, 2.8 g of the title compound are obtained in a yield of 68% of theory. The compound exhibits the following physicochemical characteristics: 1% UV spectrum: λ max (m / ι) Ejcm 20 238 508.5 296 343 378 106 455 137 25 IR spectrum: characteristic absorption bands observed at the following frequencies (in cm "1): 3430 (b), 3200 (w), 3090 (w), 2960 (m), 2920 (m), 2870 (w), 1712 (s), 1635 (s), 1595 (s), 1575 (s).

b = wide; s = strong; w = weak; m * medium.

30 H-NMR spectrum: characteristic resonance peaks were observed at the following 8 (expressed as ppm): -0.63 (d, 3H); 0.12 (d, 3H); 0.77 (d, 3H); 0.93 (d, 3H); 1.89 (s, 3H); 1.94 (s, 3H); 1.99 (s, 3H); 2.24 (s, 3H); 2.83 (d, 1H); 2.94 (s, 3H); 3.25 (d, 1H); 3.57 (d, 1H); 3.30-4.00 (m, 2H); 4.82 (d, 1H); 4.96 (q, 1H); 5.97 (d, 1H); 5.80-6.96 (m, 3H); 7.74 (m, 2H); 8.51 (s, 1H), 8.62 (d, 1H); 15.56 (broad, s, 1H); 16.75 (s, 1H).

s = singlet; d = doublet; q = quartet; m = multiplied.

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π 13 C-NMR spectrum: characteristic resonance peaks were observed at the following 8 (expressed as ppm): 6.81; 7.73; 7.95; 10.05; 16.98; 20.02; 20.07; 20.10; 32.57; 36.55; 37.60; 38.22; 56.78; 72.43; 73.36; 76.42; 5, 77.33; 98.12; 103.52; 104.87; 108.99; 112.31; 115.24; 115.78; 120.98; 122.55; 123.31; 125.11; 127.00; 128.32; 144.62; 146.37; 147.18; 151.82; 151.98; 155.52; 170.78; 171.42; 171.74; 182.36; 187.79.

Example 4

3β, 5β-Dibromo-4-deox, γ-pyridorr, 2β: 21, 1imidazof5,4-clrifamycin SV

Proceeding in substantially the same manner as described in Example 1, starting with 1.39 g (0.002 mol) of rifamycin S, 1.76 g (0.007 mol) of 2-amino-3,5-dibromo-pyridine and 0 , 25 g (0.001 mol) of iodine in 15 ml of methylene chloride, 1.35 g of the title product is obtained in a yield of 71% of the theoretical.

The compound exhibits the following physicochemical characteristics: 1% 20 UV spectrum: λ max (m / ί) Ejcm 241 470 300 311 382 76 455 94 25 IR spectrum: characteristic absorption bands observed at the following frequencies (in cm -1): 3480 ( b), 3350 (b), 3200 (w), 2980 (m), 2940 (m), 2880 (w), 1715 (s), 1650 (s), 1625 (m), 1600 (s); 1580 (m).

B = wide; s = strong; w = weak; m = medium.

1 H-NMR spectrum: characteristic resonance peaks were observed at the following 8 (expressed as ppm): -0.47 (d, 3H); 0.30 (d, 3H); 0.80 (d, 3H); 0.98 (d, 3H); 1.96 (s, 6H); 1.99 (s, 3H); 2.25 (s, 3H); 2.88 (d, 1H); 3.03 (s, 3H); 3.20-4.00 (m, 4H); 4.87 (d, 1H); 5.11 (q, 1H); 6.12 (d, 1H); 6.00-7.00 (m, 3H); 7.94 (d, 1H); 8.52 (d, 1H), 15.48 (wide, s, 1H); 16.66 (broad, s, 1H).

s * singlet; d = doublet; m = multiplied; q = quartet.

12

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13 C-NMR spectrum: characteristic resonance peaks were observed at the following 6 (expressed as ppm): 7.46; 7.89; 8.38; 11.92; 18.22; 20.40; 21.07; 22.38; 33.19; 37.49; 38.94; 39.99; 40.71; 56.37; 72.38; 73.01; 5, 76.13; 76.42; 99.04; 104.07; 104.73; 107.40; 109.36; 110.35; 112.31; 116.29; 118.40; 121.77; 124.90; 126.20; 126.92; 130.56; 137.68; 138.62; 140.44; 141.82; 142.73; 157.29; 170.01; 170.72; 183.49; 185.85.

Example 5

4-Deoxy-isoquinolinorr, 2; 1,2,2imidazoF5,4-cifrifamycin SV

By proceeding essentially as described in Example 2, starting with 6.95 g (0.01 mole) of rifamycin S, 4.32 g (0.03 mole) of 1-amino-isoquinoline and 3.80 g (0.015) mole) iodine is obtained 5.9 g of the title compound in a yield of 72% of theory.

The compound exhibits the following physicochemical characteristics:

Snip: 181 ° -186 ° C (decomp.).

1% 20 UV spectrum: λ max (ηιμ) Ejcm 253 532 288 363 300 346 320 290 25 382 120 430 120 IR spectrum: characteristic absorption bands were observed at the following frequencies (in cm ”1): 3440 (b), 3140 (b) , 2910 (s), 2850 (w), 1700 (s), 30 1630 (b), 1610 (b), 1580 (w), 1555 (vw), 1535 (vw).

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

1 H-NMR spectrum: characteristic resonance peaks were observed at the following S (expressed as ppm): -0.65 (d, 3H); 0.04 (d, 3H); 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, 1H); 2.94 (s, 3H); 3.00-3.90 (m, 4H); 4.78 (d, 1H); 4.93 (q, 1H); 5.75-7.00 (m, 4H); 7.34 (d, 1H); 7.6-8.0 (m, 6H); 16.6 (m, 1H).

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13 s = singlet; d = doublet; m = multiplied; q - quartet.

EXAMPLE 6 3 ', 5'-Dichloro-4-deoxy-pyridofT, 2': 1,1,2-imidazoro5,4-clrifamycin SV By proceeding essentially as described in Example 2 starting with 4.9 g (0.007 mol ) rifamycin S, 3.42 g (0.021 mol) of 2-amino-3,5-dichloropyridine and 2.66 g (0.0105 mol) of iodine yield 4 g of the title compound in a yield of 67% of theory. This compound exhibits the following physicochemical characteristics: 1% UV spectrum: λ max (m / j) Ejcm 239 527 15 289 366 380 95 450 122 IR spectrum: characteristic absorption bands were observed at the following 20 frequencies (in cm -1): 3450 (b), 3250 (w), 2970 (m), 2930 (m), 2880 (m), 1710 (s), 1640 (s), 1585 (s).

b = wide; s = strong; w = weak; m = medium.

25 N NMR spectrum: characteristic resonance peaks were observed at the following S (expressed as ppm): -0.56 (d, 3H); 0.23 (d, 3H); 0.78 (d, 3H); 0.94 (d, 3H); 1.92 (s, 3H); 1.97 (s, 6H); 2.25 (s, 3H); 2.70-3.00 (m, 1H); 2.98 (s, 3H); 3.10-3.80 (m, 4H); 4.84 (d, 1H); 5.05 (q, 1H); 6.03 (d, 1H); 6.00 - 7.00 (m, 3H); 7.18 (s, 1H); 8.13 (s, 1H), 8.35 (s, 1H); 16.00 (broad, s, 1H); 16.45 (large, s, 1H).

s = singlet; d = doublet; m = multiplied; q = quartet.

13 C-NMR spectrum: characteristic resonance peaks were observed at the following S (expressed as ppm): 7.03; 8.34; 8.58; 11.08; 17.53; 20.54; 20.88; 21.82; 33.41; 37.23; 38.25; 38.69; 57.16; 74.17; 77.16; 78.14; 78.76; 99.49; 105.59; 106.15; 110.52; 112.50; 116.80; 116.95; 119.97; 121.23; 124.96; 125.57; 125.62; 126.00; 128.45; 132.03; 137.53; 138.06;

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14, 142.83; 142.07; 155.15; 170.74; 170.96; 172.21; 181.66; 184.91.

Example 7 4-Deoxy-47-methyl-pyrido [1 ', 27: 1, 21imidazoro5,4-clrifamycin SV A solution of 6.95 g (0.01 mole) of rifamycin S and 3.24 g (0.03 mole) 2-amino-4-methyl-pyridine in 20 ml of acetonitrile is added portionwise 3.80 g (0.015 mole) of iodine over 1 hour and the reaction is continued for an additional 6 hours with stirring at room temperature. Then, the reaction mixture is added 20 ml of a 20% (w / v) aqueous solution of ascorbic acid and stirred for an additional 30 minutes. Then, 5 ml of acetic acid and 25 ml of 0, 1N aqueous solution of hydrochloric acid are added and the reaction mixture is allowed to stand overnight at 5 ° C. The crystallized solid is filtered off and dried to give 5.1 g of product in a yield of 65% of theory. The compound obtained has the same physicochemical characteristics as the compound of Example 1.

Example 8

4-deoxy-4β-methyl-1β, yridori [1,2]: 1 -imidazor [5,4-c] trifamycin SV

A solution of 4.9 g (0.007 mol) of rifamycin S, 3 g (0.028 mol) of 2-20 amino-4-methyl-pyridine and 3 g (0.012 mol) of iodine in 30 ml of methylene chloride is heated to the boiling point of the reaction mixture for 1 hour. After cooling to room temperature, the solution is added 20 ml of a 25% (w / v) aqueous solution of ascorbic acid and stirred for 30 minutes. The two layers are separated, the organic is washed twice with 30 ml of 1N aqueous solution of hydrochloric acid 25 and then with water for neutrality and then dried over sodium sulfate. After filtration and evaporation of the solvent, a residue is obtained, which is crystallized from a 7/3 (v / v) ethanol / water mixture to give 4.4 g of product in 80% of theory. The compound has the same physicochemical characteristics as the compound 30 of Example 1.

Example 9

4-Deoxy-57-methyl-pyridori7,27: 1,2,2imidazoro5,4-clrifamycin SV

A solution of 4.9 g (0.007 mol) of rifamycin S, 3 g (0.028 mol) of 2-35 amino-3-methyl-pyridine, 3.3 g (0.014 mol) of 2-amino-3-methyl-pyridine, -dioiodide and 1.8 g (0.0071 mol) of iodine in 35 ml of methylene chloride are heated to the boiling point of the reaction mixture for a period of 4 hours. After cooling, add 10 ml of a 25% (w / v) aqueous solution of ascorbic acid, 15

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and stirring for 30 minutes. The two layers are separated and the organic layer is washed twice with 30 ml of 1N aqueous solution of hydrochloric acid and then with water for neutrality and subsequently dried over sodium sulfate. After filtration and evaporation of the solvent, a residue is obtained which is crystallized from a 7/3 (v / v) ethanol / water mixture to give 4.1 g of product in 75% yield of theory.

This product exhibits the following physicochemical characteristics:

Mp: 185 ° -190 ° C (decomp.).

10 1% UV spectrum: λ max (m / ί) Ejcm 217 470 235 544 15 262 333 273 303 292 295 320 205 356 99 20 373 122 - 440 164 454 166 IR spectrum: characteristic absorption bands were observed at the following 25 frequencies (in cm -1): 3440 (b), 3300 (b), 3200 (b), 2960 (s), 2920 (w), 2850 (vw), 1730 (s), 1710 (w), 1640 (s), 1595 (s), 1580 (b), 1555 (w).

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

30 N NMR spectrum: characteristic resonance peaks were observed at the following 8 (expressed as ppm): -0.64 (d, 3H); 0.02 (d, 3H); 0.45 (d, 3H); 0.90 (d, 3H); 1.75 (s, 3H); 1.94 (s, 3H); 1.97 (s, 3H); 2.23 (s, 3H); 2.45 (s, 3H); 2.95 (s, 3H); 2.6-5.8 (m, 5H); 4.5-5.25 (m, 2H); 5.5-7.0 (m, 4H); 7.25-7.75 (m, 2H); 8.27 (s, 1H); 8.47 (s, 1H); 14.86 (s, 1H); 16.77 (s, 1H).

s = singlet; d = doublet; m = multiplied.

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16

Example 10

4-Deoxy-47-methyl-pyridoT7,27: 1,2,2imidazo [5,4-clrifamycin SV

A solution of 6.95 g (0.01 mole) of rifamycin S, 4.32 g (0.04 mole) of 2-amino-4-methyl-pyridine, 2.4 g (0.04 mole) of acetic acid and 0, 25 g (0.001 5 moles) of iodine in 40 ml of methylene chloride are kept at room temperature for 5 days.

Then, the reaction mixture is added 0.37 g (0.002 mol) of ascorbic acid and stirred for 30 minutes. Then it is washed with a 0.5 N aqueous solution of hydrochloric acid and then with water and finally evaporated to dryness under reduced pressure. The residue is crystallized from a 7/3 (vol / -10 vol) ethanol / water mixture to give 5.74 g of product in 73% yield of theory.

The product has the same physicochemical characteristics as the product of Example 1.

Example 11

4-deoxy-4β-methyl] -pyridorr, 2β: 21imidazo [5,4-ciflamycin SV

A solution of 4.9 g (0.007 mol) of rifamycin S, 3 g (0.028 mol) of 2-amino-4-methyl-pyridine, 0.45 g (0.0018 mol) of iodine and 1.65 ml (0.029 mol) acetic acid in 15 ml of acetonitrile is kept at room temperature for 48 hours.

Then, the reaction mixture is added an additional 0.2 g (0.0008 mole) of iodine and kept at room temperature for another 16 hours. Then, 3 ml of a 25% (w / v) aqueous solution of ascorbic acid is added and diluted with 85 ml of methylene chloride after 30 minutes. The organic solution is washed twice with 30 ml of an 1N aqueous solution of hydrochloric acid, then with water to neutral and dried over sodium sulfate. After filtration and evaporation of the solvent in vacuo, a residue is obtained which is crystallized from a 7/3 (v / v) mixture of ethanol / water to give 4.2 g of product in a yield of 77% of theory. .

The product has the same physicochemical characteristics as the product 30 of Example 1.

Example 12

4-deoxy-47-methylpyridorr, 2 ': 1,1,2imidazorene-5,4-clifamycline SV

4.9 g (0.007 mol) of rifamycin S, 3 g (0.028 mol) of 2-amino-4-methylpyridine, 3.3 g (0.014 mol) of 2-amino-4-methyl-pyridine, hydroiodide and 0, 89 g (0.0035 mol) of iodine are dissolved in 20 ml of dimethoxyethane and the reaction mixture is allowed to stand at room temperature for 20 hours. Then, the reaction mixture is added 5 ml of a 25% (w / w) aqueous solution of ascorbic acid

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17 and allowed to stir for 30 minutes. Then, the reaction mixture is diluted with 100 ml of methylene chloride, washed twice with 30 ml of a 1 N aqueous solution of hydrochloric acid, and then with water for neutrality.

The organic phase is dried over anhydrous sodium sulfate and filtered and the solvent is evaporated.

The residue is crystallized from a 7/3 (v / v) mixture of ethanol and water to give 3.7 g of product in a yield of 68% of theory. The product has the same physicochemical characteristics as the product of Example 1.

10

Example 13

4-deoxy-4'-methyl-pyridofT, 2 ': I, 21imidazoro5,4-clrifamycin SV

696 g (1 mole) of rifamycin S, 324 g (3 mole) of 2-amino-4-methyl-pyridine and 127 g (0.5 mole) of iodine are dissolved in 3 L of methylene chloride and the reaction mixture is kept at room temperature for 24 hours. hours. Then, the reaction mixture is added 0.5 liters of a 20% (w / w) aqueous solution of ascorbic acid and stirred for 1 hour. The aqueous phase is discarded and the organic phase is first washed three times with 1 liter of a 1 N aqueous solution of hydrochloric acid to remove the unreacted excess of 2-amino-4-methyl-pyridine, then with water for neutrality. , and finally it is evaporated to dryness under vacuum. The solid is crystallized from a 7/3 (v / v) mixture of ethanol and water to give 613 g of product in a yield of 78% of theory.

The product thus obtained exhibits the same physicochemical characteristics as the product of Example 1.

Example 14

4-deox, γ-4'-methyl-pyridolT, 2 ': 1,21 imidazoro5,4-clrifamycin SV

487 g (0.7 mole) of rifamycin S, 303 g (2.8 mole) of 2-amino-4-methylpyridine and 254 g (1 mole) of iodine are dissolved in 3 liters of methylene chloride and the reaction mixture is kept at room temperature for 4 hours. hours. Then add 1.5 liters of a 25% (w / w) aqueous solution of ascorbic acid and stir for 30 minutes. The aqueous phase is discarded and the organic phase is first washed four times with 1 liter of a 1 N aqueous solution of hydrochloric acid to remove the unreacted excess of 2-amino-4-methyl-pyridine, then washed with water neutrality, and finally dried over sodium sulfate. After filtration and evaporation of the solvent, a residue is obtained which is crystallized from a 7/3 (v / v) mixture of ethanol

DK 160829 B

18 and water to give 440 g of product in 80% yield of theory.

The product thus obtained exhibits the same physicochemical characteristics as the product of Example 1.

Claims (5)

A process for the preparation of pyrido-imidazo-rifamycins of the general formula 013-0 ° / 1 OCH ^ j ° jj Oh xr ch3 1 10. O 2 CO 3 CH 3 NH 2 R2 CH R1 wherein R 2 and R 2 independently of the free moiety are (C 14) alkyl or halogen, or R 2 and R 2 together with two consecutive carbon atoms in the pyridine nucleus form a benzene ring, characterized in that a mole equivalent of ri-famycin S of the formula CH3 CH3 ™ 3 CH COO I) 25 is converted to Y CH S CH3 in X As CH2 OH O CO CH. having from 1 to 8 molar equivalents of a 2-amino-pyridine of the formula DK 160829B R1 R2 5 wherein R 1 and R 2 have the above meanings, in the presence of from 0.1 to 4 molar equivalents of iodine or iodide together with an iodide oxidant capable of releasing the corresponding amount of iodine, optionally in the presence of an acidic agent and in the presence of a solvent or solvent system in a for a period of time between 10 hours and 120 hours, at a temperature between room temperature and the boiling point of the reaction mixture, treat the reaction mixture with a suitable reducing agent selected from ascorbic acid, isoascorbic acid and dihydroxyacetone, and recover the compounds of formula (I) from the reaction medium by known techniques. 15 2. A process according to claim 1, characterized in that for each mole of rifamycin S from 3 to 6 mole equivalents of the 2-aminopyridine of formula (III) are used. 3. A process according to claim 1, characterized in that the solvent or solvent system is selected from lower halogenated hydrocarbons, lower alkanols, lower alkyl esters of lower aliphatic acids, acetonitrile, dimethoxyethane, dioxane, tetrahydrofuran and aromatic hydrocarbons. 25 4. A process according to claim 3, characterized in that the solvent is methylene chloride. 5. A process according to claim 1, characterized in that the reaction temperature is between room temperature and 60 ° C. 35