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CAS No. : | 13195-50-1 | MDL No. : | MFCD00022493 |
Formula : | C4H2BrNO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZPNFMDYBAQDFDY-UHFFFAOYSA-N |
M.W : | 208.03 | Pubchem ID : | 83222 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 40.84 |
TPSA : | 74.06 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.59 cm/s |
Log Po/w (iLOGP) : | 1.5 |
Log Po/w (XLOGP3) : | 2.79 |
Log Po/w (WLOGP) : | 2.42 |
Log Po/w (MLOGP) : | 1.39 |
Log Po/w (SILICOS-IT) : | 1.21 |
Consensus Log Po/w : | 1.86 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.23 |
Solubility : | 0.122 mg/ml ; 0.000585 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.0 |
Solubility : | 0.0207 mg/ml ; 0.0000996 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -1.91 |
Solubility : | 2.58 mg/ml ; 0.0124 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.64 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | at 100℃; for 0.5 h; | To a solution of 2-bromo-5-nitrothiophene (2 g, 10 mmol) in acetic acid (15 mL) and acetic anhydride (15 mL) was added iron powder (2.8 g, 50 mmol). The reaction was heated under 100°C for 30 minutes. The reaction mixture was put into 2M NaOH aqueous (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was dried over Na2S04, filtered, and concentrated. The crude product was purified on ISCO columns. Fractions containing pure product were combined and evaporated to give 70 (0.76 g, 35percent) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 20 - 60℃; for 2h; | A solution of compound 52ii (100 mg, 0.48 mmol), 52iii (73 mg, 0.48 mmol), and KOAc (190 mg, 1.92 mmol) in DMF (5 ml) was degassed thrice and PdCl2(drhopf) (36 mg, 0.048 mmol) added to it at rt under an argon atmosphere. The reaction mixture was heated at 6O0C for two hours, diluted with ethyl acetate (EA) and washed with brine. The organic layer was dried, concentrated, and the residue separated by column chromatography on silica gel employing as eluent EA/Hex (0 - 80percent) to yield 52i. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; copper(l) iodide; In N,N-dimethyl-formamide; at 20 - 60℃; for 2h; | A solution of compound 59ii (200 mg, 0.96 mmol) and 59iii (127 mg, 0.96 mmol) in DMF (3 ml) was degassed thrice and PdCl2(dppf) (50 mg, 0.07 mmol) was added to it, EPO <DP n="135"/>followed by CuI (8.5 mg, 0.043 mmol) and TEA (0.27 ml, 1.92 mmol), at rt, under argon atmosphere and the reaction mixture was heated at 60 0C for two hours. The reaction mixture was diluted with EA, washed with brine, the organic layer separated, dried, and concentrated to yield a residue which was separated by column chromatography on silica gel employing as eluent EA\\Hex (0-70percent) to yield compound 5Si. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; toluene; at 90℃; | Example 6B methyl flJR,2i')-2-f4-(5-ni |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 24h; | To a solution of tert-hutyl 4-(2-fluoro-4-{(5S)-2-oxo-5-[(2-oxopyridin-l(2H)- yl)methyl]-l,3-oxazolidin-3-yl}phenyl)piperazine-l-carboxylate (Prepared according to Poster No. 1825, 40th ICAAC, 2000) (0.35g),in acetonitrile (20ml> was added 2-bromo-5- nitro-thiophene (0.18g) in presence of N-ethyl-diisopropylamine (O.95g). The reaction mixture was heated at 600C for 24 hrs and the solvent was evaporated. The residue was taken in dichloromethane, washed with water, dried over anhydroialphas sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography, eluting in 1percent methanol-dichloromethane. The product was sonicated in ether and filtered to get the title compound (0.15 g). Melting point: 220 0C (dec).1H NMR (DMSO) deltappm: 7.96 (d, 1Eta), 7.68 (d, 1Eta), 7.49 (m, 2Eta), 7.16 (m, 2H), 6.42 (m, 2H), 6.27 (t, IH), 4.99 (m, IH), 4.4-4.10 (m, 3H), 3.85 (m, IH), 3 .62 (m, 4H), 3.14 (m, 4H) Mass: M+l= 500.3, M-NO2 = 454.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 4h; | Step a: Preparation of (S)-N- [ (3- {3-Fluoro-4- [4- (5-nitro-thiophen-2-yl)-piperazin-1- yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide; To (S)-N- (f3- [3-Fluoro-4- (piperazin-1-yl) phenyl]-2-oxo-oxazolidin-5-yll methyl] ) acetamide trifluroacetate prepared by the method given in U. S. Patent No. 5,700, 799 (4.58 mmol) in acetonitrile (40 ml), N-ethyl-diisopropylamine (5.9 g, 0.045 mol) and 2-bromo- 5-nitro-thiophene (0.86g, 5.27 mmol) (commercially available) were added and heated at 60°C for 4 hrs. The reaction mixture was cooled and evaporated in vacuo. The residue was dissolved in dichloromethane and washed with water and saturated sodium chloride solution. The organic layer was dried over sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography using dichloromethane500mL, 1percent methanol/dichloromethane 200 mL, 2percent methanol/dichloromethane 200 mL, 3percent methanol/dichloromethane 500mL. The product eluted in 3percent methanol/dichloromethane. The product was sonicated in diethylether for 10 min, filtered and dried in air to get 0.493 g of the title compound. m. p. 171-174°C 'H NMR (CDC13) 6ppm : 7.8 (d, 1H), 7.5 (dd, 1H), 6.97 (t, 1H), 6.02 (m, 2H), 4.77 (m, 1H), 4.01 (t, 1H), 3.5-3. 85 (m, 7H), 3.23 (m, 4H), 2.03 (s, 2 H) M+1=464, M+Na=486, M+K=502, M-NO2 = 418 | |
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 4h; | To the (S)-N-[[3-[3-Fluoro-4-(1-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide [TRIFLUOROACETATE] prepared by the method given in U. S. latent No 5,700, 799 (4.58 mmol) in acetonitrile (40 mL), [N-ETHYL-DIISOPROPYLAMINE] (5.9 g, 0.045 mol) and 5- bromo-2-nitro-thiophene (0.86 g, 5.27 mmol) were added and heated at [60 XB0;C] for 4 hrs. The reaction mixture was cooled and evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) and washed with water and saturated sodium chloride solution. The organic layer was dried over sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography using [DCM-500] mL, [1O/D] MeOH/DCM-200 mL, 2percent [MEOH/DCM-200ML,] 3percent MeOH/DCM-500 mL. The product eluted in 3percent MeOH/DCM. Product was sonicated in diethylether for 10 min, filtered and dried in air to get 0.493 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 17h; | Example 6: Preparation of analogues of (S)-N- ( {3- [3. 5-Difluoro-4- (piperazin-l-yl) phenyl]-2-oxo-oxazolidin-5-vl} methyl) acetamide; Compound No. 33: Preparation of (S)-N- [ (3-13, 5-difluoro-4- [4- (5-nitro-thiophen-2- yl)-piperazin-1-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyls acetamide; To a solution of (S)-N- ( {3- [3, 5-Difluoro-4- (piperazin-1-yl) phenyl] -2-oxo- oxazolidin-5-yl} methyl) acetamide trifluoroacetate (0.0026 mmol. ), prepared by the method given in U. S. Patent No. 5,547, 950 in acetonitrile (60 mL), N-ethyl- diisopropylamine (2 mL, 0.0264 mmol) and <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (0.0029 mmole) was added and the reaction mixture was heated to 60 °C for about 17 hours. The reaction mixture was cooled; water was added and the reaction mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography to yield 700 mg of the title compound. 'H NMR (DMSO) 8ppm : 8.22 (m, 1H), 7.92-7. 94 (d, 1H), 7.28-7. 31 (d, 2H), 6.38-6. 40 (d, 1H), 4.7 (m, 1H), 4.06-4. 12 (t, 1H), 3.70-3. 73 (t, 1H), 3.58 (m, 4H), 3.40-3. 42 (m, 2H), 3.22 (m, 4H), 1.83 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(S)-N-[[3-[4-(1-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide trifluoroacetate (1.076 mmol) was stirred with acetone and [K2C03] (200mg) for 5 minutes, then filtered and concentrated under reduced pressure. The residue was dissolved in DMSO and stirred at room temperature. To this, a stirred solution of [K2CO3] (224 mg, 1.61 mmol) and <strong>[13195-50-1]2-bromo-5-nitro-thiophene</strong> (246 mg, 1.18 mmol) was added at room temperature and stirred for overnight. The reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over anhydrous [NA2S04] and concentrated under reduced pressure to get the crude product which was purified by column [CHROIMATOGRAPHY.] (Silica gel-100-200 mesh sige) eluent: 1-2percent MeOH in DCM to yield 75 mg of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 16h; | A mixture of <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (478 mg, 2.3 MMOL), 3-cyclobutyl-2, 3,4, 5-tetrahydro- 1 H-BENZO [d] azepin-7-ol (E3) (500 mg, 2.3 MMOL) and potassium carbonate (765 mg, 5.5 mmol) in dimethylformamide (10 ml) was stirred at 80 °C for 16 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with water, brine and dried (sodium sulfate). CONCENTRATION IN VACUO and purification of the resulting residue by column chromatography. 880 ammonia: methanol : DICHLOROMETHANE (1: 8: 300) afforded the title compound (E211) ; MS (ES+) m/e 345 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 14h; | Compound No. 14 (S)-N-[[3-[3-Fluoro-4-[N-1-{2-thienyl-(5-nitro)}piperidinyl-4- OXY] PHENYL]-2-OXO-5-OXOZOLIDINYL] METHYL] ACETAMIDE To a solution of compound (S)-N- [ [3- [3-FLUORO-4- (PIPERIDINYL-4-OXY) PHENYL]-2-OXO-5- oxozolidinyl] methyl] acetamide (0.665mmole) in DMSO (8ML), potassium carbonate (1. 330MMOLE) and <strong>[13195-50-1]2-bromo-5-nitro-thiophene</strong> (0.789mmole) were added and stirred for 14 hr at RT. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography using 1-2percent methanol in dichloromethane as eluent to get the product, and triturated with ether. The solid obtained was filtered and dried to yield 130 mg of the title compound. HINMR (CDC13) 8 PPM: 7.80-7. 78 (m, LH), 7.50 (dd, LH), 7.05 (t, LH), 6.03-5. 97 (m, 2H), 4.78-4. 77 (m, lH), 4.55-4. 52 (m, lH), 4.03 (t, lH), 3.77 (t, lH), 3.74-3. 62 (m, 4H), 3.44-3. 36 (m, 2H), 2.07-2. 05 (m, 4H), 2.03 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 6 - 8h; | Preparation of (S)-N-[[3-[3-Fluoro-4-[N-1-{4-(5-nitro-2- [THIERIYL) PIPERAZINYL}]-PHENYL]-2-OXO-5-OXAZOLIDINYL]-METHYL]-2-CHLORO-PROPIONAMIDE. <P> (S)-N- [ [3-FL-UORO- [4- (L-PIPERAZINYL)-PHENYL]-2-OXO-5-OXAZOLIDINYL]-2-CHLORO-] [PROPIONAMIDE] (WO 00/32599) (0.22gm, 0.454 moles) was taken in acetonitrile. To this, [N-ETHYLDIISOPROPYLAMINXE8;] (0.117 gm, 0.9 moles) and [5-NITRO-2-BROMO-THIOPHENE] (0.13 gm, 0.681 moles) were added and the reaction mixture was heated at [60XB0;C] for 6-8 hrs. The reaction mixture was concentrated and the crude compound was purified by column chromatography eluting with 2percent MeOH in dichloromethane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 5h; | To the ! (S)-N-[[3-[3-Fluoro-4-(1-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl] methyl] - difluoroacetamide (1. [06] mmol, prepared as described in WO 00/32599) in acetonitrile (15 mL), [N-ETHYL-DIISOPROPYLAMINE] [(0.] 27 g, 2.11 mol) and 5-bromo-2-nitro-thiophene (0.2 g, 1.21 mmol) were added and the reaction mixture was heated at [60XB0;C] for 5 hrs. The reaction mixture was cooled and evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) and washed with water and sodium chloride solution. The organic layer was dried over sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography using DCM-200 mL, 1percent MeOH/DCM-100 mL, 2percent [MEOH/DCM-300ML.] The product eluted in 2percent MeOH/DCM. The product was triturated with hexane, filtered and dried in air to get 0.05 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 6 - 8h; | (S)-N-[[3-Fluoro-[4-(1-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]-dichloroacetamide (0.996 [RNMOLES,] WO 00/32599) was taken in acetonitrile. To this, were added N- [ETHYLDIISOPROPYLAMINE] (0.35 ml, 1.984 m. moles) and 5-nitro-2-bromo-thiophene (309 mg, 1. 48 m.moles). The reaction mixture was heated at [60XB0; C] for 6-8 hrs. The reaction mixture was concentrated. The residue obtained was dissolved in ethyl acetate, washed with water. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the crude product. The crude compound was purified by column chromatography eluting with [21/O] MeOH in dichloromethane. The product was triturated with ether, filtered and dried in air to get 0.15 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 6 - 8h; | (S)-N-[[3-[-3-Fluoro-4-[4-(5-nitro-2-thienyl)-3-methyl-1- piperazinyl] [PHENYL]-2-OXO-5-OXOZOLIDINYL]] methyl] acetamide : (S)-N-[[3-Fluoro-[4-(3-methyl-1-piperazinyl0-phenyl] -2-oxo-5-oxazolidinyl]-acetamide (1. [5L ! 5 MMOLES)] was taken im acetonitrile. To this, were added [N-ETHYLDIISOPROPYLAMINE] (1. 09 ml, 6.22 m. moles) and [5-NITRO-2-BROMO-THIOPHENE] (485 mg, 2.33 m. moles). The reaction mixture was heated at [60XB0; C] for 6-8 hrs. The reaction mixture was concetrated. The [RGMUUC UOTAINED WAS] dissolved in ethyl acetate, washed with water. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the crude product. The crude compound was purified by column chromatography eluting with 2percent MeOH in dichloromethane. The product was triturated with ether, filtered and dried in air to get 0.07 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 17h; | 7 Analogues of (S)-N-[[3-[3-Fluoro-4-(N-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]- methyls [FLUOROACETAMIDE (CORE] VII) Compound No. 11 : (S)-N-[[3-[3-Fluoro-4-[4-(5-nitro-2-thienyl)-1- [PIPERAZINYL] ! PHENYL]-2-OXO-5-OXAZOLIDINYL] METHYL] FLUOROACETAMIDE] To the (S)-N-[[3-[3-Fluoro-4-(1-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl] [FHIOIJOACETANIDE] (0.88 mmol, prepared as described in WO 00/32599) in acetonitrile (15 mL), N-ethyl-diisopropylamine (0.23 g, [1.] 75 mol) and [5-BROMO-2-NITRO-THIOPHENE] (0.16 g, 1 mmol) were added and heated at 60 °C for 17 hrs. The reaction [MI-TURE] was cooled and evaporated in vacuo. The residue was taken in dichloromethane (DCM) and washed with water and satd. sodium chloride solution. The organic layer was dried over anhyd. sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography using DCM-400 mL, 1percent [MEOH/DCM-200] mL, [20/E)] MeOH/DCM- 600mL. The product eluted in 2percent [MEOH/DCM.] The product was triturated with hexane, filtered and dried in air to get 0.08 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 48h; | [ (S)-N-[[3-[3-FLUORO-4-[3-(1ALPHA;,5ALPHA;,6ALPHA;)-[6-(N-METHYL)AMINOMETHYL]-3-AZABICYCLO-] [3.1. 0] hexane] phenyl]-2-oxo-5-oxazolidinyl] nethyl] acetamide (0.84 [MM-OL,] prepared as described in WO 0206278) was taken in acetonitrile (20 mL). To this, were added N- [ETHYLDIISOPROPYLAMINE] (0. [43G,] 3.36 mmol) and [5-NITRO-2-BROMO-THIOPHENE] (0.262 g, 1.26 [RILMOL)] and the reaction mixture was heated at [60XB0; C] for 48 hrs. The reaction mixture was [CONCLENTRATEDL THE RESIDU ; E OBTAINED] was dissolved in ethyl acetate and washed with water. The organic ; Layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the crude product. The crude compound was purified by column chromatography eluting with 2percent MeOH in dichloromethane. The product was triturated with ether, filtered and dried in air to get 0.12 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 17h; | Example 2: Preparation of analogues of L)-N- (f3-13-Fluoro-4- (N-piperazinyl) phenyll 2-oxo-oxazolidin-5-yl methyl) acetamide (Core II); Compound No. 26: Preparation of ()-N- [(3-{3-Fluoro-4- [4-(5-nitro-thiophen-2-yl)- 1-piperazinyl] phenyl}-2-oxo-oxazolidin-5-yl) methyls acetamide; To a solution of ()-N- ({3-[3-Fluoro-4- (piperazin-1-yl) phenyl]-2-oxo- oxazolidin-5-yl} methyl) acetamide trifluoroacetate prepared by the method given in WO 93/23384 (1.15 mmol) in acetonitrile (10 mL), N-ethyl-diisopropylamine (2.6 mL, 15 mmol) and <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (0.28g, 1.3 mmole) (commercially available) was added and the reaction mixture was heated to 60 °C for about 17 hours. The reaction mixture was cooled; water was added and the reaction mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography to yield 0.24 g of the title compound. 'H NMR (DMSO) 8ppm : 8.23 (t, 1H), 7.94 (d, 1H), 7.16 (dd, 1H), 7.20 (dd, 1H), 7.12 (t, 1H), 6.41 (d, 1H), 4.70 (m, 1H), 4.09 (t, 1H), 3.71 (m, 2H), 3.62 (m, 4H), 3.14 (m, 4H), 1.83 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; | Example 5: Preparation of Analogues of (S)-N- [(3-{3-Fluoro-4-[3-(1alpha,5alpha,6alpha)-6-(N- methyl-N-amino)-3-azabicyclo-3. 1. 0] hexyl] phenyl}-2-oxo-oxazolidin-5- yDmethyl] acetamide (Core V); Compound No. 32: Preparation of (S)-N- [3-(3-Fluoro-4-{3-(la, 5a, 6a)-6- [N-methyl- N- (5-nitro-furan-2-yl) amino]-3-azabicyclo- [3. 1.0] hexyl} phenyl)-2-oxo-oxazolidin-5- yl] methyl} acetamide; To a solution of (S)-N- [ (3- {3-Fluoro-4- [3- (la, 5a, 6a)-6- (N-methyl-N-amino)-3- azabicyclo- [3. 1.0] hexyl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide trifluoroacetate prepared by the method given in WO 02/06278 (0.868 mmol) in dimethylformamide (10 mL), potassium carbonate (8.68 mmol) and 2-bromo-5-nitro-furan (1.12 mmole) was added and the reaction mixture was stirred at room temperature for overnight. The reaction mixture was cooled; water was added and the reaction mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography to yield 110 mg of the title compound. 'H NMR (DMSO) 8ppm : 8.223 (m, 1H), 7.81-7. 82 (d, 1H), 7.38-7. 43 (d, 1H), 7.09-7. 12 (d, 1H), 6.80 (t, 1H), 5.87-5. 88 (d, 1H), 4.66 (m, 1H), 4.02 (t, 1H), 3.77-3. 80 (d, 2H), 3.67 (t, 1H), 3.41 (m, 4H), 3.17 (s, 3H), 2.81 (m, 1H), 2.07-2. 13 (m, 2H), 1.83 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Step 9.2 2-Bromo-5-nitrothiophene. Nitric acid (24.00 g, 1.42 sp gr, 0.381 mol) in acetic anhydride (50 ml) at 0° C. was added dropwise to a cooled (0° C.) rapidly stirred solution of the compound of step 5.1 (24.77 g, 0.152 mol) in acetic anhydride (50 ml). At the end of the addition the stirring was continued for 0.5 hr and the mixture was refrigerated overnight. The mixture was poured into ice water (400 ml) and the precipitate was filtered off, dissolved in ether (2*200 ml), and washed with water until free of acid. The solvent was removed in vacuo and the residue was purified by column chromatography silica gel/petroleum fraction (bp 40°-60° C.), dichloromethane, 5:1! and was recrystallized from ethanol/dimethoxyethane, 100:1 to give a pale yellow solid which was dried in vacuo (P2 O5) to give 66percent yield of 20.89 g. | |
66% | Step 5.2 2-Bromo-5-nitrothiophene Nitric acid (24.00 g, 1.42 sp gr, 0.381 mol) in acetic anhydride (50 ml) at 0° C. was added dropwise to a cooled (0° C.) rapidly stirred solution of the compound of step 5.1 (24.77 g, 0.152 mol) in acetic anhydride (50 ml). At the end of the addition the stirring was continued for 0.5 hr and the mixture was refrigerated overnight. The mixture was poured into ice water (400 ml) and the precipitate was filtered off, dissolved in ether (2*200 ml), and washed with water until free of acid. The solvent was removed in vacuo and the residue was purified by column chromatography [silica gel/petroleum fraction (bp 40°-60° C.), dichloromethane, 5:1] and was recrystallized from ethanol/dimethoxyethane, 100:1 to give a pale yellow solid which was dried in vacuo (P2 O5) to give 66percent yield of 20.89 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
118 mg (51%) | tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; | EXAMPLE 217 (+)-(4aR)-(10bR)-4-methyl-8-(5-nitro-2-thienyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one STR235 A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (135 mg, 0.65 mmol), 0.65 mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2*25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 118 mg (51percent) of the title compound as a white solid. mp 147°-149°. FDMS: m/e=356. alpha[D]589 =+83.48 (c=0.54, chloroform). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chloride; triethylamine;bis(triphenylphosphine)palladium(II) dichloride; In N-methyl-acetamide; diethyl ether; ethyl acetate; | Example 3 Preparation of [S-(R*,R*)]-3,6-anhydro-1,2-dideoxy-1-[5-[4-[(5-nitro-2-thienyl)]phenyl]-2H-tetrazol-2-yl]-D-allo-heptitol 7-(2-amino-3-methyl-1-oxopentyl)sulfamate To a solution of 4-ethynylbenzonitrile (0.5 g), <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (0.9 g) and bis(triphenylphosphine)palladium dichloride (83 mg) in anhydrous dimethylformamide (4 ml) was added triethylamine (2.2 ml). The reaction mixture was stirred at room temperature for 3 days then ethyl acetate (200 ml) and saturated sodium chloride (200 ml) were added. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude solid was triturated with 1:1 dichloromethane/hexane followed by diethyl ether to give 4-[(5-nitro-2-thienyl)ethynyl]benzonitrile as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50 mg (81%) | EXAMPLE 200 1,2-Dihydro-2,2,4-trimethyl-6-(5-nitro-2-thienyl)quinoline (Compound 300, structure 4 of Scheme II, where R1 =5-nitro-2-thienyl) This compound was prepared by General Method 2 (EXAMPLE 9) from Compound 9 (50 mg, 0.16 mmol) and <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (0.16 g, 0.79 mmol). The crude product was purified by prep TLC (20*20 cm, 1000 mm, 25percent EtOAc:hexane) to afford 50 mg (81percent) of Compound 300 as a purple solid. Data for compound 300: Rf=0.40 (silica gel, 25percent EtOAc:hex); 1 H NMR (400 MHz, CDCl3) 7.85 (d, J=4.3, 1H), 7.27 (m, 2H), 7.04 (d, J=4.3, 1H), 6.43 (d, J=8.5, 1H), 5.38 (brs, 1H), 4.13 (brs, 1H), 2.03 (s, 3H), 1.32 (s, 6H). | |
50 mg (81%) | EXAMPLE 200 1,2-Dihydro-2,2,4-trimethyl-6-(5-nitro-2-thienyl)quinoline (Compound 300, Structure 4 of Scheme II, where R1 =5-nitro-2-thienyl) This compound was prepared by General Method 2 (EXAMPLE 9) from Compound 9 (50 mg, 0.16 mmol) and <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (0.16 g, 0.79 mmol). The crude product was purified by prep TLC (20*20 cm, 1000 mm, 25percent EtOAc:hexane) to afford 50 mg (81percent) of Compound 300 as a purple solid. Data for compound 300: Rf=0.40 (silica gel, 25percent EtOAc:hex); 1 H NMR (400 MHz, CDCl3) 7.85 (d, J=4.3, 1 H), 7.27 (m, 2 H), 7.04 (d, J=4.3, 1 H), 6.43 (d, J=8.5, 1 H), 5.38 (brs, 1 H), 4.13 (brs, 1 H), 2.03 (s, 3 H), 1.32 (s, 6H). | |
50 mg (81%) | EXAMPLE 200 1,2-Dihydro-2,2,4-trimethyl-6-(5-nitro-2-thienyl)quinoline (Compound 300, structure 4 of Scheme II, where R1 =5-nitro-2-thienyl) This compound was prepared by General Method 2 (EXAMPLE 9) from Compound 9 (50 mg, 0.16 mmol) and <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (0.16 g, 0.79 mmol). The crude product was purified by prep TLC (20*20cm, 1000 mm, 25percent EtOAc:hexane) to afford 50 mg (81percent) of Compound 300 as a purple solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In water; toluene; | Example 32 A specific procedure for the synthesis of: N-5-[(4-fluoro)phenyl-thien-2-yl]methanesulfonamide (32) STR20 <strong>[13195-50-1]2-Bromo-5-nitrothiophene</strong> (3.50 g, 16.8 mmol) was dissolved in toluene (50 mL). To this solution was added 4-fluorophenyl boronic acid (2.52 g, 18.0 mmol), tetrakis(triphenylphosphine)paJladium (0) (0.58 g, 3 molepercent), potassium carbonate (4.56 g, 33.0 mmol) and water (25 mL) and the resulting mixture refluxed for 18 hours after which time the layers were separated. The organic layer was evaporated to a crude solid which was recrystallized from ethanol-water to give 2-nitro-5-(4-fluoro)phenylthiophene (2.99 grams (80percent)1. Mp 129°-130° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 17h; | To the solution of compound tert-butyl 4-(2-fluoro-4-{(5S)-5-[(isoxazol-3- ylamino)methyl]-2-oxo- 1 ,3-oxazolidin-3-yl}phenyl)piperazine- 1 -carboxylate obtained from the Step b of Compound No. 1, in acetonitrile (10 ml) was added 2-bromo-5-nitro- thiophene , in presence of N-ethyl-diisopropylamine (1.49 g). The reaction mixture was heated at 60 0C for 17 hrs and the resulting solution was evaporated under reduced pressure. The residue left was taken in dichloromethane, w^ashed with water, dried over anhydrous sodium sulphate and evaporated. The residue was purified by column chromatography using 1percent methanol-dichloromethane as eluant. The product was sonicated in ether and filtered to get the title compound (0.O43 g). Melting point = 234-2380C.1H NMR (DMSO) deltappm: 8.38 (s, IH), 7.95 (d, IH), 7.53 (dd, IH), 7.21 (dd, IH)5 7.12 (t, IH), 6.55 (t, IH), 6.41 (d, IH), 6.00 (s, IH), 4.85 (m, IH), 4.13 (t, 2H), 3.79 (m, 2H), 3.13(m, 4H);Mass: M+H = 489.3, M+Na = 511.3, M+K = 527.4, M-ND2= 443.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 17h; | To a solution of tert-tmtyl 4-(2-fluoro-4-{(5S)-2-oxo-5-[(pytauidin-2-yloxy)methyl]- l,3-oxazolidin-3-yl}phenyl)piperazine-l-carboxylate (0.25g)(prepared by procedures similar to that in WO 99/64416 and WO 99/64417),in acetonitrile (2OmI) was added 2- bromo-5-nitro-thiophene (0.12g) in presence of N-ethyl-diisopropylamine (0.7g). The reaction mixture was heated at 60 0C for 17 hrs. and the solvent wa.s evaporated. The residue was taken in dichloroxnethane, washed with water, dried o^er anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography, eluting in 1 percent methanol-dichloromethane. The product was sonicated in ether and filtered to get the title compound (0.07 g). Melting point: 194-1970C1H NMR (DMSO) deltappm: 8.20 (d, IH), 7.99 (d, IH), 7.76 (t, IH), 7.59 (dd, IH), 7.27 (dd, IH), 7.16 (t, IH), 7.05 (t, IH), 6.88 (d, IH), 6.46 (d, IH), 5.09 (m, IH), 4.55 (m, 2H), 4.22 (t, IH), 3.94 (t, IH), 3.66 (m, 4H), 3.17 (m, 4H)Mass: M+l=500.5, M+Na - 522.2, M-NO2 = 454.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sodium hydroxide; triethylamine; In dichloromethane; water; | EXAMPLE 27 2-(5-nitro-2-thienyl)thio-5-chloropyrimidine A mixture of 5-chloropyrimidine-2-thione (7.5 mmol), triethylamine (9 mmol) and <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (9 mmol) in dichloromethane (50 ml) was stirred at room temperature for 2 days. The resultant solution was then diluted with dichloromethane (50 ml), the solution shaken with 1 M NaOH (2*10 ml) and subsequently with water (10 ml), the dried (MgSO4) solution evaporated and the solid residue recrystallized from pet. ether; yield 63percent, m.p. 141°-143° C. 1 H NMR (CDCl3): delta7.16 and 7.83 (H-31, H-41), 8.53 (H-4, H-6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium; In N-methyl-acetamide; Petroleum ether; | A mixture of 18.6 g (0.1 mole) of 2-mercapto-5-trifluoromethyl-1,3,4-thiadiazole and 5.6 g (0.1 mole) of powdered potassium hyroxide in 100 ml of absolute dimethylformamide was stirred for 30 minutes. 20.8 g (0.1 mole) of <strong>[13195-50-1]2-bromo-5-nitro-thiophene</strong> were added in a single portion. The mixture was stirred for 3 hours at 50° C, diluted with water and extracted with methylene chloride and after drying the organic phase was evaporated over sodium sulfate. Vacuum distillation gave 24.4 g of crude product of boiling point 160°-163° C/0.3 mm Hg, which was recrystallized from hexane/ethyl acetate (10:1). After further recrystallization ether/petroleum ether (4:3), 17.3 g (55percent of theory) of pure 2-(5'-nitro-thiophen-2'-yl-thio)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 57° c were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 120℃; for 1h; | 1-[(4-Methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1H-pyrrolo[2,3-b]pyridine (880 mg, 2.2 mmol) and <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (416 mg, 2 mmol) were dissolved in DME (10 ml_) and aqueous Na2COa (2M, 2 ml_). The resulting solution and Pd(PPh3)4 (100 mg, 0.087 mmol) was added to the Microwave vial. After capping, the mixture was heated with Creator at 120 0C for 60 min. The crude was extracted with CH2CI2, and washed with aqueous NH4CI solution. After removing the solvent, the residue was directly used for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 70℃; for 4h; | To a solution of <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (0.23 g, 1 .08 mmole) in dioxane (9 imL) and H2O (1 .8 mL) was added K2CO3 (0.40 g, 4.33 mmole), tetrakistriphenylphosphine Pd(O) (0.06 g, 0.056 mmole), and 1-(phenylsulfonyl)-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrolo[2,3-b]pyridine (0.5 g, 1.29 mmole). The reaction mixture was heated to 70° C in a sealed tube for 4h. The reaction solution was concentrated under vacuum, and purified on silica gel (hexanes/EtOAc, 3:1 ) to give the title compound (400 mg, 80percent) as a brown solid: LC-MS (ES) m/z = 386 (M+1 )+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 80℃; for 12h; | To a solution of percent-bromo-2-nitrothiophene (1.08 g, 5.2 mmole) in dioxane (40 mL) and H2O (8 mL) was added K2CO3 (2.15 g, 16.74 mmole), tetrakistriphenylphosphine Pd(O) (0.60 g, 0.52 mmole), and 1-(phenylsulfonyl)-3- (4,4,5,5-tetramethyl-1 J3.2-dioxaborolan-2-yl)-1H-pyrro.o[2,3-ib]pyridine (2.0 g, 5.2 mmole). The reaction mixture was heated to 80° C in a sealed tube for 12h. The reaction solution was poured onto H2O (100 mL) and extracted with DCM. The organics were dried (Na2SO4), concentrated under vacuum, and purified on silica gel (hexanes/EtOAc, 1 :1 ) to give the title compound (1.1 g, 55percent) as a tan foam: LC- MS (ES) m/z = 386. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N-methyl-acetamide; | Production Example 226-2 6,7-Dimethoxy-4-(5-nitrothiophen-2-ylsulfanyl)quinoline 6,7-Dimethoxy-1H-quinolin-4-thione (2.21 g, 10.0 mmol), <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (2.29 g, 11.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were stirred in dimethylformamide (30 ml) at room temperature for 1 hour. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with 1N aqueous sodium hydroxide, water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent-ethyl acetate:hexane=3:1), and the fraction containing the target substance was concentrated to obtain the title compound (1.93 g, 5.54 mmol, 55percent) as yellow crystals. 1H-NMR Spectrum (CDCl3) delta (ppm): 4.04 (3H, s), 4.06 (3H, s), 7.10 (1H, d, J=4.8 Hz), 7.22 (1H, d, J=4.4 Hz), 7.37 (1H, s), 7.46 (1H, s), 7.89 (1H, d, J=4.4 Hz), 8.60 (1H, d, J=4.8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N-methyl-acetamide; water; | Production Example 247-2 2-[7-(Benzyloxy)-6-methoxy-4-quinolyl]sulfanyl}-5-nitrothiophene 7-(Benzyloxy)-6-methoxy-1,4-dihydro-4-quinolinethione (14.3 g), <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (10 g), potassium carbonate (9.9 g) and dimethylformamide (150 ml) were stirred together at room temperature for 6 hours. Water was added, and the precipitated solid was filtered out and washed with water and then ethyl acetate to obtain 15.7 g of a yellow powder. 1H-NMR (DMSO-d6) delta (ppm): 3.92 (3H, s), 5.29 (2H, s), 7.23 (1H, dd, J=4.8 Hz, 1.6 Hz), 7.32-7.44 (4H, m), 7.49 (2H, d, J=8.0 Hz), 7.55 (1H, s), 7.57 (1H, dd, J=4.4 Hz, 1.6 Hz), 8.16 (1H, dd, J=4.4 Hz, 2.0 Hz), 8.58 (1H, dd, J=4.8 Hz, 1.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Production Example 252-2 7-(2-Methoxyethoxy)-4(5-nitrothiophen-2-ylsulfanyl)quinoline-6-carbonitrile The title compound (2.2 g) was obtained as a solid from 7-(2-methoxyethoxy)-4-thioxo-1,4-dihydroquinoline-6-carbonitrile (7.1 g) and <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (6.3 g), by the same procedure as in Production Example 226-2. 1H-NMR Spectrum (DMSO-d6) delta (ppm): 3.35 (3H, s), 3.75-3.78 (2H, m), 4.41-4.44 (2H, m), 7.18 (1H, d, J=4.4 Hz), 7.68 (1H, d, J=4.8 Hz), 7.69 (1H, s), 8.23 (1H, d, J=4.4 Hz), 8.70 (1H, s), 8.79 (1H, d, J=4.8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 2h; | <strong>[13195-50-1]2-Bromo-5-nitrothiophene</strong> (2.2 g), {4-[[(frans-4-methylcyclohexyl)carbonyl](1- methylethyl)amino]-5-[(methyloxy)carbonyl]-2-thienyl}boronic acid (4.0 g, a synthesis of which is described as Intermediate 4) and cesium fluoride (8.0 g) were dissolved inDME/water (100 ml_, 1 :1 ), then tetrakis(triphenylphosphine)palladium(0) (616 mg) was added. The reaction was heated at 9O0C for 2 h and was then cooled and partitioned between EtOAc and water. The organic phases were separated, dried using a hydrophobic frit and evaporated in vacuo. The crude material was purified by ISCO Companion.(TM). silica chromatography, eluting with a gradient 5-60percent EtOAc in cyclohexane to give the title compound.MS calcd for (C2i H26N2O5S2 + H)+: 541MS found (electrospray): (M+H)+ = 541 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at -78 - -60℃; | A solution of <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (29 g, 139 mmol) and chloroform (12.37 mL, 153 mmol) in DMF (110 mL) was added dropwise to a solution of potassium toet-butoxide (62.6 g, 558 mmol) in THF (225 mL)/DMF (180 mL). The internal temperature was monitored and maintained at < -600C during the addition. Upon complete addition, the reaction was stirred at -780C for 30 minutes. 2 N HCl was added and the products were extracted into EtOAc (3x). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash silica gel column chromatography (0- 10percent EtOAc-hexanes) gave the title compound as a brown oil. 1H NMR (600 MHz, DMSO): delta 7.88 (s, 1 H), 7.70 (s, 1 H). | |
Step 1. 5-Bromo-3-rdichloromethyl-2-nitrotauhiopheneA solution of <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (29 g, 139 mmol) and chloroform (12.37 mL, 153 mmol) in DMF (110 mL) was added dropwise to a solution of potassium ?er/-butoxide (62.6 g, 558 mmol) in THF (225 rnL)/DMF (180 mL). The internal temperature was monitored and maintained at < -600C during the addition. Upon complete addition, the reaction was stirred at -78 0C for 30 minutes. 2 N HCl was added and the products were extracted into EtOAc (3x). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash silica gel column chromatography (0- 10percent EtOAc-hexanes) gave the title compound as a brown oil. 1H NMR (600 MHz, DMSO): delta 7.88 (s, 1 H), 7.70 (s, 1 H). | ||
With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at -78 - -60℃; for 0.5h; | A solution of <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (29 g, 139 mmol) and chloroform (12.37 mL, 153 mmol) in DMF (110 mL) was added dropwise to a solution of potassium tert-butoxide (62.6 g, 558 mmol) in THF (225 mL)/DMF (180 mL). The internal temperature was monitored and maintained at < -60°C during the addition. Upon complete addition, the reaction was stirred at -780C for 30 minutes. 2 N HCl was added and the products were extracted into EtOAc (3x). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash silica gel column chromatography (0- 10percent EtOAc-hexanes) gave the title compound as a brown oil. 1H NMR (600 MHz, DMSO): 7.88 (s, 1 H), 7.70 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of tert-butyl 4-(2-fluoro-4-{(5i?)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-l,3- oxazolidin-3~yl}phenyl)piperazine-l-carboxylate (prepared by procedures similar to that in WO 99/64416 and WO 99/64417) (0.5Ig) in dichloromethane(lpsiml) was added trifluoroacetic acid (2ml) and stirred for 2 hours, the solvent was concentrated .To the residue, in acetonitrile (15ml) was added <strong>[13195-50-1]2-bromo-5-nitro-thiophene</strong> (0.27g) in presence of N-ethyl-diisopropylamine (1.47g) and heated at 60 0C for 17 hrs. The reaction mixture was then evaporated .The residue was taken in dichloromethane, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography, eluting in 0.5percent methanol-dichloromethane. Tlie product was sonicated in ether and filtered to get the title compound (0.72 g). Melting point: 201-2020C1H NMR (CDC13) deltappm: 8.16 (s, IH), 7.8 (d, IH), 7.62 (dd, IH), 7.14 (dd, IH), 6.02 (m, 2H), 5.03 (m, IH), 4.7-4.4 (m, 2H), 4.15 (t, IH), 3.96 (t, IH), 3.66 (m, 4H), 3.4(m, 4H),Mass: M +1 = 490.4, M + Na = 512.2, M-NO2 = 444.5 |
Tags: 13195-50-1 synthesis path| 13195-50-1 SDS| 13195-50-1 COA| 13195-50-1 purity| 13195-50-1 application| 13195-50-1 NMR| 13195-50-1 COA| 13195-50-1 structure
[ 166887-84-9 ]
2-(Bromomethyl)-5-nitrothiophene
Similarity: 0.65
[ 68236-26-0 ]
N-(5-Bromothiophen-2-yl)acetamide
Similarity: 0.57
[ 166887-84-9 ]
2-(Bromomethyl)-5-nitrothiophene
Similarity: 0.65
[ 16689-02-4 ]
5-Nitrothiophene-2-carbonitrile
Similarity: 0.63
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P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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