ZA200206734B - Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same. - Google Patents
Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same. Download PDFInfo
- Publication number
- ZA200206734B ZA200206734B ZA200206734A ZA200206734A ZA200206734B ZA 200206734 B ZA200206734 B ZA 200206734B ZA 200206734 A ZA200206734 A ZA 200206734A ZA 200206734 A ZA200206734 A ZA 200206734A ZA 200206734 B ZA200206734 B ZA 200206734B
- Authority
- ZA
- South Africa
- Prior art keywords
- clarithromycin
- oxime
- erythromycin
- methyl
- protected silylated
- Prior art date
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- 229960002626 clarithromycin Drugs 0.000 title claims description 96
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 title claims description 94
- 238000000034 method Methods 0.000 title claims description 77
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 83
- MWBJRTBANFUBOX-UHFFFAOYSA-N 6-[4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-12,13-dihydroxy-10-hydroxyimino-4-(5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl)oxy-7-methoxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradecan-2-one Chemical compound CC1C(OC2C(C(CC(C)O2)N(C)C)O)C(C)(OC)CC(C)C(=NO)C(C)C(O)C(O)(C)C(CC)OC(=O)C(C)C1OC1CC(C)(OC)C(O)C(C)O1 MWBJRTBANFUBOX-UHFFFAOYSA-N 0.000 claims description 68
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 46
- 239000003795 chemical substances by application Substances 0.000 claims description 38
- 239000002904 solvent Substances 0.000 claims description 36
- 229960003276 erythromycin Drugs 0.000 claims description 34
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 32
- 150000002923 oximes Chemical class 0.000 claims description 27
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 25
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 24
- 229930006677 Erythromycin A Natural products 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 23
- 238000010992 reflux Methods 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 239000012022 methylating agents Substances 0.000 claims description 14
- 239000011541 reaction mixture Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- 235000019253 formic acid Nutrition 0.000 claims description 13
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 8
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims description 6
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical group [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 6
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 6
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 claims description 3
- 229940102396 methyl bromide Drugs 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 16
- -1 6-O-methyl-2’ Chemical compound 0.000 description 15
- 239000012535 impurity Substances 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 7
- 238000007069 methylation reaction Methods 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 230000011987 methylation Effects 0.000 description 5
- 238000006146 oximation reaction Methods 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000001035 methylating effect Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000003386 deoximation reaction Methods 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000003544 oxime group Chemical group 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- KYTWXIARANQMCA-PGYIPVOXSA-N (3r,4s,5s,6r,7r,9r,10z,11s,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-10-hydroxyimino-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradec Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N\O)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 KYTWXIARANQMCA-PGYIPVOXSA-N 0.000 description 1
- TVEXGJYMHHTVKP-UHFFFAOYSA-N 6-oxabicyclo[3.2.1]oct-3-en-7-one Chemical compound C1C2C(=O)OC1C=CC2 TVEXGJYMHHTVKP-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 101000713585 Homo sapiens Tubulin beta-4A chain Proteins 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 102100036788 Tubulin beta-4A chain Human genes 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- FGRVOLIFQGXPCT-UHFFFAOYSA-L dipotassium;dioxido-oxo-sulfanylidene-$l^{6}-sulfane Chemical compound [K+].[K+].[O-]S([O-])(=O)=S FGRVOLIFQGXPCT-UHFFFAOYSA-L 0.000 description 1
- GRWZHXKQBITJKP-UHFFFAOYSA-L dithionite(2-) Chemical compound [O-]S(=O)S([O-])=O GRWZHXKQBITJKP-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229940079826 hydrogen sulfite Drugs 0.000 description 1
- 150000002443 hydroxylamines Chemical class 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 1
- 229940043349 potassium metabisulfite Drugs 0.000 description 1
- 235000010263 potassium metabisulphite Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000011935 selective methylation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- CSMWJXBSXGUPGY-UHFFFAOYSA-L sodium dithionate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 description 1
- 229940075931 sodium dithionate Drugs 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- JXAZAUKOWVKTLO-UHFFFAOYSA-L sodium pyrosulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OS([O-])(=O)=O JXAZAUKOWVKTLO-UHFFFAOYSA-L 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical class S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Description
PROCESSES FOR PREPARING CLARITHROMYCIN AND
CLARITHROMYCIN INTERMEDIATE, ESSENTIALLY OXIME-FREE ss 5 CLARITHROMYCIN, AND PHARMACEUTICAL COMPOSITION
COMPRISING THE SAME
The present application claims the benefit of U.S. Provisional Application Nos. 60/185,888 filed on February 29, 2000, 60/189,120 filed on March 14. 2000, and 60/213,239 filed on June 22, 2000.
The present invention relates to methods for preparing a protected silylated clarithromycin oxime, such as 6-O-methyl-2’, 4°’-bis(trimethylsilyl)-erythromycin A 9-O- (2-methoxyprop-2-yl)oxime (hereinafter “S-MOP oxime’), which include reacting a silyl oxime derivative with methylating agent while stirring in the presence of at least one solvent, where the solvent includes at least methyl tert-butyl ether (MTBE), and a base.
The present invention also relates to a method of converting the protected silylated clarithromycin oxime to clarithromycin, which includes reacting the protected silylated clarithromycin oxime with acid and deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1. The reaction mixture is cooled to about 20°C and a base, preferably sodium hydroxide, is added. The method does not include any additional water addition to process clarithromycin.
The present invention further relates to a method of converting a protected silylated clarithromycin oxime, such as S-MOP oxime, to clarithromycin, which includes heating a mixture of the protected silylated clarithromycin oxime, acid, and deoximating agent in an ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of said deoximating agent. The invention further relates to the essentially oxime-free y clarithromycin produced by such a method and pharmaceutical compositions containing the same. -1-
SUBSTITUTE SHEET (RULE 26)
‘» - BACKGROUND OF THE INVENTION 6-O-methyl ervthromycin A (clarithromycin) is a semisynthetic macrolide .- antibiotic related to erythromycin A. It exhibits excellent antibacterial activity against gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria. Mycoplasma. and . 5 Chlamydia. It is stable under acidic conditions and is efficacious when administered orally.
Clarithromycin is a useful therapy for infections of the upper respiratory tract in children and adults. Clarithromycin is stable under acidic conditions and is efficacious when administered orally.
The chemical structure of clarithromycin 1s: 0
HC lL ..CHy
HC. Lo; _ wT : ABC. ° ‘ © CH;
Cm ki OCH; 0 OH
CLM CH,
Various methods of preparing 6-O-methylerythromycin A from erythromycin A have been described in the patent literature. One of the most effective methods includes the following steps: 1) protecting the 9-oxo group with a substituted oxime group, 2) protecting the hydroxy! groups in positions 2° and 4°°, 3) methylating the hydroxyl in position 6 to give a protected sililated clarithromycin oxime, and 4) removing the protecting groups at the 2°, 4°” and 9 position.
The third step, which comprises methylating the hydroxyl group at position 6. is performed in the presence of a solvent. This 6-O-methylation of various erythromycin derivatives in converting erythromycin A to clarithromycin has been reported in several ’ U.S. Patents including U.S. Patent Nos. 4.680.386 and 4,672.109.
U.S. Patent No. 4,680.386 for example, describes a method of methyvlating the hydroxyl group at the 6 position by reacting the compound with a methylating agent in the 22-
SUBSTITUTE SHEET (RULE 26)
presence of a base in an aprotic solvent at a temperature of between 0°C and room temperature. The 386 patent describes the use of solvents including N.N- dimethylformamide. dimethyl sulfoxide, hexamethylphosphoric triamide. and a mixture of 7 one or more of these solvents. U.S. Patent No. 4,672,109 describes the use of solvents . 5 such as dimethyl sulfoxide. N.N-dimethylformamide, hexamethyl phosphoric triamide, a mixture of two or more of these solvents or a mixture of one of these solvents and tetrahydrofuran, 1, 2-dimethoxyethane and the like. The ‘109 patent further describes a preferred embodiment of this step using a mixture of dimethyl sulfoxide and tetrahydrofuran. WO 97/19096 describes a mixture of solvents including N,N- dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, hexamethyl phosphoric triamide. tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile and ethyl acetate for use in the methylating step.
However. several of the above-described solvents are expensive. do not enable selective methylation, produce significant unwanted side products and/or cause complications during later phase separation steps.
The fourth step includes removing the protecting groups, and thus, converts : protected silylated clarithromycin oxime to clarithromycin. Described methods of converting a protected silylated clarithromycin oxime, such as S-MOP oxime, to clarithromycin include reacting the protected silylated clarithromycin oxime with ethanol in the presence of an acid and a deoximating agent. The product of the reaction is then washed with water one or more times. The ethanol generally also contains water.
U.S. Patent No. 4,990.602 has an ethanol to water ratio of 1:4 and does not involve cooling. U.S. Patent No. 4,670,549 adds sodium hydroxide after cooling at an ethanol to water ratio of 1:3. Neither of these methods lowers the impurity content of clarithromycin.
The present invention relates to methods for preparing a protected silylated . clarithromycin oxime, such as 6-O-methyl-2’, 4’’-bis(trimethylsilyl)-erythromycin A 9-O- (2-methoxyprop-2-yl)oxime (“S-MOP oxime”), which include reacting a silyl oxime : 30 derivative with methvlating agent while stirring in the presence of at least one solvent and -3-
SUBSTITUTE SHEET (RULE 26)
a base, where the solvent includes methyl tert-butyl ether (MTBE). In the method for preparing the protected silylated clarithromycin oxime, the methylating agent is preferably . one or more of methyl iodide, methyl bromide, dimethylsulfate, methyl p-toluenesulfonate. ) or methanesulfonate. The base is preferably sodium hydride, potassium hydroxide, or - 5 sodium hydroxide.
Further embodiments of the present invention relates to methods of converting a protected silylated clarithromycin oxime, such as S-MOP oxime, to clarithromycin. One such method includes reacting the protected silylated clarithromycin oxime with acid and a deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1. The reaction mixture is cooled to about 20°C and a base, preferably sodium hydroxide solution, is added. In this method, no additional water is added to process clarithromycin. Another method of converting a protected silylated clarithromycin oxime to clarithromycin includes heating a mixture of the protected silylated clarithromycin oxime, acid, and deoximating agent in an ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of deoximating agent. In the latter method, essentially oxime-free clarithromycin is produced, which contains less than 40 ppm of the corresponding oxime intermediate. -4-
SUBSTITUTE SHEET (RULE 26)
Clarithromycin is described, inter alia, in the following publications, which are hereby : incorporated herein by reference: U.S. Patent Nos. 3,922.379. 4,331,803. 4,670,549, 4,672,109, « 3 4.680,386,4.808.411.4.957.905, 4.990.602, 5.837.829, 5.844,105. 5,852,180, 5.858.986, 5,919,489, 5.932.710. and 5.945405.
The terms “6-O-methylerythromycin A’ and “clarithromycin” are used interchangeably herein and are meant to include clarithromycin in any form (such as crystalline Form 0, Form I,
Form II or Form IV) or pharmaceutical salts thereof or mixtures thereof, as well as amorphous solids, syrups, or semisolids comprising clarithromycin in any state of purity, unless specified otherwise.
The present invention relates to increasing the product yield and unwanted side effects produced various steps included in converting erythromycin A to clarithromycin.
Clarithromycin is prepared from erythromycin A by a variety of synthetic routes. Some of these routes include oximation steps and the use of a protected silylated clarithromycin oxime, such as an S-MOP oxime intermediate. ocr
HyC—C—CH; o
N
HC ~CHs
OHY ’ Y" OCH; Si(CHC. CH;
HC... | J IN — N
RN 0 © CH:
Lo buy Ne) OCH;
Lo]
CH; Hs =a
CH;
S-MOP Oxime -5-
SUBSTITUTE SHEET (RULE 26)
The synthetic routes of converting erythromycin A to clarithromycin that are improved herein. are those that utilize a protected silylated clarithromycin oxime intermediate. such an S-MOP oxime intermediate. ) Synthetic routes of converting erythromycin A to clarithromycin include methylation of -~ 5 the 6-hydroxy group of erythromycin A. In the conversion process it is necessary to protect various groups, such as the hydroxy groups at the 2° and 4°" positions of ervthromycin A. which are potentially reactive with alkylating agents. prior to alkylation of the 6-hvdroxy group.
Examples of methods of preparing clarithromycin using oxime intermediates are described for example, in U.S. Patent Nos. 4,990,602 and 5.858,986. which each describe a method of preparing clarithromycin from erythromycin A by oximation of the C-9 carbonyl, protection of the C-2’ and C-4’" hydroxy groups, methylation of the C-6 hydroxy group. and deoximation and removal of the protecting groups.
An example of a synthetic route of converting erythromycin A to clarithromycin via oximation, that utilizes a protected silylated clarithromycin oxime, specifically S-MOP oxime, as an intermediate, is as follows in Scheme 1 (each compound in the process is numbered for ease of referencing them herein).
Scheme 1 1 2
Oo
TN Re: N—OH
OHY ’ YY oH HC, CH HiC LCi
HC. Ls 13 cH HO zo, OH OH HC CH (He. 0 CH, HC big CH HO— As i 0 “0 \ 3 - id H +o 3 a
NEE : CH;
CH, 0 OCH: NH,0H ? 0
CH; * CHy cn 0 OCH; 2-methoxypropenc : ro \—OH . | Cis Py-HCI
CH; CH; )
Erythromycin 0 OH
CHa -6-
SUBSTITUTE SHEET (RULE 26)
3 4
OCH; OCH,
I
H;C—C—CH; H:C—C—CHs 0 0 - N N
N HyC A ~CHs HC .CH3
SN HC . ’ Ny ©
FL Ot ACH OH OH sicHy HC. CH;
HAC... : . . of 1 HOO CH TET HC Non ~N ~CHs Ors
HC. as - 0 / * : ~ - 0] ! ch RES . A TCH: - i \ | CHAVKOH
CH ; SR > uv o OCH; {CH3);Si-Cl Ct iy 0 OCH: DMSO
CH, poh ‘—CH, (CH3)Si-Im | — ] -.
Son osc
CH; CH -7-
SUBSTITUTE SHEET (RULE 26)
OCH; ; H,C—C—CHs
N oH - H;C | . Hj i HC CH 8 ) ] ST OCH: SicHIC, Ci OH Lg Ro ~CH3 hb) . ! HiCroll, . 3 the Fo] “CH TT Cet re
HiC. - HsC. N Lo CH; . . 3 o . CH; ©
CH; CL
CH . HCOOH 5 ? CH; A oO ? CH;
EtOH - CH;
CH; V CH, CH \ lo} OH x _s N “T=
S—MOP-Oxime lo HCH3)s CLM —Oxime CH; , :
NaHSO; / NaHS,
E1OH/H-0 \HCOOH / H:O/EOH
J
7 0]
HC ~CHs
OHY ° YY" OCH; HC CH,
HC z N
H;C.. . © CH
I 0 Xe) r 3
CHy /° . 0 0 OCH;
CHa I" CH; 0) OH
CLM CH;
The present invention is directed to improved methods of preparing a protected silylated clarithromycin oxime, preferably an S-MOP oxime (compound 5 in Scheme 1) from a 9-oxim silyl derivative (such as compound 4 in Scheme 1) and of converting a protected silylated . clarithromycin oxime, preferably an S-MOP oxime (compound 7 in Scheme 1). to clarithromycin. -8-
SUBSTITUTE SHEET (RULE 26)
The methods described herein are not limited to use in the process shown in Scheme 1.
Scheme 1 is provided as a representative scheme in which a protected silylated clarithromycin . oxime, such as an S-MOP oxime. is prepared from a silyl derivative and another step includes : converting the protected silylated clarithromycin oxime to clarithromycin. It would be ~ 5 understood by those in the art that the methods described herein may be used in various schemes for converting erythromycin A to clarithromycin. which employ a protected silylated clarithromycin oxime compound as an intermediate therein.
In the representative process of converting erythromycin A to clarithromycin shown above in Scheme 1, ervthromycin A is first converted to a protected silylated oxime, such as 2’, 47-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime (compound 4 in Scheme 1), by methods generally known in the art. As indicated above, protecting groups protect certain positions from potentially reacting with alkylating agents during the subsequent methylation of the 6-hydroxy group, and also protect 3’-dimethylamino groups from quaternary alkylation.
Although the conversion from erythromycin A to a protected silylated oxime (e.g., 2’, 4”’- bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime) may be accomplished by any methods known to those in the art, in a preferred method, erythromycin A is first oximated and subsequently protecting groups are added initially to the oxime group and then to the 2’ and 4” positions. Suitable methods for oximation and the addition of protecting groups are set forth in U.S. Patent Nos. 5,858,986 and 4,990,602, which teach general methods of oximation that may be used in accordance with the present invention, such as by reacting erythromycin A with the substituted hydroxylamine R'ONH,, or by reacting erythromycin A with hydroxylamine hydrochloride in the presence of base. or hydroxylamine in the presence of acid, followed by reaction with R'X, where R' is alkoxyalkyl. U.S. Patent Nos. 5,858,986 and 4,990,602 further describe suitable methods for protecting the oxime group and two hydroxy groups (i.e., at the 2’ and 4” positions) with silyl groups. The hydroxy groups may be protected simultaneously or in different steps from one another. Preferred methods of converting the silyl derivative to a protected silylated clarithromycin oxime and converting the protected silylated clarithromycin . oxime to clarithromycin are set forth below. 9.
SUBSTITUTE SHEET (RULE 26)
The step of converting a silyl derivative such as compound 4 to a protected silylated clarithromycin oxime (such as S-MOP oxime) is a methylation step. In this methylation step. . one or more hydroxy groups. such as that at the 6-position, is methylated. One embodiment of : the present invention relates to methods for preparing a protected silylated clarithromycin oxime. - 5 which includes reacting a silvl oxime derivative with a methylating agent while stirring in the presence of a solvent and a base.
The solvent in this embodiment includes MTBE (methyl tertbutyl ether), preferably along with another aprotic solvent(s). The most preferable solvent is a mixture of DMSO (dimethyl sulfoxide) and MTBE. The present inventors have found the MTBE is more selective. cheaper and easier to recover than solvents described in the literature. including the primarily used combination of DMSO with THF (tetrahydrofuran).
In this embodiment, the silyl derivative is stirred in a solvent at about ambient temperature until the silyl derivative is dissolved. For purposes of this specification, ambient temperature is from about 20°C to about 25°C. A further solvent may then be added. The solution is cooled to a temperature of between about 0°C and about 20°C, preferably between about 5 and about 15°C, even more preferably about 10°C.
In this embodiment, a methylating agent is added while stirring the solution. The methylating agent is preferably an agent such as methyl iodide, methyl bromide. dimethylsulfate, methyl p-toluenesulfonate, methyl methanesulfonate, dimethyl sulfate, and the like. The methylating agent is most preferably methyl iodide. Although 1.0 to 10 molar equivalents of methylating agent can be used per mole of silyl derivative. it is sufficient to use between about 1.0 and about 3.0 molar equivalents of methylating agent per mole of silyl oxime derivative.
A base is added to the solution of silyl oxime derivative, solvent(s) and methylating agent in this embodiment, and stirred at a temperature of between about 9°C and about 25°C, preferably between about 9°C and about 15°C until the reaction is essentially completed. The base is preferably one or more of sodium hydride, potassium hydroxide. sodium hydroxide. sodium hydride, potassium tert-butoxide, potassium hydride, and the like. Most preferably. the : base is powdered potassium hydroxide, which is added to the solution and stirred at about 10°C. -10-
SUBSTITUTE SHEET (RULE 26)
The amount of base used is usually from about 1 to about 3 molar equivalents of the silyl oxime derivative. . Preferably the temperature is maintained at about 10°C to about 12°C while stirring is taking place and the reaction is occurring. The progress of the reaction is monitored by HPLC. = 5 When MTBE is used as a solvent in this embodiment. two phases may form. making it easier to separate the protected silylated clarithromycin oxime. than if other solvents are used that form a single phase. The separation of protected silylated clarithromycin oxime may be performed by conventional methods. For example, once the reaction is complete, the workup of the reaction mixture may include phase separation, washing of the MTBE layer with water and evaporation to dryness.
Another embodiment of the present invention relates to converting a protected silylated clarithromycin oxime, preferably S-MOP oxime, (whether it is arrived at by the method of the above embodiment or by another method) to clarithromycin, by reacting the protected silylated clarithromycin oxime with an acid and a deoximating agent in the presence of aqueous ethanol where the ethanol to water ratio is about 1:1. The reaction of the protected silylated clarithromycin oxime with deoximating agent and acid brings about deoximation together with elimination of the protecting groups. The reaction mixture is then cooled to between about 15°C and about 25°C, more preferably about 20°C, and subsequently a base, preferably sodium hydroxide solution, is added.
Previously described methods of converting a protected silylated clarithromycin oxime to clarithromycin include introducing the protected silylated clarithromycin oxime into a water/ethanol system in the presence of an acid and a deoximating agent and refluxing at 80°C.
Subsequently, a large amount of water is added. According to this process, the mass ratio between the protected silylated clarithromycin oxime:ethanol:water is about 1:5:5 before the addition of the large amount of water. The ratio of ethanol to water is about 1:1. before adding additional water and about 1:4 after adding additional water. Then, NaOH is added and the solution is cooled to 0°C. This method results in the precipitation of clarithromycin. However. : this process is disadvantageous because it doesn’t allow purification of the product from an impurity, the 11-methyl derivative of clarithromycin. This impurity is referred to as the -11-
SUBSTITUTE SHEET (RULE 26)
“dimethyl” form of clarithromycin. which is difficult to remove. When the ethanol to water ratio is 1:3 or 1:4 for example, it is difficult to remove the impurity. If the reaction mixture is not . cooled prior to addition of sodium hydroxide, the impurity content may not decrease. ) The present invention relates to an improved process for obtaining clarithromycin from a . 5 protected silylated clarithromycin oxime, such as S-MOP oxime. in which the obtained clarithromycin contains significantly reduced amounts of the “dimethyl” impurity. The method includes reacting a protected silylated clarithromycin oxime with an acid (such as formic acid) and a deoximating agent in the presence of aqueous ethanol at an ethanol/water ratio of about 1:1, refluxing the solution at 80°C, cooling the solution to about 20°C. and adding NaOH.
In the present method, acid is added to the mixture of protected silylated clarithromycin oxime, ethanol, water and deoximating agent and the mixture is heated at reflux (about 80°C.)
Heating is then continued and the suspension is stirred for an amount of time sufficient to finish the reaction. The mixture is then cooled to about 20°C and sodium hydroxide solution having a concentration of from about 20% to about 47%, preferably 47%, is added at this temperature until the pH of the reaction mixture reaches about 10 to about 11, preferably about 10.2 to about 10.5. Crystalline clarithromycin is then isolated, preferably by filtration. with no further water addition. The obtained clarithromycin may subsequently be further purified and/or isolated and the crystalline form of clarithromycin may be altered to the desired form (such as crystal form 0,
LL II, or IV) for use.
There is need to add no additional water in the method of the present invention. Since additional water (that is, water other than the water present with the ethanol in a ratio of about 1:1 and in sodium hydroxide solution) is not required in the present method, clarithromycin may be formed with a significant decrease in the amount of impurities.
The advantages of the present method are inter alia that the clarithromycin produced contains about 50% less of the dimeric impurity than clarithromycin produced by other processes, and the working volumes are lower. Preferably, the volume ratio of protected silylated clarithromycin oxime oxime: water:ethanol is about 1:3:3. : Another embodiment of the present invention also relates to converting a protected silylated clarithromycin oxime, such as S-MOP oxime, (whether it is arrived at by the method -12-
SUBSTITUTE SHEET (RULE 26)
described hereinabove or by another method) to clarithromycin. by heating a mixture of a protected silylated clarithromycin oxime. acid, and two-fold addition of deoximating agent in an ; cthanol/water solvent to reflux for more than 4 hours. Essentially oxime-free clarithromycin, that is clarithromycin, which contains less than 40 ppm of the corresponding oxime intermediate, may - 5 be produced by this method.
As in the previous embodiment. the reaction of protected silylated clarithromycin oxime with deoximating agent and acid brings about deoximation together with elimination of the protecting groups. The reaction mixture is then cooled to between about 15°C and about 25°C, more preferably about 20°C. and subsequently a base, preferably sodium hydroxide solution, is added.
Previously described methods of converting a protected silylated clarithromycin oxime to clarithromycin include introducing the protected silylated clarithromycin oxime into a water/ethanol system in the presence of an acid and a deoximating agent and refluxing for 2 hours in an ethanol/water solvent. The product of this process contains clarithromycin oxime as an impurity.
By two-fold addition of deoximating agent refluxing for over four hours, the clarithromycin oxime impurity is largely removed, resulting in relatively pure (essentially oxime- free) clarithromycin. Accordingly, the present invention is also directed to this essentially oxime-free clarithromycin and pharmaceutical compositions containing the essentially oxime- free clarithromycin. Pharmaceutical compositions containing clarithromycin are described for example in US Patent No. 5,858,986.
In the present method, acid is added to the mixture of S-MOP oxime, ethanol, water and deoximating agent and the mixture is heated at reflux (about 80°C). Heating is then continued and the suspension is stirred for at least four hours. The mixture is then cooled, preferably to about 20°C. and sodium hydroxide solution having a concentration of from about 20% to about 47%, preferably 47%. is added at this temperature until the pH of the reaction mixture reaches about 10 to about 11. preferably about 10.2 to about 10.5. Crystalline clarithromycin is then : isolated, preferably by filtration, with no further water addition. The obtained clarithromycin may subsequently be further purified and/or isolated and the crystalline form of clarithromycin -13-
SUBSTITUTE SHEET (RULE 26)
may be altered to the desired form (such as crystal form 0. I. II. or IV) for use.
Examples of suitable deoximating agents for use in the methods of producing clarithromycin according to the present invention include inorganic sulfur oxide compounds such : as sodium hydrogen sulfite, sodium pyrosulfate. sodium thiosulfate. sodium sulfite. sodium . 5 hydrosulfite, sodium metabisulfite. sodium dithionate, postassium hydrogen sulfite, potassium thiosulfate, potassium metabisulfite and the like. A particularly preferred deoximating agent is sodium metabisulfite. The amount of deoximating agent is about | to 10 molar equivalents, preferably 4 to 7 molar equivalents relative to the protected silylated clarithromycin oxime.
A non-limiting example of a suitable acid for use in the present invention is formic acid.
The amount of formic acid added to the mixture of protected silylated clarithromycin oxime is about 1.5 to 10 molar equivalents, preferably 2 to 5 equivalents relative to the protected silylated clarithromycin oxime.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims.
Example 1
This example is directed to a method for preparing a protected silylated clarithromycin oxime, particularly the preferred S-MOP oxime, according to the present invention. The example involves reacting a silylated erythromycin A oxime derivative with a methylating agent while stirring in the presence of at least one solvent and a base.
MTBE is charged at about ambient temperature (12 liters) and a 9-oxime silyl derivative (1 kg) is charged at about ambient temperature, stirring the 9-oxime silyl derivative in the MTBE solvent for several minutes until the silyl derivative is dissolved and a clear solution is obtained.
DMSO (10.0 liters) is added to the clear solution and the solution is cooled to about 10°C.
Methyl iodide (0.218 kg) is added to the solution while stirring. Powdered potassium hydroxide (0.1 kg) is also added at 10°C with stirring. . Stirring is continued while maintaining the temperature at about 10°C to about 12°C.
The progress of the reaction is monitored by HPLC. The reaction is completed after about 60 -14-
SUBSTITUTE SHEET (RULE 26)
min. After the reaction is completed it is quenched by adding dimethyl amine solution (40%, 0.6 liters) at 10-12°C and stirring for 30 min. The stirring is then stopped and the layers are , separated. The lower layer is extracted out with MTBE (4.0 liters). Both MTBE layers. from : reaction and from extraction, are combined and washed with water (5.0 liters). The MTBE layer - 5 isdistilled under reduced pressure to dryness to receive S-MOP oxime (crude). vield: 1.05 kg.
The DMSO layer is taken for recovery.
Examples 2 and 3 are directed to methods of converting a protected silylated clarithromycin oxime, particularly the preferred S-MOP oxime, to clarithromycin.
Example 2
S-MOP oxime (20 g) is mixed with aqueous ethanol (120 ml) where the water to ethanol ratio is about 1:1 and sodium metabisulfite (13.6 g). Formic acid (2.6 g) is added and the mixture is stirred at about 80°C to the reflux temperature to give clarithromycin. Heating is continued and the suspension is stirred for 2 hours. The mixture is then cooled to about 20°C and sodium hydroxide solution in a concentration of about 47% is added at about this temperature until the pH reaches about 10.5. The solid is filtered and dried to give 8.3 g of clarithromycin, (about 78% based on assay).
Example 3
S-MOP-oxime (20 g) was mixed with aqueous ethanol (120 ml) where the water to ethanol ratio is about 1:1 and sodium metabisulfite (13.6 g). Formic acid (2.6 g) was added and the mixture was stirred at reflux temperature for 3-4 hours. The second portion of sodium metabisulfite (13.6 g) was added and the reflux was continued for an additional 3-4 hours. The work up procedure was performed as described in Example 2. The crude clarithromycin was obtained (8.7g, 82% based on assay) which after crystallization from ethanol gives essentially pure clarithromycin, which does not contain any detectable amount of clarithromycin oxime. 15
SUBSTITUTE SHEET (RULE 26)
The present invention provides methods for preparing a protected silylated clarithromycin oxime and for converting a protected silylated clarithromycin oxime to clarithromycin. The invention further provides essentially oxime-free clarithromycin and compositions containing essentially oxime-free clarithromycin. Although the present invention has been described with ® 5 respect to certain exemplary embodiments, such as those in which the method of preparing a protected silylated clarithromycin oxime includes reaction in the presence of specific solvents, bases, or methylating agents, there are many other variations of the above-described embodiments which will be apparent to those skilled in the art, even where elements or steps have not explicitly been designated as exemplary. It is understood that these modifications are within the teaching of the present invention. 16
SUBSTITUTE SHEET (RULE 26)
Claims (29)
1. A method of converting protected silylated clarithromycin oxime to clanthromycin including reacting the protected silylated clarithromycin oxime with acid and deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1 to form a reaction mixture; cooling the reaction mixture to about 15°C to about 25°C; and adding sodium hydroxide solution to the reaction mixture, wherein essentially no additional water 1s added to process clarithromycin.
2. The method of claim 1 wherein the protected silylated clarithromycin oxime 1s 6- O-methyl-2’, 4 -bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxy prop-2-yl) oxime.
3. The method of claim 1, wherein the cooling is to about 20°C.
4. The method of claim 1, wherein the acid is formic acid.
3. The method of claim 1, wherein the deoximating agent is sodium metabisulflite.
6. Clarithromycin formed by a process comprising converting erythromycin A to 2°, 4 -bis(trimethylsilyl)-erythromycin A 9-O-(2- methoxyprop-2-yl) oxime; SUBSTITUTED SHEET (RULE 26) 17 Amended Sheet — 2004-04-26 reacting 2°. 4°" -bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime with methylating agent while stirring in the presence of at least one solvent and a base. wherein the at least one solvent comprises methyl tertbutyl ether, to form 6-O-methyl-2’, 4°"-bis(trimethylsilyl)- ; erythromycin A 9-O-(2-methoxyprop-2-yl) oxime; and reacting the 6-O-methyl-2’, 4" -bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop- 2-yl) oxime with an acid and a deoximating agent in the presence of aqueous ethanol to form clarithromycin.
7. The clarithromycin of claim 6, wherein the methylating agent is selected from the group consisting of methyl iodide, methyl bromide, dimethylsulfate, methyl p- toluenesulfonate, and methanesulfonate.
8. The clarithromycin of claim 6, wherein the base is selected from the group consisting of sodium hydride, potassium hydroxide, and sodium hydroxide.
9. Clarithromycin formed by a process comprising converting erythromycin A to protected silylated clarithromycin oxime; reacting the protected silylated clarithromycin oxime with acid and deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1 to form a reaction mixture; cooling the reaction mixture to about 15°C to about 25°C; and adding sodium hydroxide solution to the reaction mixture.
10. The clarithromycin of claim 9, wherein the protected silylated clarithromycin oxime is 6-O-methyl-2’, 4>’-bis(trimethylsilyl)-erythromytin A 9-O-(2-methoxy prop-2-yl) oxime. N
11. The clarithromycin of claim 9, wherein the cooling is to about 20°C.
12. The clarithromycin of claim 9, wherein the acid 1s formic acid. 18 Amended Sheet — 2004-04-26 SUBSTITUTE SHEET (RULE 25)
13. The clarithromycin of claim 9. wherein the deoximating agent is sodium metabisulfite.
14. A method of converting erythromycin A to clarithromycin comprising converting erythromycin A to protected silylated clarithromycin oxime; reacting protected silylated clarithromycin oxime with methylating agent while stirring in the presence of at least one solvent, wherein the at least one solvent comprises methyl! tertbutyl ether, and a base to form 6-O-methyl protected silylated clarithromycin oxime; and reacting the 6-O-methyl- protected silylated clarithromycin oxime with acid and a deoximating agent in the presence of aqueous ethanol to form clarithromycin.
15. A method of converting erythromycin A to clarithromycin comprising converting erythromycin A to protected silylated clarithromycin oxime; and reacting the protected silylated clarithromycin oxime with an acid and deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1, cooling to about 20°C, and adding sodium hydroxide solution, wherein essentially no additional water is added to process clarithromycin.
16. The method of claiml5, wherein the protected silylated clarithromycin oxime is 6-O-methyl-2’, 4’’-bis(trimethylsilyl)-ervthromycin A 9-O-(2-methoxy prop-2-yl) oxime.
17. A method for preparing essentially oxime-free clarithromycin, which comprises heating a mixture of protected silylated clarithromycin oxime, formic acid and a deoximating agent in a ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of said deoximating agent. :
18. The method of claim 17, wherein the protected silylated clarithromycin oxime is 6-O-methyl-2°, 4”’-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxy prop-2-yl) oxime. 19 Amended Sheet — 2004-04-26 SUBSTITUTE SHEET (RULE 268)
19. Clarithromycin comprising less than 40 ppm of its corresponding oxime intermediate formed by heating a mixture of protected silylated clarithromycin oxime, formic acid and deoximating agent in an ethanol/water solvent to reflux for more than 4 hours, with a ) two-fold addition of said deoximating agent.
20. Clarithromycin comprising less than 40 ppm of its corresponding oxime intermediate formed by a method that includes converting a clarithromycin oxime intermediate to clarithromycin.
21. Clarithromycin comprising less than 40 ppm of its corresponding oxime intermediate formed by a method that includes converting 6-O-methyl-2’, 4°’ -bis(trimethylsilyl)- erythromycin A 9-O-(2-methoxy prop-2-yl) oxime intermediate to clarithromycin.
op. Clarithromycin comprising less than 40 ppm of its corresponding oxime intermediate formed by heating a mixture of protected silylated clarithromycin oxime, formic acid and deoximating agent in an ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of said deoximating agent.
93. Clarithromycin comprising less than 40 ppm of clarithromycin-S-MOP-Oxime intermediate formed by a method that includes converting a clarithromycin oxime intermediate 10 - clarithromycin.
24. Clarithromycin comprising less than 40 ppm of its corresponding oxime intermediate formed by heating a mixture of 6-O-methyl-2’, 4’'-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime, formic acid and deoximating agent in an ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of said deoximating agent. Amended Sheet —- 2004-04-26 SUBSTITUTE SHEET (RULE 25)
25. A pharmaceutical composition comprising the product of any one of claims 19, 20, 21, 22,23 or 24.
26. A method of claim 1, substantially as herein described with reference to any one of the illustrative examples.
27. A method of claim 14, substantially as herein described with reference to any one of the illustrative examples.
28. A method of claim 15, substantially as herein described with reference to any one of the illustrative examples.
29. A method of claim 17, substantially as herein described with reference to any one of the illustrative examples. SUBSTITUTED SHEET (RULE 26) 21 Amended Sheet — 2004-04-26
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