AU479260B2 - 1, 3-OXAZINO (5, 6-c) RIFAMYCINS AND METHOD FOR PREPARING SAME - Google Patents

Description

69,905/74 This invention relates to 1, 3-oxazino (5,6-c) rifamycins and a method for preparing the same.

It is known that phenols and hydroquinones react with primary amines in the presence of two molecular equiv-

alents of formaldehyde to give benzoxazines or bis oxazines (J.Am. Chem. Soc. 21, 609; 1949-72, 4691; 1950 74, 3601; 1952 26,1677; 1954 and J. Org. Chem. 26, 4403; 1961). It is also known Org. Chem..2, 2749; 1962) that bis (alkoxymethyl) amines, i.e. the compounds obtained by reacting primary amines with two molecular equivalents

of formaldehyde and of an alkanol, are useful reagents capable of converting hydroquinones into bis- oxazines On the basis of the above processes attempts have been made to obtain oxazino rifamycins from rifamycin SV having a hydroquinone-like structure; it has however been found the rifamycin SV does not react at all.

Surprisingly it has now been found that rifamycin S. a quinone- like compound can be converted into an oxazine by reaction with a bis-(oxymethyl)-or with a bis- (alkoxymethyl) amine. More particularly, it has been found that by reacting rifamycin S. characterized by the following formula 32 31

47 9.2 6 0 with a bis-(oxymethyl)-or abis- alkoxymethyl) amine, there are obtained new rifamycin compounds (1,3-oxazino (5,6-c) rifamycins) of the following general formula:

32 31 C3 CH3 18 HO 21 0 1 17

CH C8 8J C OH 00H °1 325 14 0 1Hr 3 HC OH 24 CH3 NH

a o c* 13

in which R 1 is lower alkyl, lower alkenyl, cycloalkyl having

to 6 carbon atoms, phenyl, benzyl, A or phenethyl. These new rifamycin compounds have the following physical-

chemical features: the U.V. spectrum in buffer pH 7 solution

shows three absorption maxima respectively near 305 m, 355 m, and 560 u; the NMR spectrum in dimethylsulfoxide solution shows, interalia, two characteristic singlet near S14, 3 and 9,5; the molecular ion in mass spectrography corresponds, for each compound, to the calculated molecular

weicht; the I.R. spectrum in nujol mull shows, inter alia, an absorption peak near 3400 cm- 1 attributed to the NH of the amide group. It has also been found that these 1,3- oxazino rifamycins of formula (II) are useful antibiotic substances and useful intermediates in preparing

3- iminomethyl derivatives of rifamycin SV, in particular rifanoicin.

47 9,2

69, 905/74 As used herein, the term "lower alkyl" is

intended to include straight and branched saturated

aliphatic hydrocarbon radicals having 1 to 6 carbon

atoms such as methyl, ethyl, propyl,

47 92

69, 9095/74 isotrotr~l, n-butvl, isobutvl, sec.butyl, tert. butvl, n-oent-l, 2-methyl-butvl, n-hexvl, 2-methvl--pentYl and the like. The term "lower alkenvi" is intended to include ethvlenicallv unsaturated aliphatic hydrocarbon radicals having 7 to 6 carbp atoms such as alivi, crotyl, methacr~l, 7-nentenvl, and the like. The method acccrdirip to the nresent invention is characterised in that rifamvcin S is reacted with a comnound of formula 2 CH 2 OR

2OR 2 (1)

in which R1is lower alkyl, lower alkenvl, c-'cloalkvl having to 6 carbon atoms, phenvl, benzvl,.d. -or P -tdienethvl and

R2is hvdrogcen or lower alkyl, in an inert organic solvent at a temoerature range of 000C to boiling temnerature of the solvent. The reaction is Dreferablv carried out in a dinolar aiorotic solvenit, but it is understood that rifamycin S reacts with the '~OMDOtrndS of the above formula (l11) in anv other connon organic solvent to Drovide 1,3-oxazino rifamicins of said formula (11). The term "dinolar anrotic solvent" is intended to include a highlv Dolar solvent which is no more than a very weak hvdro=-en bond donor Par!ker, Chemical Reviews 1, 1969). Thus, such term includes solvents such as dimethvl-sulfoxide, di-ethylacetride, dimethvlformamide, hexamethvlnhosohotria- mide, acetonitrile, N-methvlnvrrolidone, acetone and the like. The reaction time denends both on the solvent

6 479i.26 0

69.905/74 emDloved and the comnound of formula (111) used as a reactant. Practically by increasing the molecular weight of the amine (111) and decreasing the polarity of the solvent, the reaction time is Drolonged and the vields of oroduct (11) diminish because of the oresence of reaction bv-nroducts and/or unreacted stertin; materi-l which must be removed. When a comoound of the above formula (111), where R1 is for example methyl, ethyl, tert. but-'l, or allvl is used and the reaction is carried out in a dipolar anrotic solvent, such as dimethvl-sulfoxide, dimethvlaceta-

mide or dimethylformamide at a temoerature range of 15 to 100 0 C, substantially oure compound (11) is obtained in about quantitative vield and in a very short reaction time, ranging from a few minutes to 2 hours. Where a compound of 1 the above formula (111) wherein R is a c"cloalkvl, nhenyl or phenylalkvl sroup, is used as a reactant, the reaction time can increase. Generally, when the reaction is carried out in apolar or

in protic polar solvent, such as benzene, dioxane, tetrahy- dro'uran or alcohols, the reaction time can be as high as -4 hours and the desired final product should be separated from the by-oroducts by fractional crystallization or extraction from suitable solvents. The oxazino rifamvcins (11) thus obtained are isolated according to well known methods, such as by simole filtration or extraction, evanoration and crystalli- zation. The new 1,7- oxazino rifam-cins of the nresent

invention are useful antibiotic substances which are very active against pathogenic bacteria, oarticularlr against 479.260

69, 90574 such gram-ositive and gram-neqative micro-orx'fnismS as Staphylococcus aureus, Streptococcus pvogenes, Escherichia coli.

Furthermore, the 1,q-oxazino rifamycins, which of the present are now available because of the new method 3- invention, are useful intermediates in Dreparing described in the iminomethyl derivatives of rifamycin SV 4'o. French Patent 1,457,475,Darticularlv the very important The antibiotic comooun! referred to as rifamvicin.

conversion of the oxazino rifamvcins of formula SV (11) to the 71-iinomethvl derivatives of rifamvrin hvdrazine, is accomolished bv reaction with nrimarv amines. monosubstiuted hvdrazines. asimmetric disubstituted of formula hvdrazines. For examnle, by reactina a comnound the Dresence of a (11) with l-amino-4-methyl-iperazine in is obtained in secondary or a tertiary amine, rifampicin short period of sulistantialv auantitative yield in a very- The comnounds time, ranzing from 15 minutes to 3 hours. reacting an cf the above formula (111) are Drenared by amine of formHula2 either with two equivalents of derivative formaldehyde to obtain a bis hvdroxymethvl

(formula 111, R 2 H) or with two molar equivalents of hoth OH to obtain a formaldehyde and an alcohol of formula R2 ill, R lower is (lower alkoxymethyl) derivative (formula is described in alk-rl). Thetocedure of this nrenaration J. Chem. Soc. 123, 572, (1923).

The following examnles illustrate the invention. FXP77LE 1 C=-)oqnd offormula 11 R t.-hutVl.

T.N dihydroxvmethvl-t-butvlamine, 40 ml. A solution of 6.5g. 479.260

69,905/ 7 dimethvlformamide and 1l.0.. rifamvcin S was stirred in

a 100 ml. four necked flask for 61 minutes at '73C. The reaction mixture was noured into 100 ml. water acidified with 2 ml. acetic acid. The nrecipitate thus obtained was 0 filtered, washed with water and dried at 40 C. under vacuum. Yield: 14,5 r. The infrared snectrum in chloroform solution showed peaks -l1 at 7500, 1715, 1680, 1650, 1605, 1380, 1325, 975 cm- EXA!MLE 2 Comnound of formula 11. R allvl. In a 100 ml. four-necked flask, 13.9 g. rifamycin S were dissolved in 40 ml. of dimethvlacetanide, then 7 g. N,N diisoDropoxvmethyl-allvlamine were added and the solution 0 heated for 15 minutes at 70 C. The reaction mixture was poured into 700 ml. water acidified with 2 ml. acetic acid and the precinitate obtained filtered, washed with water and dried at 400 C, under vacuum. Yield: 11.' g.

The infrared snectrum in chloroform solution showed neaks at 3500, 1740, 1720, 1650, 1605, 1770, 975 cml. EXAIPLE 3 1 Conoound of formula 11, R cvclohexvl. A mixture cf 13.9 e. rifamvcin S, 6,5 g. N,I dimethoxvmethyl-

cyclohexvlamine and 40 ml. dimethvlsulfoxide was keot in a 100 ml. four necked flask at 50°c for 45 minutes. The reaction mixture was poured into 500 ml. water acidified with 2 ml. acetic acid. The Drecipitate thus obtained was filtered, washed with water and dried at 40°C, under vacuum. Yield: 15.3 g.

The infrared spectrum in chloroform solution showed peaks -1 at 3500, 1720, 1610, 1380, 1740, 990 cm- 47 9.2 6 0

69, 905/74 In the same manner, b'r reacting rifamvcin S with H,N- dimethoxvmethyl-cyclopentylamine, the corresponding

comDound of the above formula 11, where R1 is cvclopentvl,

was obtained. AMrPLE 4

Comnound of formula 11. R benzvl.

In a 100 ml. four-necked flask 1'.9 g. rifamvcin S were dissolved in 40 ml. hexamethylphosphotriamide, then

g. N,N diethoxvmethvlbenzvlamine were added and the

solution was keot for 20 minutes at 600C. The reaction

mixture was poured into 400 ml. water acidified with 2 ml.

acetic acid and the precinitate thus obtained was filtered,

washed with water and dried at A0 C, under vacuum. Yield:

15.8 g. The infrared snectrum in chloroform solution showed peaks

at 7500, 1740 1710, 180, 1650, 1605, 1380, 1320, -1 980 cm-. In the same manner, by reacting rifamycin S with N,N-

dimethoxvmethvl phenethylamine and with N,N-

dimethoxvmethyl- B -nhenethvlamine, the corresnonding 1 compounds of the above formula 11 where R is -phenethvl

or R -ohenethvl, were obtained. ?LE Connound of formula 11. R methyl.

In a 100 ml. four-necked flask 14 R. rifemvcin S were

dissolved in 40 ml. acetone then 5 g. N,N- diisobutoxy- methvl-methylamine were added and the solution was stirred

for 3 hours at 400C. The reaction mixture was coured into

"00 ml. water acidified with I ml. acetic acid and the

nrecinitate thus obtained was filtered, washed with water and

47 9.2

69. 905/ 74 dried at 40°C, under vacuum. Yield: 1.S3 g. crude product.

The crude oroduct was mixed with 60 ml. toluene in a

100 al.flask, the mixture stirred for 10 minutes at 60 0 C and then filtered to give 12.5 g. pure oroduct. The U.V. spectrum in ohcsphate buffers pH 7 showed the

following absorption maximas max 05 mp '54 mu 560

In the mass snectrometrv the ion-molecular neak had a mass of 750.

Furthermore, the snectrum NMR of solution in dimethvl- sulfoxide showed Fin-lets ato 1.65, 1.92, 1.99, 2.96,

7.71, 9.49, 14.24. There were no neaks in negative fields. EXAMPLE 6

Compound of formula 11, R methyl.

A mixture of 14 g. rifamycin S. 50 ml. n-pronyl alcohol and 5.5. g. N,N- diisobutoxymethyl- methylamine was stirred 0 in a 100 ml. four-necked flask at 60 C for 40 minutes. The

reaction solution was poured into 500 ml. water acidified

with 5 ml.acetic acid, then the precipitate thus obtained was filtered, washed with water and dried at 40C0, under

vacuum to 7ive 12.2 g. crude product. The crude product was dissolved in 100 ml. chloroform and a mixture of 250 ml.

toluene and 750 ml. petroleum ether was added. The precip- 0 itate thus obtained was filtered and dried at 40 C, under

vacuum to vield 4.2 g. nure Drodulct, identical to that described in examnle

In the same manner, by reacting rifem-cin S with N,N-

diisobutoxvmethyl-aniline, the corresnonding ccmoound of the

above formula 11, where R1 is ohenl-l. was obtained.

EXAMPL 7

47 2 60

69. 905/74 7.9 g. compound of formula 11, where R1 is t. butvl, prepared as described in Examole 1, were dissolved in ml. tetrahydrofuran in a 100 ml. four nec'ed flask. A mixture of 2,8 e. pvrroliding and 1.38 g. 1-amino- 4-meth7lpioerazine was added. After 20 minutes stirring at rocm tenserature the reaction was over. The reaction mixture was dissolved in 100 ml. chloroform, acidified. to pH 5 with diluted acetic acid and washed with water. The chloroforic phase was dried with sodium sulfate and, after filtration, the solvent was eva.orated. Yield:8.2 g. Recrystallization from acetone yielded 7.2 q. unitary nroduct as thin laver chromatoaraohy shcwed. The product was identical to an authentic sDecimen of rifamoicin.

12 47 9,2 0

Claims (2)

69, 905/74 The clais.definirg the invention are as follows:

1. 1,3 -oxzir-o(5,-c)rifamycin comnounds, characterized by the formula

32 31 cy 3 C3 e d

23 116 17325 24030 34 14 OH 0 c:-C

28 6 29

-13 wherein R is lower alkyl, lower alkenyl, cycloalkyl having to 6 carbon atcms, phenyl, benzyl,K-or -henethyl..

2. Rifarnycin-ccmounds according to Claim ]',herein Rlis

t.butyl.

3. ?ifamycin comrounds accordinC to Claim 1, wherein R is allyl.

4. Riffamycin comrounds according to Claim 1, wherein R is methyl.

A method for zreiarine 1,3-oxazino(5,6-c)rifamycins of formula

69 905/74 32 31

CH3C11 w~~sereH a2 3 lo e l es l 18 l al y 5Ko6 c r o having~2 t m ph n l e s l o o~ pheetl 33~ h cmrs hi S ecti rfr~crSvt

0

ata-, :ro ab otert ab o6,ewe olventandl the being to6removedatoms iveansl masszy withthedesred-

b. whietho a cor srecing toCaim5,her in ai iert

ori solvent is a ieotrganric solvent an sereaidr

tm atr is' from 150t to abu1 6 Cesovn hewtr n

7. A. method according to Claim 6, wherein said dinoer

14 4 7 92 6

69 90 5/74 arrotic solvent is imethylsulfoxide, dimethylforma--ide

or d=ethylacetanmide.

D 5 j-uy, 1976.

jC-tors. LE E 10u:I A L

0B 47 R2 6 0