MRX I
MRX-I
1112968-42-9 cas no
C18 H15 F3 N4 O4
- 4(1H)-Pyridinone, 2,3-dihydro-1-[2,3,6-trifluoro-4-[(5S)-5-[(3-isoxazolylamino)methyl]-2-oxo-3-oxazolidinyl]phenyl]-
IN phase 1 FOR GRAM POSITIVE BACTERIA
MicuRx Pharmaceuticals (USA)
MicuRx Pharmaceuticals is developing two oxazolidinone compounds MRX-I and MRX-II. MRX-I is an oral oxazolidinone antibiotic that targets infections due to resistant Gram-positive bacteria, including MRSA and vancomycin-resistant enterococci (VRE). The company announced the completion of a double-blinded, placebo-controlled Phase 1 clinical study, and that the compound has been shown to be safe and well-tolerated at all doses tested with no evidence of myelosuppression.
In October 2012, the company announced the establishment of Shanghai MengKe Pharmaceuticals, a joint venture with Shanghai Zhangjiang Biomedical Industry Venture Capital formed to fund the development and commercialization of MRX-I for the Chinese market. MRX-II is currently under pre-clinical development [1,2].
MRX-I: A Potent and Safe Oxazolidinone Antibiotic
MRX-I is a next-generation oral oxazolidinone antibiotic for treating Gram-positivebacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). In April 2012, MicuRx announced positive Phase I clinical results demonstrating that MRX-I is safe and well tolerated in human subjects, with no signs of myelosuppression, a major toxicity concern for most oxazolidinone agents, including linezolid.In preclinical studies, MRX-I cures in vivoinfections due to Gram-positive bacteria including MRSA and VRE effectively. In addition, MRX-I exhibits 2-fold improved activity against MRSA strains as compared to linezolid.
WO 2009020616 OR
http://www.google.fm/patents/US20090048305?cl=ja
Example 1 Compound of Structure
Scheme for the Compound of Example 1
Intermediate 17. 2,3,4,5-Tetrafluoronitrobenzene (1.17 g, 6.0 mmol) in N-methylpiperidone (NMP; 25 mL) was added dropwise with stirring to 4-piperidone hydrochloride (0.84 g, 6.2 mmol) and N,N-diisopropyl-N-ethylamine (DIEA; 2.45 mL, 14.0 mmol) in NMP (20 mL) at ca.-10 to −5° C. under nitrogen. The mixture was allowed to warm up to r.t. and stirred o.n. The mixture was taken into EtOAc (ca. 100 mL), washed with 2% aq. citric acid (2×50 mL), water (10×50 mL), brine, and dried (Na2SO4). Solvent was removed under vacuum, and the crude product was washed with hexanes (4×20 mL) and dried. Yellow crystals.1H NMR (400 MHz): 7.74 (m, 1H); 3.73 (t, J=6.0 Hz, 4H); 2.66 (t, J=6.0 Hz, 4H). MS (m/z): 275 [M+H].
Intermediate 18. Triethylamine (TEA; 5.6 mL, 43.87 mmol) was added to the Intermediate 17 (8.1 g, 29.56 mmol) in THF (120 mL) at 0° C., followed by triisopropylsilyl triflate (TIPSOTf; 10.7 g, 34.97 mmol). The mixture was allowed to warm up to r.t. over ca. 40 min, and stirred for another 2 h. Solvent was removed on a rotary evaporator. EtOAc (180 mL) was added, and the solution washed with 10% aq. NaHCO3 (40 mL), brine (60 mL) and dried (Na2SO4). Solvent was removed under vacuum and to afford the product as a red-brownish oil. This was directly used at the next step without purification.
Intermediate 19. Ceric ammonium nitrate (CAN, 19.0 g, 34.65 mmol) was added portionwise with stirring to a solution of the Intermediate 18 (12.4 g, 28.80 mmol) in dry DMF (100 mL) at 0° C. The reaction mixture was allowed to warm up to r.t. and stirred for another 4 h. Most of solvent was removed under vacuum. Water (ca. 75 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine and dried (Na2SO4). Solvent was removed and the residue purified by column chromatography (gradient 20% to 30% EtOAc in petroleum ether). The product was obtained as a yellow solid. 1H NMR (400 MHz): 7.84 (m, 1H); 7.14 (m, 1H); 5.43 (d, J=8.2 Hz, 1H); 4.06 (t, J=7.2 Hz, 2H); 2.74 (t, J=7.2 Hz, 2H). MS (m/z): 273 [M+H].
Intermediate 20. NH4Cl (0.33 g, 6.2 mmol) in water (5 mL) was added to a hot solution of the Intermediate 19 (0.170 g, 0.62 mmol) in EtOH (10 mL). Iron powder (0.173 g, 3.1 mmol) was added portionwise with stirring, and the mixture at ca. 100-105° C. for 50 min. The solution was filtered, and the precipitate washed with EtOH (5×10 mL). EtOH was removed under vacuum, and residue distributed between EtOAc (ca. 50 mL) and water (10 mL). Aq. layer was washed with EtOAc (3×20 mL), and combined organic layers were washed with water (3×7 mL), brine, and dried (MgSO4). Solvent was removed under vacuum to afford the product as yellow crystals. 1H NMR (400 MHz): 7.03 (m, 1H); 6.36 (m, 1H); 5.19 (d, J=8.0 Hz, 1H); 4.12 (d, J=7.2 Hz, 2H); 3.80 (t, J=7.2 Hz, 2H); 2.66 (t, J=7.2 Hz, 2H). MS (m/z): 243 [M+H].
Intermediate 21.60% NaH in mineral oil (1.4 g, 36.0 mmol) was added portionwise with stirring to the Intermediate 20 (2.9 g, 11.94 mmol) in THF (20 mL) at 0° C. under Ar, and the mixture was stirred at this temperature for 30 min. Benzyl chloroformate (4.1 g, 24.03 mmol) was added dropwise with stirring. The reaction mixture was allowed to warm up to r.t. and stirred o.n. The reaction was carefully quenched with water (10 mL), and THF was removed under vacuum. The residue was taken in DCM (80 mL). Organic layer was washed with brine (50 mL) and dried (Na2SO4). Solvent was removed under vacuum, and the residue dissolved with MeOH (40 mL). Aq. NH3 (25 mL) was added with stirring, and the mixture was stirred at r.t. for 2 h. Solvent was removed under vacuum, and EtOAc (100 mL) was added. The organic layer was washed with brine and dried (Na2SO4). Solvent was removed under vacuum, and the residue purified by column chromatography (gradient 25% to 100% DCM/petroleum ether). White solid. 1H NMR (400 MHz): 7.95 (m, 1H); 7.41 (m, 6H); 7.07 (m, 2H); 5.28 (s, 2H); 3.88 (t, J=7.6 Hz, 2H); 2.69 (t, J=7.6 Hz, 2H). MS (m/z): 377 [M+H].
Compound of Example 1. 1.06M Lithium hexamethyldisilylamide (LHMDS; 3.0 mL, 3.18 mmol) in THF was added dropwise with stirring to a solution of the Intermediate 21 (1.0 g, 2.66 mmol) in THF (8.0 mL) at −78° C., and the mixture was stirred at this temperature for 30 min. (R)-Glycidyl butyrate (0.8 mL, 5.55 mmol) was added dropwise, and the mixture was allowed to warm up to r.t. and stirred o.n. The reaction was quenched with 10% aq. NH4Cl (15 mL), and THF was removed under vacuum. The residue was extracted with EtOAc (2×30 mL). Combined organic layers were washed with brine and dried (Na2SO4). Solvent was removed under vacuum. MeOH (5 mL) and 20% aqueous Cs2CO3 (5 mL) were added, and the mixture was stirred at r.t. for 20 min. The mixture was taken into EtOAc (50 mL), washed with water (2×15 mL), brine, and dried (Na2SO4). Solvent was removed under vacuum and the crude product was purified by column chromatography (2% methanol/DCM). Off-white solid. 1H NMR (400 MHz): 7.44 (m, 1H); 7.10 (d, J=7.6 Hz, 1H); 5.33 (d, J=8.0 Hz, 1H); 4.84 (m, 1H); 4.19 (m, 1H); 4.08 (m, 2H); 3.92 (t, J=7.4 Hz, 2H); 3.81 (dd, J=12.4, 3.2 Hz, 1H); 2.71 (t, J=7.4 Hz, 2H); 2.14 (br, 1H). MS (m/z): 343 [M+H].
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WO2010091272A1
http://www.google.com/patents/WO2010091272A1?cl=en
Scheme 4 below.
Scheme 4. Example for synthesis of (isoxazole-3-yl)amino compounds of formula I.
a) Piperidin-4-one hydrochloride, DIEA, NMP, -5 0C to r.t; b) TMSOTf,
TEA, THF, 0 0C to r.t.; c) O-allyl-0′ -methyl carbonate, Pd(OAc)2, DMSO, 2,3,4,5-tetrafluoronitrobenzene, 60 0C; d) Fe, NH4Cl, EtOH, 95 0C; e) isobutyl chloroformate, Py, DCM, 0 0C to r.t.; f) two steps: 1) (Λ)-glycidyl butyrate or chlorohydrine, Bu1OLi, THF, MeCN, 0-30 0C; 2) 10% aq. K2CO3; g) MsCl, TEA, THF, 0 0C; h) 3-[N-(/er/-butoxycarbonyl)amino]isoxazole, Bu1OK, DMF, 20-40 0C; i) aq. HCl, EtOH, EtOAc, 0 0C to r.t.
Select innovative steps pertaining to the particular utility of Scheme 4 for an efficient synthesis and production of the compounds of formula I (illustrated by structure 26 in the Scheme 4) are summarized in paragraphs (i-iv) below:
i) The novel efficient method for an installation of the dihydropyridone ring into an ortho-F compound of formula I provided herein involve the use of an alkoxide (e.g, methoxide) capture reagent (e.g., 2,3,4,5-tetrafluoronitrobenzene). The dihydropyri done-forming step for a transformation of the compounds 19 to compounds 20 performed in absence of the methoxide-capture reagent(s) is accompanied by formation of the hard-to-remove ort/zo-methoxy impurity (e.g., l-(2,6-difluoro-3-methoxy-4-nitrophenyl)-2,3-dihydropyridone) resulted from undesired substitution of ortho-F atom with MeOH, AIkOH, or anion thereof. This is a serious problem specific for the synthesis of ortho-F dihydropyridone compounds, arising from the unique reactivity of ortho-F substrates 19 and may not be encountered in synthesis of des-ortho-F compounds lacking the key ortho-F substitution. The methods disclosed herein involve the use of a methoxide-capture nitrobenzene additive to eliminate or minimize above methoxy-aryl by-product to allow for a high-yielding preparation and manufacture of precursors 19 and compounds of formula I, with a purity suitable for pharmaceutical applications (generally, better than 90-95%). Additional MeO-capture additives may include acylating, alkylating, or arylating agents (e.g., carboxylic acid anhydride or an active ester capable of methoxide acylation). Optionally, one or more alkoxide-capture reagent(s), or a combination thereof can be used.
ii) New practical method for the key oxazolidinone-forming step (from
22 to 23) provided herin involves the use of an alkali metal alkoxide (e.g., LiOBu- 1) instead of the conventionally used BuLi (as more generally described, e.g., in J. Med. Chem., 1988, vol. 41, pp. 3727-3735). The procedure provided herein thus eliminates the use of a highly flammable and unstable organometallic chemical. Moreover, the new processes provided herein also eliminates the need for costly cryogenic (-78 0C) conditions impractical for the industrial manufacture of the reagents 23 and of the compounds of formula I. [00111] iii) Novel process for the preparation of 5-[(isoxazole-3-yl)amino]methyl derivatives 25 that employs an alkali metal alkoxide ( e.g., KOBu-t) in place of previously used NaH (as more generally described, e.g., in International Patent Publication No. WO 00/21960, incorporated herein by reference in its entirety). This eliminates the use of an extremely flammable base and allows for an efficient preparation and manufacture of the precursors 25 and the compounds of formula I.
iv) New practical method for the synthesis of the compounds of formula I
(Ri = (isoxazole-3-yl)amino; structure 26 in Scheme 4) employing aq. HCl – organic solvent(s) system for deprotection of acid-cleavable protective groups (PG; e.g., PG = tert-butoxycarbonyl or Boc group). The method provided herein eliminates the use of highly toxic and expensive reagents conventionally employed for des-ortho-F 1-phenyldihydropyridone compounds (the method as described, for example, in International Patent Publication No. WO 2004/033449, advocating the use of trifluoroacetic acid and 1 ,2-dichloroethane Boc-deprotection system). The efficiency of the new deprotection method invented herein is particularly surprising in view of the fact that enamino ketones (such as dihydropyridones) are generally degradable by a strong aqueous acids, such as aq. HCl (as more generally described, e.g., by Katritzky et al. in J. Chem. Research, Miniprint, 1980, pp. 3337-3360).
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US8178683
https://www.google.com/patents/US8178683
Example 5 Compound of Structure
Scheme for Compound of Example 5
Intermediate 25.
Method A. A solution of tert-butyl isoxazol-3-ylcarbamate (187 mg, 1.00 mmol) in DMF (1 mL) was added dropwise with stirring to a suspension of NaH (60% in mineral oil, 48 mg, 1.20 mmol) in DMF (2 mL). The mixture was stirred under N2 for 15 min. at 35° C. The Intermediate 22 (357 mg, 0.85 mmol) in DMF (1 mL) was added, and the mixture was stirred at 50° C. for 1.5 h. The reaction mixture was taken into EtOAc (30 mL), washed with 10% aq. NH4Cl (2×15 mL), brine, and dried (Na2SO4). Solvent was removed under vacuum and the crude material was purified by column chromatography (2% MeOH/DCM) to afford the product as a light yellow solid.
Method B. A solution of tert-butyl isoxazol-3-ylcarbamate (694 mg, 3.8 mmol) in DMF (3 mL) was added dropwise with stirring to ButOK (439 mg, 3.8 mmol) in DMF (3 mL) at 0° C. The mixture was warmed up to r.t. and stirred for 30 min. The Intermediate 22 (1.34 g, 3.2 mmol) in DMF (6 mL) mL) was added, and the mixture was stirred at 35° C. for 2 h. The reaction was quenched with saturated aq. NH4Cl solution (10 mL), and isolation performed just as described above for Method A to afford the product as a light yellow solid. 1H NMR (400 MHz): 8.28 (s, 1H), 7.44 (m, 1H), 7.09 (d, J=7.6 Hz, 1H), 7.00 (s, 1H, 5.32 (d, J=7.6 Hz, 1H), 5.15 (m, 1H), 4.44 (m, 1H), 4.20 (m, 2H, 3.94 (m, 3H), 2.70 (t, J=7.4 Hz, 2H), 1.45 (s, 9H). MS (m/z): 509 [M+H].
Compound of Example 5
Method A. TFA (2.0 mL) was added dropwise to the solution of the Intermediate 25 (310 mg, 0.61 mmol) in 1,2-dichloroethane (DCE; 2 mL) at 0° C., and the solution was stirred at 0° C. for 30 min. Volatiles were removed under vacuum, and the residue taken into EtOAc (30 mL). The solution was washed with saturated NaHCO3 solution (2×15 mL), brine, and dried (Na2SO4). Solvent was removed under vacuum and the crude product was purified by column chromatography (3% MeOH/DCM). Light-yellow solid.
Method B. 4M HCl in THF (56 mL) was added dropwise to the Intermediate 25 (3.0 g, 5.9 mmol) at 0° C. Water (0.59 mL) was added, and the solution was stirred at r.t. for 2 h. Most of volatiles were removed under vacuum, the residue taken into water (30 mL) and sat. aq. NaHCO3 (15 mL), and pH adjusted to ca. 8. After stirring for 15 min, the mixture was extracted with EtOAc (3×60 mL). Combined organic layers were washed with brine (2×30 mL), and dried (Na2SO4). Solvent was removed under vacuum. The residue was re-dissolved in 2% MeOH in DCM (3 mL), and passed through a short pad of silica, eluting the product with 2% MeOH in DCM. Light-yellow solid. 1H NMR (400 MHz, DMSO-d6): 8.41 (d, J=1.6 Hz, 1H); 7.57 (m, 1H), 7.50 (d, J=8.0 Hz, 1H), 6.58 (t, J=5.8 Hz, 1H), 6.02 (d, J=1.6 Hz, 1H), 5.08 (d, J=8.0 Hz, 1H), 4.90 (m, 1H), 4.17 (t, J=8.6 Hz, 1H), 3.86 (m, 3H), 3.48 (t, J=5.6 Hz, 2H), 2.49 (m, overlapped with DMSO-d6, 2H). MS (m/z): 409 [M+H].
pick up int 22
from below
Example 3 Compound of Structure
Scheme for Compound of Example 3
Intermediate 22. Methylsulfonyl chloride (MsCl; 79 uL, 1.00 mmol) was added dropwise with stirring to the compound of Example 1 (290 mg, 0.85 mmol) and TEA (177 uL, 1.27 mmol, 1.50 equiv.) in DCM (5 mL) at ca. 0° C. The mixture was stirred for 20 min and allowed to warm up to r.t. The reaction mixture distributed between water and the DCM. Aq. layer was extracted with DCM (2×10 mL), and the combined organic layers washed with brine and dried (Na2SO4). Solvent was removed under vacuum to afford the product that was used for the next step without purification.
Intermediate 23. A mixture of the Intermediate 22 (567 mg, 1.35 mmol) and NaN3 (438 mg, 6.75 mmol) in DMF (5 mL) was stirred at 55° C. o.n. After cooling to r.t., water (15 mL) was added, and the reaction mixture was extracted with DCM (3×30 mL). Combined organic layers were washed with brine (30 ml) and dried (Na2SO4). Solvent was removed under vacuum to afford the product as a light yellow solid. This was used directly for the next step without further purification.
Compound of Example 3. A mixture of the Intermediate 23 (785 mg, 2.14 mmol) and bicyclo[2.2.1]hepta-2,5-diene (2.2 mL, 21.4 mmol) in 1,4-dioxane (22 mL) under N2 was heated at 100° C. for 3 h. Most of volatiles were removed under vacuum, and the residue was purified by column chromatography (1% MeOH/DCM). Thus isolated product was recrystallized from MeOH. White solid. 1H NMR (400 MHz): 7.83 (s, 2H), 7.05 (m, 2H), 5.30 (d, J=8 Hz, 1H), 5.16 (m, 1H), 4.83 (d, J=3.6 Hz, 2H), 4.33 (m, 1H), 4.06 (m, 1H), 3.91 (t, J=14.8 Hz, 2H), 2.69 (t, J=14.8 Hz, 2H). MS (m/z): 394 [M+H].
- MicuRx Pharmaceuticalsresistant Gram-positive bacteria, Inc. MicuRx and Shanghai Zhangjiang biomedical industry venture capital partner to develop next-generation antibiotic MRX-I for Chinese market. Available online: http://www.micurx.com/doc/10-24-12%20JV-FINAL.doc (accessed on 11 April 2013).
- MicuRx Pharmaceuticals. Discovery and development. Available online: http://www.micurx.com/d1.htm(accessed on 12 December 2012).
- CN 102206213
- CN 102485224
- CN 102485225
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