How to obtain clarithromycin

 

(57) Abstract:

The invention relates to a process for the preparation of clarithromycin of formula (I), including the interaction of the N-oxide erythromycin And formula (II) with meteorous agent with obtaining N-oxide 6-O-methyl-erythromycin a of formula (III) and processing of N-oxide-6-O-methylerythromycin And a reducing agent. The technical result is an increase in the yield of the target product. 8 C.p. f-crystals.

The scope of the invention

The present invention relates to a method for clarithromycin using N-oxide erythromycin And and a new intermediate compound obtained by this method.

Background of invention

Clarithromycin, 6-O-methylerythromycin And is a semi-synthetic macrolide antibiotic that has a broad range of antibacterial activity against gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria, Mycoplasma, chlamydia and Helicobacter pylori.

Clarithromycin can be obtained by methylation of 6-hydroxy-group of erythromycin A. However, the implementation of selective methylation of 6-hydroxy-group is difficult as erythromycin And, in addition to 6-HYDR is to ergatis quaternization of the reaction of methylation.

To solve this problem have been developed various methods of obtaining clarithromycin.

So, for example, was described a General method of obtaining clarithromycin using a 9-oxime erythromycin derivative as intermediate compounds (see EP patent No. 0158467, 0195960, 0269938 and 0272110 and publication of international application number WO 97/36912 and WO 97/36913). Although this method gives a relatively high yield, but it is ineffective due to poor performance, due to the fact that this method requires the implementation of a number of reaction stages, including the stage of oxymorphine, protection of the oxime group transformation of, removal exisestnet group and deoxyinosine.

Another common method of obtaining clarithromycin described in EP patent No. 0147062 and 0177696. The method described in EP patent No. 0147062, involves the following stages: protection 2-hydroxy - and amino-groups of erythromycin And benzyloxycarbonyl groups; methylation of 6-hydroxy-group; removal of two benzyloxycarbonyl protective groups; and methylation of the amino group with receiving clarithromycin. However, when mass production this way, in addition to the difficulties of using the separation of the product by chromatography on columns, has nedostate the reed.

Accordingly there is a need to develop an improved method for receiving clarithromycin.

Brief description of the invention

Therefore, the aim of the present invention is the provision of a method of receiving clarithromycin.

Another objective of the present invention to provide a new intermediate compounds obtained in this way.

In accordance with one aspect of the present invention provides a method of obtaining clarithromycin of formula (I), comprising the stage of:

(a) interaction of the N-oxide erythromycin And formula (II) with meteorous agent with obtaining N-oxide 6-O-methylerythromycin And formula (III);

(b) processing the N-oxide 6-O-methylerythromycin And obtained at stage (a), a reducing agent with obtaining clarithromycin:

In accordance with another aspect of the present invention provides N-oxide 6-O-methylerythromycin And formula (III).

Detailed description of the invention

The compound of formula (I) can be obtained from the N-oxide erythromycin And, as described below.

Stage (a)

N-oxide 6-O-methylerythromycin And formula (III) is e than 98%, according to a well-known method [E. N. Flynn et al., J. Am. Chem. Soc., 76, 3121 (1954) & P. H. Jones & E. K. Rowley., J. Org.Chem., 33, 665(1968)] meteorous agent in an organic solvent in the presence of a base.

Examples meteorous agents, which can be suitably used in the present invention are the methyl, methyliodide, dimethylsulfate, methyl-p-toluensulfonate, methylmethanesulfonate and mixtures thereof. Metymirumi agent may be used in amounts of from 1 to 3 equivalents relative to the amount of N-oxide erythromycin And formula (II).

Examples of solvents that can be used in the above reaction, methylation, include N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, sulfolane, N,N,N’,N’,N”,N”-hexamethylphosphoramide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, 2-methoxyethylamine ether, 2-ethoxyethyl ether, 1,2-bis(2-methoxyethoxy)ethane, dimethyl ether of tetraethyleneglycol, acetone, acetonitrile and mixtures thereof.

In addition, this method can be used a base selected from the group consisting of hydrides, hydroxides and alkoxides of alkali metals, for example sodium hydride, hydride feces is e from 0.9 to 2 equivalents relative to the amount of N-oxide erythromycin And formula (II). The methylation reaction can be conducted at temperatures from -15 to 40°C, preferably from 0°C. to room temperature.

After the methylation reaction to the resulting mixture, water is added and the mixture extracted with chloroform. The extract was concentrated and to the residue add acetone, and then stirred for deposition of by-products. The resulting mixture was filtered to remove by-products and the filtrate concentrated to obtain the crude N-oxide 6-O-methylerythromycin (output: 67-73% purity: 50-57%).

The crude N-oxide 6-O-methylerythromycin And received, as described above, can be used as in stage (b), or it can be purified by recrystallization from ethyl acetate to obtain purified N-oxide 6-O-methylerythromycin And (purity: 83-88% output: 40-44%), which can be further purified by recrystallization from chloroform to obtain crystals of N-oxide 6-0-methylerythromycin And having a purity of more than 95%.

Stage (b)

Clarithromycin of formula (I) are obtained by reaction of N-oxide 6-O-methylerythromycin And obtained at stage (a) with a reducing agent in an organic solvent to remove N-oxide.

Examples of suitable Vosstania hydrogenation, such as palladium, Nickel Raney catalyst or a platinum oxide (PtO2); an alloy of Nickel and aluminum (Ni-Al) combined with potassium hydroxide; metal zinc in the presence of formic acid or acetic acid; hydrocolloid sodium (NaTeH); samarium iodide (SmI2); dichloride, tin (SnCl2); hexabutylditin (Bu3SnSnBu3); cyclohexen and tetroxide osmium (OsO4); and ferrous sulfate (2), and the preferred reducing agents for the implementation of the present invention are tin dichloride (SnCl2); hexabutylditin (VI3SnSnu3); an alloy of Nickel and aluminum, combined with potassium hydroxide; and hydrogen in the presence of Nickel catalyst or Raney catalyst is platinum oxide (PtO2).

In the case of using tin dichloride as a reducing agent can be used solvents such as methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, acetone, tetrahydrofuran, 1,2-dimethoxyethane, dichloromethane, chloroform and mixtures thereof. The amount of tin dichloride is from 1 to 3 molar equivalents relative to the amount of N-oxide 6-O-methylerythromycin And formula (III), and the reaction can be carried out at temperatures from 0°C to tempering can be selected (1) neutralizing the reaction mixture with a base, such as triethylamine; adding to the mixture of water and extraction of this mixture with an organic solvent; or (2) adding to the reaction mixture water; neutralizing the resulting mixture with base, such as sodium bicarbonate, sodium carbonate, sodium hydroxide solution and aqueous ammonia; and extraction of the mixture with an organic solvent.

In the case of hexabutylditin as a reducing agent can be used solvents such as ethyl acetate, acetonitrile, acetone, tetrahydrofuran, 1,2-dimethoxyethane and mixtures thereof. Hexabutylditin is used in an amount of from 1 to 3 molar equivalents relative to the amount of N-oxide 6-O-methylerythromycin And formula (III), and the reaction can be carried out at a temperature ranging from room temperature to the boiling point of the used solvent.

If the reductant is used, the Ni-Al alloy with potassium hydroxide as solvent a mixture of water and lower alcohol, such as methanol and ethanol. The number of Ni-Al alloy and potassium hydroxide ranges from 0.5 to 3 g and 2 to 20 mol, respectively, per one mole of the N-oxide 6-O-methylerythromycin And formula (III). Ispolzuemogo solvent.

If the carrying out of the reaction stage (b) is a catalytic hydrogenation, the solvent can be used a lower alcohol or a mixture of water and lower alcohol, and the catalyst can be used as a hydrogenation catalyst, such as Nickel Raney catalyst, at a temperature ranging from room temperature to the boiling point of the used solvent in a hydrogen atmosphere.

Reaction stage (b) can also be carried out using an inorganic reducing agent such as sodium bisulfite (NS3), sodium sulfite (PA2SO3), sodium thiosulfate (PA2S2ABOUT3), hydrosulfite sodium (Na2S2O4), pyrosulfite sodium (Na2S2O5), tional sodium (Na2S2O6), potassium bisulfite (S3), potassium thiosulfate (K2S2ABOUT3and persulfate potassium (K2S2O5). This reaction can be carried out in a mixture of water and lower alcohol, such as methanol, ethanol and isopropanol, at a temperature from 0°C to the boiling point of the used solvent. The reducing agent may be used in an amount of from 1 to 20 equivalents, preferably from 1 to 4 ei reaction stage (b) with the use of sulfur dioxide as a reducing agent, in addition to clarithromycin of formula (I), may form a 3’-N-dimethyl-6-O-methylerythromycin And formula (IV) as a by-product. In this case, by-products can be converted to clarithromycin by methylation of the secondary amino group of the specified by-product of using formic acid and formaldehyde in accordance with a known method [see Eschweiler & Clarke, Org.React., 5, 290(1945)]

The following comparative example and the examples are only for purposes of illustrating the present invention and in no way limit its scope; experimental methods used in the present invention, can be carried out in accordance with the above comparative example and the examples below, unless otherwise specified.

In addition, the percentages given below for solids in solid mixtures, liquid substance in the liquid and solids in the liquid are given in wt./wt., about./about. and wt./about. accordingly, unless otherwise specified.

Comparative example

Obtaining N-oxide erythromycin AND

220,2 g (0.3 mole) of erythromycin And dissolved in a mixture of 1500 ml of methanol and 1000 ml of water. To the solution are added dropwise 79 ml (0.9 mol) todom, similar to that described in E. N. Flynn et al., J. Am. Chem. Soc., 76, 3121 (1954) & P. H. Jones et al., J. Org.Chem., 33, 665 (1968). The resulting mixture was concentrated to half volume under reduced pressure and successively extracted with 1000-ml and 500-ml portions of chloroform. The combined chloroform extract is washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to get foamy residue. To the residue add 1000 ml of acetone and stirred at room temperature for 3 hours. Formed crystalline product is filtered and dried overnight at 45°C to obtain 220 g of N-oxide erythromycin And with the release of 98%.

So pl. 218~221°C (so square in the literature: 222~224°C).

1H-NMR (CDCl3, M. D.): 5,00(DD, 1H, 13-H), a 4.86(d, 1H, 1"-H), 4,50(d, 1H, 1'-H), to 3.34 (s, 3H, cladinose-och3), 3,17 (d, 6N, desosamine-N(CH3)2), was 1.43(s, 3H, 18-H) of 0.82(t, 3H, 15-N).

MS (m/z): ESI 750[M+1]+.

Example 1

Obtaining N-oxide 6-O-methylerythromycin AND

75,0 g (0.1 mol) of N-oxide erythromycin And obtained in the comparative example, suspended in a mixture of 450 ml of dimethyl sulfoxide and 450 ml of tetrahydrofuran and cooled to 5°C. Then add to 8.1 ml iodomethane and 7,26 g of powdered 85% hydroxide coextrusion 1000-ml and 500-ml portions of chloroform. The combined extract washed twice with 500 ml of water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the foamy residue is added 500 ml of acetone and stirred at room temperature for 5 hours. The resulting mixture was filtered to remove the precipitated by-products. The filtrate is concentrated under reduced pressure to get 52.7 g of the crude N-oxide 6-O-methylerythromycin And having a purity of 57%.

To the obtained crude product add 300 ml of ethyl acetate and the mixture is stirred to obtain crystals. The crystals are filtered and dried overnight at 45°C with the receipt of 30.3 g of N-oxide 6-O-methylerythromycin And in the form of a crystalline powder, having a purity of 88%.

The resulting crystalline powder is recrystallized from chloroform to obtain of 20.1 g of target compound having a purity higher than 95%, and the yield of 27%.

So pl.: 204~207°C.

IR(KBR, cm-1): 3446, 2972, 2938, 1733, 1693, 1462, 1379, 1169, 1111, 1079.1H-NMR (CDCl3, M. D.): is 5.06(DD, 1H, 13-H), is 4.93(d, 1H, 1”-H), 4,55(d, 1H, 1’-H), was 4.02(DQC, 1H, 5"-H), 3,76(d, 1H, 11-H), to 3.73(DD, 1H, 3-H), 3,70(d, 1H, 5-H), 3,65 (ddcv, 1H, 5’-H), to 3.38 (s, 3H, 3"-och3), 3,19(d, 6N, 3’-N(CH3)2), was 3.05 (s, 3H, 6-och3), 2.91 in(DQC, 1H, 2-H), 2,59(ddcv,), 176,2(C9=O), 102,9(C1’), 96,5(C1”), 81,6(C5), 79,0(C6), 78,7(C3), 78,2(C4”), And 77.6(C3’), 77,0(C13), 76,7(C2’), 74,7(C12), 73,1(C3”), 69,5 (C11), 67,4(C5’), 66,3(C5”), 59,1(C8’), 52,8(C7’), 51,0(C22), 50,1(C8”), 45,7(C8), 45,4(C2), And 39.7(C7), 39,6(C4), 37,7(C10), 35,3(C2”), 32,0(C4’), 22,0(C6’), 21,7(C7”), 21,4 (C14), 20,2(C18), 19,1(C6”), An 18.4(C19), And 16.4(C21), And 16.3(C16), 12.7mm(C20), 11,0(C15), 9,4(C17), MS (m/z): ESI 764[M+1]+.

Example 2

Obtaining N-oxide 6-O-methylerythromycin AND

75,0 g (0.1 mol) of N-oxide erythromycin And obtained in the comparative example, suspended in a mixture of 450 ml of dimethyl sulfoxide and 450 ml of tetrahydrofuran and cooled to 5°C. Then add to 8.1 ml iodomethane and 7,26 g of powdered 85% potassium hydroxide and the mixture is stirred for 1.5 hours. To the resulting mixture add 1000 ml of cold water and successively extracted with 1000-ml and 500-ml portions of chloroform. The combined extract washed twice with 500 ml of water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to get foamy residue. To this residue is added 500 ml of acetone and the mixture is stirred at room temperature for 5 hours. The resulting mixture was filtered to remove the precipitated by-products. The filtrate is concentrated under reduced pressure obtaining of 50.4 g of the crude N-oxide 6-O-meiler is hydrate tin dichloride as a reductant

3,82 g (5 mmol) of N-oxide 6-O-methylerythromycin As obtained in example 1 are suspended in 30 ml of isopropanol. Then add of 2.26 g (2.0 mmol) of the dihydrate of tin dichloride and the mixture is stirred at a temperature of from 30 to 40°C for 2 hours. To the obtained mixture is added a saturated solution of sodium bicarbonate and the mixture extracted twice with ethyl acetate. The combined organic layer washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure obtaining of 3.60 g of clarithromycin in the form of a white powder with a yield of 96%.

So pl. 220~223°C (so square in the literature: 222~225°C).

1H-NMR (CDCl3, M. D.): is 5.06(DD, 1H, 13-H), to 4.92(d, 1H, 1"-H), of 4.44(d, 1H, 1'-H), was 4.02(DQC, 1H, 5”-H), of 3.78(DD, 1H, 3-H), of 3.77(d, 1H, 11-H), to 3.67(d, 1H, 5-H), 3,57(ddcv, 1H, 5’-H), of 3.33(s, 3H, 3”-och3), 3,20(DD, 1H, 2’-H), 3,07~2,95 (m, 2H, 10-H and 4”-H), 3,03 (s, 3H, 6-och3), 2,87(DQC, 1H, 2-H), 2,58(ddcv, 1H, 8-H), 2.40 a(DDD, 1H, 3’-H), is 2.37(d, 1H, 2”-H), 2,28 (s, 6N, 3’-N(CH3)2), 2,00~of 1.80 (m, 3H, 4-H and 7-H2), of 1.41 (s, 3H, 18-H) of 1.13(s, 3H, 6-CH3) to 0.85(t, 3H, 14-CH3).

Example 4

Obtaining clarithromycin using hexabutylditin as reductant

3,82 g (5 mmol) of N-oxide 6-O-methylerythromycin As obtained in example 1 are suspended in the IR within 24 hours. The solvent is concentrated under reduced pressure and to the residue is added isopropyl ether and hexane. The resulting crystals filtered and washed with hexane, resulting in a gain 3,55 g of clarithromycin in the form of a white powder with a yield of 95%.

Example 5

Obtaining clarithromycin using alloy of Nickel and aluminum as the reductant

3,82 g (5 mmol) of N-oxide 6-O-methylerythromycin As obtained in example 1 are suspended in a mixture of 100 ml methanol and 50 ml of 1N potassium hydroxide. Then within 30 minutes, add 5 g of Nickel alloy-aluminum, while maintaining the temperature of 35-40°C, and stirred for 3 hours. The resulting mixture was diluted with methanol and filtered through a layer of celite to remove solids. The filtrate is concentrated under reduced pressure to remove methanol and the residue diluted with water. The resulting crystals filtered, washed with water and dried to obtain 3,44 g of clarithromycin in the form of a white powder with a yield of 92%.

Example 6

Obtaining clarithromycin by hydrogenation using a Nickel catalyst Raney

3,82 g (5 mmol) of N-oxide 6-O-methylerythromycin As obtained in example 1 are suspended in 100 is 50°C in an atmosphere of hydrogen for 3 hours. The resulting mixture was filtered through a layer of celite at 50°C. or higher to remove the spent catalyst. The filtrate is concentrated under reduced pressure to 30 ml and cooled to room temperature. The resulting crystals filtered and dried to obtain 3,44 g of clarithromycin in the form of a white powder with a yield of 92%.

Example 7

Obtaining clarithromycin using sodium bisulfite as a reductant

3,82 g (5 mmol) of N-oxide 6-O-methylerythromycin As obtained in example 1 are suspended in a mixture of 15 ml of ethanol and 15 ml of water. Then add 1,05 g (10 mmol) of sodium bisulfite and the mixture is stirred at room temperature for 1 hour. The resulting mixture is concentrated, water is added and then the mixture is brought to pH 10 by adding 10% sodium carbonate. The resulting mixture was extracted three times with ethyl acetate, the organic layers combined, washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure and the obtained residue was dissolved in 20 ml of ethanol. After addition of 0.55 ml of formic acid and 0.8 ml of 35% formaldehyde mixture is refluxed for 2 hours. The resulting mixture conc the ATA sodium and receive 3,44 g of clarithromycin in the form of a white powder with a yield of 92%.

Example 8

Obtaining clarithromycin

The procedure of example 1 is repeated with the use of 75.0 g (0.1 mol) of N-oxide erythromycin And obtained in the comparative example, resulting in a gain of 54.0 g of the crude N-oxide 6-O-methylerythromycin And having a purity of about 54%.

of 54.0 g of the thus obtained N-oxide 6-O-methylerythromycin And dissolved in 400 ml of dichloromethane and to this solution add a 32.6 g (144 mmol) dichloride dihydrate tin, and then stirred at room temperature for 1.5 hours. To the obtained mixture is added 300 ml of 10% sodium carbonate and dichloromethane is removed under reduced pressure. The residue is successively extracted with 400-ml and 200-ml portions of ethyl acetate, the organic layers combined washed twice with 300 ml of water, and then dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure, to the residue was added 100 ml of ethanol is refluxed for 30 minutes and stirred at room temperature for 3 hours. The resulting solid collected and dried to obtain 24,0 g of clarithromycin in the form of a white crystal, with yield of 32%.

Example 9

Obtaining clarithromycin

Procedure p the resulting receive a 33.2 g of N-oxide 6-O-methylerythromycin And in the form of a crystalline powder, having a purity of approximately 85%.

the 33.2 g of pure 85% N-oxide 6-O-methylerythromycin And dissolved in a mixture of 70 ml of ethanol and 70 ml of water, the resulting solution was added of 6.52 g (and 62.6 mmol) of sodium bisulfite, and then the mixture is stirred at room temperature for 1 hour. The resulting mixture was concentrated to small volume, the concentrate water is added, and then brought to pH 10 by adding 10% sodium carbonate. The resulting mixture was extracted three times with ethyl acetate, the organic layers combined, washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure and the residue is dissolved in 80 ml of ethanol. To a solution of ethanol, add 5.0 ml of formic acid and 7.1 ml of 35% formaldehyde, and then it is refluxed for 2 hours. To the obtained mixture is added 200 ml of water, pH adjusted to 11 by addition of concentrated aqueous ammonia solution, and then cooled to room temperature. The formed solid is filtered and dried, resulting in a gain of 22.5 g of clarithromycin in the form of a white powder with a yield of 30%.

Although the present invention is illustrated and described above in specific versions of its domestic is from the essence of the present invention, which is determined by the scope of the claims.

1. The method of obtaining clarithromycin of formula (I), which includes stages

(a) interaction of the N-oxide erythromycin And formula (II) with meteorous agent with obtaining N-oxide 6-O-methyl-erythromycin a of formula (III);

(b) processing the N-oxide 6-O-methylerythromycin And obtained at stage (a), a reducing agent with obtaining clarithromycin:

2. The method according to p. 1, in which stage (a) is carried out in an organic solvent at a temperature in the range of (-15) - (+40)°C in the presence of a base.

3. The method according to p. 1, in which metymirumi agent selected from the group consisting of bromide, under the conditions, dimethylsulfate, methyl-p-toluensulfonate, methylmethanesulfonate and mixtures thereof.

4. The method according to p. 1, in which the number meteorologi agent is 1 to 3 equivalents relative to the amount of N-oxide erythromycin A.

5. The method according to p. 2, in which the specified organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, sulfolane, N,N,N’,N’,N”,N”-hexamethylphosphoramide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, 2nd, acetone, acetonitrile or mixtures thereof.

6. The method according to p. 2, wherein the specified base selected from the group consisting of hydrides, hydroxides and alkoxides of alkali metals and mixtures thereof.

7. The method according to p. 2, in which the number of bases is 0.9 to 2 equivalents relative to the amount of N-oxide erythromycin A.

8. The method according to p. 1, in which the reducing agent is chosen from the group consisting of a hydrogen in the presence of a hydrogenation catalyst; Nickel alloy and aluminum (Ni-Al) combined with potassium hydroxide; metal zinc in the presence of formic acid or acetic acid; hydrocolloid sodium (NaTeH); samarium iodide (SmI2); tin dichloride (SnCl2); hexabutylditin (VI3SnSnu3); cyclohexene and osmium tetroxide (OsO4); sulphate of iron (2); NS3; Na2SO3; PA2S2O3; Na2S2O4; Na2S2O5; PA2S2O6; S3;2S2O3;2S2O5; and mixtures thereof.

9. The method according to p. 1, in which the specified reducing agent is tin dichloride (SnCl2); hexabutylditin (VI3SnSnu3); an alloy of Nickel and aluminum, combined with hydro is SUB>).

 

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