CA1215976A - New process for the synthesis of imidazo rifamycins - Google Patents
New process for the synthesis of imidazo rifamycinsInfo
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- CA1215976A CA1215976A CA000480320A CA480320A CA1215976A CA 1215976 A CA1215976 A CA 1215976A CA 000480320 A CA000480320 A CA 000480320A CA 480320 A CA480320 A CA 480320A CA 1215976 A CA1215976 A CA 1215976A
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- alkyl
- pyridine
- amino
- rifamycin
- methyl
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Abstract
ABSTRACT
A process for the synthesis of imidazo rifamycins of for-mula wherein R is hydrogen or acetyl, R1 and R2 independently re-present hydrogen, (C1-4)-alkyl, benzyloxy, mono- or di-(C1-3)--alkylamino-(C1-4)-alkyl, (C1-3)-alkoxy-(C1-4)-alkyl, hydroxy--(C1-4)-alkyl, cyano, halogen, nitro, mercapto, (C1-4)-alkylthio, phenylthio, carbamoyl, mono- or di-(C1-4)-alkyl-carbamoyl, or R1 and R2 taken together with two consecutive carbon atoms of the pyridine nucleus form a benzene ring optionally substituted by 1 or 2 methyl or ethyl groups.
The process comprises reacting the rifamycin S of formula II
with a 2-aminopyridine of formula III
wherein R1 and R2 have the above seen meanings.
A process for the synthesis of imidazo rifamycins of for-mula wherein R is hydrogen or acetyl, R1 and R2 independently re-present hydrogen, (C1-4)-alkyl, benzyloxy, mono- or di-(C1-3)--alkylamino-(C1-4)-alkyl, (C1-3)-alkoxy-(C1-4)-alkyl, hydroxy--(C1-4)-alkyl, cyano, halogen, nitro, mercapto, (C1-4)-alkylthio, phenylthio, carbamoyl, mono- or di-(C1-4)-alkyl-carbamoyl, or R1 and R2 taken together with two consecutive carbon atoms of the pyridine nucleus form a benzene ring optionally substituted by 1 or 2 methyl or ethyl groups.
The process comprises reacting the rifamycin S of formula II
with a 2-aminopyridine of formula III
wherein R1 and R2 have the above seen meanings.
Description
2~5~76 The present invention rela-tes to a process for preparing imidazo rifamycins of formula I given hereaf-ter~
Some of the compounds of formula I
lo f ~co C~l3 ¦ ~ R2 more exactly those wherein R is hydrogen or acetyl and R
and R2 independently represent hydrogen, (Cl 4)-alkyl, benzyloxy, mono- or di-(Cl 3)-alkylamino-(Cl_4)-alkyl, (Cl_3)-alkoxy-(Cl_4)alkyl, hydroxy-(Cl 4)-alkyl, nitro or R
and R2 taken together with two consecutive carbon atoms of the pyridine nucleus form a benzene ring optionally sub-s-tituted by one or two methyl groups! are known from the literature, see U.S. patent No. 4,341,785, published on July 27, 1982.
Some other compounds of formula I, more exactly those wherein R is hydrogen or acetyl and at least one of R
or R2 represents halogen, cyano, mercapto, (Cl 4)-alkylthio, phenylthio, carbamoyl or mono- or di-(Cl 4)-alkylcarbamoyl have been described.
Some of the compounds of formula I
lo f ~co C~l3 ¦ ~ R2 more exactly those wherein R is hydrogen or acetyl and R
and R2 independently represent hydrogen, (Cl 4)-alkyl, benzyloxy, mono- or di-(Cl 3)-alkylamino-(Cl_4)-alkyl, (Cl_3)-alkoxy-(Cl_4)alkyl, hydroxy-(Cl 4)-alkyl, nitro or R
and R2 taken together with two consecutive carbon atoms of the pyridine nucleus form a benzene ring optionally sub-s-tituted by one or two methyl groups! are known from the literature, see U.S. patent No. 4,341,785, published on July 27, 1982.
Some other compounds of formula I, more exactly those wherein R is hydrogen or acetyl and at least one of R
or R2 represents halogen, cyano, mercapto, (Cl 4)-alkylthio, phenylthio, carbamoyl or mono- or di-(Cl 4)-alkylcarbamoyl have been described.
- 3 -LS97~;
A process for preparing the compounds of formula I
has also been described.
Briefly, the known method considered -the reac-tion between a molar amount of a 3-halo-rifamycin S of formula oc~
~C~13 ~ IV
C~ C C~13 O ~ O
1 ~0 wherein R represented hydrogen or acetyl and halo preferably represented bromine or iodine, and from about 2 to about 8 molar equivalents of a suitable 2-aminopyridine of formula H N N
2 , ~ ~3 Rl R2 or of an its salt.
A compound of formula C~ ~ ~ C~
~Xc~13 ' c113 ~ ~, h C~13 y 0 ¦ ~ R2 was obtained which was preferably isolated and characterized and then -treated with ascorbic acid -to give the end com-pounds of formula I.
The yields of the cited steps, calculated over -the starting compound IV, are some-times quite good (varyiny frorn about ~5~ to about 75~), but the process described in the U.S. patent is heavily impaired by the fac-t that the start-ing compound IV is not commercially available. In fact i-t lQ has to be prepared starting from rifamycin S by means of suitable, of-ten cumbersome, halogenation processes. Because of this fact, the methods for preparing the compounds of formula I described in U.S. patent No. 4,3~1,785 give global yields far lower than those pointed out and do not allow to obtain the desired products with satisfactory yield from -the industrial point of view.
' S~76 The presen-t invention provides a me-thod, for preparing imidazo rifamycins of general formula Ctl3 CH3 CH3 \~/ CH3 ~ CO CH3 wherein R is hydrogen or acetyl, R1 and R2 independently re-present hydrogen, (Cl 4)-alkyl, benzyloxy, mono- or di-(C1 )--alkylamino-(Cl ~ )-alkyl, tCl 3)-alkoxy-(C1 4)-alkyl, hydroxy--tCl 4)-alkyl~ cyano, halogen, nitro, rnercapto, (C1 4)-alkylthio, phenylthio, carbamoyl, mono- or di-(Cl 4)-alkyl-carbamoyl, or R1 and R ~ taken together with two consecutive carbon atoms of the pyridine nucleus form a benzene ring optionally substituted by 1 or 2 methyl or ethyl groups.
As used herein, the term (C1 4)-alkyl indicates straight or branched alkyl groups as, for instance, methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, isobutyl and tert.-butyl, while the ~2~sg7~
terrm (C1 3)-alkoxy mainly designates methoxy, ethoxy, propoxy or isop ropoxy g roups.
The compounds of forrnula 1 are endowed with outstanding antibacterial properties either in vitro and in vivo. In particular, they proved to be very useful in combatting gastro-int~stinal rrlicrobial infections, owing to their scarce absorption in the animal organs and tissues when a dministered by oral route .
The process described in the present invention represents a remarkable improvement over the method described in the prior art. In fact rifamycin S of formula CH CH CH
C~13COO~
~'3$~,h~
is used as the starting rifarriycin substrate, which is a commercial product easily obtainable either by chemical transformation of ri-famycin B as described in French Patent FM 739, Gr by acid hydrolysis of rifamycin 0, as described in Belgian patent N. 820517, or by halomycins oxidation by means of nitrous acid, -- ~Z~L5~317G
as described in U.S. patent N. 3800839 or by ~ermen~tation o~ Micro-monospora Chalcea strains, as described in U.S. patent N. 3884763.
I t is reacted with a molar excess of a 2-amino-pyridine of formula H2N N
~X
Rl R2 wherein Rl and R2 have the above given meanings, in the presence of iodine or of a suitable iodide/oxidizing agent system, optionally in the presence of an acidic agent, organic or inorganic, at a temperature comprised between the room temperature and the boiling tenlperature of the reaction mixture, in a suitable solvent or solvent system from which, by means of techniques known to a man skilled in ehe art, the desired end products are recovered, wherein R1 and R2 have the above meanings and R is acetyl, with yields from about 60% to about 80% calculated over the starting rifamycin S. The so obtained compounds of formula I can subsequently be subjected to an alkaline hydrolysis to give the corresponding compounds of formula I wherein R is hydrogen.
The reaction therefore takes place in only one step and is illustrated by the following scheme which does not report the hydrolytic step R = COCH3~ R = H.
..~
--`` 12159i'1G
~ g S C H E M E
GH ~ CH CH
0~
0~ (111) O ,~ O
CH3 ( I I ) 0-~3~
~I r~ 2 Rl and R2 as above R = acety i 2~S~
In practice, a molar amount of rifamycin S o~ formula 11 is reacted with from about 1 to about 8 rr~olar equivalents of a 2--aminopyridine of formula 111 and, preferably, with from about 3 to about 6 molar equivalents of said aminopyridine, optionally in presence of an acidic agent, organic or inorganic, as, for instance, hydriodic acid or acetic acid, in the presence of iodine or of a corresponding iodide/oxidizing agent system, in which the iodide can be, for instance, the iodide of an alkali or of an alkaline-earth metal or the iodhydrate of the same starting 2-aminopyridine and the oxidizing agent an agent capable to oxidize, under the employed reaction conditions, the iodide ion, in order to release iodine in the reaction ambient.
The iodine or the iodide/oxidizing agent system can respec-~ively be present in the reaction medium in amounts varying from about 0.1 to about 4 molar equivalents for each mole of starting rifamycin S or in amounts capable of releasing from about 0.1 to about 4 molar equivalents of iodine per mole of starting rifamycin S. The reaction is carried out in a solvent or solvent system generally selected among those comlnonly used in the rifamycins chemistry. For instance, lower halogenated hydrocarbons, like methylene chloride, chloroform, 1,2-dichloroethane and analogs, or lower alkanols like, for instance, methanol, ethanol, propanol, isopropanol or 4-butanol are used. Also lower alkyl esters of lower aliphatic acids, acetonitrile, dimethoxyethane, dioxane, tetra-~2~
hydrofuran, aromatic hydrocarbons proved to be good reactionsolvents. All of these solvents can be used alone or in admixture alnong them or with water in various ratios. The best results were obtained with solvents like 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 interval com-prised between the room temperature and the boiling temperature of the reaction mixture; generally, an interval comprised between the room temperature and abou-t 60DC is sufficient for obtaining the most satisfactory results.
The reaction is completed in a period of time which essentially depends vn the nature of the pyridine substrate of ~ormula lll, on the ratios of the reactants and on the reaction temperature. Generally, from about l to about 120 hours are required in order to obtain the end products of formula I with the desired yields.
The reaction solution must subsequently be treated by means of a suitable reducing agent, like, for instance, ascorbic acid, isoascorbic acid, or dihydroxyacetone. All the above mentioned operations take place without isolating the intermediate products so preserving the "one step reaction" character typical of the process of the present invention. The so obtained compounds of formula l wherein R is the acetyl group are recovered from the L5~76 reaction ambient according to known techniques.
Thus, for instance, the excess of unreacted aminopyridine of formula 111 is removed from the organic phase by treating it with an aqueous solution of a mineral acid. Subsequently the organic phase is separatecl, optionally dried on a suitable agent like, for instance, anhydrous sodiuln sulfate, and the end product is obtained by evaporating the solvent. Alternatively, the desired products are obtained by crystalli~ation from the reaction ambient at a temperature from about O~C to about 10C, when solvent systems are used which contain water.
If necessary, the compounds of formula I can be purified by crystallization from suitable solvents or solvent systems.
The compounds of formula l wherein R is acetyl can subse-quently be transformed into the corresponding compounds wherein R
is hydrogen by a mild alkaline hydrolysis. Alternatively, the same starting rifamycin S can be transformed into the corresponding desacetyl derivative and the process of the invention can be carried out~it according to scheme 1.
The present invention is illustrated by means of the following examples which nevertheless are not to be interpreted as a limitation of its aims.
The U.V. spectra were performed in absolute methanol with a Perkin-Elmer 552 spectrophotometer, the l.R. Spectra were perfor-med in KBr with a Perkin-Elmer 281-B spectrophotometer, while the ~ 59~7~
-- 13 -- , nuclear-magnetic resonance spectra }I-Nh/lR and 3C-NMR were performed in deuterochloroform, by using tetramethylsilarle as refe-rence standard, with a Varian XL100 spectrophotometer.
EXAMPL~ 1
A process for preparing the compounds of formula I
has also been described.
Briefly, the known method considered -the reac-tion between a molar amount of a 3-halo-rifamycin S of formula oc~
~C~13 ~ IV
C~ C C~13 O ~ O
1 ~0 wherein R represented hydrogen or acetyl and halo preferably represented bromine or iodine, and from about 2 to about 8 molar equivalents of a suitable 2-aminopyridine of formula H N N
2 , ~ ~3 Rl R2 or of an its salt.
A compound of formula C~ ~ ~ C~
~Xc~13 ' c113 ~ ~, h C~13 y 0 ¦ ~ R2 was obtained which was preferably isolated and characterized and then -treated with ascorbic acid -to give the end com-pounds of formula I.
The yields of the cited steps, calculated over -the starting compound IV, are some-times quite good (varyiny frorn about ~5~ to about 75~), but the process described in the U.S. patent is heavily impaired by the fac-t that the start-ing compound IV is not commercially available. In fact i-t lQ has to be prepared starting from rifamycin S by means of suitable, of-ten cumbersome, halogenation processes. Because of this fact, the methods for preparing the compounds of formula I described in U.S. patent No. 4,3~1,785 give global yields far lower than those pointed out and do not allow to obtain the desired products with satisfactory yield from -the industrial point of view.
' S~76 The presen-t invention provides a me-thod, for preparing imidazo rifamycins of general formula Ctl3 CH3 CH3 \~/ CH3 ~ CO CH3 wherein R is hydrogen or acetyl, R1 and R2 independently re-present hydrogen, (Cl 4)-alkyl, benzyloxy, mono- or di-(C1 )--alkylamino-(Cl ~ )-alkyl, tCl 3)-alkoxy-(C1 4)-alkyl, hydroxy--tCl 4)-alkyl~ cyano, halogen, nitro, rnercapto, (C1 4)-alkylthio, phenylthio, carbamoyl, mono- or di-(Cl 4)-alkyl-carbamoyl, or R1 and R ~ taken together with two consecutive carbon atoms of the pyridine nucleus form a benzene ring optionally substituted by 1 or 2 methyl or ethyl groups.
As used herein, the term (C1 4)-alkyl indicates straight or branched alkyl groups as, for instance, methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, isobutyl and tert.-butyl, while the ~2~sg7~
terrm (C1 3)-alkoxy mainly designates methoxy, ethoxy, propoxy or isop ropoxy g roups.
The compounds of forrnula 1 are endowed with outstanding antibacterial properties either in vitro and in vivo. In particular, they proved to be very useful in combatting gastro-int~stinal rrlicrobial infections, owing to their scarce absorption in the animal organs and tissues when a dministered by oral route .
The process described in the present invention represents a remarkable improvement over the method described in the prior art. In fact rifamycin S of formula CH CH CH
C~13COO~
~'3$~,h~
is used as the starting rifarriycin substrate, which is a commercial product easily obtainable either by chemical transformation of ri-famycin B as described in French Patent FM 739, Gr by acid hydrolysis of rifamycin 0, as described in Belgian patent N. 820517, or by halomycins oxidation by means of nitrous acid, -- ~Z~L5~317G
as described in U.S. patent N. 3800839 or by ~ermen~tation o~ Micro-monospora Chalcea strains, as described in U.S. patent N. 3884763.
I t is reacted with a molar excess of a 2-amino-pyridine of formula H2N N
~X
Rl R2 wherein Rl and R2 have the above given meanings, in the presence of iodine or of a suitable iodide/oxidizing agent system, optionally in the presence of an acidic agent, organic or inorganic, at a temperature comprised between the room temperature and the boiling tenlperature of the reaction mixture, in a suitable solvent or solvent system from which, by means of techniques known to a man skilled in ehe art, the desired end products are recovered, wherein R1 and R2 have the above meanings and R is acetyl, with yields from about 60% to about 80% calculated over the starting rifamycin S. The so obtained compounds of formula I can subsequently be subjected to an alkaline hydrolysis to give the corresponding compounds of formula I wherein R is hydrogen.
The reaction therefore takes place in only one step and is illustrated by the following scheme which does not report the hydrolytic step R = COCH3~ R = H.
..~
--`` 12159i'1G
~ g S C H E M E
GH ~ CH CH
0~
0~ (111) O ,~ O
CH3 ( I I ) 0-~3~
~I r~ 2 Rl and R2 as above R = acety i 2~S~
In practice, a molar amount of rifamycin S o~ formula 11 is reacted with from about 1 to about 8 rr~olar equivalents of a 2--aminopyridine of formula 111 and, preferably, with from about 3 to about 6 molar equivalents of said aminopyridine, optionally in presence of an acidic agent, organic or inorganic, as, for instance, hydriodic acid or acetic acid, in the presence of iodine or of a corresponding iodide/oxidizing agent system, in which the iodide can be, for instance, the iodide of an alkali or of an alkaline-earth metal or the iodhydrate of the same starting 2-aminopyridine and the oxidizing agent an agent capable to oxidize, under the employed reaction conditions, the iodide ion, in order to release iodine in the reaction ambient.
The iodine or the iodide/oxidizing agent system can respec-~ively be present in the reaction medium in amounts varying from about 0.1 to about 4 molar equivalents for each mole of starting rifamycin S or in amounts capable of releasing from about 0.1 to about 4 molar equivalents of iodine per mole of starting rifamycin S. The reaction is carried out in a solvent or solvent system generally selected among those comlnonly used in the rifamycins chemistry. For instance, lower halogenated hydrocarbons, like methylene chloride, chloroform, 1,2-dichloroethane and analogs, or lower alkanols like, for instance, methanol, ethanol, propanol, isopropanol or 4-butanol are used. Also lower alkyl esters of lower aliphatic acids, acetonitrile, dimethoxyethane, dioxane, tetra-~2~
hydrofuran, aromatic hydrocarbons proved to be good reactionsolvents. All of these solvents can be used alone or in admixture alnong them or with water in various ratios. The best results were obtained with solvents like 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 interval com-prised between the room temperature and the boiling temperature of the reaction mixture; generally, an interval comprised between the room temperature and abou-t 60DC is sufficient for obtaining the most satisfactory results.
The reaction is completed in a period of time which essentially depends vn the nature of the pyridine substrate of ~ormula lll, on the ratios of the reactants and on the reaction temperature. Generally, from about l to about 120 hours are required in order to obtain the end products of formula I with the desired yields.
The reaction solution must subsequently be treated by means of a suitable reducing agent, like, for instance, ascorbic acid, isoascorbic acid, or dihydroxyacetone. All the above mentioned operations take place without isolating the intermediate products so preserving the "one step reaction" character typical of the process of the present invention. The so obtained compounds of formula l wherein R is the acetyl group are recovered from the L5~76 reaction ambient according to known techniques.
Thus, for instance, the excess of unreacted aminopyridine of formula 111 is removed from the organic phase by treating it with an aqueous solution of a mineral acid. Subsequently the organic phase is separatecl, optionally dried on a suitable agent like, for instance, anhydrous sodiuln sulfate, and the end product is obtained by evaporating the solvent. Alternatively, the desired products are obtained by crystalli~ation from the reaction ambient at a temperature from about O~C to about 10C, when solvent systems are used which contain water.
If necessary, the compounds of formula I can be purified by crystallization from suitable solvents or solvent systems.
The compounds of formula l wherein R is acetyl can subse-quently be transformed into the corresponding compounds wherein R
is hydrogen by a mild alkaline hydrolysis. Alternatively, the same starting rifamycin S can be transformed into the corresponding desacetyl derivative and the process of the invention can be carried out~it according to scheme 1.
The present invention is illustrated by means of the following examples which nevertheless are not to be interpreted as a limitation of its aims.
The U.V. spectra were performed in absolute methanol with a Perkin-Elmer 552 spectrophotometer, the l.R. Spectra were perfor-med in KBr with a Perkin-Elmer 281-B spectrophotometer, while the ~ 59~7~
-- 13 -- , nuclear-magnetic resonance spectra }I-Nh/lR and 3C-NMR were performed in deuterochloroform, by using tetramethylsilarle as refe-rence standard, with a Varian XL100 spectrophotometer.
EXAMPL~ 1
4-Deoxy=4'--methyl-pyrido~!.~',2'.1,~ imidazo ~,4-c7 rifamycin SV
4.9 Grams (0.007 moles) of rifamycin S, 2.27 g (0.021 nloles ) of 2-amino-4-methyl-pyridine and 0.89 g (0.0035 moles ) of iodine are dissolved in 30 rnl of methylene chloride and the resulting reaction mixture is stirred at room ternperature for 30 hours. Then the reaction mixture is added with 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 subsequen~ly with water to neutrality. Then the solvent is evaporated off under vacuum and the residue is crystallized from a 7/3 tv/v) mixture of ethanol/wa-ter. After filtering and drying g 4.2 of product are obtained with a yielcl of 76% of theoretical, which has the following chemico-- p hys ic al c harac teris tics:
1%
U.V. Spectrum~ max (my) ~lcm ~2~59b7/~;
I.R. Spectrum: characteristic absorption bands were observed at the following frequencies (in cm ): 3440 (b), 2960 (s), 2920 (s), 2~60 (w), 2820 (vw), 1705 (s), 1640 (s), 1580 (s), 1500 (s).
b = broad; s = strong; w = weak; vw = very weak.
~ NMR Spectrum: characteristic resonance peaks were observed at the following~ (expressed as p.p.m.): -0.56 (d,3H); 0.14 (d,3}1);
0.74 (d,311); 0.''4 (d,3H); 1.94 (s,31-1); 1.98 (s,31~); 2.02 (s,3~
2.26 (s,3H); 2.63 (s,3H); 3.00 (s,3H); 3.2-3.9 (m,3~1); 4.15-5.20 (m,211); 5.9-6.9 (m,4~1); 7.06 (dd,lH); 7.38 (s, lH); 8.39 (s, lH);
8.43 (d,lH); 11.0 (s,lH); 13.12 (s,lH).
s = singlet; d ~ doublet; m = multiplet; dd = double of doublet.
3C-NMR Spectrum: characteristic resonance peaks were observed at the followingol'? (expressed as p.p.m.): 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;
123.96; 136.21; 138.87; lLl.75; 142.10; 147.74; 155.10; 170.63;
171.89; 182.19; 188.84.
4-Deoxy-4'-methyl-pyrido ~',2':1,2~7imidazo ~,4-~7rifamycin SV6.95 Grams(0.01 moles) of rifamycin S and 3.24 g (0.03 moles) of 2-amino-4-methyl-pyridine are dissolved in 20 ml of me-thylene chloride and the reaction mixture is added with a solution of 3.8 g (0.015 moles ) of iodine in 100 ml of methylene chloride in z~
one hour under vigorous stirring. The reaction mixture is stirred for further four hours at room teMperature and is subsequently ad-ded with 20 ml oF a 20% (w/v) aqueous solution of ascorbic acid.
Stirring is continued for further 30 nlinutes, then the phases are separated and the organic layer is first washed with a 0.5 N
aqueous solution of hydrochloric acid and subsequently with water to neutrality. After evaporating in vacuo the methylene chloride, a residue is obtained, which is crystallized from a 7:3 (v/v) mixture of ethanol/water to give 6.1 g of product having the same chemico-physical characteristics as those of the compound de-scribed in Example 1. The yield is 78% of theoretical.
E~AMPLE 3 3 ' -Chloro-4-deoxy-pyrido ~',2 ': 1,27 imidazo ~,4-c7 rif amycin SV
By substantially operating as described in Example 1, starting from 3.47 g (0.005 moles) of rifamycin S, 1.54 g (0.012 moles) of 2-amino-5-chloro-pyridine and 0.63 g (0.0025 moles) of iodine in 20 ml of methylene chloride, 2.8 g of the title product are obtained with a yield of 68% of theoretical.
The compound shows the following chemia~physical charac-teristics:
U.V. Spectrum: ¦ max (m~l) E1Y
238 508,5 I.R. Spectrum: characteristic absorption bands werè observed at the ~ollowing frequencies (in cm ): 3430 (b); 3200 (w); 3090 (w);
2960 (m); 2920 (nl); 2870 (w); 1712 (s); 1635 (s); 1595 (s); 1575 ( s ) .
b = broad; w = weak; m = medium; s = strong.
Il-NMR Spectrum: characteristic resonance peaks were observed at the folls)wing ~ (expressed as p.p.m.): -0.63 (d,3H); 0.12 (d,3~1);
0.77 (d,3~1j; 0.93 (d,3H); 1.89 (s,3H); 1.94 (s,3H); 1.99 (s,3H);
2.24 (s,3H); 2.83 (d,lH); 2.94 (s,3H); 3.25 (d,lll); 3.57 (d,lH);
3.30-4.00 (m,2H~; 4.82 ~d,lH); 4.96 (q,lH); 5.97 (d,lH); 5.80-6.96 (m,3H); 7.74 (m,2H); 8.51 (s,lH); 8.62 (d,lH); 15.56 (broad, s,lH); 16.75 (s,lH).
s = singlet; d = doublet; q = quartet; m = multiplet.
3C-NMR Spectrum: characteristic resonance peaks were observed at the followingd~ (expressed as p.p.m.): 6.81; 7.73; 7.95; 10.05;
16.9~; 20.02; 20.07; 20.10; 32.57; 36.55; 37.60; 38.22; 56.78; 72.43;
73.36; 76.42; 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.
EXAMP 1~ E 4 3' ,5'-Dibrom~4-deoxy-pyrido ~' ,2':1,2,7 imidazo ~5,4-c~ rifa-myc in SV
By substantially operating as described in Example 1, starting from 1.39 g (0.002 moles) of rifamycin S`, 1.76 g (0.007moles) of 2-arnino-3,5-dibrorno-pyridine and 0.25 g (0.001 moles) of iodine in 15 ml of me~hylene chloride, 1.35 g of the title product are obtained with a yield of 71% of theoretical.
The compound shows the following chemico-physical charac-teristics:
1%
U.V~ Spectrum: lmax (m~)1 cm I.R. Spectrum: characteristic absorption bands were observed at the following frequencies (in cm ): 3480 (b~; 3350 (b); 3200 (w);
2980 (m); 2940 (m); 2880 (w); 1715 (s); 1650 (s); 1625 ~m); 1600 (s); 1580 (m), b = broad; w = weak; m = medium; s = strong.
I_NMR Spectrum: characteristic resonance peaks were observed atthe following c~(expressed as p.pOm.): ~.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,lH); 3.03 (s,3H); 3.20-4.00 (m,4H); 4.87 (d,lII~; 5.11 (q,lH); 6.12 (d,lH); 6.00-7.00 (rm,3H); 7.94 (d,lH~; 8.52 (d,lH);
15.48 (broad, s,lH); 16.66 (broad, s,l~I).
s = singlet; d = doublet; q = quartet; m = multiplet.
, .
- ~-z~s~
C-NMR Spectrunl: characteristic resonance peaks w`ere observed at the following ~ (expressed as p.p.m.): 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; 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.
4-Deoxy-isoquinolino ~',1':1,~7 imidazo ~,4-c~7 rifamycin SV
By substan~ially operating as described in Example 2, starting frorn 6.95 g (0.01 moles) of rifamycin S, 4.32 g (0.03 moles) of 1-amino-isoquinoline and 3.80 g (0.015 moles) of iodine,
4.9 Grams (0.007 moles) of rifamycin S, 2.27 g (0.021 nloles ) of 2-amino-4-methyl-pyridine and 0.89 g (0.0035 moles ) of iodine are dissolved in 30 rnl of methylene chloride and the resulting reaction mixture is stirred at room ternperature for 30 hours. Then the reaction mixture is added with 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 subsequen~ly with water to neutrality. Then the solvent is evaporated off under vacuum and the residue is crystallized from a 7/3 tv/v) mixture of ethanol/wa-ter. After filtering and drying g 4.2 of product are obtained with a yielcl of 76% of theoretical, which has the following chemico-- p hys ic al c harac teris tics:
1%
U.V. Spectrum~ max (my) ~lcm ~2~59b7/~;
I.R. Spectrum: characteristic absorption bands were observed at the following frequencies (in cm ): 3440 (b), 2960 (s), 2920 (s), 2~60 (w), 2820 (vw), 1705 (s), 1640 (s), 1580 (s), 1500 (s).
b = broad; s = strong; w = weak; vw = very weak.
~ NMR Spectrum: characteristic resonance peaks were observed at the following~ (expressed as p.p.m.): -0.56 (d,3H); 0.14 (d,3}1);
0.74 (d,311); 0.''4 (d,3H); 1.94 (s,31-1); 1.98 (s,31~); 2.02 (s,3~
2.26 (s,3H); 2.63 (s,3H); 3.00 (s,3H); 3.2-3.9 (m,3~1); 4.15-5.20 (m,211); 5.9-6.9 (m,4~1); 7.06 (dd,lH); 7.38 (s, lH); 8.39 (s, lH);
8.43 (d,lH); 11.0 (s,lH); 13.12 (s,lH).
s = singlet; d ~ doublet; m = multiplet; dd = double of doublet.
3C-NMR Spectrum: characteristic resonance peaks were observed at the followingol'? (expressed as p.p.m.): 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;
123.96; 136.21; 138.87; lLl.75; 142.10; 147.74; 155.10; 170.63;
171.89; 182.19; 188.84.
4-Deoxy-4'-methyl-pyrido ~',2':1,2~7imidazo ~,4-~7rifamycin SV6.95 Grams(0.01 moles) of rifamycin S and 3.24 g (0.03 moles) of 2-amino-4-methyl-pyridine are dissolved in 20 ml of me-thylene chloride and the reaction mixture is added with a solution of 3.8 g (0.015 moles ) of iodine in 100 ml of methylene chloride in z~
one hour under vigorous stirring. The reaction mixture is stirred for further four hours at room teMperature and is subsequently ad-ded with 20 ml oF a 20% (w/v) aqueous solution of ascorbic acid.
Stirring is continued for further 30 nlinutes, then the phases are separated and the organic layer is first washed with a 0.5 N
aqueous solution of hydrochloric acid and subsequently with water to neutrality. After evaporating in vacuo the methylene chloride, a residue is obtained, which is crystallized from a 7:3 (v/v) mixture of ethanol/water to give 6.1 g of product having the same chemico-physical characteristics as those of the compound de-scribed in Example 1. The yield is 78% of theoretical.
E~AMPLE 3 3 ' -Chloro-4-deoxy-pyrido ~',2 ': 1,27 imidazo ~,4-c7 rif amycin SV
By substantially operating as described in Example 1, starting from 3.47 g (0.005 moles) of rifamycin S, 1.54 g (0.012 moles) of 2-amino-5-chloro-pyridine and 0.63 g (0.0025 moles) of iodine in 20 ml of methylene chloride, 2.8 g of the title product are obtained with a yield of 68% of theoretical.
The compound shows the following chemia~physical charac-teristics:
U.V. Spectrum: ¦ max (m~l) E1Y
238 508,5 I.R. Spectrum: characteristic absorption bands werè observed at the ~ollowing frequencies (in cm ): 3430 (b); 3200 (w); 3090 (w);
2960 (m); 2920 (nl); 2870 (w); 1712 (s); 1635 (s); 1595 (s); 1575 ( s ) .
b = broad; w = weak; m = medium; s = strong.
Il-NMR Spectrum: characteristic resonance peaks were observed at the folls)wing ~ (expressed as p.p.m.): -0.63 (d,3H); 0.12 (d,3~1);
0.77 (d,3~1j; 0.93 (d,3H); 1.89 (s,3H); 1.94 (s,3H); 1.99 (s,3H);
2.24 (s,3H); 2.83 (d,lH); 2.94 (s,3H); 3.25 (d,lll); 3.57 (d,lH);
3.30-4.00 (m,2H~; 4.82 ~d,lH); 4.96 (q,lH); 5.97 (d,lH); 5.80-6.96 (m,3H); 7.74 (m,2H); 8.51 (s,lH); 8.62 (d,lH); 15.56 (broad, s,lH); 16.75 (s,lH).
s = singlet; d = doublet; q = quartet; m = multiplet.
3C-NMR Spectrum: characteristic resonance peaks were observed at the followingd~ (expressed as p.p.m.): 6.81; 7.73; 7.95; 10.05;
16.9~; 20.02; 20.07; 20.10; 32.57; 36.55; 37.60; 38.22; 56.78; 72.43;
73.36; 76.42; 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.
EXAMP 1~ E 4 3' ,5'-Dibrom~4-deoxy-pyrido ~' ,2':1,2,7 imidazo ~5,4-c~ rifa-myc in SV
By substantially operating as described in Example 1, starting from 1.39 g (0.002 moles) of rifamycin S`, 1.76 g (0.007moles) of 2-arnino-3,5-dibrorno-pyridine and 0.25 g (0.001 moles) of iodine in 15 ml of me~hylene chloride, 1.35 g of the title product are obtained with a yield of 71% of theoretical.
The compound shows the following chemico-physical charac-teristics:
1%
U.V~ Spectrum: lmax (m~)1 cm I.R. Spectrum: characteristic absorption bands were observed at the following frequencies (in cm ): 3480 (b~; 3350 (b); 3200 (w);
2980 (m); 2940 (m); 2880 (w); 1715 (s); 1650 (s); 1625 ~m); 1600 (s); 1580 (m), b = broad; w = weak; m = medium; s = strong.
I_NMR Spectrum: characteristic resonance peaks were observed atthe following c~(expressed as p.pOm.): ~.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,lH); 3.03 (s,3H); 3.20-4.00 (m,4H); 4.87 (d,lII~; 5.11 (q,lH); 6.12 (d,lH); 6.00-7.00 (rm,3H); 7.94 (d,lH~; 8.52 (d,lH);
15.48 (broad, s,lH); 16.66 (broad, s,l~I).
s = singlet; d = doublet; q = quartet; m = multiplet.
, .
- ~-z~s~
C-NMR Spectrunl: characteristic resonance peaks w`ere observed at the following ~ (expressed as p.p.m.): 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; 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.
4-Deoxy-isoquinolino ~',1':1,~7 imidazo ~,4-c~7 rifamycin SV
By substan~ially operating as described in Example 2, starting frorn 6.95 g (0.01 moles) of rifamycin S, 4.32 g (0.03 moles) of 1-amino-isoquinoline and 3.80 g (0.015 moles) of iodine,
5.9 g of the title compound are obtained with a yield of 72% of t heoretic al .
This compounds shows the following chemico-physical characteristics:
~lelting point: 181-186C (decomposition).
U.V,_ Spectrum: A rllaX (m~)Ellyocm -` ~L2~LS~
-- 19 -- .
_R. Spectrum characteristic absorption bands were observed at the following frequencies (in cm ): 3440 (b), 3140 (b), 2910 (s), 2850 (w), 1700 (s), 1630 (b), 1610 (b), 1580 (w), 1555 (vw), 1535 ( vw ) .
b = broad; s = strong; w = weak; vw = very weak.
_I~IMR Spectrum: characteristic resonance peaks were observed at the following S (expressed as p.p.m.): -0.65 (d,3H); 0.04 (d,3H);
0.7 (d,311); 0.88 (d,311); 1.55 (s,3H); 1.92 (s,3H); 2.02 (s,3H);
2.27 (s,3H); 2.77 (d,1H); 2.94 (s,31-1); 3.00-3.90 (m,4H); 4.78 - (d,1H); 4.93 (q,llI); 5.75-7.00 (m,4H); 7.34 (d,lH); 7.6-8.0 (m,6H); 16.6 (m,111).
s = singlet; d = doublet; m = multiplet; q = quartet.
3',5'-dichloro-4-deoxy-pyrido ~',2':1,2~7 imidazo ~,4-c7 rifa-mycin 5V
By substantially operating as described in Example 2, starting from 4.9 g (0.007 moles) of rifamycin S, 3.42 g (0.021 moles) oï 2-amino-3,5-dichloropyridine and 2.66 g (0.0105 moles) of iodine, 4 g of the title product are obtained with a yield of 67% of theoretical. This compound shows the following chemico-physical characteristics:
-^``` ~Z~5~7~
U.V. Spectrum: ~max (m)l) E
1 cm _R. Spectrum: characteristic absorption bands were observed at the following frequencies (in Clll ): 3450 ~b); 3250 (w); 2970 (m);
2930 (m); 2880 (m); 1710 (s); 1640 (s); 1585 (s).
b = broad; m = medium; w = w~ak; s = strong.
_NMR Spectrurm: characteristic resonance peaks were observed at the following d~(expressed as p.p.m.): -0.56 (d,3H); 0.23 (d,3H);
0.78 (d,3H); O.9L (d,3H); 1.92 (s,3H); 1.97 (s,6H); 2.25 (s,3H);
2.70-3.00 ~ ,1H); 2.98 (s,3H); 3.10-3.80 (m,4H); 4.84 (d,lH); 5.05 (q,lH); 6.03 (d,lH); 6.00-7.00 (m,3~1); 7.18 (s,lH); 8.13 (s,lH);
8.35 (s,1H); 16.00 (broad, s,lH); 16.45 (large; s,lH) s = singlet; d = doublet; q = quartet; m = rnultiplet C-N~IR Spectrum: characteristic resonance peaks were observed at the following ~(expressed as p.p.m.): 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.S9; 106.15; 110.52; 112.50; 116.80;
116.95; 119.97; 121.23; 124.96; 125.57; 125.62; 126.00; 128.45;
13~.03; 137.53; 138.06; 142.07; 142.83; 155.15; 170.74; 170.9~;
172.21; 181.66; 184.91 ~ L5~7~
4-Deoxy-4'-methyl-pyrido ~' ,2' ~ 7 imidazo ~,4=c7 rifalllycin SV
l\ solu~ion of 6.95 g (0.01 moles) of rifamycin S and of 3.24 g (0.03 nloles) of 2-amino-4-methyl-pyridine in 20 nll of acetonitrile is added portionwise with 3.80 g (0.015 moles) of iodine in one hour and the reaction is continued for further six hours under stirring at room ternperature. Then the reaction mixture is added with 20 rnl of a 20% (w/v) aqueous solution of ascorbic acid and stirred for further 30 minutes. Subsequently 5 ml of acetic acid and 25 rnl of a O.lN ~queous solution of hydrochloric acid are added and the reaction mixture is left standing overnight at 5C. The crystallized solid is filtered and dried giving 5.1 g of product with a yield of 65% of ~heoretical. The obtained compound has the same chemico-physical characteristics as that of Fxam-ple l.
EXA~I P LE 8 _ 4-Deoxy-4'-methyl-pyrido ~',2':1,2~ imidazo ~4-c7 rifamycin SV
A solution of 4.9 g (0.007 moles) of rifamycin S, 3 g (0.028 moles ) of 2-amino-4-methylpyridine and 3 g (0.012 moles ) of iodine in 30 ml of methylene chloride is heated at the boiling temperature of the reaction mixture for one hoilr. After cooling to room tempe-rature, the solution is added with 20 ml of a 25% (w/v) aqueous solution of ascorbic acid and is stirred for 30 minutes. The two layers are separated, the organic one is twice washed with 30 ml ~LZ~5~7~
- 22 - , of 1 N aqueous solution of hydrochloric acid and a~fterwards with water to neutrality and subsequently dried over sodium sulfate.
After filtering and evaporating the solvent, a residue is obtained, which is crystallized from 7/3 (v/v) mixture of ethanol/water to give 4.4 g of product with a yield of 80% of theoretical. The compound has the same chemico-physical characteristics as that obtained in Example 1.
4-Deoxy-S'-methyl-pyrido ~',2':1,27 imidazo ~,4-c7 rifamycin SV
A solution of 4.9 g (0.007 moles) of rifamycin S, 3 g (0.028 moles) of 2-amino-3-methyl-pyridine, 3.3 g (0.014 moles) of 2~anlino-3-methyl-pyridine hydroiodide and 1.8 g (0.0071 nloles ) of iodine in 35 ml of methylene chloride is heated at the boiling temperature of the reaction mixture for a period of 4 hours. After cooling, the solution is added wi~h 10 ml of a 25% (w/v) aqueous solution of ascorbic acid and stirred for 30 minutes. The two layers are separated, the organic one is twice washed with 30 ml of a 1 N aqueous solution of hydrochloric acid and then with water to neutrality and subsequently dried over sodium sulfate.
After filtering and evaporating the solvent, a residue is obtained which is crystallized from a 7/3 (v/v) mixture of ethanol/water, thus obtaining 4.1 g of product with a yield of 75% of theoretical.
This product shows the following chemico-physical charac-teristics:
.
-- ~3 --Melting point: 185~-190C (decomposition).
U.V. Spectrum: ,~ max (Iny) E
1 cm _R. Spectrum: characteristic absorption bands were observed at the following frequencies (in cm ): 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 = broad; s = strong; w = weak; vw = very weak.
_NMR Spectrum: characteristic resonance peaks were observed at the ~ollowing d~(expressed as p.p.m.): -o.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,21-1); 8.27 (s,lH); 8.47 (s,ll-l); 14.86 ls,lil); 16.77 (s,lH).
s = singlet; d = doublet; m = multiplet.
5~t'6 -~ -- 24 --4-Deoxy-41-methyl-pyrido ~', 2':1,2J imidazo ~ c7 rifamycin SV
-A solution of 6.95 g (0.01 moles) of rifamycin S, 4.32 g (0.04 moles) of 2-arnino-4-methyl-pyridine, 2.4 g (0.04 moles) of acetic acid and 0.25 g (0.001 moles) of iodine in 40 ml of methylene chloride is kep~ at room temperature for 5 days. Then the reaction rtlixture is added with 0.37 g (0.002 moles) of ascorbic ~Lcid and is stirred for 30 minutes. Afterwards, it is washed with a 0.5 N aqueous solution of hydrochloric acid and then with water and lastly it is evaporated to dryness under reduced pressure. The residue is crystallized from a 7/3 (v/v) Inixture of ethanol/water to give 5.74 g of product with a yield of 73% of theoretical.
The product has the same chemico-physical characteristics as the product of Example 1.
4-Deoxy-4'-methyl-pyrido ~' ,2':1,~7 imidazo ~,4-c,7 rifamycin SV
A solution of 4.9 g (0.007 moles) of rifamycin S, 3 g (0.028 moles) of 2-amino-4-methyl-pyridine, 0.45 g (0,0018 rnoles) of iodine and 1.65 ml (0.029 rnoles) of acetic acid in 15 ml of acetonitrile is kept at room temperature for 48 hours. Afterwards, the reaction mixture is added with further 0.2 g (0.0008 moles) of iodine and kept at room temperature for further 16 hours. Then it is added with 3 ml of a 25% (w/v) aqueous solution of ascorbic acid and, after further 30 rninutes, it is cliluted with 85 ml of methylene chloride. The organic solution is twice washed with ~2~1L5~7 30 ml of a l N aqueous solution of hydrochloric acid 9 then with water to neutrality and dried over sodiur" sulfate. After filtering and evaporating the solvent in vacuo a residue is obtained which is crystallized fronl a 7/3 (v/v) mixture of ethanol/water, thus obtaining 4.2 g of product with a yield of 77% of theoretical.
The product has the same chemico-physical characteristics as that described in Example 1.
EXAI~/I P L E 12 4-Deoxy-4'-methyl-pyrido ,~'2' :1,27 imidazo ~,4-~7 rifamycin SV
4.9 Grams (0.007 moles) of rifamycin S, 3 g (0.028 moles) of 2-amino-4-methyl-pyridine, 3.3 g (0.014 moles) of 2-arnino-4--methyl-pyridine hydroiodide and 0.89 g (0.0035 moles) of iodine are dissolved in 20 ml of dimethoxyethane and the reaction is left standing at room temperature for 20 hours. The reaction mixture is then added with 5 rnl of a 25% (w/v) aqueous solution of ascorbic acid and left under stlrring for 30 minutes. Afterwards the reaction is diluted with 100 ml of methylene chloride, twice washed with 30 ml of a 1 N aqueous solution of hydrochloric acid, then with water to neutrality. The organic phase is dried on anhydrous sodium sulfate and filtered and the solvent is evaporate off.
The residue is crystallized from a 7/3 (v/v) mixture of ethanol and water, thus obtaining 3.7 g, with a yield of ~8% of theoretical, of product having the same chenlico-physical charac-teristics as those of the product described in Example 1.
_Deoxy~4'-methyl-pyrido ~' ,2' :1,27 imidazo ~5,4-c7 rifamycin SV
696 Grams (1 mole) of rifamycin S, 324 g (3 rnoles) of 2-amino-4-nlethyl-pyridine and 127 g (0.5 moles) of iodine are dissolved in 3 liters of methylene chloride and the reaction is kept at room temperature for 24 hours. Afterwards it is added with 0.5 liters of a 20% (w/v) aqueous solution of ascorbic acid and stirred for one hour. The aqueous phase is cast off and the organic phase is first washed three times with 1 liter of a 1 N aqueous solution of hydrochloric acid in order to eliminate the unreacted excess of 2-amino-4-methyl~pyridine, then with water to neutrality, and finally it is evaporated to dryness under vacuum. The solid residue is crystallized fronl a 7/3 ~ v/v ) mixture of ethanol/water whereby 613 g of product are obtained, with a yield of 78% of theoretic al .
The so obtained product shows the same chemico-physical characteristics as those of the product described in Example 1.
4'-Deoxy-4'-methyl-pyrido 6',2':1,27 imidazo ~,4-c7 rifamycin SV
487 Grarns (0.7 moles) of rifamycin S, 303 g (2.8 moles) of 2-amino-4-methyl-pyridine and 254 g (1 mole) of iodine are dissolved in 3 liters of methylene chloride and the reaction is kept at roorn temperature for 4 hours. Afterwards it is added with 1.5 liters of a 25% (w/v) aqueous solution of ascorbic acid and stirred L2~5~7~
for 30 minutes. The aqueous phase is discarded, the organic phase is washed four times with 1 liter of a 1 N aqueous solution of hydrochloric acid in order to eliminate the unreacted excess of 2-am ino-4-methyl-pyridine, then it is washed with water to neutrality and finally dried over sodium sulfate. After filtering and evaporating the solvent, a residue is obtained, which is crystallized from a 7/3 (v/v) mixture of ethanol/water whereby 440 g of product are obtained, with a yield of 80% of theoretical.
The so obtained product shows the same chemico-physical characteristics as those of the product described in Example 1.
By substantially operating as described in the previous Examples, the following compounds of formula 1 can be prepared.
s~
R Rl 2 COC~13 11 -4 '-C~120~1 COCH3 H -4 ' -CH -C}12-N (Cl-13 )2 COCH3 H -4 '-OCH2C6115 COCH3 H -4 '-NO
~- ~ 3 -3'-CH _4~-cll2-c}l2-cll2 N(CH3 ~L
C OCH3 -5 ~ -CH3 -3 ~ -cH2-cH2-N ( C H3 ) 2 COCH3 H -3 ' -SH
COCH3 H 3 ' -CH3 COCH3 H -4 '-CO-NH2 COCH3 H -4 '-CO-N(CH3)2 COCH3 -3'-Br _4'-c~12-N(cll3 2 COCH3 H -4 '-S-C6H5
This compounds shows the following chemico-physical characteristics:
~lelting point: 181-186C (decomposition).
U.V,_ Spectrum: A rllaX (m~)Ellyocm -` ~L2~LS~
-- 19 -- .
_R. Spectrum characteristic absorption bands were observed at the following frequencies (in cm ): 3440 (b), 3140 (b), 2910 (s), 2850 (w), 1700 (s), 1630 (b), 1610 (b), 1580 (w), 1555 (vw), 1535 ( vw ) .
b = broad; s = strong; w = weak; vw = very weak.
_I~IMR Spectrum: characteristic resonance peaks were observed at the following S (expressed as p.p.m.): -0.65 (d,3H); 0.04 (d,3H);
0.7 (d,311); 0.88 (d,311); 1.55 (s,3H); 1.92 (s,3H); 2.02 (s,3H);
2.27 (s,3H); 2.77 (d,1H); 2.94 (s,31-1); 3.00-3.90 (m,4H); 4.78 - (d,1H); 4.93 (q,llI); 5.75-7.00 (m,4H); 7.34 (d,lH); 7.6-8.0 (m,6H); 16.6 (m,111).
s = singlet; d = doublet; m = multiplet; q = quartet.
3',5'-dichloro-4-deoxy-pyrido ~',2':1,2~7 imidazo ~,4-c7 rifa-mycin 5V
By substantially operating as described in Example 2, starting from 4.9 g (0.007 moles) of rifamycin S, 3.42 g (0.021 moles) oï 2-amino-3,5-dichloropyridine and 2.66 g (0.0105 moles) of iodine, 4 g of the title product are obtained with a yield of 67% of theoretical. This compound shows the following chemico-physical characteristics:
-^``` ~Z~5~7~
U.V. Spectrum: ~max (m)l) E
1 cm _R. Spectrum: characteristic absorption bands were observed at the following frequencies (in Clll ): 3450 ~b); 3250 (w); 2970 (m);
2930 (m); 2880 (m); 1710 (s); 1640 (s); 1585 (s).
b = broad; m = medium; w = w~ak; s = strong.
_NMR Spectrurm: characteristic resonance peaks were observed at the following d~(expressed as p.p.m.): -0.56 (d,3H); 0.23 (d,3H);
0.78 (d,3H); O.9L (d,3H); 1.92 (s,3H); 1.97 (s,6H); 2.25 (s,3H);
2.70-3.00 ~ ,1H); 2.98 (s,3H); 3.10-3.80 (m,4H); 4.84 (d,lH); 5.05 (q,lH); 6.03 (d,lH); 6.00-7.00 (m,3~1); 7.18 (s,lH); 8.13 (s,lH);
8.35 (s,1H); 16.00 (broad, s,lH); 16.45 (large; s,lH) s = singlet; d = doublet; q = quartet; m = rnultiplet C-N~IR Spectrum: characteristic resonance peaks were observed at the following ~(expressed as p.p.m.): 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.S9; 106.15; 110.52; 112.50; 116.80;
116.95; 119.97; 121.23; 124.96; 125.57; 125.62; 126.00; 128.45;
13~.03; 137.53; 138.06; 142.07; 142.83; 155.15; 170.74; 170.9~;
172.21; 181.66; 184.91 ~ L5~7~
4-Deoxy-4'-methyl-pyrido ~' ,2' ~ 7 imidazo ~,4=c7 rifalllycin SV
l\ solu~ion of 6.95 g (0.01 moles) of rifamycin S and of 3.24 g (0.03 nloles) of 2-amino-4-methyl-pyridine in 20 nll of acetonitrile is added portionwise with 3.80 g (0.015 moles) of iodine in one hour and the reaction is continued for further six hours under stirring at room ternperature. Then the reaction mixture is added with 20 rnl of a 20% (w/v) aqueous solution of ascorbic acid and stirred for further 30 minutes. Subsequently 5 ml of acetic acid and 25 rnl of a O.lN ~queous solution of hydrochloric acid are added and the reaction mixture is left standing overnight at 5C. The crystallized solid is filtered and dried giving 5.1 g of product with a yield of 65% of ~heoretical. The obtained compound has the same chemico-physical characteristics as that of Fxam-ple l.
EXA~I P LE 8 _ 4-Deoxy-4'-methyl-pyrido ~',2':1,2~ imidazo ~4-c7 rifamycin SV
A solution of 4.9 g (0.007 moles) of rifamycin S, 3 g (0.028 moles ) of 2-amino-4-methylpyridine and 3 g (0.012 moles ) of iodine in 30 ml of methylene chloride is heated at the boiling temperature of the reaction mixture for one hoilr. After cooling to room tempe-rature, the solution is added with 20 ml of a 25% (w/v) aqueous solution of ascorbic acid and is stirred for 30 minutes. The two layers are separated, the organic one is twice washed with 30 ml ~LZ~5~7~
- 22 - , of 1 N aqueous solution of hydrochloric acid and a~fterwards with water to neutrality and subsequently dried over sodium sulfate.
After filtering and evaporating the solvent, a residue is obtained, which is crystallized from 7/3 (v/v) mixture of ethanol/water to give 4.4 g of product with a yield of 80% of theoretical. The compound has the same chemico-physical characteristics as that obtained in Example 1.
4-Deoxy-S'-methyl-pyrido ~',2':1,27 imidazo ~,4-c7 rifamycin SV
A solution of 4.9 g (0.007 moles) of rifamycin S, 3 g (0.028 moles) of 2-amino-3-methyl-pyridine, 3.3 g (0.014 moles) of 2~anlino-3-methyl-pyridine hydroiodide and 1.8 g (0.0071 nloles ) of iodine in 35 ml of methylene chloride is heated at the boiling temperature of the reaction mixture for a period of 4 hours. After cooling, the solution is added wi~h 10 ml of a 25% (w/v) aqueous solution of ascorbic acid and stirred for 30 minutes. The two layers are separated, the organic one is twice washed with 30 ml of a 1 N aqueous solution of hydrochloric acid and then with water to neutrality and subsequently dried over sodium sulfate.
After filtering and evaporating the solvent, a residue is obtained which is crystallized from a 7/3 (v/v) mixture of ethanol/water, thus obtaining 4.1 g of product with a yield of 75% of theoretical.
This product shows the following chemico-physical charac-teristics:
.
-- ~3 --Melting point: 185~-190C (decomposition).
U.V. Spectrum: ,~ max (Iny) E
1 cm _R. Spectrum: characteristic absorption bands were observed at the following frequencies (in cm ): 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 = broad; s = strong; w = weak; vw = very weak.
_NMR Spectrum: characteristic resonance peaks were observed at the ~ollowing d~(expressed as p.p.m.): -o.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,21-1); 8.27 (s,lH); 8.47 (s,ll-l); 14.86 ls,lil); 16.77 (s,lH).
s = singlet; d = doublet; m = multiplet.
5~t'6 -~ -- 24 --4-Deoxy-41-methyl-pyrido ~', 2':1,2J imidazo ~ c7 rifamycin SV
-A solution of 6.95 g (0.01 moles) of rifamycin S, 4.32 g (0.04 moles) of 2-arnino-4-methyl-pyridine, 2.4 g (0.04 moles) of acetic acid and 0.25 g (0.001 moles) of iodine in 40 ml of methylene chloride is kep~ at room temperature for 5 days. Then the reaction rtlixture is added with 0.37 g (0.002 moles) of ascorbic ~Lcid and is stirred for 30 minutes. Afterwards, it is washed with a 0.5 N aqueous solution of hydrochloric acid and then with water and lastly it is evaporated to dryness under reduced pressure. The residue is crystallized from a 7/3 (v/v) Inixture of ethanol/water to give 5.74 g of product with a yield of 73% of theoretical.
The product has the same chemico-physical characteristics as the product of Example 1.
4-Deoxy-4'-methyl-pyrido ~' ,2':1,~7 imidazo ~,4-c,7 rifamycin SV
A solution of 4.9 g (0.007 moles) of rifamycin S, 3 g (0.028 moles) of 2-amino-4-methyl-pyridine, 0.45 g (0,0018 rnoles) of iodine and 1.65 ml (0.029 rnoles) of acetic acid in 15 ml of acetonitrile is kept at room temperature for 48 hours. Afterwards, the reaction mixture is added with further 0.2 g (0.0008 moles) of iodine and kept at room temperature for further 16 hours. Then it is added with 3 ml of a 25% (w/v) aqueous solution of ascorbic acid and, after further 30 rninutes, it is cliluted with 85 ml of methylene chloride. The organic solution is twice washed with ~2~1L5~7 30 ml of a l N aqueous solution of hydrochloric acid 9 then with water to neutrality and dried over sodiur" sulfate. After filtering and evaporating the solvent in vacuo a residue is obtained which is crystallized fronl a 7/3 (v/v) mixture of ethanol/water, thus obtaining 4.2 g of product with a yield of 77% of theoretical.
The product has the same chemico-physical characteristics as that described in Example 1.
EXAI~/I P L E 12 4-Deoxy-4'-methyl-pyrido ,~'2' :1,27 imidazo ~,4-~7 rifamycin SV
4.9 Grams (0.007 moles) of rifamycin S, 3 g (0.028 moles) of 2-amino-4-methyl-pyridine, 3.3 g (0.014 moles) of 2-arnino-4--methyl-pyridine hydroiodide and 0.89 g (0.0035 moles) of iodine are dissolved in 20 ml of dimethoxyethane and the reaction is left standing at room temperature for 20 hours. The reaction mixture is then added with 5 rnl of a 25% (w/v) aqueous solution of ascorbic acid and left under stlrring for 30 minutes. Afterwards the reaction is diluted with 100 ml of methylene chloride, twice washed with 30 ml of a 1 N aqueous solution of hydrochloric acid, then with water to neutrality. The organic phase is dried on anhydrous sodium sulfate and filtered and the solvent is evaporate off.
The residue is crystallized from a 7/3 (v/v) mixture of ethanol and water, thus obtaining 3.7 g, with a yield of ~8% of theoretical, of product having the same chenlico-physical charac-teristics as those of the product described in Example 1.
_Deoxy~4'-methyl-pyrido ~' ,2' :1,27 imidazo ~5,4-c7 rifamycin SV
696 Grams (1 mole) of rifamycin S, 324 g (3 rnoles) of 2-amino-4-nlethyl-pyridine and 127 g (0.5 moles) of iodine are dissolved in 3 liters of methylene chloride and the reaction is kept at room temperature for 24 hours. Afterwards it is added with 0.5 liters of a 20% (w/v) aqueous solution of ascorbic acid and stirred for one hour. The aqueous phase is cast off and the organic phase is first washed three times with 1 liter of a 1 N aqueous solution of hydrochloric acid in order to eliminate the unreacted excess of 2-amino-4-methyl~pyridine, then with water to neutrality, and finally it is evaporated to dryness under vacuum. The solid residue is crystallized fronl a 7/3 ~ v/v ) mixture of ethanol/water whereby 613 g of product are obtained, with a yield of 78% of theoretic al .
The so obtained product shows the same chemico-physical characteristics as those of the product described in Example 1.
4'-Deoxy-4'-methyl-pyrido 6',2':1,27 imidazo ~,4-c7 rifamycin SV
487 Grarns (0.7 moles) of rifamycin S, 303 g (2.8 moles) of 2-amino-4-methyl-pyridine and 254 g (1 mole) of iodine are dissolved in 3 liters of methylene chloride and the reaction is kept at roorn temperature for 4 hours. Afterwards it is added with 1.5 liters of a 25% (w/v) aqueous solution of ascorbic acid and stirred L2~5~7~
for 30 minutes. The aqueous phase is discarded, the organic phase is washed four times with 1 liter of a 1 N aqueous solution of hydrochloric acid in order to eliminate the unreacted excess of 2-am ino-4-methyl-pyridine, then it is washed with water to neutrality and finally dried over sodium sulfate. After filtering and evaporating the solvent, a residue is obtained, which is crystallized from a 7/3 (v/v) mixture of ethanol/water whereby 440 g of product are obtained, with a yield of 80% of theoretical.
The so obtained product shows the same chemico-physical characteristics as those of the product described in Example 1.
By substantially operating as described in the previous Examples, the following compounds of formula 1 can be prepared.
s~
R Rl 2 COC~13 11 -4 '-C~120~1 COCH3 H -4 ' -CH -C}12-N (Cl-13 )2 COCH3 H -4 '-OCH2C6115 COCH3 H -4 '-NO
~- ~ 3 -3'-CH _4~-cll2-c}l2-cll2 N(CH3 ~L
C OCH3 -5 ~ -CH3 -3 ~ -cH2-cH2-N ( C H3 ) 2 COCH3 H -3 ' -SH
COCH3 H 3 ' -CH3 COCH3 H -4 '-CO-NH2 COCH3 H -4 '-CO-N(CH3)2 COCH3 -3'-Br _4'-c~12-N(cll3 2 COCH3 H -4 '-S-C6H5
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1) A process for preparing imidazo rifamycins of formula I
wherein R is hydrogen or acetyl;
R1 and R2 independently represent hydrogen, (C1-4)-alkyl, benzyloxy, mono- or di-(C1-3)-alkylamino-(C1-4)-alkyl, (C1-3)--alkoxy-(C1-4)-alkyl, hydroxy-(C1-4)-alkyl, cyano, halogen, nitro, mercapto, (C1-4)-alkylthio, phenylthio, carbamoyl, mono-or di-(C1-3-alkyl-carbamoyl, or R1 and R2 taken together with two consecutive carbon atoms of the pyridine nucleus form a benzene ring optionally substituted by one or two methyl or ethyl groups, which comprises reacting a molar equivalent of rifamycin S of formula II
with from about 1 to about 8 molar equivalents of a 2-amino-pyridine of formula III
in the presence of from about 0.1 to about 4 molar equivalents of iodine or of a suitable system iodide/oxidizing agent, optionally in the presence of an acidic agent, in the presence of a solvent or of a solvent system, at a temperature comprised between the room temperature and the boiling temperature of the reaction mixture, for a period of time comprised between about 1 hour and about 120 hours, treating the reaction mixture with a suitable reducing agent and recovering the products from the reaction medium.
wherein R is hydrogen or acetyl;
R1 and R2 independently represent hydrogen, (C1-4)-alkyl, benzyloxy, mono- or di-(C1-3)-alkylamino-(C1-4)-alkyl, (C1-3)--alkoxy-(C1-4)-alkyl, hydroxy-(C1-4)-alkyl, cyano, halogen, nitro, mercapto, (C1-4)-alkylthio, phenylthio, carbamoyl, mono-or di-(C1-3-alkyl-carbamoyl, or R1 and R2 taken together with two consecutive carbon atoms of the pyridine nucleus form a benzene ring optionally substituted by one or two methyl or ethyl groups, which comprises reacting a molar equivalent of rifamycin S of formula II
with from about 1 to about 8 molar equivalents of a 2-amino-pyridine of formula III
in the presence of from about 0.1 to about 4 molar equivalents of iodine or of a suitable system iodide/oxidizing agent, optionally in the presence of an acidic agent, in the presence of a solvent or of a solvent system, at a temperature comprised between the room temperature and the boiling temperature of the reaction mixture, for a period of time comprised between about 1 hour and about 120 hours, treating the reaction mixture with a suitable reducing agent and recovering the products from the reaction medium.
2. A process as defined in claim 1, wherein for each mole of rifamycin S are used from 3 to 6 molar equi-valents of 2-aminopyridine of formula III.
3. A process as defined in claim 1, wherein the solvent or the solvent system is selected among lower halo-genated hydrocarbons, lower alkanols, lower alkyl esters of lower aliphatic acids, acetonitrile, dimethoxyethane, dioxane, tetrahydrofuran and aromatic hydrocarbons.
4. A process as defined in claim 3, wherein the solvent is the methylene chloride.
5. A process as defined in claim 1, wherein the reaction temperature is comprised between the room tempera-ture and about 60°C.
6. A process as defined in claim 1, in which R is acetyl.
7. A process as defined in claim 6, in which R1 is hydrogen or methyl.
8. A process as defined in claim 7, in which R2 is selected from -CH2OH, -CH2-CH2-N(CH3)2, -CH2-N(CH3)2, _OCH2C6H5, -NO2, -CH2-CH2-CH2-N(CH3)2, -CH2-CH2-N(CH3)2, -SH, -CH3, -cO-NH2, -CO-N(CH3)2, -CH2-N(CH3)2, and -S-C6H5.
9. A process as defined in claim 1 which compri-ses reacting rifamycin S with 2-amino-4-methyl pyridine;
2-amino-5-chloro pyridine; 2-amino-3,5-dibromo pyridine;
1-amino-isoquinoline; 2-amino-3,5-dichloro pyridine or 2-amino-3-methyl pyridine.
2-amino-5-chloro pyridine; 2-amino-3,5-dibromo pyridine;
1-amino-isoquinoline; 2-amino-3,5-dichloro pyridine or 2-amino-3-methyl pyridine.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT03464/84A IT1199375B (en) | 1984-05-15 | 1984-05-15 | PROCESS FOR THE PREPARATION OF IMIDAZO RIFAMICINE |
| IT3464A/84 | 1984-05-15 | ||
| IT3465A/84 | 1984-05-15 | ||
| IT03465/84A IT1199376B (en) | 1984-05-15 | 1984-05-15 | IMIDAZO-RIFAMICINE PREPARATION PROCESS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1215976A true CA1215976A (en) | 1986-12-30 |
Family
ID=26325399
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000480320A Expired CA1215976A (en) | 1984-05-15 | 1985-04-29 | New process for the synthesis of imidazo rifamycins |
Country Status (9)
| Country | Link |
|---|---|
| AR (1) | AR242795A1 (en) |
| AT (1) | AT386829B (en) |
| CA (1) | CA1215976A (en) |
| DK (1) | DK160829C (en) |
| ES (1) | ES8603490A1 (en) |
| FI (1) | FI83874C (en) |
| GR (1) | GR851146B (en) |
| NO (1) | NO164030C (en) |
| PT (1) | PT80447B (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7709634B2 (en) | 2007-09-20 | 2010-05-04 | Apotex Pharmachem Inc. | Amorphous form of rifaximin and processes for its preparation |
| WO2010067072A1 (en) | 2008-12-10 | 2010-06-17 | Cipla Limited | Rifaximin complexes |
| US7902206B2 (en) | 2003-11-07 | 2011-03-08 | Alfa Wassermann, S.P.A. | Polymorphic forms α, β and γ of rifaximin |
| US7906542B2 (en) | 2004-11-04 | 2011-03-15 | Alfa Wassermann, S.P.A. | Pharmaceutical compositions comprising polymorphic forms α, β, and γ of rifaximin |
| US7915275B2 (en) | 2003-11-07 | 2011-03-29 | Alfa Wassermann, S.P.A. | Use of polymorphic forms of rifaximin for medical preparations |
| US8193196B2 (en) | 2005-03-03 | 2012-06-05 | Alfa Wassermann, S.P.A. | Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations |
| US8633234B2 (en) | 2006-09-22 | 2014-01-21 | Cipla Limited | Rifaximin |
| US9452157B2 (en) | 2012-07-06 | 2016-09-27 | Alfa Wassermann S.P.A | Pharmaceutical compositions comprising rifaximin and amino acids, preparation methods and use thereof |
| EP3134415A4 (en) * | 2014-04-19 | 2017-10-25 | Granules India Limited | An improved process for the preparation of rifamycin derivatives |
| US10428086B2 (en) | 2014-05-12 | 2019-10-01 | Alfasigma S.P.A. | Solvated crystal form of rifaximin, production, compositions and uses thereof |
| US10556915B2 (en) | 2014-03-31 | 2020-02-11 | Euticals Spa | Polymorphic mixture of Rifaximin and its use for the preparation of solid formulations |
-
1985
- 1985-04-29 CA CA000480320A patent/CA1215976A/en not_active Expired
- 1985-05-13 PT PT8044785A patent/PT80447B/en unknown
- 1985-05-13 GR GR851146A patent/GR851146B/el unknown
- 1985-05-14 NO NO851920A patent/NO164030C/en unknown
- 1985-05-14 FI FI851908A patent/FI83874C/en not_active IP Right Cessation
- 1985-05-14 AT AT145085A patent/AT386829B/en not_active IP Right Cessation
- 1985-05-14 DK DK214585A patent/DK160829C/en not_active IP Right Cessation
- 1985-05-14 ES ES543116A patent/ES8603490A1/en not_active Expired
- 1985-05-15 AR AR30038685A patent/AR242795A1/en active
Cited By (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8173801B2 (en) | 2003-11-07 | 2012-05-08 | Alfa Wassermann, S.P.A. | Processes for the production of polymorphic forms of rifaximin |
| US8404704B2 (en) | 2003-11-07 | 2013-03-26 | Alfa Wassermann S.P.A. | Use of polymorphic forms of rifaximin for medical preparations |
| US7902206B2 (en) | 2003-11-07 | 2011-03-08 | Alfa Wassermann, S.P.A. | Polymorphic forms α, β and γ of rifaximin |
| US7915275B2 (en) | 2003-11-07 | 2011-03-29 | Alfa Wassermann, S.P.A. | Use of polymorphic forms of rifaximin for medical preparations |
| US8158644B2 (en) | 2003-11-07 | 2012-04-17 | Alfa Wassermann, S.P.A. | Pharmaceutical compositions comprising polymorphic forms α, β, and γ of rifaximin |
| US8158781B2 (en) | 2003-11-07 | 2012-04-17 | Alfa Wassermann, S.P.A. | Polymorphic forms α, β and γ of rifaximin |
| US7906542B2 (en) | 2004-11-04 | 2011-03-15 | Alfa Wassermann, S.P.A. | Pharmaceutical compositions comprising polymorphic forms α, β, and γ of rifaximin |
| US8518949B2 (en) | 2005-03-03 | 2013-08-27 | Alfa Wassermann S.P.A. | Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations |
| US8193196B2 (en) | 2005-03-03 | 2012-06-05 | Alfa Wassermann, S.P.A. | Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations |
| US10703763B2 (en) | 2005-03-03 | 2020-07-07 | Alfasigma S.P.A. | Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations |
| US8633234B2 (en) | 2006-09-22 | 2014-01-21 | Cipla Limited | Rifaximin |
| US7709634B2 (en) | 2007-09-20 | 2010-05-04 | Apotex Pharmachem Inc. | Amorphous form of rifaximin and processes for its preparation |
| US8916193B2 (en) | 2008-12-10 | 2014-12-23 | Cipla Limited | Rifaximin complexes |
| WO2010067072A1 (en) | 2008-12-10 | 2010-06-17 | Cipla Limited | Rifaximin complexes |
| US9452157B2 (en) | 2012-07-06 | 2016-09-27 | Alfa Wassermann S.P.A | Pharmaceutical compositions comprising rifaximin and amino acids, preparation methods and use thereof |
| US10556915B2 (en) | 2014-03-31 | 2020-02-11 | Euticals Spa | Polymorphic mixture of Rifaximin and its use for the preparation of solid formulations |
| US10745415B2 (en) | 2014-03-31 | 2020-08-18 | Amri Italy S.R.L. | Polymorphic mixture of Rifaximin and its use for the preparation of solid formulations |
| US10961257B2 (en) | 2014-03-31 | 2021-03-30 | Amri Italy S.R.L. | Polymorphic mixture of rifaximin and its use for the preparation of solid formulations |
| US11739099B2 (en) | 2014-03-31 | 2023-08-29 | Curia Ip Holdings, Llc | Polymorphic mixture of Rifaximin and its use for the preparation of solid formulations |
| EP3134415A4 (en) * | 2014-04-19 | 2017-10-25 | Granules India Limited | An improved process for the preparation of rifamycin derivatives |
| US10428086B2 (en) | 2014-05-12 | 2019-10-01 | Alfasigma S.P.A. | Solvated crystal form of rifaximin, production, compositions and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| NO164030C (en) | 1990-08-22 |
| NO851920L (en) | 1985-11-18 |
| DK160829C (en) | 1991-10-07 |
| AR242795A1 (en) | 1993-05-31 |
| DK160829B (en) | 1991-04-22 |
| NO164030B (en) | 1990-05-14 |
| GR851146B (en) | 1985-11-25 |
| ES543116A0 (en) | 1986-01-01 |
| FI851908L (en) | 1985-11-16 |
| PT80447A (en) | 1985-06-01 |
| FI851908A0 (en) | 1985-05-14 |
| FI83874B (en) | 1991-05-31 |
| ATA145085A (en) | 1988-03-15 |
| PT80447B (en) | 1987-11-11 |
| DK214585A (en) | 1985-11-16 |
| ES8603490A1 (en) | 1986-01-01 |
| AT386829B (en) | 1988-10-25 |
| FI83874C (en) | 1991-09-10 |
| DK214585D0 (en) | 1985-05-14 |
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