KR810000103B1 - Process for preparing rifamycin compounds - Google Patents

Abstract

The bactericidal-(no data) rifamycin derivs. [I; X = H, carboxyl, c<10 alkyl, c<7 cycloalkyl, c<4 alkenyl, c<7 cycloalkenyl, c<13 aryl, c<14 arylalkyl, c<11 arylalkenyl, Y = H or acetyl were prepd. By reaction of II and III in the presence of metal and acetic acid. Thus, 3-amino-4-deoxo-4-iminorifamycin S reacted with acetic acid and trioxymethylene to give the title compd.

Description

Method of Preparation of Rifamycin Compound

The present invention provides a method for preparing a lipamicin compound of formula (I), 16,17,18,19-tetrahydro derivatives and 16,17,18,19,28,29-hexoxide derivatives having high antibacterial activity It is about.

In the above structural formula

X is hydrogen, carboxyl, alkyl of 10 or less carbohydrates, cycloalkyl of 7 or less carbohydrates, alkenyl of 4 or less carbon atoms, cycloalkenyl of 7 or less carbon atoms, aryl of 13 or less carbon atoms, arylalkyl of 13 or less carbon atoms, aryl alkenyl of 11 or less carbon atoms, Five- and six-membered heterocycles containing up to five heteroatoms of nitrogen, oxygen, and sulfur; five- and six-membered heterocycles condensed with aromatic rings of heterocycles containing up to three heteroatoms of oxygen and sulfur; Substituted with at least one of said groups halogen, hydroxy, alkoxy, nitro, amino, N-alkylamino, formyl, carboxy, carboalkoxy, carboxyalkoxy, N, N'-dialkyl aminoalkoxy, acyloxy, acetamide or alkylenedioxy Can be

Y is hydrogen or acetyl.

In addition, the present invention also encompasses the corresponding oxidation products of the following formula (II).

Where X is as defined above.

The compounds according to the invention have a high antibacterial activity against gram positive and negative bacteria and in particular against tuberculosis bacteria.

The compounds according to the invention are yellow orange to reddish purple, powdery, soluble in most organic solvents such as chlorinated solvents, alcohols, esters, ethers and the like and are particularly soluble in aromatic hydrocarbons. The compound of formula (I) is generally soluble in aqueous solutions of pH 7-7.8, but the oxidized form is insoluble in water.

Rifamycin compounds according to the present invention can be prepared by several different methods, which are the claims of the present invention. In the first method, the following compound of formula (III), its 16,17,18,19-tetra hydro derivative and 16,17,18,19,28,29-hexahydro derivative, are prepared in the presence of acetic acid and metal such as zinc and iron. Reaction with the aldehyde of the following formula (V) yields the rifamycin compound of the formula (I).

In the above structural formula

Y is hydrogen or acetyl,

X is as defined above.

Structural formula (III) compounds are pending patent applications by the same applicant as the present patent.

As another method, 3-amino-rifamycin S, 16,17,18,19-tetrahydro derivative and 16,17,18,19,28,29-hexahydro derivative of the following structural formula (IV) The rifamycin compound of formula (I) is obtained by reacting ammonia gas with an aldehyde of formula (V) in a hydrocarbon solvent.

Compounds of formula (IV) and their 16,17,18,19 tetrahydro derivatives and 16,17,18,19,28,29 hexahydro derivatives are described in German Patent No. 1,670,377, the preparation of which is disclosed in It is disclosed in specification 2548,148.

Finally, according to the preparation method of the rifamycin compound of formula (I), the compound of formula (III) as defined above, its 16,17,18,19 tetrahydro derivative and 16,17,18,19,28,29 hexahydro The derivative is reacted with a halogen derivative of the following structure (VI) in the presence of zinc and acetic acid to obtain rifamycin of the structural formula (I).

As defined herein between X |

In order to obtain an oxidized product of formula (II), the compound of formula (I), its 16,17,18,19 tetrahydro derivative, and 16,17,18,19,28,29 hexahydro derivative were fermented in an inert organic solvent. Oxidizing with an oxidizing agent such as potassium cyanide, potassium persulfate, manganese dioxide or nitrous acid.

The following examples are detailed above for the compounds according to the present invention and their preparation in order to more clearly understand the features of the present invention and do not limit the present invention to these examples.

Example 1

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is dissolved in 15 ml of tetrahydrofuran, 5 ml of benzaldehyde and 25 ml of acetic acid. 1 g of zinc is added and the solution is stirred for 10 minutes. Unreacted zinc is filtered and the reaction solution is added dropwise to a 20 g sodium sulfite solution in 300 ml of water. The precipitate obtained is filtered off, washed with water and dried in vacuo at 40 ° C.

The product was recrystallized from chloroform to obtain 6.5 g of compound of formula (I) wherein Y is acetyl and X is phenyl. For NMR spectra conducted with CDCl ₃ using tetramethylsilane for internal comparison, the most significant peaks are δ: 0.81, 0.92, 1.00, 1.9, 1.97, 2.14, 2.14, 2.26, 3.02, 3.33, 3.47, 3.59, 3.77 , 4.65, 4.75, 4.82, 4.93, 5.06, 5.15, 5.27, 6.22, 6.42, 6.58 and 7.31 ppm, and there is an insignificant signal between 7.47 and 8.25 ppm.

The most significant peaks in the IR spectrum in potassium bromide are 3460, 3360, 3190, 2970, 2930, 2880, 2830, 1710, 1670, 1640, 1600, 1575, 1550, 1528, 1460, 1410, 1370, 1320, 1255, 1242 , 1215, 1192, 1160, 1150 (sh), 1125, 1095, 1060, 1050 (sh), 1020, 975, 945, 920, 880, 798, 780 and 695 cm ^-1 .

The electron absorption spectra in the methanol solution have peaks at 435, 320 and 265 nm.

Example 2

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 7 ml 2-chloro-benzaldehyde and 30 ml 96% acetic acid. After stirring for 10 minutes at room temperature, excess zinc is filtered off, and the filtrate is added dropwise to 300 ml of water containing 20 g of sodium sulfite, followed by vigorous shaking. The solution is filtered, washed with water and dried in an oven at 40 ° C. The product is again treated with 100 ml xylene at 80 ° C., filtered hot, and filtered again after standing at room temperature for 3 hours. The filtrate is concentrated to half the capacity and left to crystallize in the refrigerator.

After filtration and drying on a stove, 6.1 g of the product of formula (I) are obtained. Wherein the compound of formula (I) is Y is acetyl and X is 2-chlorophenyl. The electron absorption spectrum in methanol solution is 435 nm (εmol = 12900); There are peaks at 320 (sh) nm and 317 nm (εmol = 41700).

IR spectra in nujol are 3375, 3225, 1730 (sh), 1715, 1685, 1640, 1605, 1750, 1555, 1530, 1315, 1255, 1235, 1210, 1165, 1100, 1045, 1015, 970, There are peaks at 945, 920, 895, 880, 820, 795, 780, 725 and 685 cm ^-1 .

Example 3

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 3 g of iron, 9 ml of 2-thiophenecarboxaldehyde and 30 ml of acetic acid. After stirring at 35 ° C. for 15 min, excess iron is filtered off, the filtrate is stirred and added dropwise to 300 ml of water containing 20 g sodium sulfite. The resulting precipitate is filtered, washed with water, dried, recrystallized with isopropyl ether to give 5.1 g of compound of formula (I) wherein Y is acetyl and X is 2-thienyl.

NMR spectra in CDCl ₃ using tetramethylsilane for internal comparison are at δ: 0.87, 1.00, 1.10, 1.20, 1.87, 1.98, 2.12, 2.27, 3.02, 6.22, 6.42, 6.61, 8.81, 12.50, 12.76 and 13.95 ppm There is a significant peak. In the presence of deuterated water, the last four peaks disappear.

IR spectra in potassium bromide are 3500, 3460, 3350, 3180, 3120, 2970, 2930, 2880, 2830, 1715, 1670, 1640, 1600, 1560, 1525, 1480, 1460, 1410, 1370, 1315, 1255, 1240, There are peaks at 1230, 1210, 1185, 1165, 1145, 1125 (sh), 1100, 1050, 1018, 973, 942, 900, 875, 850, 830, 798, 755, 742, 722 and 698 cm ⁻¹ . The electron absorption spectra in the methanol solution have peaks at 440 and 322 nm and solder (Shoulder: sh) at 335 nm.

The corresponding 25-deacetyl derivatives as defined in the above examples are obtained by reacting 3-amino-4-deoxo-4-imino-25-deacetyl-rifamycin S in a similar manner.

Example 4

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 15 ml of dioxane, 25 ml of 96% acetic acid and 1.5 g of trioxymethylene. After reacting at 45 ° C. for 30 minutes, excess zinc is filtered and the filtrate is added to 400 ml of water containing 15 g of sodium sulfite to filter the resulting precipitate. After vacuum drying at 40 ° C., the product is recrystallized from methyl alcohol to give 3.6 g of product of formula (I) wherein Y is acetyl and X is hydrogen. The electron absorption spectra in the methanol solution have peaks at 410 nm (εmol = 15400) and 300 nm (εmol = 24400).

Example 5

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 10 ml of isopropyl alcohol, and 6 g of heliorpin dissolved in 25 ml of acetic acid for 10 minutes at room temperature. . Excess zinc is filtered off and the filtrate is added to 300 ml of water containing 18 g of sodium sulfite. The resulting precipitate is filtered off, washed with water and dried on a stove at 50 ° C. The product is recrystallized from chloroform to give 4.9 g of product of formula (I) wherein Y is acetyl and X is 3,4-methylenedioxyphenyl.

The electron absorption spectra in the methanol solution have peaks at 435 nm (εmol = 12900), 320 nm (εmol = 41900) and 225 nm (εmol = 42400).

In a similar manner, 3-amino-4-deoxo-4-imino-16,17,18,19,28,29-hexahydro-25-deacetyl-rifamycin S was reacted to produce the products defined in the above examples. Obtain 25-deacetyl-16,17,18,19,28,29-hexahydro derivative.

Example 6

1.2 g of the product obtained in Example 1 are dissolved in 20 ml of dichloromethane. 0.5 g of manganese dioxide is added to the solution and stirred at room temperature for 30 minutes. Manganese dioxide is filtered off and the solvent is evaporated. 0.8 g of Y is acetyl and X is phenyl to yield a product of formula (I).

IR spectra in potassium bromide are 3460, 3180, 2970, 2930, 2180, 1710, 1665, 1635, 1595, 1525, 1500, 1470, 1455, 1420, 1370, 1305, 1255, 1195, 1180, 1150 (sh), 1120 , 1075, 1060, 1035, 975, 950 (sh), 905, 835, 795, 780, 760, 705, 690 and 660 cm ^-1 are the most significant peaks.

[Example 7]

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 15 ml of tetrahydrofuran, 30 ml of acetic acid and 5.3 ml of heptane. After stirring for 10 minutes, the unreacted zinc was filtered and the filtrate was added dropwise to 15 g of sodium sulfite solution in 350 ml of water. After vacuum drying at 40 ° C., the product is recrystallized from ethyl ether to give 3.5 g of compound of formula (I) wherein Y is acetyl and X is 1-hexyl. The electron absorption spectra in the methanol solution have peaks at 228, 304 and 415 nm.

Example 8

8 g of 2-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 5 ml of cyclohexanealdehyde, 30 ml of acetic acid and 15 ml of tetrahydrofuran. After stirring for 30 minutes, unreacted zinc is filtered off and the filtrate is added to 600 ml of water containing 15 g of sodium sulfite.

The resulting precipitate is filtered, washed with water, dried in vacuo at 40 ° C. and suspended in 100 ml of ethyl ether. After stirring for 30 minutes ethyl ether is filtered off and the solid is dissolved in 70 ml of methyl alcohol.

0.5 g of sodium ascorbate is added and the pH is adjusted to 7.2 by addition of 1% sodium hydroxide solution and precipitated in 300 ml of water. The product is filtered off, washed with water and dried in vacuo at 40 ° C. Yield: 6 g (compound of formula (I) wherein Y is acetyl and X is cyclohexyl), the electron absorption spectrum in methanol solution has peaks at 415 and 300 nm.

Reaction of 8 g of 3-amino-4-deoxo-4-imino-rifamycin S with 1 g of zinc, 15 ml of tetrahydrofuran, 25 ml of acetic acid and 4.9 g of N-formyl-morpholine dimethyl-acetyl Let's do it. After stirring for 1 hour at room temperature, the unsolution zinc is filtered off and the filtrate is added to 600 ml of water. The resulting precipitate is filtered off, washed with water and dried in vacuo at 40 ° C. On the other hand, the aqueous layer is extracted with chloroform and then the organic layer is evaporated. The obtained residue is first mixed with dry precipitate at 40 ° C. and then extracted with ethyl ether. The ether solution is concentrated to 70 ml and left to crystallize. Yield: 0.800 g (the compound of formula (I) wherein Y is acetyl and X is N-morphoryl), and the electron absorption spectra in the methanol solution had peaks at 302 and 412 nm.

Example 9

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 15 ml of tetrahydrofuran, 5 ml of nicotine aldehyde and 30 ml of acetic acid. After stirring for 10 minutes, the unreacted zinc is filtered off and the filtrate is added dropwise to 500 g of water containing 15 g of sodium sulfite. The resulting precipitate is filtered off, washed with water and dried in vacuo at 40 ° C. The solids are treated with acetone, the undissolved solids are removed and the solvent is evaporated. The obtained residue is heated to dissolve 100 ml of benzene, and the mixture is left for several hours at 10 ° C. and then filtered. After almost completely evaporating benzene, the residue is diluted with petroleum ether. After a few minutes the solution is filtered to give 2.5 g of compound of formula (I) wherein Y is acetyl and X is 3-pyridyl.

Example 10

8 g of 3-amino-4-deoxo-4-imino-rifamycin S was added with 1 g of zinc, 15 ml of tetrahydrofuran, 6.5 g of 3,4,5-trimethoxy-benzaldehyde and 30 ml of acetic acid. React with

The reaction is warmed to 50 ° C. and complete in 20 minutes. The solution is filtered and the filtrate is added dropwise with a 15 g solution of sodium sulfite in 400 ml of water. The resulting precipitate is filtered off, washed with water and evaporated to dryness at 40 ° C. The product is dissolved in the best amount of methyl alcohol, diluted with 200 ml ethyl ether and extracted with pH 7.5 phosphate buffer. The aqueous layer is acidified to pH 4 with dilute hydrochloric acid, extracted with chloroform, the solvent is evaporated and recrystallized with xylene. Yield: 2.7 (Formula (I) compound wherein Y is acetyl and X is 3,4,5-trimethoxy-phenyl)

Example 11

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 15 ml of tetrahydrofuran, 5 g of 2-formyl-thianaprene and 25 ml of acetic acid. After stirring for 30 minutes at room temperature, unreacted zinc is filtered off and the filtrate is added dropwise to 500 ml of water containing 15 g of sodium sulfite. The resulting precipitate is filtered off, washed with water and dried in vacuo at 40 ° C.

The product is then dissolved in ethyl ether and the ether solution is extracted with pH 7.5 phosphate buffer. The aqueous layer is then acidified to pH 3 and then extracted with chloroform. The chloroform layer is washed with water and dehydrated to evaporate the solvent. The residue is recrystallized from cyclohexane to give 3.2 g of compound of formula (I) wherein Y is acetyl and X is 2-thianaphthyl. Electron absorption spectra in methanol solutions peak at 330, 345 and 44 nm.

Example 12

Reaction of 8 g of 3-amino-4-deoxo-4-imino-rifamycin S with 1 g of zinc, 15 ml of tetrahydrofuran, 4.5 g of 2-fluoro-6-chlorobenzaldehyde and 25 ml of acetic acid Let's do it. After stirring at room temperature for 30 minutes, unreacted zinc is filtered off and the filtrate is added dropwise to a 500 ml aqueous solution containing 15 g of sodium sulfite. The resulting precipitate is filtered off, washed with water and dried in vacuo at 40 ° C. Then extracted with ethyl ether and the ether solution is washed with phosphate buffer pH 7.5. The aqueous layer is acidified to pH 3 and extracted with dichloromethane. After washing with water, dehydration with sodium sulfate and evaporation of the solvent gave 3.5 g of compound of formula (I) wherein Y is acetyl and X is 2-fluoro-6-chlorophenyl. The electron absorption spectra in the methanol solution have peaks at 312 and 425 nm.

Example 13

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 15 ml of tetrahydrofuran, 5 ml of 2-formyl-phenoxyacetic acid and 25 ml of acetic acid. After stirring for 20 minutes at room temperature, unreacted zinc is filtered off and the filtrate is precipitated by placing it in 500 ml of water containing 15 g of sodium sulfite. The resulting precipitate is filtered off, washed with water and dried in vacuo at 40 ° C. The product is taken up in 150 ml of acetone, the unreacted portion is filtered and diluted with 200 ml of ethyl ether. After filtration again, the solvent mixture is evaporated to obtain 3 g of the compound of formula (I) wherein Y is acetyl and X is 2-phenoxy-acetic acid.

Example 14

Reaction of 8 g of 3-amino-4-deoxo-4-imino-rifamycin S with 1 g of zinc, 15 ml of tetrahydrofuran, 3.5 g of 2-methyl-4-formylthiazole and 25 ml of acetic acid Let's do it.

After stirring for 30 minutes at room temperature the solution is filtered and diluted with 300 ml of ethyl ether. The resulting precipitate is taken up in 100 ml of acetic acid and again precipitated with 300 ml of water. After filtration the product is washed with water and dried. 4.5 g of the compound of formula (I) wherein Y is acetyl and X is 2-methyl-4-thiazolyl are obtained. The electron absorption spectra in the methanol solution have peaks at 315 and 435 nm.

Example 15

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 5 ml croton aldehyde and 35 ml acetic acid. After stirring for 10 minutes at room temperature, unreacted zinc is filtered off and the filtrate is added to 500 ml of water containing 5 g of sodium sulfite. The resulting precipitate is filtered off and washed with water. After vacuum drying at 40 ° C., the impure product is dissolved in methyl alcohol, diluted with phosphate buffer pH 7.5 and extracted with benzene. The aqueous layer is acidified to pH 2.5 with dilute hydrochloric acid and the resulting precipitate is filtered and washed with water. Obtain 3.7 g of product of formula (I) wherein Y is hydrogen and X is 1-propen-1-yl. Electron absorption spectra in methanol solutions peak at 307, 375 and 425 nm.

Example 16

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 15 ml of tetrahydrofuran, 3.5 ml of cyclohexenealdehyde and 25 ml of acetic acid. After stirring for 3 hours at room temperature, zinc is filtered off and the filtrate is added to 700 ml of water containing 10 g of sodium sulfite and the resulting precipitate is isolated by filtration. In the same manner as in Example 8, 3.3 g of the compound of formula (I) wherein Y is acetyl and X is 3-cyclohexenyl is obtained. Electron absorption spectra have peaks at 307 and 417 nm.

Example 17

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 15 ml of tetrahydrofuran, 5 ml of salicylaldehyde and 25 ml of acetic acid. After stirring at room temperature for 1 hour, the reaction mixture was treated with 200 ml of chloroform, and unreacted zinc was filtered to wash the chloroform layer with an aqueous sodium sulfite solution and again with water. After dehydration with sodium sulfate, the solvent is evaporated to yield 3.6 g of the compound of formula II wherein Y is acetyl and X is 2-hydroxyphenyl.

The electron absorption spectra in the methanol solution have peaks at 333 and 435 nm.

Example 18

8 g of 3-amino-4-deoxo-4-imino-rifamycin S with 1 g of zinc, 15 ml of tetrahydrofuran, 5 ml of 1-phenyl-5-formyl-tetrazole and 25 ml of acetic acid React. After reacting for 2 hours at room temperature, unreacted zinc is filtered off and the filtrate is added dropwise to 500 ml ethyl ether. The obtained solid material is dissolved in 500 ml of ethyl acetate and the solution is extracted with a pH 7.5 buffer solution. The aqueous layer is acidified to pH 3 and then extracted again with chloroform. After the last wash with water the product is dehydrated with sodium sulfate and the solvent is evaporated to yield 2.7 g of compound of formula (I) wherein Y is acetyl and X is 5 (1-phenyl) tetrazolyl.

Example 19

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 15 ml of tetrahydrofuran, 8 ml of cinnamic aldehyde and 30 ml of acetic acid. After stirring for 10 minutes at room temperature, unreacted zinc is filtered off and the solution is added dropwise to 500 ml of water containing 30 g of sodium sulfite. The precipitate obtained is filtered off, washed with water and dried on a vacuum stove at 40 ° C. The residue is taken up in a minimum amount of methylisobutyl ketone and then precipitated with petroleum ether. After filtration, 9 g of the compound of formula (I) wherein Y is acetyl and X is β-styryl. The electron absorption spectra in the methanol solution have peaks at 325, 350 and 437 nm.

Example 20

Dissolve 7 g of 3-amino-4-lipamycin S in 20 ml of tetrahydropurin, add 4 ml of benzaldehyde and add ammonia gas for 45 minutes. Add 2 ml of benzaldehyde and add ammonia gas for 60 minutes. The reaction mixture is diluted with 50 ml of chloroform and the solution is washed with dilute acetic acid followed by washing with sodium metabisulfite and finally with water. After dehydration with sodium sulfate, the chloroform solution is concentrated to half the capacity, evaporated and left to crystallize at 5 ° C. overnight. The product is filtered and vacuum dried at 40 ° C. to give 5.5 g of the compound as described in Example 1.

Example 21

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 50 ml of dimethyl sulfoxide, 3.5 ml of benzylbromide and 20 ml of acetic acid. The reaction mixture is heated at 60 ° C. for 2 hours and added to a mixture of 400 ml ethyl ether and 100 ml methyl alcohol. The mixture is washed with water and then with phosphate buffer pH 7.5. The aqueous layer is acidified to pH 3 and extracted again with ethyl ether. The solvent is evaporated and the residue is recrystallized from chloroform. 1.2 g of the same product as in Example 1 is obtained.

Example 22

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 15 ml of tetrahydrofuran, 3 g of monohydrate glyoxylic acid and 25 ml of acetic acid. Unreacted zinc is filtered off and the filtrate is added to 500 ml of water containing 15 g of sodium sulfite and the resulting precipitate is filtered and dried in vacuo at 40 ° C. The residue is recrystallized from ethyl ether to obtain 1.8 g of compound of formula (I) wherein Y is acetyl and X is carboxyl.

Example 23

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 25 ml of dioxane, 5 g of P-nitro-benz-aldehyde and 35 ml of acetic acid. The reaction mixture is allowed to react at 70 ° C. for 30 minutes, after which the unreacted zinc is filtered and the filtrate is added dropwise to 200 ml of water containing 15 g of sodium sulfite and 2 g of sodium ascot bade. The resulting precipitate is filtered off, dried in vacuo at 40 ° C. and recrystallized from coylene. Yield: 3.9 g (Formula (I) compound wherein Y is acetyl and X is 4-nitrophenyl) Electron absorption spectra in methanol solution were pico at 315, 370 and 460 nm.

In a similar manner, 3-amino-4-deoxo-4-imino 16,17,18,19-tetrahydro-rifamycin S was reacted to give 16,17,18,19 corresponding to the product defined in the above examples. Obtain a tetrahydro derivative.

Example 24

8 g of 3-amino-4-deoxo-4-imino-rifamycin S was added with 1 g of zinc, 15 ml of tetrahydrofuran, 3 ml of 5-methyl-2-furylaldehyde, 25 ml of acetic acid and 40 ° C. React for 1 hour at. Unreacted zinc is filtered off and the filtrate is placed in 600 ml of water containing 15 g of sodium sulfite and 2 g of sodium ascorbate. The precipitate obtained is filtered, dried in vacuo at 40 ° C. and dissolved in 100 ml of methyl alcohol. After dilution with 400 ml of ethyl ether, the reaction mixture was extracted with a pH 7.5 phosphate buffer solution. The aqueous layer was acidified to pH 3 and extracted with chloroform. The chloroform layer is washed again with water, dehydrated with sodium sulfate and evaporated to reduce capacity. Petroleum ether precipitates to obtain 4.8 g of the compound of formula (I) wherein Y is acetyl and X is 2 (5-methyl) furyl.

Example 25

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 15 ml of tetrahydrofuran, 3.2 ml of 2-methylbutanal and 25 ml of acetic acid. After stirring at 40 ° C. for 1 hour, unreacted zinc is filtered and the filtrate is added to 400 ml of ethyl ether and extracted with a pH 7.5 phosphate buffer solution. The aqueous layer is acidified to pH 3 and extracted with chloroform.

After washing with water, the chloroform solution was dried over sodium sulfate, evaporated and the obtained residue was crystallized with ethyl ether. Yield: 3.3 g (compound of formula (I) wherein Y is acetyl and X is 2-butyl)

Example 26

8 g of 3-amino-4-deoxo-4-imino-rifamycin S was added with 1 g of zinc, 15 ml of tetrahydrofuran, 4.5 ml of 4-isopropyl-benzaldehyde, 25 ml of acetic acid and 30 minutes at room temperature. React. Unreacted zinc is filtered off and the solution is added to 500 ml of water containing 15 g sodium sulfite and 0.5 g sodium ascorbate. The resulting precipitate is filtered off, washed with water and dried in vacuo at 40 ° C. The residue is recrystallized from a mixed solution of coylene-cyclohexane (1: 1) to obtain 2.9 g of the compound of formula (I) wherein Y is acetyl and X is 4-isopropylphenyl.

Example 27

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 15 ml of tetrahydrofuran, 3.5 ml of 2-fluorobenzenealdehyde and 25 ml of acetic acid. After stirring for 10 minutes unreacted zinc is filtered off and the filtrate is added to 500 ml of water containing 15 g of sodium sulfite and 1 g of sodium ascorbate. The resulting precipitate is filtered off, washed with water and dried in vacuo at 40 ° C. Recrystallization with ethyl ether gives 3.6 g of the compound of formula (I) wherein Y is acetyl and X is 2-fluorophenyl. Electron absorption spectra in methanol solutions have pico at 260, 315 and 420 nm.

Example 28

8 g of 3-amino-4-deoxo-4-imino-rifamycin S was added to 1 g of zinc, 15 ml of tetrahydrofuran, 4.3 g of 3-carbethoxy cyclohexane aldehyde and 25 ml of acetic acid at room temperature. React for 1 hour. Unreacted zinc is filtered off and the filtrate is added dropwise to 500 ml of water containing 15 g of sodium sulfite. The precipitate obtained is filtered off, washed with water and dried in vacuo at 40 ° C. Recrystallization with ethyl ether gives 5.8 g of the compound of formula (I) wherein Y is acetyl and X is carethoxy cyclohexyl. Electron absorption spectra in methanol solutions have pico at 410 and 300 nm.

Example 29

8 g of 3-amino-4-deoxo-4-imino-rifamycin S was added with 1 g of zinc, 15 ml of tetrahydrofuran, 4.6 g of 7-hydroxy-citroneral and 25 ml of acetic acid for 1 hour. Reaction at room temperature. Unreacted zinc is filtered off, the filtrate is added dropwise to 600 ml of water containing 10 g of sodium sulfite and the resulting precipitate is filtered off. After washing with water, put into ethyl ether for 30 minutes with a product dried at 40 ℃, stirred, and dried by filtration. Yield: 6.2 g (Formula (I) compound wherein Y is acetyl and X is 2,6-dimethyl-6-hydroxy-heptyl)

Example 30

8 g of 3-amino-4-deoxo-4-imino-rifamycin S was added with 1 g of zinc, 15 ml of tetrahydrofuran, 3.5 ml of 2-ethyl-butanal and 25 ml of acetic acid at room temperature for 30 minutes. React. The zinc is filtered off and the filtrate is added to 500 ml of water containing 15 sodium sulfite and 1 g of ascorbic acid. The resulting precipitate is filtered off, washed with water and dried in vacuo at 40 ° C. The residue is recrystallized from ethyl ether. Yield: 3.8 g (Formula (I) compound wherein Y is acetyl and X is 3-pentyl)

Example 31

8 g of 3-amino-4-deoxo-4-imino-rifamycin S is reacted with 1 g of zinc, 15 ml of tetrahydrofuran, 5 g of 2-carboxybenzaldehyde and 30 ml of aceic acid at room temperature for 30 minutes. Unreacted zinc is filtered off and the filtrate is added to 300 ml of chloroform. The reaction mixture is washed with water, dehydrated with sodium sulfate and the solvent is evaporated. The residue is dissolved in 100 ml of benzene, 0.500 g of manganese dioxide is added and stirred at room temperature for 15 minutes. After filtration, the benzene layer is extracted with a pH 7.5 buffer solution and the aqueous layer is treated with ascorbic acid and acidified to pH 3 with dilute hydrochloric acid. The aqueous layer is extracted with dichloromethane, the organic layer is washed with water, dehydrated with sodium sulfate and the solvent is evaporated. Yield: 2.5 g (Formula (I) compound wherein Y is acetyl and X is 2-carboxyphenyl)

Claims (1)

The compound of formula (III), 16,17,18,19-tetrahydro derivative or 16,17,18,19,28,29-hexahydro derivative thereof is prepared in the presence of acetic acid with a metal such as zinc or iron and Or a compound such as a compound of formula (IV), a 16,17,18,19-tetrahydro derivative or a 16,17,18,19,28,29-hexahydro derivative and an ethyl or aromatic hydrocarbon In which ammonia gas is reacted with a compound of formula (V) or a compound of formula (III), or a 16,17,18,19-tetrahydro derivative or a 16,17,18,19,28,29-hexahydro derivative thereof Is reacted with a compound of formula (VI) in the presence of zinc and acetic acid to prepare formula (I) and its 16,17,18,19-tetrahydro or 16,17,18,19,28,29-hexahydro derivatives If necessary, such as potassium ferricyanide, potassium perphosphate, manganese dioxide or nitrous acid in an inert solvent It is oxidized with an oxidizing agent process for producing a derivative of formula (Ⅰ) the type (formula Ⅱ) oxide.

In the above formula, X is hydrogen, carboxyl, alkyl having 10 or less carbon atoms, cycloalkyl having 7 or less carbon atoms, alkenyl having 4 or less carbon atoms, cycloalkenyl having 7 or less carbon atoms, aryl having 13 or less carbon atoms, arylalkyl having 14 or less carbon atoms, arylal atoms having 11 or less carbon atoms 5- and 6-membered heterocycles containing up to 5 heteroatoms of Kenyl, Nitrogen, Oxygen and Sulfur; 5- and 6-membered heterocycles condensed with aromatic rings of heterocycles containing up to 3 heteroatoms of oxygen and sulfur Cyclic, halogen, hydroxy, alkoxy, nitro, amino, N-alkylamino, formyl, carboxy, carboalkoxy, carboxyalkoxy, N, N-dialkylaminoalkoxy, acyloxy, acetamido or alkylene dioxy At least one may be substituted, and Y is hydrogen or acetyl.