DK161706B - Process for preparing pyridoimidazorifamycins - Google Patents

Description

DK 161706 B

The present invention relates to a particular process for the preparation of pyrido-imidazo-rifamycins of the formula:

10 OH OH CO

c H 3 ^ Η H

0 ιΟύ 2 15 ° -I-Ν »\ ^ / CH p 3 R1 where R 1 and R 2 independently represent hydrogen, (C 1-6 alkyl, or halogen, 20 or R 1 and R 2 together with two neighboring carbon atoms in the pyridine nucleus form a benzene ring.

The process according to the invention is characterized by reacting one molar equivalent rifamycin B of the formula 25 CH CH ch 3

C H 3 C O

AND I OH OH I

v 3 l II

30 s? \

^ OH OH CO CH

".. [Yr

35 O-CH-COOH

xO 2 CH3

DK 161706 B

2 having from 1 to 9 molar equivalents of 2-aminopyridine of formula s I 111 E2 wherein R 1 and R 5 have the meanings set forth above, and having from 1 to 4 10 mol equivalents of a suitable oxidant in the presence of a solvent or solvent system at a temperature between room temperature and the boiling point of the reaction mixture for a period of time between 10 and 100 hours and, if necessary, then treat the reaction mixture with an appropriate reducing agent.

Some of the compounds of formula (I), more particularly those compounds wherein R 1 and R 9 independently represent hydrogen or (C 1 -C 6) alkyl, or R 2 and R 9 together with two neighboring carbon atoms in the pyridine nucleus form a benzene ring, are known in the art. tour, see e.g.

U.S. Patent No. 4,341,785.

Other compounds of formula (I), more particularly those compounds wherein at least one of R 1 or R 6 represents halogen, is disclosed in the publicly available Italian Patent Application No. 3626 A / 82.

These two references also describe a process for preparing the compounds of formula (I).

Briefly, the known process was carried out by reacting a molar amount of 3-halogen rifamycin S of the formula

p ii C H CH

i 3 i 3 I 3

30 AND OH OH L

X / C '! IN

^ CO CH3

° k o I

CH3 1 X .NR

halo ° 4-A °.

CH3

35 VVV

DK 161706 B

3 wherein R represents hydrogen or acetyl and halo preferably represents bromine or iodine, with from 2 to 8 molar equivalents of a suitable 2-amino-pyridine of formula (III).

There is thus obtained a compound of formula 5? H3 ^ 3 fH3 RO .A.

OCH3 OH oh cHo il 10 1 3 Jl J n (50 ° CH3 eq * 1 20 wherein R, Rj and Rg have the above meanings, which compound is preferably isolated and characterized and then treated with ascorbic acid to obtain the final products of formula (I) ) or the corresponding deacetyl compound.

Although the yield of the two mentioned steps calculated relative to the starting compound (IV) is sometimes quite good (between about 45% and about 75%), the method described in U.S. Pat.

4,341,785 serious restrictions, the starting compound (IV) not being a commercial product, but each time having to be prepared from rifamycin S by appropriate halogenation processes, e.g. known from DK 30 Patent Application No. 5309/78. Thus, from DK Patent Application No. 5309/78, a process for the preparation of 3-iodo-rifamycin S and 3-bromo-rifamycin S is known in a yield of, respectively. 81.5% and 85.5%. Combining the process known from DK Patent Application No. 5309/78 with that known from the aforementioned US Patent No. 4,341,785 provides a three-step process, in which e.g. the yield of 4-deoxy-4, -methyl-pyrido [r, 2 /; 1,2] imidazo [5,4-c] rifamycin SV becomes 62.5%, which is substantially inferior to the yield obtained by the method of the invention, especially considering that the process of the invention is industrially more attractive, since

DK 161706 B

4 it proceeds in a single step and does not require the use of expensive and toxic reagents such as bromine and iodine.

In the present invention (C Cj ^ alkyl) represents straight or branched chain alkyl groups, namely methyl, ethyl, propyl, isopropyl, butyl, 5 sec.-butyl, isobutyl and tert-butyl.

The compounds of formula (I) have excellent anti-bacterial properties both in vitro and in vivo. Due to their poor absorption in animal organs and tissues by oral administration, they have been found to be particularly suitable for the treatment of microbial infections of the gastrointestinal tract.

The method of the present invention is a significant improvement over the prior art method. Rifamycin B, a commercial product, is used according to the invention as a starting compound. This compound is readily obtained by fermentation of 15 Streptomyces Mediterranean! as described in Antibiotics Annual 1959-1960, pp. 262-270, 1960 and in German Patent No. 1,113,288 and by Streptomyces Mediterranean! ATCC 21789 as described in Belgian Patent No. 799,122.

Rifamycin B is reacted according to the invention under mild conditions with a selected 2-aminopyridine of formula (III) and with a suitable oxidizing agent in a suitable solvent or solvent system from which the desired end products are isolated by methods known to those skilled in the art. of formula (I), wherein R 1 and R 2 are the above meanings, in yields ranging from about 65% to about 25 80% calculated from the starting material rifamycin B.

The reaction of the compounds of formula (II) and (III) in the presence of a suitable oxidizing agent proceeds in only one step and is illustrated by the following reaction scheme, wherein R 1 and R 2 have the meanings given above.

in

DK 161706 B

5 Schedule i

CH CH CH

I 3 I 3 I 3

CH ^ COO

° CH3 i

see “S

OH OH 9 ° CH3 CH3 Jh

MM

/ y * + j oxidation 0 I Γ ^ ~ T ~ R2 agent *

0 χ O-CH 2 -COOH

ch3 III

II

CH "CH" CH I 3 I 3 i 3 ^ "^ ΛΛΛ", I T T i

T \ OH OH

CH3 I

° H OH Cq CH2 CH3

CH3 Jv NH

0 ~ ίΑ V

DK 161706 B

In practice, a molar amount of rifamycin B of formula (II) is reacted with from 1 to 9 molar equivalents of a 2-aminopyridine of formula (III) and preferably from 2 to 4 molar equivalents of said aminopyridine and from 1 to 4 molar equivalents. of a suitable oxidizing agent.

The oxidant can be used either in solution in the reaction medium, in suspension or dissolved in a solvent which is not miscible with the reaction solvent. When a molar excess of oxidant relative to rifamycin B is used, the siut reaction reaction must be treated with a suitable reducing agent, usually an aqueous solution of ascorbic acid, to obtain the final product of formula (I).

Many oxidation systems can be used advantageously, either organic or inorganic, such as alkyl nitrites, quinones, organic peroxides, hydrogen peroxide, air and oxygen optionally in the presence of catalysts, iodine, manganese dioxide, lead tetracetate, all potassium persulfates, ferric salts, mercuric salts, al potassium ferric cyanides, mercuric oxides and alkali hypochlorites. solute, manganese dioxide, potassium ferricyanide and sodium hypochlorite in aqueous solution are preferred.

The reaction is carried out in the presence of a solvent or solvent system generally 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 analogous lower alkanes such as methanol, ethanol, propanol, isopropanol or n-butanol are advantageously used. Lower alkyl esters of lower aliphatic acids, acetonitrile, dioxane and tetrahydrofuran can also be used advantageously. These solvents can be used alone, mixed with each other or mixed with water in various volumetric conditions. The best performing solvents are benzene, toluene, lower halogenated hydrocarbons, lower all channels alone or mixed with water, acetonitrile, dioxane and tetrahydrofuran.

The reaction takes place at normal pressure and within wide temperature limits, namely between room temperature and the boiling point of the reaction mixture. A temperature between room temperature and about 60 ° C usually produces absolutely satisfactory results.

The reaction ends within a time period which is substantially dependent on the nature of the aminopyridine of formula (III) and the conditions under which the reaction is carried out. It takes from 10 to 100 hours to obtain the final products of formula (I) in the desired yields.

DK 161706 B

7

The compounds of formula (I) thus obtained are isolated from the reaction medium in accordance with conventional techniques.

Thus, for example, the excess of unreacted aminopyridine of formula (III) is removed from the organic phase by means of an aqueous solution of 5 a mineral acid. The organic phase is then separated and optionally dried over a suitable agent such as sodium sulfate, and the final product of formula (I) is obtained by evaporating the solvent. Alternatively, the desired compounds are obtained by crystallization from the reaction medium at a temperature of about 0 ° C to 10 ° C when using 10 solvent systems containing water.

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

The invention will now be further illustrated by way of example.

15 IR spectra were made in KBr with a "Perkin-Elmer 281-B" spectrophotometer.

13 H-NMR and C-NMR spectra were performed in deuterochloroform with a "Varian XL 100" spectrophotometer using tetramethylsilane as an internal standard. UV spectra were performed in absolute methanol with a 20 "Perkin-Elmer 552" spectrophotometer.

Example 1

4-Deoxy-4, -methyl-pyrido [2,2-a] 21imidazo [5,4-c] trifamycin SV

7.5 g (0.01 mole) of rifamycin B, 4.3 g (0.04 mole) of 2-amino-4-methyl-pyridine and 2.5 g (0.01 mole) of iodine were dissolved in 60 ml of methylene chloride and the solution thus obtained was left at room temperature for 15 hours. After the reaction mixture was washed, first with 40 ml of an aqueous 2N solution of hydrochloric acid and then with water and the organic phase dried over sodium sulfate, the methylene chloride was removed by evaporation under vacuum.

A residue was obtained which crystallized with ethanol and water 7: 3 (v / v). Yield 5.3 g (67% of theory). Mp. 200 ° -205 ° C (decomposition).

DK 161706 B

8 UV Spectrum: λ max (m / i) E * lcm 232 489 5 260 339 292 295 320 216 370 119 450 159 10 IR Spectrum: characteristic absorption bands were observed at the following frequencies (in cm "1): 3440 (b), 2960 (st), 2920 (st), 2860 (sv), 2820 (msv), 1705 (st), 1640 (st), 1580 (st), 1500 (st) .b = wide, s = strong, sv = weak , msv = very weak.

15 N NMR Spectrum: characteristic resonance peaks were observed at the following δ (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 = doublet, m = multiplet, dd = doublet of doublet.

13 C-NMR Spectrum: characteristic resonance peaks were observed at the following δ (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, 141.75, 142.10, 147.74, 155.10, 170.63, 171.89, 182.19, 188.84.

30

Example 2

4-deoxyl-isoquinolinyl [beta], 1,2-imidazo [5,4-clrifamycin]

Following essentially the preceding example, from 7.5 (0.01 mole) of rifamycin B and 4.3 g (0.03 mole) of 1-amino-35 in soquinoline and 2.5 g (0.01 mole) was obtained. mole) iodine, 5.8 g of the title compound (71% of theory). Mp. 181-186 ° C (decomposition).

DK 161706 B

9 UV Spectrum: λ max (m / j) E ^ crn 253 532 5 288 363 300 346 320 290 382 120 430 129 10 IR Spectrum: characteristic absorption bands were observed at the following frequencies (in cm-1): 3440 (b), 3140 (b), 2910 (st), 2850 (sv), 1700 (st), 1630 (b), 1610 (b), 1580 (sv), 1555 (msv), 1535 (msv). b = broad, s = strong, sv = weak, msv = very weak.

15 H-NMR Spectrum: characteristic resonance peaks were observed at the following 8 (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).

s = singlet, d = doublet, m = multiplet, q - quartet.

Example 3 3β-Bromo-4-deoxy-pyridori [2 ': 1,2] imidazo [5,4-clrifamycin SV 25 Following Example 1 was obtained from 7.5 g (0.01 mole) rifamycin B, 3.5 g (0.02 mole) of 2-amino-5-bromo-pyridine and 2.5 g (0.01 mole) of iodine 6.4 g (yield 75% of theory) of title compound late.

UV Spectrum: 30 λ max (πιμ) Ejlcm 225 481 238 502 298 345 35 330 185 378 107 450 133

DK 161706 B

IR Spectrum: characteristic absorption bands were observed at the following frequencies (in cm-1): 3440 (b), 3220 (sv), 2960 (st), 2925 (m), 2870 (m), 1725 (sv), 1715 (st) ), 1655 (sv), 1635 (st), 1600 (mst). b - wide, m = medium, sv = weak, st = strong, mst = very strong.

5 H-NMR Spectrum: characteristic resonance peaks were observed at the following δ (expressed as ppm): -0.56 (d, 3H), 0.13 (d, 3H), 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, 1H), 3.56 (s, 1H), 3.38-3.80 (m, 2H), 4.84 ( d, 1H), 5.00 (q, 1H), 6.02 (d, 1H), 6.00-7.00 (m, 3H), 7.60 (d, 1H), 7.87 (q , 1H), 8.39 (s, 1H), 8.56 (d, 1H), 16.80 (s, 1H) s * singlet, d = doublet, q = quartet, m = multiplet.

13 C-NMR Spectrum: characteristic resonance peaks were observed at the following δ (expressed as 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, 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.

20

Example 4

4-deoxy-4'-methyl-pyridoT1 ', 2': 1,21imidazo [5,4-c] rifamycin SV

To a solution of 7.5 g (0.01 mole) of rifamycin B and of 3.2 g (0.03 mole) of 2-amino-4-methyl-pyridine in 60 ml of methylene chloride was added 3.3 g (0.01 mole) potassium ferricyanide and the reaction mixture is stirred at room temperature for 24 hours. The reaction mixture was washed first with 40 ml of 1N aqueous solution of hydrochloric acid and then with water for neutralization. The organic layer was isolated, dried over sodium sulfate, the solvent evaporated under vacuum and a residue obtained 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 characteristics as that obtained in Example 1.

35

DK 161706 B

11

Example 5

4-deoxy-4'-methyl-pyridolT, 2 ': 1,2] imidazor5,4-c] rifamycin SV

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

Example 6

4-Deoxy-4'-methyl-pyridoFl ', 2': 1,21imidazoro-5,4-clrifamycin

A suspension of 75 g (0.1 mole) of rifamycin B, 43 g (0.4 mole) of 2-amino-4-methyl-pyridine and 26 g (0.3 mole) of manganese dioxide in 250 ml of acenitri 1 was stirred at room temperature for 24 hours. 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 ascorbic acid.

Next, the organic layer was washed with 400 ml of 2N aqueous solution of hydrochloric acid and then with water for neutralization. After drying over sodium sulfate, the solvent was evaporated, the residue crystallized from 7/3 (v / v) ethanol / water and, after drying, 61 g (78% 25 of theory) of the same chemical-physical characteristics as obtained were obtained. in Example 1.

in

Claims (5)

A process for the preparation of pyrido-imidazo-rifamycins of the formula e CH Ch ch 5 ch 3 - 1 ^ 1 ^ OCH 3 f OH OH II V ^ CH, in IJ CO ^ CH 10 / S OH OH in 3 VyY I T- / ^ f 15 o-I-s. Wherein R 2 and R 2 independently represent hydrogen, (C 2 _) - all alkyl or halogen, 20 or R 2 and R 2 together with two neighboring carbon atoms in the pyridine nucleus form a benzene ring, characterized in that one mole equivalent is reacted rifamycin B of the formula 25 F ** 3 T * 3 j ^ 3 AND OH OH I I]; j '1 30. OH OH CO CH3 • "YYVV1" \\ O- CH2 -COOH 35 0 2 CH3 DK 161706 B 'having from 1 to 9 molar equivalents of 2-aminopyridine of formula η N Ό "p R Rn 2 10 R 2 has the meanings set forth above and with from 1 to 4 molar equivalents of a suitable oxidizing agent in the presence of a solvent or solvent system at a temperature between room temperature and the boiling point of the reaction mixture for a period of time between 10 and 100 hours and, if necessary, thereafter The reaction mixture with a suitable reducing agent. 2. A process according to claim 1, characterized in that for each mole equivalent of rifamycin B, from 2 to 4 mole equivalent enter 2-aminopyridine of formula (III) is used. 3. A process according to claim 1, characterized in that the oxidizing agent is selected from alkyl nitrites, quinones, organic peroxides, hydrogen peroxide, air and oxygen optionally in the presence of catalysts, iodine, manganese dioxide, lead tetraacetate, all caliper sulphates, ferric salts, cupric salts, mercuric salts. , alkaliferric cyanides, mercuric oxide and alkali hypochlorites. 4. A process according to claim 3, characterized in that the oxidizing agent is selected from iodine, potassium ferricyanide, sodium hypochlorite in aqueous solution and manganese dioxide. 5. A process according to claim 1, characterized in that the solvent or solvent system is selected from lower halogenated hydrocarbons, lower all channels, lower alkyl esters of lower aliphatic acids, acetonitrile, dioxane and tetrahydrofuran alone, mixed with each other. or mixed with water in various volumetric conditions.