AU2001275937A1 - 5-trityloxymethyl-oxazolidinones and process for the preparation thereof - Google Patents
5-trityloxymethyl-oxazolidinones and process for the preparation thereofInfo
- Publication number
- AU2001275937A1 AU2001275937A1 AU2001275937A AU2001275937A AU2001275937A1 AU 2001275937 A1 AU2001275937 A1 AU 2001275937A1 AU 2001275937 A AU2001275937 A AU 2001275937A AU 2001275937 A AU2001275937 A AU 2001275937A AU 2001275937 A1 AU2001275937 A1 AU 2001275937A1
- Authority
- AU
- Australia
- Prior art keywords
- organic solvent
- oxazolidinone
- trityloxymethyl
- trityl
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims description 27
- NONOANCJDOAYFL-UHFFFAOYSA-N 5-(trityloxymethyl)-1,3-oxazolidin-2-one Chemical class O1C(=O)NCC1COC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NONOANCJDOAYFL-UHFFFAOYSA-N 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- WPOHUQOEJUSLGO-UHFFFAOYSA-N 3,4-dihydroxybutanamide Chemical compound NC(=O)CC(O)CO WPOHUQOEJUSLGO-UHFFFAOYSA-N 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 8
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- HGGZDNIQKMWKDC-UHFFFAOYSA-N 5-(trityloxymethyl)-1,3-oxazolidine Chemical compound C1NCOC1COC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 HGGZDNIQKMWKDC-UHFFFAOYSA-N 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- QMKNPOSXKWCRLB-UHFFFAOYSA-N 5-(2,2,2-triphenylethyl)-1,3-oxazolidin-2-one Chemical compound O1C(=O)NCC1CC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 QMKNPOSXKWCRLB-UHFFFAOYSA-N 0.000 claims 2
- 239000002274 desiccant Substances 0.000 claims 2
- 125000000532 dioxanyl group Chemical group 0.000 claims 2
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Chemical group Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 claims 2
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical group Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims 2
- 238000000638 solvent extraction Methods 0.000 claims 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 6
- NONOANCJDOAYFL-NRFANRHFSA-N (5s)-5-(trityloxymethyl)-1,3-oxazolidin-2-one Chemical compound O1C(=O)NC[C@H]1COC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NONOANCJDOAYFL-NRFANRHFSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 5
- WPOHUQOEJUSLGO-VKHMYHEASA-N (3s)-3,4-dihydroxybutanamide Chemical compound NC(=O)C[C@H](O)CO WPOHUQOEJUSLGO-VKHMYHEASA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- XXFXTBNFFMQVKJ-UHFFFAOYSA-N [diphenyl(trityloxy)methyl]benzene Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 XXFXTBNFFMQVKJ-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000012948 isocyanate Substances 0.000 description 4
- 150000002513 isocyanates Chemical class 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 230000008707 rearrangement Effects 0.000 description 4
- TWONBQKNUBYLDQ-UHFFFAOYSA-N 3-hydroxy-4-trityloxybutanamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(O)CC(=O)N)C1=CC=CC=C1 TWONBQKNUBYLDQ-UHFFFAOYSA-N 0.000 description 3
- LSYOFPBORRARMF-UHFFFAOYSA-N 5-(hydroxymethyl)-1,3-oxazolidin-2-one Chemical compound OCC1CNC(=O)O1 LSYOFPBORRARMF-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- FUDDLSHBRSNCBV-UHFFFAOYSA-N 4-hydroxyoxolan-2-one Chemical compound OC1COC(=O)C1 FUDDLSHBRSNCBV-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 238000005810 carbonylation reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- -1 isopropylidene acetals Chemical class 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- JJYKJUXBWFATTE-VIFPVBQESA-N (2s)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid Chemical compound CO[C@@](C(O)=O)(C(F)(F)F)C1=CC=CC=C1 JJYKJUXBWFATTE-VIFPVBQESA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- UPUSBBKJEKFTLM-UHFFFAOYSA-N 1,3-oxazolidin-2-ylmethanol Chemical compound OCC1NCCO1 UPUSBBKJEKFTLM-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- DZAIOXUZHHTJKN-UHFFFAOYSA-N 3,4-dihydroxybutyric acid Chemical class OCC(O)CC(O)=O DZAIOXUZHHTJKN-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound 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 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
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- 239000002253 acid Substances 0.000 description 1
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- 239000004599 antimicrobial Substances 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
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- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
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- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
Description
5-TRITYLOXYMETHYL-OXAZOLIDINO ES AND PROCESS FOR THE PREPARATION THEREOF
CROSS-REFERENCE TO RELATED APPLICATION
None STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT None
BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to a one-step route to 5-trityloxymethyl-oxazolidinone from 3-hydroxy- 4-trityloxy butyramide. In particular, the present invention relates to the preparation of chiral forms of the 5-trityloxymethyl-oxazolidinone .
(2) Description of Related Art
Optically pure oxazolidinones can be obtained by carbonylation of vicinal a ino alcohols with reagents such as phosgene, ethyl chloroformate and carbonyl imidazole. The preparation of optically-pure 5- trityloxymethyl-oxazolidinone would normally require the preparation of the corresponding optically-pure 5- hydroxymethyl-oxazolidinone followed by a tritylation step to produce 5-trityloxymethyl oxazolidinone.
Oxazolidinones have emerged as a very important class of compounds in drug development especially in the areas of antimicrobials (Diekema, D. J. , et al., Drugs 59 7-16 (2000)) and behavioral
disorders (Brenner, R., et al., Clin. Therapeut. 22 4 411-419 (2000)). They are especially active against some of the most resistant human pathogens including vancomycin-resistant enterococci , methicillin-resistant Staphylococcus aureus, cephalosporin-resistant
Streptococcus pneumoniae and several organisms that display penicillin resistance (Diekema, D. J., et al., Drugs 59 7-16 (2000)). Linezolid (4) was recently recommended for approval for the treatment of infections from antibiotic resistant bacterial strains especially those that are resistant to vancomycin.
4
Optically active 3, 4-dihydroxybutanoic acids and their γ-lactones are important sources of chirality. They can be obtained in commercial quantities from carbohydrates such as starch, lactose, maltodextrins, cellulose and arabinose by oxidative degradation (Hollingsworth, R. I. Biotechnology Annual Review 2281- 291 (1996); Hollingsworth, R. I., J. Org. Chem. 647633- 7634 (1999)). See also U.S. Patent Nos . 5,292,939, 5,808,107, 5,319,110 and 5,374,773 to Hollingsworth. Chiral a ino propane diols can be made by Hoffman degradation of the isopropylidene acetals of optically active 3, 4-dihydroxybutyric acid amides (Wang, G., et al., J. Org. Chem. 64 1036-1038 (1999)).
SUMMARY OF THE INVENTION
The present invention relates to A process for the preparation of 5-trityloxymethyl-oxazolidinone which comprises: (a) reacting with stirring a 4-trityl ether of
3,4-dihydroxybutyramide with an alkali or alkaline earth hypohalite in water in the presence of an alkali alkaline earth metal hydroxide and an organic solvent in a reaction mixture to produce the 5- trityloxymethyloxazolidine;
(b) separating the 5-trityloxymethyl- oxazolidinone from the reaction mixture in the organic solvent; and
(c) removing the organic solvent to produce the 5-trityloxymethyl-oxazolidinone.
The present invention also relates to the novel 5-trityloxymethyl-oxazolidinone 1 produced by the process. Preferably the compounds are chiral. OBJECTS It is thus an object of the present invention to provide a one step process enabling the production of novel 5-trityloxymethyl-oxazolidinone from a trityl ether of an amide. Further, it is an object of the present invention to provide for the preparation of chiral products. Further still, it is an object of the present invention to provide a process which is relatively simple and economical by comparison to the prior art and produces the product in high yield and purity. These and other objects will become increasingly apparent by reference to the following
description.
DESCRIPTION OF PREFERRED EMBODIMENTS
The reaction involved in the present process is as follows in Scheme 1
1
Scheme 1 where Tr is a trityl (triphenylmethyl) group. The bracketed compound (3) is a hypothesized isocyanate intermediate which is unstable and forms the ring structure of the 5-trityloxymethyl-oxazolidinone (1) from the starting 3-hydroxy-4-trityloxybutyramide 2. The preferred product is the chiral (S)-5- trityloxymethyl-oxazolidinone .
In Scheme 1, the alkali metal hydroxide can be lithium, sodium or potassium hydroxide. The alkaline earth metal hydroxide can be calcium hydroxide, or magnesium hydroxide. Preferably there is an excess of 2 to 6 moles of OH" over the moles of the 4-trityl ether of the amide.
The hypohalite(OCl" or OBr") can also be an alkali metal or alkaline earth metal hypohalite as discussed above for the base. Usually the alkaline earth metal is the same for both OH~ and 0C1~ or OBr";
however they can be different.
Most preferably the reaction in step (a) is conducted with an organic solvent which form a 2-phase system with water under the reaction conditions. Besides tetrahydrofuran other solvents are dioxane, propanol and ether. The yields are better with the organic solvent, probably since the product 1 separates into the organic solvent as it is formed. The reaction is conducted at a temperature between about 10° and 80oc and at atmospheric pressures.' The reaction is complete in 6 to 8 hours at 55o-60°C.
The product 1 is purified by removing the miscible organic solvent by evaporation or other means and recrystallizing from a second organic solvent.' Dichloro ethane is preferred; however other solvents are chloroform, hexanes, alcohol or mixtures of these.
The 4-trityl ether of 3, 4-dihydroxybutyramide in step (a) is prepared by reacting excess trityl chloride (preferably in a molar ratio 1.1 to 1.5 to 1 based upon the amide) . Other halides such as Br, F or I could be used. The amine base is preferably pyridine although other amines such as triethylamine can be used to react with the HC1 or other acid produced in the reaction. The organic solvent is preferably a mixture of dimethyl formamide and tetrahydrofuran with the exclusion of water. The solvent is removed preferably by vacuum and then the ether is washed with hexane to remove excess trityl chloride. The temperature is between about 5° and 40°C and the pressures are atmospheric. The reaction is complete in 24 to 48
hours. This trityl ether is then used to form the oxazolidinone .
Thus this invention provides a trityl protected, optically pure 5-hydroxymethyl-oxazolidinone such as (S) -5-trityloxymethyl-oxazolidinone (1) in a simple high-yield process from optically active 3- hydroxy-γ-butyrolactone using the 4-O-trityl ether of chiral 3, 4-dihydroxybutyramide as the starting material. Because an isocyanate that is hydrolyzed with water is an intermediate species in the Hoffman rearrangement, in principle a vicinal hydroxyl group can act as a nucleophile resulting in cyclization to form an oxazolidinone system. In the present invention, a separate carbonylation reaction using phosgene, ethyl chloroformate or some similar reagent would be avoided. This is illustrated in Scheme 1 for the 4-trityl ether of (S) -3, 4-dihydroxybutyric acid amide (2) via the isocyanate 3.
The overall process involves essentially only two steps, only one of which involves the formation of the oxazolidinone 1. The first step is the preparation of the trityl ether from the dihydroxybutyamide 2, a known compound. This amide is obtained in quantitative yield by treating the 3-hydroxy-γ-butyrolactone with aqueous ammonia at room temperature. The second step is the rearrangement of the trityl ether (2) under conditions where the intermediate isocyanate (3.) is protected from water, allowing the neighboring hydroxyl group to participate, whilst protecting the final product from base hydrolysis. Hoffman rearrangement
using a 2-phase solvent system, in this case tetrahydrofuran / water,- gave the protected hydroxymethyl oxazolidine 1 directly in >90% isolated yield and in >99% optical purity. This represents a very significant economy in the synthesis of an important, optically-pure, protected 5- (hydroxymethyl) - 2-oxazolidinone in essentially 4 steps from starch, maltose, lactose or similar 4-linked carbohydrate source. The trityl group can be selectively removed allowing the hydroxymethyl function to be transformed into a wide variety of substituents. The ring nitrogen can also be alkylated or actylated by replacing the hydrogen. These two features allow ready access to a large spectrum of possible drug candidates. Example
The following are the steps in preparing the protected 5-trityloxymethyl-oxalidinone . Preparation of 3-Hydroxy-4-tri.ty-l.oxy butyramide (2) : 11.9g (0.10 mol) (S) -3, 4-dihydroxy-butyramide was dissolved in 50 ml of tetrahydrofuran and 50 ml of di ethylformamide and 10 ml of pyridine followed by 30.6 g (0.11 mol) of trityl chloride was added to the flask. A drying tube filled with calcium chloride was used to exclude moisture. The reaction mixture was stirred at room temperature for 36 hours. After this period of time, it was filtered to remove the solid. The liquid was concentrated under reduced pressure to remove most of the solvent. The solution was poured into ice water, stirred for half an hour and the water layer was removed from the trityl protected amide. The product which was
obtained as a semicrystalline liquid was dried under vacuum. The excess trityl chloride was washed away by trituration with hexane. The yield was 33. Og (91%).
Physical data: m.p. 59.0-60.0°C (from solvent dichloromethane :hexane :acetone=6: 3: 0.5) [ ] 25 D=-53.5°
(c=0.5,, ethanol) . XH NMR (300MHz, CDC13) δ pp , 7.50-
7.20 ( , 15 H) , 6.17 (s, 1H) , 5.62 (s, 1H) , 4.19 (m,
1H) , 3.17 (d, 2H, J=5.7Hz), 2.41 ( , 2H) . 13C NMR (75
MHz, CDC13) δ ppm, 174.8, 143.5, 128.3, 127.5, 126.7, 86.3, 67.4, 39.2. FTIR cm"1 3345, 1667, 1600, 1490,
1448, 1218, 1074, 763, 703.
Preparation of the (S) -5-trityloxymethyl-2-oxazolidinone (1): 3-Hydroxy-4-trityloxy butyramide 3 3.61 g (0.01 mol) was dissolved in 30 ml THF. Fifteen ml of 13% sodium hypochlorite solution was added to the solution and the mixture was stirred vigorously and then 1.6 g of sodium hydroxide dissolved in 10 ml of water was added. The reaction was stirred at 55-60°C for 8 hours after which time the rearrangement was completed as indicated by TLC and 1H NMR spectroscopy. The THF layer was separated from the water layer. The water layer was extracted 3 times with THF. The combined organic layers was concentrated to remove solvent. The residue was taken up in dichloromethane and the ,solution dried over sodium sulfate. It was concentrated to remove solvent again and oxazolidinone was obtained as white crystalline product (3.4 g, yield 95%). This crude product normally did not need further purification. M.p. (Solvent: chloroform: hexane :acetone=6: 3 : 1) , 206.0-
207.0 oc. [ ]25 D= +35.50 (c=1.0, methanol) . 1H NMR (300MHz, CDCI3) δ PPm, 7.50-7.20 (m, 15 H) , 5.88 (s, 1H) , 4.75 (m, 1H) , 3.61 (m, 1H) , 3.45 (m, 1H) , 3.40 (dd, 1H, J=10.2, 4.5 Hz), 3.23 (dd, 1H, -7=10.2, 4.5Hz) 13C NMR (75 MHz, CDC13) δ ppm 159.8, 143.4, 128.6, 127.9, 127.2, 86.8, 75.4, 64.2, 42.6. IR cm"1 3272, 1753, 1489, 1448, 1085, 748.5 705.5. ■ MS (FAB) low res, MH+ 360.19. HRMS:MH+ C23H22N03, 360.1590, theoretical molecular mass 360.1600. The optical purity of the product was >99.9% e.e. based on GC analysis of (S)-(-)- -Methoxy-α- (trifluoromethyl) phenylacetic acid (Mosher' s acid) derivative after deprotection with HBr / acetic acid.
One skilled in the art can deprotect the 5- tritoxymethyl-oxazlidinone in the customary fashion (e.g. hydrogenolysis or HBr treatment) and use it for the preparation of important 5-acetamidomethyl oxazolidinones (as described in various patents, e.g. Pearlman et al U.S. Patent No. 5,837,870. The hydroxyl group can be converted to a nitrogen-containing function by any of the methods that are known. These include mesylation or tosylation followed by displacement with ammonia, azide, benzylamine and other nitrogen nucleophiles as shown in Scheme 2.
. Mesyl ctøoride O π . [ > ilf .or_H2
Scheme 2
It is intended that the foregoing description be only illustrative of the present invention and that the present invention be limited only by the hereinafter appended claims.
Claims
AMENDED CLAIMS
[received by the International Bureau on 21 December 2001 (21.12.01); original claim 7 amended; remaining claims unchanged (1 page)]
A process for the preparation of 5- trityloxymethyl-oxazolidinone which comprises:
(a) reacting with stirring a 4-trityl ether of 3,4-dihydroxybutyramide with an alkali or alkaline earth hypohalite in water in the presence of an alkali alkaline earth metal hydroxide and an organic solvent in a reaction mixture to produce the 5- trityloxymethyloxazolidine;
(b) separating the 5-trityloxymethyl- oxazolidinone from the reaction mixture in the organic solvent; and
(c) removing the organic solvent to produce the 5-trityloxymethyl-oxazolidinone .
-2- The process of Claim 1 wherein the alkali or alkaline earth metal hydroxide is sodium hydroxide. c
-3- The process of Claims 1 or 2 wherein the organic solvent is separated from the water in step (b) by layer separation.
-4- The process of Claim 1 wherein the organic solvent is removed by evaporation.
The process of Claim 1 wherein after step (c) the 5-tritylmethyl-oxazolidinone is purified by being dissolved in dichloromethane over a drying agent and then the dichloromethane is removed.
-6- The process of Claim 1 wherein the 4-trityl ether of 3,4-dihydroxybutyramide in step (a) is prepared by reacting excess trityl chloride with 3,4- dihydroxbutyramide in an organic solvent in the presence of an a ine base, to produce the 4-trityl ether which is washed with water which is removed and then the excess trityl chloride is removed by solvent extraction.
-7- The process of any one of Claims 1 to 12 wherein the 5-trityloxymethyl-oxazolidinone is optically pure.
-8- The process of Claim 1 wherein the organic solvent is tetrahydrofuran.
-9- The process of Claim 1 wherein the organic solvent is dioxane.
-10- The process of Claim 1 wherein hypohalite is hypochlorite .
-11- The process of Claim 1 wherein the hypohalite is hypobromite.
-12- The process of Claim 1 wherein the organic solvent is water-insoluble alcohol.
-13- 5-Trityloxymethyl-oxazolidinone .
The process of Claim 1 wherein after step (c) the 5-tritylmethyl-oxazolidinone is purified by being dissolved in dichloromethane over a drying agent and then the dichloromethane is removed.
-6- The process of Claim 1 wherein the 4-trityl ether of 3,4-dihydroxybutyramide in step (a) is prepared by reacting excess trityl chloride with 3,4- dihydroxbutyramide in an organic solvent in the presence of an amine base, to produce the 4-trityl ether which is washed with water which is removed and then the excess trityl chloride is removed by solvent extraction.
-7- The process of any one of Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 wherein the 5-trityloxymethyl- oxazolidinone is optically pure.
The process of Claim 1 wherein the organic solvent is tetrahydrofuran.
-9- The process of Claim 1 wherein the organic solvent is dioxane.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/665,508 US6288239B1 (en) | 2000-09-19 | 2000-09-19 | 5-trityloxymethyl-oxazolidinones and process for the preparation thereof |
| US09/665,508 | 2000-09-19 | ||
| PCT/US2001/022296 WO2002024670A1 (en) | 2000-09-19 | 2001-07-16 | 5-trityloxymethyl-oxazolidinones and process for the preparation thereof |
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| Publication Number | Publication Date |
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| AU2001275937A1 true AU2001275937A1 (en) | 2002-06-20 |
| AU2001275937B2 AU2001275937B2 (en) | 2005-08-11 |
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| AU2001275937A Ceased AU2001275937B2 (en) | 2000-09-19 | 2001-07-16 | 5-trityloxymethyl-oxazolidinones and process for the preparation thereof |
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| EP (1) | EP1324989B1 (en) |
| JP (1) | JP3974035B2 (en) |
| KR (1) | KR100525882B1 (en) |
| AT (1) | ATE329910T1 (en) |
| AU (2) | AU7593701A (en) |
| CA (1) | CA2418200C (en) |
| DE (1) | DE60120729D1 (en) |
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| HK1049656A1 (en) | 1999-10-08 | 2003-05-23 | Smithkline Beecham Corporation | Fab i inhibitors |
| DK1560584T3 (en) * | 2001-04-06 | 2009-05-18 | Affinium Pharm Inc | Fab I inhibitors |
| EP1578723A4 (en) * | 2001-10-18 | 2006-11-02 | Univ Michigan State | PROCESS FOR THE PREPARATION OF OXAZOLIDINONES AND METHOD OF USE THEREOF |
| ES2518316T3 (en) * | 2002-12-06 | 2014-11-05 | Debiopharm International Sa | Heterocyclic compounds, their manufacturing methods and their use in therapy |
| CA2519429C (en) * | 2003-03-17 | 2013-08-06 | Affinium Pharmaceuticals, Inc. | Pharmaceutical compositions comprising inhibitors of fab i and further antibiotics |
| SI1828167T1 (en) * | 2004-06-04 | 2014-12-31 | Debiopharm International Sa Forum "Apres-Demain" | Acrylamide derivatives as antibiotic agents |
| WO2007067416A2 (en) * | 2005-12-05 | 2007-06-14 | Affinium Pharmaceuticals, Inc. | Heterocyclylacrylamide compounds as fabi inhibitors and antibacterial agents |
| CA2658506C (en) | 2006-07-20 | 2016-01-26 | Affinium Pharmaceuticals, Inc. | Acrylamide derivatives as fab 1 inhibitors |
| EP2125802A4 (en) | 2007-02-16 | 2014-08-20 | Debiopharm Int Sa | Salts, prodrugs and polymorphs of fab i inhibitors |
| KR200453944Y1 (en) * | 2011-03-08 | 2011-06-03 | 조명호 | Food delivery container |
| LT2861608T (en) | 2012-06-19 | 2019-07-10 | Debiopharm International Sa | Prodrug derivatives of (e)-n-methyl-n-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide |
| WO2017144717A1 (en) | 2016-02-26 | 2017-08-31 | Debiopharm International S.A. | Medicament for treatment of diabetic foot infections |
| CA3129508A1 (en) | 2019-02-14 | 2020-08-20 | Debiopharm International S.A. | Solid formulations of afabicin with histidine |
| UA129222C2 (en) | 2019-06-14 | 2025-02-12 | Дебіофарм Інтернешнл С.А. | Afabicin for use for treating bacterial infections involving biofilm |
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| US5122601A (en) * | 1990-12-07 | 1992-06-16 | Hawaiian Sugar Planters'association | Synthesis of 2,3,3',4,4'-penta-o-methylsucrose |
| CA2049536C (en) | 1991-05-13 | 1999-07-06 | Rawle I. Hollingsworth | Process for the preparation of 3,4-dihydroxybutanoic acid and salts thereof |
| ES2166073T3 (en) | 1996-04-11 | 2002-04-01 | Upjohn Co | PROCEDURE TO PREPARE OXAZOLIDINONES. |
| US5808107A (en) | 1997-10-31 | 1998-09-15 | Board Of Trustees Operating Michigan State University | Process for the preparation of hydroxy substituted gamma butyrolactones |
| IT1301977B1 (en) * | 1998-07-31 | 2000-07-20 | Sigma Tau Ind Farmaceuti | PROCEDURE FOR THE PREPARATION OF R - (-) - CARNITINA |
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- 2001-07-16 WO PCT/US2001/022296 patent/WO2002024670A1/en not_active Ceased
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