CA2466358C

CA2466358C - Method for the production of desclarithromycin, and intermediate products

Info

Publication number: CA2466358C
Application number: CA2466358A
Authority: CA
Inventors: Heiner Jendralla; Gerhard Korb; Juergen Mueller-Lehar
Original assignee: Sanofi Aventis Deutschland GmbH
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 2001-11-07
Filing date: 2002-11-02
Publication date: 2010-02-09
Anticipated expiration: 2022-11-02
Also published as: IL161800A; JP4344243B2; IL161800A0; JP2005508391A; MXPA04003026A; ATE298762T1; DK1444244T3; PT1444244E; AU2002357482B2; EP1444244A1; WO2003040162A1; ES2243798T3; DE50203529D1; EP1444244B1; CA2466358A1

Abstract

A novel method using novel intermediate products, suitable for advantageous production of desclarithromycin.

Description

Description Method for the production of desclarithromycin, and intermediate products The present invention describes a method for the production of desclarithromycin via the novel intermediates of erythromycin N-oxide and 6-O-methylerythromycin N-oxide which are protected with silyl groups. In addition, the novel intermediate of desclarithromycin N-oxide is described.
Desclarithromycin (II) is a building block for new types of macrolide antibiotics. The production of desclarithromycin (II) starting from clarithromycin (I), which can be produced from erythromycin A (III) by various synthetic routes, is known (see, for example, Abbott Laboratories WO 97/36912). In this case, desclarithromycin (II) is obtained by acid treatment of clarithromycin (I). There is in this case selective elimination of the cladinose, and the resulting desclarithromycin (II) is obtained (J. Med.
Chem. 1998, 41, 4080 - 4100) (formula scheme I) HCr ~ OH OH

Clarithromycin (t) Desctarithromycin (II) Formula scheme I
A further possibility is to produce desclarithromycin (II) directly from erythromycin A (III) in accordance with the following synthetic sequence:
Firstly, erythromycin A (III) is oximated by the action of hydroxylamine (see, for example, Abbott Laboratories WO 97/38000). The cladinose is eliminated and removed by extraction from the resulting erythromycin a oxime by acid treatment (formula scheme II). Decladinosed erythromycin oxime (IV) is obtained.
,OH
NHzOH ~ HCI
OH
Erythromycin A (III) Decladinosed erythromycin oxime (IV) Formula scheme II
Subsequently (as disclosed by Bonnet et al. United States Patent 5,969,161), the oxime group is protected with methoxypropene under slightly acidic conditions and the hydroxyl groups are protected by the action of trimethylchlorosilane under basic conditions (formula scheme III).
OCH3 Trimethyl /~ chlorosilane Decladinosed erythromycin oxime (IV) Disilylated decladinosed erythromycin oxime acetonide (V) Formula scheme III

The protected compound is methylated in the 6-O position by the action of, for example, methyl iodide and a strong base (e.g. potassium hydroxide) and subsequently converted by acid elimination of the protective groups into desclarithromycin oxime (VI) (formula scheme IV).
KOH, HCI
Disilylated decladinosed erythromycin oxime acetonide (V) Desclarithromycin oxime (VI) Formula scheme IV
Desclarithromycin (II) is then obtained by the action of sodium metabisulfite on desclarithromycin (VI) (formula scheme V).
NazS205 OH
Desclarithromycin oxime (VI) Desclarithromycin (Il) i=ormelschema V
Formula scheme V

A disadvantage of this method is the production of polymethylated by-products which, besides the methylation in the 6-O position, also exhibit ' methylated hydroxyl groups in the 11 andlor 12 position of the molecule (e.g. formulae (VII) and (VIII)). They interfere with further processing of desclarithromycin (II) to macrolide antibiotics and must therefore be removed beforehand by elaborate purification processes. A further disadvantage is the use of oximated intermediates because, in this case, E/Z isomers occur and have different physical properties (e.g. solubility) and therefore lead to losses of yield during reworking.

H
OH
Formula (VII) Formula (VIII) It is an object of the present invention to find a method for the production of desclarithromycin (II) which avoids the disadvantages described above.
This can be achieved by following the synthetic route, what is characterized by new types of intermediate compounds, as follows:
The present invention relates to a method for the production of desclarithromycin in which erythromycin A (III) is initially silylated in the 2'-O position and 4"-O position by silylation with basic agents, trialkylchlorosilane and trialkylsilylimidazole are preferred) in a known manner Y. Kawashima et al., Chem. Pharm. Bull. 38, 1485-1489, 1990 (IX).
The conditions described in Y. Kawashima et al., Chem. Pharm. Bull. 38, 1485-1489, 1990, are preferred (formula scheme VI).

Rssicuaase ~H R = CH3, I
__ Erythromycin A (III) Silylated erythromycin A (IX) 5 Formula scheme VI
The silylated erythromycin A is subsequently converted by oxidation with customary oxidizing agents, hydrogen peroxide or m-chloroperbenzoic acid are preferred, into the silylated erythromycin A N-oxide (X) (formula scheme VII).
H202 or m-CPi3 R = CH3, C2Hs R'= H or Sins __ __..3 Silylated erythromycin A (IX) Silylated erythromycin N-oxide (X) Formelschema VII
Formula scheme VII
It is optionally possible also to change the sequence of the first two steps (that is to say firstly to N-oxidize erythromycin and then to introduce the silyl protective groups), or the two steps can be linked in a one-pot reaction.

The protected compound is then methylated selectively in the 6-O position with a methylating agent, methyl iodide or dimethyl sulfate are preferred, ' under basic conditions, basification by addition of potassium hydroxide is preferred (formula scheme VIII).
CH31 or (CH3)2SO,MOH

+_-R3Si0 O N~ 0 R = CH9, C2H5 OCH OR, R' = H or SiR3 --s Silylated erythromycin N-oxide (X) Sifyated 6-O-methylerythromycin N-oxide (XI) Formelschema (VIII) Formula scheme (VIII) The cladinose and the silyl protective groups are eliminated from the silylated 6-O-methylerythrornycin N-oxide (XI) by acid treatment, the addition of HCI is preferred (formula scheme (IX). This results in desclarithromycin N-oxide (XII).
HCI
Silylated 6-O-methylerythromycin N-oxide (XI) Desclarithromycin N-oxide (XII) Formula scheme (IX) Desclarithromycin N-oxide (XII) is then reduced by known methods, preferably catalytically with palladiumlcarbon in the presence of hydrogen or of a hydrogen donor, preferably with cyclohexene), Raney nickel and hydrogen or sodium bisulfate, to desclarithromycin (II) (formula scheme X).
irbon and hydrogen or y nickel and hydrogen or m bisulfate iui~~ u~au~~i~c OH
Desciar'tthromycin N-oxide (XII) Desclarithromycin (la) Formeaschema (X) Formula scheme (X) It is optionally possible also to change the sequence of the last two steps (formula schemes IX and X) (that is to say firstly to reduce the N-oxide to the amine and then to eliminate the cladinose and the protective groups), or the two steps can be linked in a one-pot reaction, e.g. by stirring the solution of desclarithromycin N-oxide (XII) obtained as shown in formula scheme (IX) with an aqueous sodium bisulfate solution until (XII) is reduced to desclarithromycin (II), and isolating the latter from the reaction mixture, for example by crystallization.
The described reaction steps, which are illustrated by formula schemes (VI) to (X) may proceed under various conditions. It is sensible to vary the reaction conditions, taking account of generally known relevant prior art methods, in order to find the best embodiment. According to the current state of knowledge, the following reaction conditions are preferred:
The reaction depicted in formula scheme VI takes place in an organic solvent, preferably ethyl acetate, butyl acetate, dichloromethane, MTB

ether, THF, toluene, especially ethyl acetate. The reaction can take place at various temperatures, the procedure at room temperature is preferred.
The reaction depicted in formula scheme VII takes place in an organic solvent, preferably dichloromethane, ethyl acetate, butyl acetate, DMF, N,N-dimethylacetamide, NMP, especially dichloromethane. The reaction can take place at various temperatures, the procedure at about 0°C is preferred.
The reaction depicted in formula scheme VIII takes place in an organic solvent, preferably dimethyl sulfoxide, tetrahydrofuran, DMF, N,N-dimethylacetamide, NMP, dimethyltetrahydropyrimidinone (DMPU), especially a mixture of preferably equal parts of dimethyl sulfoxide and tetrahydrofuran. The reaction can take place at various temperatures, the procedure at room temperature is preferred.
The reaction depicted in formula scheme IX preferably takes place in aqueous phase. The reaction can take place at various temperatures, the procedure at room temperature is preferred.
The reaction depicted in formula scheme X takes place in an organic solvent, preferably dichloromethane, ethyl acetate, butyl acetate, THF, DMF, N,N-dimethylacetamide, NMP, especially dichloromethane. The reaction can take place at various temperatures, the procedure at room temperature is preferred.
For the reactions shown in formula schemes VI to X it may be helpful to carry out the reaction under a protective gas atmosphere. The resulting products can be isolated in various ways, such as, for example, filtration, extraction, by chromatography etc.
The compounds of the formulae X, XI and XII have not previously been disclosed and, like the methods for producing them, the present invention likewise relates thereto. Said compounds are particularly suitable as intermediate products in chemical synthesis, especially for the production of desclarithromycin.
The following exemplary embodiments are intended to explain the present invention in detail without the invention being restricted to the embodiment described in the examples. The individual features of the examples stand for specific embodiments which can be combined with generalized features as disclosed in the descriptive text and/or in the claims.
TLC analyses were carried out on coated glass plates (5 x 20 cm, silica gel 60 F2~ from Merck Darmstadt) in ascending mode, the gas phase being saturated with eluent vapor. The staining {detection of the separated reaction products) after development of the TLC plate and drying with a hot-air blower took place by briefly immersing the TLC plate in a solution of 25 g of molybdatophosphoric acid and 10 g of cerium(IV) sulfate in 940 ml of water and 60 ml of conc. sulfuric acid, allowing the TLC plate to drip dry and finally heating it at about 160°C on a DESAGA thermoplate ST"". 'H-NMR spectrum and '3C-NMR spectrum were recorded using a Bruker 400 UItraShieIdT"" spectrometer. For the interpretation of the '3C-NMR spectra, primary, secondary, tertiary and quaternary carbon atoms were differentiated by recording DEPT 135° spectra. However, no multidimensional spectra ('H-'H or 'H-'3C correlation) were recorded. It therefore cannot be precluded that signal assignments need to be interchanged, especially for protons or'3C atoms of the same multiplicity.
Example 1:
Synthesis of 2',4"-O-bis(trimethylsilyl)erythromycin A (formula IX, R = CH3) [modified on the basis of Y. Kawashima et al. Chem. Pharm. Bull. 38, 1485-1489 (1990)]
Erythromycin A from Abbott Laboratories, which contain 94.0 HPLC area percent of erythromycin A, was employed in this approach. The water content according to Karl-Fischer titration was 0.5% by weight.
A clear solution of 36.7 g (50.0 mmol tel qel, 47.0 mmol content) of erythromycin A was prepared in 1000 ml of ethyl acetate in a 2 I flask with mechanical stirrer, thermometer and dropping funnel under a nitrogen atmosphere. While maintaining the temperature at 20°C (waterbath) a solution of 8.15 g (74.3 mmol) of trimethylchlorosilane and 10.52 g (72.7 mmol) of N-(trimethylsilyl)imidazole in 50 ml of ethyl acetate was added dropwise over the course of 30 min. The reaction was exothermic.
15 min after starting the dropwise addition, a precipitate formed and initially formed lumps but subsequently became a well-dispersed suspension. TLC
monitoring (CH2C12 / MeOH 9:1 plus 1 % 25% strength ammonia solution) after 0.25 h showed complete conversion of the erythromycin A (Rf = 0.43) . to the title compound (ca. 70%; Rf = 0.67) and the monosilyl product (ca.

30%; Rf = 0.54). After 2.5 h, the monosilyl intermediate product had been converted into the title compound, apart from about 5% remaining.
The suspension was poured into a magnetically stirred ice-cold solution of 15 g 5 (178.6 mmol) of sodium bicarbonate into 285 ml of water. The aqueous phase was separated off and the organic phase was vfiashed first with 300 ml of water and then with 300 ml of saturated brine. The organic phase was dried over magnesium sulfate, filtered, evaporated to dryness in vacuo at a bath temperature of 40C and the crystalline residue was dried under 10 high vacuum (HV) (44.6 g, 101.5% of theory of crude product).
The residue was mixed with 150 ml of n-heptane and slowly heated. A clear colorless solution formed at 84C. It was allowed to cool, removing the heating bath, and at 65C was seeded with crystals of the title compound. It was allowed to cool further with mechanical stirring (320 rpm) to room temperature, and was then cooled to 15C and stirred at this temperature for a further min. The precipitate was filtered off with suction on a G4 glass frit, washed with 20 ml of n-heptane and then dried in vacuo in a stream of nitrogen at 40C. 31.0 g of white crystals were obtained. The mother liquor was concentrated to one third of the volume under weak vacuum, whereupon this solution became slightly cloudy. It was cooled to 10C and stirred at this temperature for 15 min. The precipitate was filtered off with suction, washed with 10 ml of n-heptane and then dried under HV. 4.4 g of white crystals were obtained. Total yield: 35.4 g (40.3 mmol, 85.7%
of theory), melting point: 213-215C (Lit. 194-197C). 'H-NMR (400 MHz, CDC13):

8 =

4.98 (dd, 1 H, 13-H), 4.83 (d, 1 H, 1 "-H), 4.39 (d, 1 H, 1'-H), 4.22 (m, 1 H, 5"-H), 4.16 (d, 1 H, 3-H), 3.83 (1 H, 11-OH), 3.80 (1 H, 11-H), 3.59 (m, 1 H, 5'-H), 3.56 (d, 1 H, 5-H), 3.30 (s, 3H, 3"-OMe), 3.18 (m, 1 H, 2'-H), 3.17 (d, 1 H, 4"-H), 3.11 (qua, 1 H, 10-H), 3.01 (s, 1 H, 12-OH), 2.80 (qui, 1 H, 2-H), 2.74 (m, 1 H, 8-H), 2.53 (m, 1 H, 3'-H), 2.37 (d, 1 H, 2"-H), 2.23 (br s, 6H, NMe2), 1.97-1.82 (m, 3H, 14-H, 4-H, 7-H), 1.72-1.60 (m, 4H, 7-H, 6-OH, 4'-H), 1.55-1.45 (m, 2H, 2'-H, 14-H), 1.44 (s, 3H, 6-Me), 1.23-1.10 (22H, 6"-Me, 8-Me, 3"-Me, 4'-H, 6'-Me, 12-Me, 10-Me, 2-Me), 1.09 (d, 3H, 4-Me), 0.87 (t, 3H, 15-H), 0.16 (s, 9H, 4"-OSiMe3), 0.10 (s, 9H, 2'-OSiMe3). '3C-NMR
(100 MHz, CDC13): 8 = 221.3 (C-9), 176.4 (C-1 ), 102.9 (C-1'), 96.8 (C-1 "), 81.7 (C-5), 81.0 (C-4"), 79.6 (C-3), 77.1 (C-13), 75.3 (C-6), 75.0 (C-12), 73.3 (C-2'), 73.1 (C-3"), 69.0 (C-11 ), 67.8 (C-5'), 65.2 (C-3'), 65.1 (C-5"), 49.8 (3"-OMe), 44.9 (C-2), 44.4 (C-8), 41.0 (NMe2), 40.5 (C-4), 39.0 (C-7), 38.7 (C-10), 35.9 (C-2"), 29.8 (C-4'), 27.3 (6-Me), 22.2 (5'-Me), 21.7 (3"-Me), 21.4 (C-14), 19.4 (5"-Me), 18.3 (8-Me), 16.4 (12-Me), 15.6 (2-Me), 11.8 (10-Me), 10.9 (C-15), 9.7 (4-Me), 1.02 [2'-OSi(CH3)3], 0.96 [4"-OSi(CH3)3]. MS (ESI):
[M+H]+ m/z = 878 (Cq3H83NO13s~2)~
The product can also be recrystallized / reprecipitated in high yield and purity from acetone/water instead of n-heptane.
Example 2:
Synthesis of 4"-O-(trimethylsilyl)erythromycin A N-oxide (formula X, R=CH3, R'=H) a) Preparation of 99% pure 3-chloroperoxybenzoic acid from commercial 77% pure 3-chloroperoxybenzoic acid (Aldrich):
400 ml of phosphate buffer of pH 7 (Riedel 10240) were introduced into a 1 I round-bottomed flask with KPG stirrer, thermometer and calibrated pH
electrode under a nitrogen atmosphere. A pH of 7.5 was adjusted by adding a total of 8.47 g of disodium hydrogen phosphate. 50.16 (223.8 mmol) of 77% pure 3-chloroperoxybenzoic acid were added all at once thereto. A suspension formed. The pH fell, rapidly at first and then more slowly, until it came to a stop at pH 6.42. The pH was raised again to 6.95 by adding 13.92 g of disodium hydrogen phosphate. The suspension was filtered with suction. The solid was washed with water which had previously been adjusted to pH 7, and was then dried under HV in a desiccator. 31.9 g of white crystals (83% of theory based on the content of the commercial material employed) were obtained. The water content (K.F.- titr.) was 0.27%.
b) 4"-O-(Trimethylsilyl)erythromycin A N-oxide:
A clear solution was prepared from 13.18 g (15.0 mmol) of disilylerythromycin A (from example 1 ) in 25 ml of dichloromethane (0.025% water content according to K.-F. titrat.) in a 250 ml flask with mechanical stirrer, thermometer and dropping funnel under a nitrogen atmosphere, and 2.27 g (27.0 mmol) of dry sodium bicarbonate were added. The suspension was cooled with an icebath to 0°C. A solution of 3.12 g (17.9 mmol) of the above approx. 99% pure 3-chloroperoxybenzoic acid in 50 ml of dichloromethane was added dropwise thereto. The cooling bath was removed and the mixture was allowed to warm to 23°C and stirred at this temperature for 1 h, during which a thick suspension formed.
TLC (CH2C12 / MeOH 9:1 plus 1 % 25% strength ammonia solution) of a ' ~ sample which had been removed by filtration with suction from the precipitate showed clean quantitative conversion of the precursor (Rf =
0.67) into the product (Rf = 0.25). The suspension was cooled in the icebath at 2°C and, after addition of 40 ml of half-saturated aqueous sodium bicarbonate solution, vigorously stirred. The mixture was filtered with suction and washed with 2 X 10 ml of cold half-saturated sodium bicarbonate solution, sucked dry and then dried under HV over phosphorus pentoxide. 11.8 g (14.4 mmol, 95.6% of theory) of colorless crystals were obtained, melting point 204 - 205°C (composition). 'H-NMR (400 MHz, CDC13): 8 = 5.03 (dd, 1 H, 13-H), 4.89 (d, 1 H, 1 "-H), 4.68 (d, 1 H, 1'-H), 4.18 (m, 1 H, 5"-H), 3.98 (d, 1 H, 3-H), 3.88 (s, 1 H, 11-OH), 3.84 (m, 1 H, 5'-H), 3.80 (m, 1 H, 11-H), 3.74 (dd, 1 H, 2'-H); 3.58 (d, 1 H, 5-H), 3.47 (m, 1 H, 3'-H), 3.36 (s, 3H, 3"-OMe), 3.18 and 3.17 (2 x s, 2 x 3H, N(O)Me2), 3.16 (concealed, 1 H, 4"-H), 3.09 (qua, 1 H, 10-H), 3.05 (s, 1 H, 12-OH), 2.90 (qui, 1 H, 2-H), 2.68 (m, 1 H, 8-H), 2.38 (d, 1 H, 2"-H), 2.36 (s, 1 H, 6-OH), 2.06-1.83 (m, 4H, 4'-, 4-, 7-, 14-H), 1.71 (d, 1 H, 2'-OH), 1.57 - 1.45 (m, 3H, 4'-, 2"-, 14-H), 1.45 (s, 3H, 6-Me), 1.30 (m, 1 H, 7-H), 1.24 - 1.08 (24H, 8 x Me), 0.85 (t, 3H, 15-H), 0.15 (s, 9H, 4"-OSiMe3). '3C-NMR (100 MHz, CDC13): b = 221.7 (C-9), 175.9 (C-1 ), 101.8 (C-1'), 96.2 (C-1 "), 83.1 (C-5), 80.7 (C-3), 79.3 (C-4"), 76.6 (C-13), 75.8 (C-3'), 74.8 and 74.7 (C-6, C-12), 73.2 (C-3"), 72.8 (C-2'), 68.9 (C-11 ), 66.1 (C-5'); 65.0 (C-5"), 58.8 [N(O)-CH3], 51.8 (N(O)-CH3], 49.7 (3"-OCH3), 45.1 (C-2), 44.6 (C-8), 39.3 (C-4), 38.5 (C-7), 37.8 (C-10), 35.6 and 35.0 (C-2", C-4'), 26.8 (6-CH3), 22.2 (5'-CH3), 21.6 (3"-CH3), 21.1 (C-14), 19.3 (5"-CH3), 18.3 (8-CH3), 16.1 (12-(H3), 15.9 (2-CH3), 12.0 (10-CH3), 10.6 (C-15), 9.1 (4-CH3), 0.9 [4"-OSi(CH3)3]. MS (ESI) m/z = 822 (C4pH75NO14S~).
Reaction of 1.0 equivalent of disilylerythromycin (Example 1 ) with 1.25 equivalents of commercial 77% pure 3-chloroperoxybenzoic acid in dichloromethane at 0°C (formation of a two-phase mixture) likewise results in clean formation of the N-oxide, which can be isolated in a yield of 90-93% of theory.
Example 3:
Methylation of 4"-O-(trimethylsilyl)erythromycin A N-oxide to 4"-O-(trimethylsilyl)clarithromycin N-oxide [6-O-methyl-4"-O-(trimethylsilyl)-erythromycin A N-oxide; formula XI, R = CH3, R' = H]

r ' 13 5.48 g (6.66 mmol) of 4"-O-(trimethylsilyl)erythromycin A N-oxide (from Example 2) was stirred in 25 ml of dimethyl sulfoxide and 25 ml of tetrahydrofuran under a nitrogen atmosphere in a 100 ml flask with mechanical stirrer, thermometer and septum to give a thin suspension. This was cooled to 0°C with an icebath. 559 mg (8.47 mmol) of 85% pure potassium hydroxide powder were added ali at once. A deep yellow, cloudy solution formed, to which were added, while stirring at 0°C, 1.04 ml (16.40 mmol) of methyl iodide, during which the reaction temperature rose from +2 to +4°C. The reaction mixture was allowed to warm to room temperature while stirring over the course of half an hour, during which it became pale yellow. After stirring for a further 2 hours at room temperature, 180 ml of ethyl acetate and 120 ml of ice-water were added. The aqueous phase was separated, and the organic phase was washed with 120 ml of water and then with 50 ml of water. The combined aqueous wash phases were immediately back-extracted with 50 ml of ethyl acetate, and this extract was washed with 20 ml of water/5 ml of saturated brine. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo, and the residue was dried under HV to give a solid foam. 5.23 g (6.25 mmol, 94% of theory) of crude product were obtained, of which about 50-60% consisted of the title compound. 'H-NMR (400 MHz, CDC13): 8 = 3.37 (s, 3H, 3"-OMe), 3.22 [2 x s, 6H, 3'-N(O)Me2], 3.04 (s, 3H, 6-OMe), 0.15 (s, 9H, 4"-OSiMe3). ~3C_NMR (100 MHz, CDCI3): 8 = 221.5 (C-9), 176.2 (C-1 ), 102.6 (C-1'), 58.6 [N(O)CH3], 52.5 [N(O)CH3], 51.0 (6 OCH3), 49.9 (3"-OCH3, 0.9 [4"-OSi(CH3)3]. MS (ESI): [M+H]+ m/z = 836 (C4~H»N0~4Si).
Example 4:
Cladinose- and silyl-elimination to give desclarithromycin N-oxide [6-O-methylerythromycin A N-oxide; formula XII]
A solution of 3.2 ml of 12 N hydrochloric acid (38.4 mmol HCI) in 32 ml of water was added to 5.2 g (6.22 mmol) of the crude product from Example 3 under a nitrogen atmosphere and with icebath cooling in a 100 ml flask with mechanical stirrer. The reaction mixture was stirred for 2 h at room temperature, then saturated with sodium chloride, adjusted to pH8 with aqueous ammonia solution and extracted with 5 x 50 ml of ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, a . evaporated to dryness in vacuo and dried under HV. 4.7 g of pale brown solid were obtained.
An analytical sample was obtained by flash chromatography of a sample (200 mg) of this crude product through 40 g of silica gel 60 (Merck, 0.040 -0.063 mm) with the eluent dichlurorr~eihane i methanol 8:2. 95 mg of white crystals were obtained, melting point 209 - 210°C (decomposition), >97%
pure according to HPLC analysis (LiChroCART 125 X 4 mm LiChrospher 100 RP18e, 5 ~.m, Det. 210 nm, 25°C, flow 0.5 ml/min, eluent A: CH3CN
CF3COZH 1000 : 0.5, eluent B: H20 / CF3C02H 1000 : 0.5; linear gradient from 30% A / 70% B on injection to 50% A / 50% B after the chromatography had lasted 10 minutes; retention time: 8.55 min), single spot according to TLC analysis (CH2C12 / CH30H 8:2 plus 1 % 25% strength ammonia solution, Rf = 0.34).'H-NMR (400 MHz, CDC13): 8 = 5.17 (dd, 1 H, 13-H), 4.48 (d, 1 H, 1'-H), 3.88 (s, 1 H, 11-OH), 3.86 (d, 1 H, 11-H), 3.80 (dd, 1 H, 2'-H), 3.72 (s, 1 H, 5-H), 3.64 (m, 1 H, 5'-H), 3.57 (d, 1 H, 3-H), 3.38 (m, 1 H, 3'-H), 3.27 (s, 1 H, 12-OH), 3.18 [s, 3H, N(O)Me], 3.15 [s, 3H, N(O)Me], 3.01 (m, 1 H, 10-H), 2.97 (s, 3H, 6-OMe), 2.65 (m, 1 H, 2-H), 2.57 (m, 1 H, 8-H), 2.09 (qua, 1 H, 4'-H), 2.02 - 1.87 (m, 3H, 4-, 7-, 14-H), 1.53 (d, 1 H, 2'-OH), 1.49 (m, 1 H, 14-H), 1.40 (d, 1 H, 4'-H), 1.37 (s, 3H, 12-Me), 1.31 (d, 3H, 5'-Me), 1.27 (d, 3H, 2-Me), ca. 1.26 (m, concealed, 1 H, 7-H), 1.19 (s, 3H, 6-Me), 1.16 (d, 3H, 8-Me), 1.15 (d, 3H, 10-Me), 1.13 (d, 3H, 4-Me), 0.84 (t, 3H, 15-H). '3C-NMR (100 MHz, CDC13): b = 220.4 (C-9), 175.2 (C-1 ), 106.1 (C-1'), 89.0 (C-5), 78.7 (C-3), 78.0 (C-6), 76.5 (C-13), 75.7 (C-3'), 74.2 (C-12), 72.1 (C-2'), 69.7 (C-5'), 68.2 (C-11 ), 59.0 [N(O)-CH3], 51.9 [N(O)-CH3], 49.4 (6-OCH3), 45.4 (C-2), 44.6 (C-8), 38.7 (C-7), 37.6 (C-4), 36.0 (C-10), 34.4 (C-4'), 21.4 (C-14), 20.9 (5'-CH3), 18.7 (6-CH3), 17.7 (8-CH3), 16.2 (12-CH3), 15.3 (2-CH3), 12.5 (10-CH3), 10.3 (C-15), 8.3 (4-CH3).
MS (ESI): [M+H]+ m/z = 606 (C3pH55N011)~
Example 5:
Reduction of the crude N-oxide to desclarithromycin [6-O-methyl-erythromycin A; formula II]
4.5 g of the crude desclarithromycin N-oxide from Example 4 were mixed with 50 ml of dichloromethane and the solution of 1.5 g (7.9 mmol) of sodium metabisulfite (Na2S205) in 15 ml of water in a 100 ml flask with mechanical stirrer and the two-phase mixture was vigorously stirred at room temperature under a nitrogen atmosphere. It was possible to follow the reduction using the HPLC system described in Example 4 (retention time of II = 7.37 min) and using the TLC system described in Example 4 (Rf II = 0.52), and it was complete after 3 hours. The aqueous phase was separated off and extracted with 20 ml of dichloromethane. The combined 5 organic phases were concentrated to about 15 ml in vacuo, and then 45 ml of water were added, and the pH was adjusted to 1.0 witH 36% strength hydrochloric acid. The organic phase was separated off, and remaining cladinose and the secondary product thereof were washed out of the acidic aqueous phase by extraction with 5 x 10 ml of dichloromethane. It was 10 possible to follow this procedure using the TLC system described in Example 4. The aqueous phase was then adjusted to pH 5.3 with 25%
strength aqueous ammonia, the stirrer was switched off, a layer of 5 ml of methyl isobutyl ketone (MIBK) was put on top of the aqueous solution, and the two-phase mixture was stirred at a very low speed (about 20 rpm) with 15 negligible phase mixing at 20°C for 15 minutes. The MIBK phase (containing impurities) was separated off in a separating funnel, and the aqueous phase was slowly adjusted with 25% strength aqueous ammonia while stirring vigorously at 25°C (slight cooling) to pH 9.5, the solution being seeded with pure product crystals at pH 7.5, and the product crystallizing out from about pH 8.3 onwards. The suspension was then stirred at 25°C
for 30 minutes and at 15-20°C for a further 30 minutes. The precipitate was filtered off with suction, washed with 30 ml of water, sucked dry and dried under HV at 40°C for 16 hours. 1.8 g of white crystals were obtained (3.05 mmol, 46% of theory based on the 4"-O-(trimethylsilyl)erythromycin N-oxide employed in Example 3). Taking account of the 200 mg removed in Example 4 to obtain the analytical sample, the overall yield for the reactions described in Examples 3 to 5 is 48% of theory), melting point 154 -155°C.
'H-NMR (400 MHz, CDC13): 8 = 5.18 (dd, 1 H, 13-H), 4.38 (d, 1 H, 1'-H), 3.92 (s, 1 H, 11-OH), 3.87 (br s, 1 H, 3-OH), 3.86 (d, 1 H, 11-H), 3.68 (s, 1 H, 5-H), 3.55 (m, 2H, 3- and 5'-H), 3.26 (s, 1 H, 12-OH), 3.24 (dd, 1 H, 2'-H), 3.01 (qua, 1 H, 10-H), 2.97 (s, 3H, 6-OMe), 2.66 (m, 1 H, 2-H), 2.58 (m, 1 H, 8-H), 2.47 (m, 1 H, 3'-H), 2.26 (s, 6H, NMe2), 2.12 (m, 1 H, 4'-H), 1.94 (m, 2H, 4- and 7-H), 1.66 (d qua, 1 H, 14-H), 1.56 (dd, 1 H, 4'-H), 1.49 (m, 1 H, 14-H), 1.37 (s, 3H, 12-Me), 1.26 (d, 6H, 5'-Me and 2-Me), ca. 1.25 (m, concealed, 1 H, 7-H), 1.18 (s, 3H, 6-Me), 1.13 (d, 6H, 8-Me and 10-Me), 1.12 (d, 3H, 4-Me), 0.84 (t, 3H, 15-H). '3C-NMR (100 MHz, CDC13): 8 =
220.6 (C-9), 175.0 (C-1 ), 106.6 (C-1'), 88.2 (C-5), 78.9 (C-3), 78.1 (C-6), 76.6 (C-13), 74.2 (C-12), 70.7 (C-2'), 70.2 (C-11 ), 69.8 (C-5'), 65.6 (C-3'), 49.5 (6-OCH3), 45.5 (C-2), 44.5 (C-8), 40.2 [3'-N(CH3)2], 38.7 (C-7), 37.5 (C-4), 35.9 (C-10), 28.1 (C-4'), 21.4 (C-14), 21.2 (5'-CH3), 18.8 (6-CH3), 17.7 (8-CH3), 16.2 (12-CH3), 15.2 (2-CH3), 12.6 (10-CH3), 10.4 (C-15), 8.2 (4-CH3). MS (ESI): [M+H]+ m/z = 590 (C3pH55N~10)~
The patent claims which follow and which form part of the contents of the description contribute to the aisciosure of the invention.

Claims

claims:

1. A method for the production of desclarithromycin, which comprises a) erythromycin A being reacted with R3SiCl and/or R3Si-imidazole or (R3Si)2NH or R3SiO3SCF3 with R meaning CH3, C2H5 under basic conditions to give compounds of the formula (IX), and b) subsequently being oxidized by addition of an oxidizing agent to the compound of the formula X

and the resulting compound of the formula (X) being c) converted by addition of a methylating agent under basic conditions into the compound of the formula (XI), and subsequently d) the compound of the formula (XI) being converted by acid hydrolysis into the compound of the formula (XII) and subsequently e) the compound of the formula (XII) being converted under reducing conditions into desclarithromycin (II)

2. The method as claimed in claim 1, wherein the sequence of the chemical reactions of steps a) and b) is changed.

3. The method as claimed in claims 1 or 2, wherein the sequence of the chemical reactions of steps d) and e) is changed.

4. A compound of the formula (X) in which R is CH3 or C2H5 and in which R' is H or SiR3.

5. A method for the production of a compound of the formula (X) as claimed in claim 4, which comprises an oxidizing agent being added to a compound of the formula (IX) or which comprises erythromycin A being oxidized by an oxidizing agent and subsequently a reaction taking place with R3SiCl and/or R3Si-imidazole or (R3Si)2NH or R3SiO3SCF3 with R meaning CH3, C2H5 under basic conditions to produce the compound of the formula (X).

6. A compound of the formula (XI) in which R is CH3 or C2H5 and in which R' is H or SiR3.

7. A method for the production of a compound of the formula (XI) as claimed in claim 6, which comprises a compound of the formula (X) as claimed in claim 4 being mixed with a methylating agent under basic conditions.

8. A compound of the formula (XII)

9. A method for the production of the compound of the formula (XII) as claimed in claim 8, which comprises a compound of the formula (XI) as claimed in claim 6 being hydrolyzed under acidic conditions.

10. The use of one or more of the compounds X, XI or XII as claimed in claims 4, 6 or 8 in the production of desclarithromycin.