Structure of 130723-13-6
*Storage: {[sel_prStorage]}
*Shipping: {[sel_prShipping]}
The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
4.5
*For Research Use Only !
Change View
Size | Price | VIP Price | US Stock |
Global Stock |
In Stock | ||
{[ item.pr_size ]} |
Inquiry
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,1,item.pr_is_large_size_no_price, item.discount_usd) ]} {[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]} |
Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]} | Inquiry {[ item.pr_usastock ]} In Stock Inquiry - | {[ item.pr_chinastock ]} {[ item.pr_remark ]} In Stock 1-2 weeks - Inquiry - | Login | - + | Inquiry |
Please Login or Create an Account to: See VIP prices and availability
US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days
1-2weeks
Inquiry
{[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
{[ getRatePrice(item.pr_usd,1,item.mem_rate,item.pr_is_large_size_no_price, item.pr_usd) ]}
Inquiry
{[ getRatePrice(item.pr_usd,item.pr_rate,1,item.pr_is_large_size_no_price, item.vip_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
In Stock
- +
Please Login or Create an Account to: See VIP prices and availability
US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
CAS No. : | 130723-13-6 |
Formula : | C7H3BrF4 |
M.W : | 243.00 |
SMILES Code : | C1=C(C=C(C=C1F)C(F)(F)F)Br |
MDL No. : | MFCD00042498 |
InChI Key : | LIGBGEJPUQBLTG-UHFFFAOYSA-N |
Pubchem ID : | 2736323 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 39.1 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.34 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.6 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
5.18 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
4.51 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.95 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.92 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.92 |
Solubility | 0.0293 mg/ml ; 0.000121 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.29 |
Solubility | 0.126 mg/ml ; 0.000517 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.42 |
Solubility | 0.00922 mg/ml ; 0.0000379 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
Yes |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.23 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
1.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.63 |
* 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 |
---|---|---|
81% | With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; at 20 - 80℃; for 24h; | 6-(3-Fluoro-5-trifluoromethylphenyl)-hex-5-ynoic Acid Methyl Ester (41). Pd(PPh3)2Cl2 (236 mg, 0.336 mmol) was added to a mixture of bromide 38 (1.677 g, 6.70 mmol) and methyl 5-hexynoate (1.025 g, 8.12 mmol) in triethylamine (5.0 mL) at room temperature. Cu(I)I (136 mg, 0.714 mmol) was added. The resulting mixture was stirred at room temperature for 1.5 h and at 80 C. for 22.5 h. The reaction mixture was cooled to room temperature, filtered through a short column of silica gel (5 g), and the column was washed with ethyl acetate. The organic solution was concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (2%) to afford the product 41 (1.564 g) as a white solid in 81% yield: mp 44-45 C. IR (KBr) 3084, 2955, 2848, 2238, 1740, 1619, 1599, 1467, 1439, 1363, 1253, 1240, 1224, 1171, 1133, 1093, 1046, 995, 973, 924, 911, 875, 695 cm-1; 1H NMR (300 MHz, CDCl3) delta 7.40 (s, 1H), 7.21 (m, 2H), 3.66 (s, 3H), 2.47 (t, J=7.2 Hz, 4H), 1.90 (m, 2H); 13C NMR (75 MHz, CDCl3) delta 173.3, 163.7, 160.4, 132.8, 132.3, 126.8, 126.7, 124.7, 124.3, 121.8, 121.5, 112.3, 111.9, 79.1, 51.6, 32.7, 23.5, 18.7; ESIMS m/z (rel intensity) 288.96 (MH+, 51). Anal. (C14H12F4O2) C, H, F. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | 2-(3-Fluoro-5-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane The title compound was obtained according to example 342 as a colorless oil (48% yield) using <strong>[130723-13-6]3-bromo-5-fluorobenzotrifluoride</strong> and bis(pinacolato)diboron as the starting materials MS: m/e=290 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; water; dimethyl sulfoxide; | 1-(3-Bromo-5-trifluoromethyl-phenyl)-piperazine A solution of <strong>[130723-13-6]1-bromo-3-fluoro-5-(trifluoromethyl)-benzene</strong> (100 g, 0.41 moles), piperazine (194.9 g, 2.26 moles) in DMSO (800 ml) was heated at 100 C. for 5 hours, cooled at room temperature and stirred overnight. The mixture was poured into water and the yellow solid which separeted was filtered. The solid was suspended in a 5% THF solution in water (300 ml) water/THF, stirred for 1 hour and filtered again. 120 g, light beige solid, m.p. 74-77 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | In para-thiocresol; | The 4-[3-(4-(2-cyanoprop-2-yl)phenylthio)-5-trifluoromethylphenyl]-4-hydroxytetrahydropyran used as a starting material was obtained as follows: Using a similar procedure to that described in the 1st paragraph of Note a. above 4-toluenethiol was reacted with <strong>[130723-13-6]1-bromo-3-fluoro-5-trifluoromethylbenzene</strong> to give 3-bromo-5-trifluoromethylphenyl 4-tolyl sulphide in 63% yield as an oil. |
63% | In para-thiocresol; | The 4-[3-(4-(2-cyanoprop-2-yl)phenylthio)-5-trifluoromethylphenyl]-4-hydroxytetrahydropyran used as a starting material was obtained as follows:- Using a similar procedure to that described in the 1st paragraph of Note a. above 4-toluenethiol was reacted with <strong>[130723-13-6]1-bromo-3-fluoro-5-trifluoromethylbenzene</strong> to give 3-bromo-5-trifluoromethylphenyl 4-tolyl sulphide in 63% yield as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | In 2,4-dichlorophenoxyacetic acid dimethylamine; mineral oil; | The 4-hydroxy-4-[3-(naphth-2-ylthio)-5-trifluoromethylphenyl]tetrahydropyran used as a starting material was obtained as follows: Sodium hydride (60% w/w dispersion in mineral oil; 0.5 g) was added portionwise to a mixture of 2-naphthalenethiol (1.42 g) and DMA (30 ml) and the mixture was stirred at ambient temperature for 1 hour. A solution of <strong>[130723-13-6]1-bromo-3-fluoro-5-trifluoromethylbenzene</strong> (2.43 g) in DMA (10 ml) was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine (50 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography using hexane as eluent. There was thus obtained 3-bromo-5-trifluoromethylphenyl 2-naphthyl sulphide (1.37 g, 40%), as an oil. A solution of the product so obtained in THF (10 ml) was cooled to -60 C. and n-butyl-lithium (1.6M in hexane; 2.3 ml) was added dropwise. |
40% | In 2,4-dichlorophenoxyacetic acid dimethylamine; mineral oil; | The 4-hydroxy-4-[3-(naphth-2-ylthio)-5-trifluoromethylphenyl]tetrahydropyran used as a starting material was obtained as follows:- Sodium hydride (60% w/w dispersion in mineral oil; 0.5 g) was added portionwise to a mixture of 2-naphthalenethiol (1.42 g) and DMA (30 ml) and the mixture was stirred at ambient temperature for 1 hour. A solution of <strong>[130723-13-6]1-bromo-3-fluoro-5-trifluoromethylbenzene</strong> (2.43 g) in DMA (10 ml) was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine (50 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography using hexane as eluent. There was thus obtained 3-bromo-5-trifluoromethylphenyl 2-naphthyl sulphide (1.37 g, 40%), as an oil. A solution of the product so obtained in THF (10 ml) was cooled to -60C and n-butyl-lithium (1.6 M in hexane; 2.3 ml) was added dropwise. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With iodine; magnesium; In tetrahydrofuran; water; | Step A Synthesis of 3-fluoro-5-trifluoromethylphenylboronic acid as an intermediate A crystal of iodine and 0.5 gram (0.021 mole) of magnesium turnings were placed in a reaction vessel containing 10 mL of tetrahydrofuran. To this was added dropwise 2 mL of a solution of 5.0 grams (0.021 mole) of <strong>[130723-13-6]3-fluoro-5-trifluoromethylphenyl bromide</strong> in 65 mL of tetrahydrofuran. The Grignard formation was initiated by warming the reaction vessel to about 45 C. The remaining <strong>[130723-13-6]3-fluoro-5-trifluoromethylphenyl bromide</strong>--tetrahydrofuran solution was added portionwise at a rate which maintained gentle reflux of the reaction mixture. In a second reaction vessel, 40 mL of tetrahydrofuran was cooled to -78 C., and 2.3 mL (0.021 mole) of trimethyl borate was added dropwise as the Grignard reagent of <strong>[130723-13-6]3-fluoro-5-trifluoromethylphenyl bromide</strong> prepared above was transferred into the second reaction vessel using a cannula. The temperature of the reaction mixture was maintained below -60 C. during the additions. Upon completion of the additions, the reaction mixture was again cooled to -78 C., where it was stirred for about 45 minutes. After this time, the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was then poured into about 200 mL of water and was made acidic with aqueous 5% hydrochloric acid. The mixture was extracted with four 100 mL portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 3.3 grams of 3-fluoro-5-trifluoromethylphenylboronic acid, mp 167-168 C. The NMR spectrum was consistent with the proposed structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium; In tetrahydrofuran; water; | Step A Synthesis of 3-fluoro-5-trifluoromethylphenylboronic acid as an intermediate A crystal of iodine and 0.5 gram (0.021 mole) of magnesium turnings are placed in a reaction vessel containing 10 mL of tetrahydrofuran. To this is added dropwise 2 mL of a solution of 5.0 grams (0.021 mole) of <strong>[130723-13-6]3-fluoro-5-trifluoromethylphenyl bromide</strong> (commercially available) in 65 mL of tetrahydrofuran. The Grignard formation is initiated by warming the reaction vessel to about 45 C. The remaining <strong>[130723-13-6]3-fluoro-5-trifluoromethylphenyl bromide</strong>-tetrahydrofuran solution is added portionwise at a rate which maintained gentle reflux of the reaction mixture. In a second reaction vessel, 40 mL of tetrahydrofuran is cooled to -78 C., and 2.3 mL (0.021 mole) of trimethyl borate is added dropwise as the Grignard reagent of <strong>[130723-13-6]3-fluoro-5-trifluoromethylphenyl bromide</strong> prepared above is transferred into the second reaction vessel using a cannula. The temperature of the reaction mixture is maintained below -60 C. during the additions. Upon completion of the additions, the reaction mixture is again cooled to -78 C., where it is stirred for about 45 minutes. After this time, the reaction mixture is allowed to warm to ambient temperature. The reaction mixture is then poured into about 200 mL of water and is made acidic with aqueous 5% hydrochloric acid. The mixture is extracted with four 100 mL portions of ethyl acetate. The combined extracts are dried with magnesium sulfate and filtered. The tiltrate is concentrated under reduced pressure, yielding 3.3 grams of 3-fluoro-5-trifluoromethylphenylboronic acid, mp 167-168 C. The NMR spectrum is consistent with the proposed structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
145 mg (57%) | tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; | EXAMPLE 216 (+)-(4aR)-(10bR)-4-methyl-8-(3-fluoro-5-trifluoromethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one STR234 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>[130723-13-6]1-bromo-3-fluoro-5-trifluoromethylbenzene</strong> (158 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 145 mg (57%) of the title compound as an oil. FDMS: m/e=391. alpha[D]589 =+67.32 (c=0.55, chloroform). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.1 mg (7%) | In methanol; | EXAMPLE 174 6-[5-fluoro-3-(trifluoromethyl)phenyl]-1,2-dihydro-2,2,4-trimethylquinoline (Compound 274, structure 4 of Scheme II, where R1 =5-fluoro-3-(trifluoromethyl)phenyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (42.8 mg, 0.13 mmol) and <strong>[130723-13-6]3-bromo-5-fluorobenzotrifluoride</strong> (32.7 mg, 0.13 mmol). The crude material was purified by HPLC (reverse phase ODS column, 90% methanol/water, 3.0 mL/min) to afford 3.1 mg (7%) of Compound 274. Data for Compound 274: 1 H NMR (400 MHz, acetone-d6) 7.71 (s, 1H), 7.63 (d, J=10.5. 1H), 7.40 (d, J=2.2, 1H), 7.34 (dd, J=8.1, 2.0, 1H), 7.29 (d, J=8.6, 1H), 6.59 (d, J=8.3, 1H), 5.50 (s, 1H), 5.39 (s, 1H), 2.5 (s, 3H), 1.29 (s, 6H). |
3.1 mg (7%) | In methanol; | EXAMPLE 174 6-[5-fluoro-3-(trifluoromethyl)phenyl]-1,2-dihydro-2,2,4-trimethylquinoline (Compound 274, Structure 4 of Scheme II, where R1 =5-fluoro-3-(trifluoromethyl)phenyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (42.8 mg, 0.13 mmol) and <strong>[130723-13-6]3-bromo-5-fluorobenzotrifluoride</strong> (32.7 mg, 0.13 mmol). The crude material was purified by HPLC (reverse phase ODS column, 90% methanol/water, 3.0 mL/min) to afford 3.1 mg (7%) of Compound 274. Data for Compound 274: 1 H NMR (400 MHz, acetone-d6) 7.71 (s, 1 H), 7.63 (d, J=10.5. 1 H), 7.40 (d, J=2.2, 1 H), 7.34 (dd, J=8.1, 2.0, 1 H), 7.29 (d, J=8.6, 1 H), 6.59 (d, J=8.3, 1 H), 5.50 (s, 1 H), 5.39 (s, 1 H), 2.05 (s, 3 H), 1.29 (s, 6 H). |
3.1 mg (7%) | In methanol; | EXAMPLE 174 6-[5-fluoro-3-(trifluoromethyl)phenyl]-1,2-dihydro-2,2,4-trimethylquinoline (Compound 274, structure 4 of Scheme II, where R1 =5-fluoro-3-(trifluoromethyl)phenyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (42.8 mg, 0.13 mmol) and <strong>[130723-13-6]3-bromo-5-fluorobenzotrifluoride</strong> (32.7 mg, 0.13 mmol). The crude material was purified by HPLC (reverse phase ODS column, 90% methanol/water, 3.0 mL/min) to afford 3.1 mg (7%) of Compound 274. Data for Compound 274: 1 H NMR (400 MHz, acetone-d6) 7.71 (s, 1H), 7.63 (d, J=10.5. 1H), 7.40 (d, J=2.2, 1H), 7.34 (dd, J=8.1, 2.0, 1H), 7.29 (d, J=8.6, 1H), 6.59 (d, J=8.3, 1H), 5.50 (s, 1H), 5.39 (s, 1H), 2.05 (s, 3H), 1.29 (s, 6H). |
3.1 mg (7%) | In methanol; | EXAMPLE 174 6-[5-fluoro-3-(trifluoromethyl)phenyl]-1,2-dihydro-2,2,4-trimethylquinoline (Compound 274, structure 4 of Scheme II, where R1 =5-fluoro-3-(trifluoromethyl)phenyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (42.8 mg, 0.13 mmol) and <strong>[130723-13-6]3-bromo-5-fluorobenzotrifluoride</strong> (32.7 mg, 0.13 mmol). The crude material was purified by HPLC (reverse phase ODS column, 90% methanol/water, 3.0 mL/min) to afford 3.1 mg (7%) of Compound 274. Data for Compound 274: 1 H NMR (400 MHz, acetone-d6) 7.71 (s, 1 H), 7.63 (d, J=10.5. 1 H), 7.40 (d, J=2.2, 1 H), 7.34 (dd, J=8.1, 2.0, 1 H), 7.29 (d, J=8.6, 1 H), 6.59 (d, J=8.3, 1 H), 5.50 (s, 1 H), 5.39 (s, 1 H), 2.05 (s, 3 H), 1.29 (s, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.1 mg (7%) | In methanol; | EXAMPLE 174 6-?5-fluoro-3-(trifluoromethyl)phenyl-1,2-dihydro-2,2,4-trimethylquinoline (Compound 274, structure 4 of Scheme II, where R1 =5-fluoro-3-(trifluoromethyl)phenyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (42.8 mg, 0.13 mmol) and <strong>[130723-13-6]3-bromo-5-fluorobenzotrifluoride</strong> (32.7 mg, 0.13 mmol). The crude material was purified by HPLC (reverse phase ODS column, 90% methanol/water, 3.0 mL/min) to afford 3.1 mg (7%) of Compound 274. Data for Compound 274: 1 H NMR (400 MHz, acetone-d6) 7.71 (s, 1H), 7.63 (d, J=10.5. 1H), 7.40 (d, J=2.2, 1H), 7.34 (dd, J=8.1, 2.0, 1H), 7.29 (d, J=8.6, 1H), 6.59 (d, J=8.3, 1H), 5.50 (s, 1H), 5.39 (s, 1H), 2.05 (s, 3H), 1.29 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In diethyl ether; hexane; at -78℃; for 1h; | 5-Bromo-3-fluorobenzo trifluoride (APOLLO Co., 9.0 g) was dissolved in diethyl ether (110 ml), and the mixture was cooled to -78C. An n-butyllithium hexane solution (2.71 M, 17.5 ml) was added to this solution, and the mixture was stirred at -78C for 1 hr. Then, 1-(tert-butoxycarbonyl)-4-piperidone (6.71 g) was added. The reaction temperature was then warmed to 0C, and the mixture was further stirred for 1 hr. After completion of the reaction, water was added, and the mixture was extracted three times with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (5:1-2:1)). Then, the residue was dissolved in 1,4-dioxane (150 ml), and 10% aqueous sulfuric acid (10 ml) was added thereto. The mixture was stirred with heating at 70C for 2 hr. After completion of the reaction, the reaction system was basified (pH=9) with an 1N aqueous sodium hydroxide solution, and extracted three times with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-[3-fluoro-5-(trifluoromethyl)phenyl]piperidin-4-ol (9.89 g, yield 56%). 1H-NMR(300MHz,DMSO-d6)delta(ppm) : 1. 76-1. 81 (2H,m), 2.21-2.31(2H,m), 3.17-3.32(4H,m), 5.85(1H,s), 7.55-7.60(3H,m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | The (2RS,4SR)-4-hydroxy-2-methyl-4-[3-(naphth-2-ylmethoxy)-5-trifluoromethylphenyl]tetrahydropyran used as a starting material was obtained as follows: Using the procedure described in the first paragraph of Note e. below Table IV in Example 15, 2-naphthalenemethanol was reacted with <strong>[130723-13-6]3-fluoro-5-trifluoromethylbromobenzene</strong> to give 3-(naphth-2-ylmethoxy)-5-trifluoromethylbromobenzene (80%), m.p. 68-70 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With benzyl alcohol; In ISOPROPYLAMIDE; mineral oil; | e. The 4-ethoxy-4-(3-hydroxy-5-trifluoromethylphenyl)tetrahydropyran used as a starting material was obtained as follows: Sodium hydride (55% w/w dispersion in mineral oil; 4.36 g) was added portionwise to a mixture of benzyl alcohol (9.82 ml) and dimethylacetamide (136 ml) which had been cooled in an ice-bath. The mixture was stirred at ambient temperature for 1.5 hours and then recooled in an ice-bath. A solution of <strong>[130723-13-6]3-fluoro-5-trifluoromethylbromobenzene</strong> (22.1 g) in dimethylacetamide (136 ml) was added and the mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using hexane as eluent. There was thus obtained 3-benzyloxy-5-trifluoromethylbromobenzene (23.1 g, 77%), as a colourless liquid. NMR Spectrum 5.07(s, 2H), 7.15-7.35(3 s's, 3H), 7.36-7.42(m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With benzyl alcohol; In ISOPROPYLAMIDE; mineral oil; | The 4-(3-hydroxy-5-trifluoromethylphenyl)-4-methoxytetrahydropyran used as a starting material was obtained as follows: Sodium hydride (55% w/w dispersion in mineral oil; 4.36 g) was added portionwise to a mixture of benzyl alcohol (9.82 ml) and dimethylacetamide (136 ml) which had been cooled in an ice-bath. The mixture was stirred at ambient temperature for 1.5 hours and then recooled in an ice-bath. A solution of <strong>[130723-13-6]3-fluoro-5-trifluoromethylbromobenzene</strong> (22.1 g) in dimethylacetamide (136 ml) was added and the mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using hexane as eluent. There was thus obtained 3-benzyloxy-5-trifluoromethylbromobenzene (23.1 g, 77%), as a colourless liquid. NMR Spectrum: 5.07(s, 2H), 7.15-7.35(3 s's, 3H), 7.36-7.42(m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | (5)-2-(3-fluoro-5-(trifluoromethyl)phenyaniino)-3,3-dimethylbutanoic acid; (5)-2-amino-3,3-dimethylbutanoic acid (0.50 g, 3.81 mmol), K2CO3 (1.580 g, 11.44 mmol), copper(I) iodide (0.073 g, 0.38 mmol) and l-bromo-3-fiuoro-5- (trifluoromethyl)benzene (2.32 g, 9.53 mmol) in DMA (4 mL) was heated at 95 C for 32 hrs. H2O (15 mL) and ethyl ether (20 ml) was added. The aqueous phase was isolated and acidified with saturated KHSO4 solution, extracted with ether, dried over sodium sulfate. After removal of solvent, it gave (S)-2-(3-fluoro-5-(trifluoromethyl)phenylamino)-3,3- dimethylbutanoic acid (0.78 g, 70%) as white solid. LCMS (APCI-): 292.2. 1H NMR (400 MHz, d6-DMSO) delta 12.63 (s, 1H), 6.88 (s, 1H), 6.66 (d, 7=12.4 Hz, 1H), 6.61 (d, J-8.8 Hz, 1H), 6.40 (d, ,/=9.2 Hz, 1H), 3.71 (d, J=9.6 Hz, 1H), 0.98 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Reference 8; Synthesis of 2-(3-bromo-5-(trifluoromethyl)phenyl)propanoic acid Step 1To a slurry of sodium hydride, 60% dispersion in mineral oil (572 mg, 14.9 mmol) in NMP (5 mL) in a microwave vial under a nitrogen atmosphere was slowly added ethyl cyanoacetate (1.59 ml, 14.9 mmol). The solution was stirred until H2 evolution had ceased. 1- Bromo-3-fluoro-5-(trifluoromethyl)benzene (1.21 g, 4.98 mmol) was added to the vial which was then sealed. The reaction mixture was stirred at 110 0C for 16 h. The reaction mixture was cooled to RT and mixed with water and enough 2 N HCl to bring the pH to 2-3 and the product was extracted with ether. The organic layer was combined, dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide ethyl 2-(3-bromo-5- (trifluoromethyl)phenyl)-2-cyanoacetate (908 mg, 54% yield) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 30 (rac, cis)-1- (4-Fluoro-phenyl)-8- [2- (3-fluoro-5-trifluoromethyl-phenyl)-cyclohexyl]- 1,3, 8-triaza-spiro [4.5] decan-4-one; rac-2- (3-Fluoro-5-trifluoromethyl-phenyl)-cyclohexanol ; A stirred solution of 8. 00 g (32.9 mmol) <strong>[130723-13-6]3-fluoro-5-trifluoromethyl-bromo-benzene</strong> in 40 ml Et20 under nitrogen was cooled to-78 C and drop-wise 20.56 ml (32.9 mmol) of a 1.6 M butyl lithium solution in hexane were added. The reaction was strongly exothermic and the temperature was kept below-70 C. Then after 30 min. at-78 C 2.66 ml (2.58 g, 26.3 mmol) cyclohexene oxide were added followed by 3.75 ml (4.2 g, 29.6 mmol) boron trifluoride diethyl etherate. The latter has to be added drop-wise to keep the temperature below-70 C. The reaction mixture was stirred for 2 h at-78 C and then quenched with 40 ml saturated aqueous KHSO4 solution, warmed up to ambient temperature and extracted with tert.-butyl methyl ether. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product, 7.53 g light yellow crystals, was purified by re-crystallisation from n-heptane: 4.90 g rac- 2- (3-fluoro-5-trifluoromethyl-phenyl)-cyclohexanol as colourless crystalls: m. p. 76.5- 77. 4C. MS (EI) : 262. 1 M+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | An ether solution (2 mL) of <strong>[130723-13-6]1-bromo-3-fluoro-5-(trifluoromethyl)benzene</strong> (0.200 g, 0.826 mmol) was stirred in an oven-dried round bottom flask at -78 C. under Ar. To this solution, n-BuLi (2.0 M in cyclohexane, 0.41 mL, 0.82 mmol, 1.0 eq) was added dropwise. The resulting solution was stirred at -78 C. for 30 min. 5-Fluoropicolinonitrile (0.101 g, 0.828 mmol, 1.0 eq), prepared as described in Procedure 1, was added as a solid via addition funnel. The resulting red solution was stirred at -78 C. for 1 h. The reaction mixture was quenched with HCl (10 mL, 1.0 M) and extracted with EtOAc (3*10 mL). The combined organic portions were dried over Na2SO4, decanted and the volume was reduced to 5 mL under reduced pressure. The resulting oil was loaded directly onto a silica gel ISCO cartridge (40 g). Gradient elution from 0-70% EtOAc in hexane over 20 min yielded (3-fluoro-5-(trifluoromethyl)phenyl)(5-fluoropyridin-2-yl)methanone as a pale brown oil at a retention time of 7 min (0.117 g, 49% yield). LCMS: RT=1.91 min [M+H] 288.2 (2 min Phenomenex Luna C18 column, 4.6*30 mm eluding with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.69 min (Phenomenex Luna C18 column, 4.6*50 mm eluding with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm, purity 97%); NMR: 400 MHz 1H (CDCl3) ppm 8.50 (d, J=2.4 Hz, 1H), 8.19 (dd, J=4.0 and J=8.0 Hz, 1H), 8.15 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.57 (ddd, J=3.08, J=2.4 and J=8.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.90 g (77%) | With lithium chloride; caesium carbonate;copper(I) iodide; | General Procedure: (2S)-2-(3-Fluoro-5-trifluoromethyl-phenylamino)-3,3-dimethyl-butanoic acid (450) L-tert-leucine (4.0 g, 30.5 mmol, 1.0 eq.), lithium chloride (129 mg, 3.05 mmol, 0.1 eq.), copper(I) iodide (289 mg, 1.52 mmol, 0.05 eq.) and cesium carbonate (7.5 g, 22.9 mmol, 0.75 eq.) were charged into a 250 mL flask. tert-Butanol (100 mL) was added and the resulting mixture was stirred at 40 C. for 20 minutes, by which time the milky solution had turned blue. 3-Fluoro-5-trifluoromethyl-bromobenzene (7.41 g, 30.5 mmol, 1 eq.) was added dropwise, and the reaction mixture was heated at 100 C. for 15 hours. LCMS analysis of an aliquot showed around 20% (UV) of unreacted 3-Fluoro-5-trifluoromethyl-bromobenzene. Extra copper(I) iodide (289 mg, 0.05 eq.) was added and the reaction mixture was stirred at 100 C. for another 24 hours. LCMS analysis showed ~16% (UV) of remaining 3-Fluoro-5-trifluoromethyl-bromobenzene. Heating was stopped and the solvent removed under vacuum to give a blue solid. The solid was partitioned between ethyl acetate (100 mL) and water (100 mL). The pH of the aqueous phase was adjusted to pH=1 with 4M Hydrochloric acid (10 mL). The organic phase was collected, washed with 2M hydrochloric acid (2*100 mL) dried over sodium sulfate, filtered and the solvent removed under vacuum to give 6.90 g (77%) of the title compound as an orange solid which was used in the next step without further purification. 1H NMR (500 MHz, CHLOROFORM-d) delta ppm 6.61-6.75 (m, 2H) 6.49 (dt, J=10.68, 2.14 Hz, 1H) 4.48 (br. s., 1H) 3.79 (s, 1H) 1.11 (s, 9H) LC-MS: purity 100% (ELS) 90% (UV), tR 2.14 min m/z [M+H]+294.10 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide;1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 90℃; for 18h;Inert atmosphere; | Example 1; Preparation of Compound I as Illustrated by Scheme II; Step A3: Sulfide Formation from Thioacetate; To a 250 mL three-necked RBF with overhead stirring was charged with 8.6 g (31.5 mmol) of 3 in toluene from the last step, toluene (30 mL), 8.6 g (35.2 mmol-98% wt purity) of commercially available aryl bromide, 288 mg (0.31 mmol) of Pd2 dba3, 349 mg (0.62 mmol) of dppf, and 50 wt % KOH (13 mL (160 mmol)). Reaction solution was degassed under vacuum/N2 for 5 min (Vacuum and N2 was balanced at 600 torr for 5 min). Reaction was then heated to 90 C. for 18 h. Reaction was monitored by HPLC (Reaction conversion in 18 h depended on the work-up solvent from the last step. No thioalcohol (Rf 2.86) was observed during the reaction). Reaction was cooled down to 25 C. and was diluted with 35 mL (4 vol) of toluene and 70 mL of water (8 vol). Organic layer was washed with 2×50 mL of brine (6 vol). LC assay indicated 95% of LCAY and aqueous contained <1% of product Organic solution was treated with 10 mL of EtOAc and 100 wt % of Na2SO4. After stirring at rt for 10 min, 50 wt % Ecosorb C-941 and 10 wt % of PL-TMT was charged. Slurry was stirred at 45-50 C. for 1 h. After cooled to room temperature, mixture was filtered through 100 wt % of silica gel to produce compound 5. LC assay indicated 4% mass loss by carbon treatment, and metal analysis indicated a 600 ppm Pd level. Organic solution was then concentrated to 50 mL for the next step.HPLC Method | |
With potassium hydroxide;1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 90℃; for 18h;Inert atmosphere; | Example 1; Preparation of Compound I as Illustrated by Scheme II; Step A3: Sulfide Formation from Thioacetate; To a 250 mL three-necked RBF with overhead stirring was charged with 8.6 g (31.5 mmol) of 3 in toluene from the last step, toluene (30 mL), 8.6 g (35.2 mmol-98% wt purity) of commercially available aryl bromide, 288 mg (0.31 mmol) of Pd2 dba3, 349 mg (0.62 mmol) of dppf, and 50 wt % KOH (13 mL (160 mmol)). Reaction solution was degassed under vacuum/N2 for 5 min (Vacuum and N2 was balanced at 600 torr for 5 min). Reaction was then heated to 90 C. for 18 h. Reaction was monitored by HPLC (Reaction conversion in 18 h depended on the work-up solvent from the last step. No thioalcohol (Rf 2.86) was observed during the reaction). Reaction was cooled down to 25 C. and was diluted with 35 mL (4 vol) of toluene and 70 mL of water (8 vol). Organic layer was washed with 2×50 mL of brine (6 vol). LC assay indicated 95% of LCAY and aqueous contained <1% of product Organic solution was treated with 10 mL of EtOAc and 100 wt % of Na2SO4. After stirring at rt for 10 min, 50 wt % Ecosorb C-941 and 10 wt % of PL-TMT was charged. Slurry was stirred at 45-50 C. for 1 h. After cooled to room temperature, mixture was filtered through 100 wt % of silica gel to produce compound 5. LC assay indicated 4% mass loss by carbon treatment, and metal analysis indicated a 600 ppm Pd level. Organic solution was then concentrated to 50 mL for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Example 1 Synthesis of 1-[3-Bromo-5-(trifluoromethyl)phenyl]-4-methyl-1H- imidazole (XXVI)Scheme 12(XXVI)A 2 L, 4-neck, round-bottom flask equipped with a mechanical stirrer, a digital thermometer, heatingZcooling capacity, an addition funnel, and a nitrogen inlet/outlet is EPO <DP n="16"/>charged 1-methyl-2-pyrrolidinone (113 g) and sodium hydride (8.0 g, 60% in oil) under nitrogen purge. The mixture is stirred at 20-250C for 15 minutes. A solution of 4-methylimidazole (17.6 g) and 1-methyl-2-pyrrolidinone (181 g) is slowly added to the mixture over 30 minutes, maintaining the batch temperature between 20-25C. After the addition, the mixture is stirred at 20-250C for 2 hours. A solution of 3-bromo-5- fluorobenzotrifluoride (XXV) (40 g) and 1-methyl-2-pyrrolidinone (76 g) is slowly added into the mixture over 10 minutes, maintaining the batch temperature between 20-250C. After the addition, the mixture is stirred at 20-250C for 16 hours.Water (720 g) is slowly added to the mixture over 3 hours, maintaining the batch temperature between 20-250C. After the addition, the mixture is stirred at 20-25C for 1 hour. Any solid is isolated by filtration, rinsed with a solution of 1-methyl-2-pyrrolidinone (41 g) and water (100 g), and then rinsed with water (100 g). The solid is air-dried in the funnel for 1 hour.A 2 L, 4-neck , round-bottom flask under nitrogen purge is charged with the solid (~50 g) and ethyl acetate (361 g). The mixture is stirred for 5 minutes at 20-25C until a solution is obtained. The solution is washed with water (2 x 100 g). The organic layer is distilled at 100 mm Hg at 400C until a residual volume of 100 ml_ is reached. Heptane (342 g) is added, and the mixture is distilled at 400 mm Hg at 60C until a residual volume of 300 ml. is reached. This operation is repeated one more time. The residue is cooled from 55C to 200C over 5 hours, and stirred for an additional 1 hour at 200C. The mixture is cooled to 5C over 1 hour and stirred for an additional 1 hour at 5C. Any solid is isolated by filtration and rinsed with cold (50C) heptane (68 g). The cake is dried at 5 mm Hg/20-25C for 4 hours to yield (XXVI) (24.3 g, 48% yield) as a white solid:1H NMR 300 MHz, DMSOd6), delta 8.45 (s, 1 H), 8.30 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.70 (s, 1 H), 2.10 (s, 3H). EPO <DP n="17"/> |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | An ether solution (40 mL) of l-bromo-3-fluoro-5-(trifluoromethyl)benzene (2.0 g, 8.23 mmol) was stirred in an oven-dried round bottom flask at -78C under Ar. n-BuLi (2.5 M in hexanes, 3.6 ml, 9.05 mmol, 1.1 eq) was added dropwise. The resulting solution was stirred at -78C for 30 min. A solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (1.55 g, 8.23 mmol, 1.0 eq) in Et2O (5 mL) was added dropwise. The resulting reddish mixture was stirred at -78C for 2h. TMSCl (pretreated with Et3N (TMSCkEt3N = 10:1, v.v), 1.14 mL, 1.2 eq) was added dropwise. The dry ice bath was removed, and the resulting slurry was stirred at room temperature for 2 h. The reaction was cooled to -78C and a solution of benzyl magnesium chloride in THF (2.0 M, 8.4 mL, 2 eq) was added dropwise. The resulting mixture was slowly warmed up to room temperature and stirred at room temperature overnight. IN HCl (100 mL) was added. The mixture was stirred at room temperature for 30 min, extracted with Et2O (2x), washed with IN NaOH, H2O and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was <n="221"/>purified by flash column chromatography (silica gel, hexanes: ethyl acetate) to give 1- (4-fluoro-3-(trifluoromethyl)phenyl)-l-(3-fluoro-5-(trifluoromethyl)phenyl)-2- phenylethanamine (1.6 g, yield: 44%). LC-MS ESI 3.42 min 429.2 (M-NH3+H); 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 7.66 (dd, J=6.7, 2.3 Hz, 1 H), 7.49 - 7.59 (m, 1 H), 7.45 (s, 1 H)5 7.18 - 7.30 (m, 6 H), 6.74 (d, J=6.9 Hz, 2 H), 3.57 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | EXAMPLE 1; N-(l-(5-chloropyridin-2-yl)-l-(3-fluoro-5-(trifluoromethyl)phenyl)-2- phenylethyl)-4-(trifluoromethyl)thiazol-2-amine; Procedure 1; [00187] A dry 250 mL round bottomed flask was equipped a stirring bar and fitted to an adapter connected to the vacuum line. The flask was dried under vacuum and then purged several times with nitrogen. Under a stream of nitrogen, l-bromo-3- fluoro-5-(trifluoromethyl)benzene (2.5g, lOJmmoles) was added to the flask and dissolved in anhydrous ether (100 mL). The flask was fitted with a septum which was connected to the nitrogen line via a 16 gauge IV2 PrecisionGlide needle. The stirring solution was cooled to -78C for 10 minutes, n-BuLi (1.6M in hexanes, 6.4 mL. 10.3mmoles) was added drop wise. After 15 minutes, a solution of 5-chloro-2- cyanopyridine (1.42g, 10.3mmoles) in anhydrous THF (10 mL) was added from a syringe. The reaction was stirred for 2 hours at -78C and trimethylchlorosilane (1.41 mL, 10.3 mmoles) was added. The reaction vessel was removed from the acetone/dry ice bath and the reaction was allowed to warm up to room temperature. After 30 minutes, the reaction vessel was cooled to -78C, Benzylmagnesium chloride (2.0M in THF, 5.15 mL, 10.3 mmoles) was added and the reaction was allowed to slowly warm to room temperature for 2h. The reaction was quenched with H2O (10 mL). The crude product was poured into 200 mL ethyl acetate in a 1000 mL separatory <n="168"/>funnel. The light brown solution was washed with saturated aqueous NH4Cl (3 x 100 mL), then with water (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel ISCO with 95-75% hexanes in ethylacetate to yield 1- (5-chloropyridin-2-yl)-l-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine 994mg (24% yield). LC-MS (methanol) [MH] = 394.1H NMR (500 MHz, CDO3) delta ppm 8.58 (1 H, d, /=2.75 Hz), 7.57 - 7.64 (2 H, m), 7.45 (2 H, d, J=8.25 Hz), 7.09 - 7.24 (4 H, m), 6.81 (2 H, d, J=6.60 Hz), 3.93 (1 H, d, J=13.20 Hz), 3.46 (1 H, d, J=13.20 Hz), 1.87 (2 H, broad s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 79; 2-(5-chloropyridin-2-yl)-2-(4,5-dimethylthiazol-2-ylamino)-2-(3-fluoro-5- (trifluoromethyl)phenyl)acetonitrile; Procedure 17; [00218] At -74 C to a solution of l-bromo-3-fluoro-5-(trifluoromethyl)benzene (11 g, 45.2 mmol) in ether (200 niL) was added dropwise n-BuLi (20 mL, 2.5 M in hexane, 49.8 mmol). The reaction mixture was stirred at -74 0C for 2 h. A solution of 5-Cl-2-cyanopyridme (6.23 g, 45.2 mmol) in THF (100 mL) was added to the reaction mixture via cannulation. The yellow brown reaction solution turned into dark. The reaction mixture was quenched by the addition of dry MeOH at -70 0C and then allowed to warm up to room temperature. The reaction mixture was concentrated to a small volume, filtered and the solid was separated and rinsed with ether. The combined filtrates were concentrated to yield (5-chloropyridin-2-yl)(3- fluoro-5-(trifluoromethyl)phenyl)methanimine as a black oil. LCMS RT = 3.913 min [M+H] 303.95 (Phenomenex Luna C18 column, 4.6 x 50 mm eluting with 10-90% MeOETH2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | EXAMPLE 2; (S)-N-(l-(5-chloropyridin-2-yl)-l-(3-fluoro-5-(trifluoromethyl)phenyl)-2- phenylethyl)-4-(trifluoromethyl)thiazol-2-amine; Procedure 3; [00193] At -780C under Ar a dry 25OmL 3 neck flask was charged with l-bromo-3- fluoro-5-(trifluoromethyl)benzene (4.5g, 0.018mol). Dry ether (10OmL) was added and to the stirred solution, nBuLi (9.2mL, 0.018mol) was added dropwise via airtight syringe through a rubber septum. The resulting pale orange colored solution was stirred at -780C for 30 min. 5-chloropicolinenitrile (2.5g, 0.018mol) was then added as a thick slurry in dry ether (approx 1OmL) via wide neck tunnel. The resulting solution turned dark red in color and was stirred at -780C for 1 hr. LCMS indicated that the reaction was complete and, at -780C the reaction mixture was quenched with l.OM HCl (approx 5OmL). The cooling bath was removed and as the reaction mixture reached ambient temperature, (220C), the organic solution turned pale green in color. The solution was transferred to a separation funnel and the organic layer separated. The aqueous phase was washed with EtOAc (2OmL) and the combined organic portions dried over anhydrous Na2SO4, decanted and concentrated yielding a pale brown oil. This was dissolved in hexane (ca 15mL) and loaded directly onto a silica gel ISCO cartridge (33Og, previously equilibrated with hexanes) and elution at 100 mL/min gradient 0 to 70% EtOAc in hexanes over 45 min. Elution time of the product was 17 to 20mins and (5-chloropyridm-2-yl)(3-fluoro-5- (trifluoromethyl)phenyl)methanone (4.1g, 75% yield) was isolated as a pale yellow oil which crystallized on standing. Rf 0.74 (Hexane:EtOAc 4:1) LCMS: 2.03 min [M+l] 304.2 (2min gradient, MeOH/H2O 0.1%TFA); HPLC: 3.98 min (4min gradient, MeOH/H2O 0.2%PPA Purity 98%; NMR: 400MHz 1H (CDCl3) 8.69 ppm, IH, d, J=2.64Hz; 8.22 ppm, IH, s; 8.13 ppm, IH, d, J=8.36Hz; 8.07 ppm, IH, brd, J=8.4Hz; 7.93 ppm, IH, dd, J=2.2 and J=8.36Hz; 7.57 ppm, IH, brd, J=8.4Hz. | |
75% | At -78 C under argon, to <strong>[130723-13-6]1-bromo-3-fluoro-5-(trifluoromethyl)benzene</strong> (4.5 g, 0.018 mol) in ether (100 mL) was added n-BuLi (9.2 mL, 0.018 mol) dropwise. The resulting solution was stirred at -78 C for 30 min. 5-Chloropicolinenitrile (2.5 g, 0.018 mol) was then added as a slurry in ether (10 mL) and the solution stirred at -78 C for 1 h then quenched with 1 M HCl. The reaction mixture was extracted with EtOAc and the organic portions were combined, dried over anhydrous Na2SO4, filtered, and concentrated. Yielded a pale brown oil, which was purified by flash chromatography to give 7 (4.1 g, 75%). 1H NMR (400 MHz, CDCl3) delta 8.69 (d, J=2.64 Hz, 1H), 8.22 (s, 1H), 8.13 (d, J=8.36 Hz, 1H), 8.07 (d, J=8.40 Hz, 1H), 7.93 (dd, J=8.36, 2.20 Hz, 1H), 7.57 (d, J=8.40 Hz, 1H), 4.05 (s, 3H), 3.30 (s, 3H), 1.61 (s, 9H). 19F NMR (376 MHz, CDCl3) delta -63.23, -109.82. 13C NMR (101 MHz, CDCl3) delta 189.0, 161.9 (d, J=276 Hz), 151.5, 147.7, 138.8 (d, J=8.6 Hz), 137.2, 136.3, 132.9 (dm, J=48.9 Hz), 125.9, 123.8 (m), 121.5 (d, J=28.6 Hz), 116.9 (dm, J=35.3 Hz). LC-MS (M+1)+=303.9. HRMS (ESI) calcd for C13H7ClF4NO (M+H)+=304.01468, found 304.01587.At rt, 7 (0.17 g, 0.60 mmol) was dissolved in THF (10 mL) and (R)-(+)-2-methylpropane-2-sulfinamide (0.072 g, 0.60 mmol) and Ti(OEt)4 (0.19 mL, 0.90 mol) were added. The solution was heated to 75 C for 14 h then cooled, concentrated under vacuum to half the volume, and purified by flash chromatography to yield 8 (40 mg, 31%). 1H NMR (400 MHz, CDCl3) (two sets of peaks attributed to E/Z isomerism) delta 8.62 (d, J=2.20 Hz, 1H), 8.22 (s, 1H), 8.46 (br s, 1H), 8.18 (d, J=8.00 Hz, 1H), 8.13 (d, J=8.00 Hz, 1H), 8.02 (d, J=8.00 Hz, 1H), 7.91 (br s, 1H), 7.82 (d, J=8.00 Hz, 1H), 7.74 (d, J=8.00 Hz, 1H), 7.68 (d, J=8.00 Hz, 1H), 7.51 (br m, 1H), 1.37 (s, 9H), 1.28 (s, 9H). 19F NMR (376 MHz, CDCl3) delta -63.75, -109.56. 13C NMR (101 MHz, CDCl3) delta 188.5, 161.8 (d, J=370 Hz), 151.4, 148.5, 147.7, 138.8 (d, J=19.4 Hz), 137.4, 136.0 (m), 125.8, 123.7 (m), 121.4 (m), 116.9 (dm, J=30.6 Hz), 59.0, 55.4, 22.9, 22.1. HPLC purity 96%, tR=10.51 min (60%) and 10.68 min (36%) (method E17); 94%, tR=9.04 min (59%) and 9.19 min (35%) (method F17). LC-MS (M+1)+=406.9. HRMS (ESI) calcd for C17H16ClF4N2OS (M+H)+=407.06025, found 407.06221.At -78 C under argon, LDA (2.0 M in heptane/THF, 3.69 mL, 7.39 mmol) was added to a solution of methyl acetate (547 mg, 7.39 mmol) in ether (40 mL) dropwise. After 30 min, Ti(i-OPr)3Cl (2.64 mL, 11.1 mmol) was added and the reaction mixture stirred for a further 30 min. In a separate flask, Ti(i-OPr)3Cl (0.88 mL, 3.69 mmol) was added under argon to a solution of 8 (1.50 g, 3.69 mmol) in ether (40 mL) at rt. After 30 min, this solution was cannulated dropwise into the solution of enolate under argon at -78 C. The mixture was stirred for 1 h then quenched at -78 C with saturated NaCl. Aqueous HCl (1.0 M, 20 mL) was subsequently added and the solution extracted with EtOAc, dried over Na2SO4, decanted, and concentrated. The resulting oil was purified by flash chromatography to yield an off-white solid (1.51 g, 85%). NMR analysis indicated a 92:8 ratio of (S)-methyl 3-(5-chloropyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoate to (R)-methyl 3-(5-chloropyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoate. The solid was dissolved in MeOH (5 mL) then added two drops of water and the solution cooled to 4 C for 2.5 h. Yielded pure (S)-methyl 3-(5-chloropyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoate (1.04 g, 69%) as colorless needles. 1H NMR (400 MHz, CDCl3) delta 8.54 (d, J=2.2 Hz, 2H), 7.62 (dd, J=8.6, 2.4 Hz, 2H), 7.46-7.33 (m, 4H), 7.30-7.13 (m, 5H), 6.11 (s, 2H), 3.98 (d, J=17.4 Hz, 2H), 3.73 (d, J=17.4 Hz, 2H), 3.59 (s, 6H), 1.31 (s, 18H), 0.00 (s, 1H). 19F NMR (376 MHz, CDCl3) delta -62.81, -109.49. 13C NMR (101 MHz, CDCl3) delta 172.5, 162.4 (d, J=327 Hz), 158.1, 148.2 (d, J=8.4 Hz), 147.5, 136.6, 132.9 (dm, J=44.4 Hz), 131.6, 124.9, 118.7, 117.4 (d, J=22.1 Hz), 112.3 (dq, J=30.6, 6.7 Hz), 66.0, 57.1, 51.9, 43.7, 22.9. HPLC purity: 95%, tR=10.30 min (method E); 98%, tR=8.95 min (method F). LC-MS (M+H)+=480.9. HRMS (ESI) calcd for C20H22ClF4N2O3S (M+H)+=481.09703, found 481.09907. (S)-Methyl 3-(5-chloropyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoate (110 mg, 0.23 mmol) was dissolved in methanol (2 mL), HCl in dioxane (4 M, 1 mL) was added and stirred for 30 min. The solution was diluted with DCM and aqueous NaOH (1 M) was added until the pH of the solution was 10. The organic phase was dried over Na2SO4, decanted, and concentrated to yield 9a as solid (84 mg). 1H NMR (400 MHz, CDCl3) delta 8.47 (d, J=1.9 Hz, 1H), 7.62 (dd, J=8.4, 2.5 Hz, 2H), 7.46 (dd, J=20.7, 9.3 Hz, 2H), 7.17 (d, J=8.1 Hz, 1H), 3.71-3.55 (m, 3H), 3.19 (d, J=16.5 Hz, 2H), 2.66 (s, 2H). 13C NMR (101 MHz, CDCl... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Alternate benzylzinc bromide procedure; [00189] A dry 200 mL round bottomed flask was equipped a stirring bar and fitted to an adapter connected to the vacuum line. The flask was dried under vacuum and then purged several times with nitrogen. Under a stream of nitrogen, l-bromo-3- fluoro-5-(trifluoromethyl)benzene (972mg, 4mmoles) was added to the flask and dissolved in anhydrous ether (75 mL). The flask was fitted with a septum which was connected to the nitrogen line via a 16 gauge lV2 PrecisionGlide needle . The stirring solution was cooled to -78C for 10 minutes, n-BuLi (1.6M in hexanes, 2.25 mL. 3.6mmoles) was added drop wise. After 15 minutes, a solution of 5-chloro-2- cyanopyridine (552mg, 4mmoles) in anhydrous THF (5 mL) was added from a syringe. The reaction was stirred for 2 hours at -78C and trimethylchlorosilane (550muL, 4mmoles) was added. The reaction vessel was removed from the acetone/dry ice bath and the reaction was allowed to warm up to room temperature. After 30 minutes, the reaction vessel was cooled to -780C, Benzylzinc chloride (0.5M in THF, 9.6 mL, 4.8 mmoles) was added and the reaction was allowed to slowly warm to room temperature for 3h. The reaction was quenched with H2O (1O mL). The crude product was poured into 200 mL ethyl acetate in a 1000 mL separatory funnel. The <n="169"/>light brown solution was washed with saturated aqueous NH4Cl (3 x 100 niL), then with water (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified on SCX column (1Og, high load, 0.65mmole/g) to yield l-(5-chloropyridin-2-yl)-l-(3-fluoro-5- (trifluoromethyl)phenyl)-2-phenylethanamine 890mg (56% yield). LC-MS (methanol) [M+l] = 394. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | At -78 C. under Ar a dry 250 ml 3 neck flask was charged with <strong>[130723-13-6]1-bromo-3-fluoro-5-(trifluoromethyl)benzene</strong> (4.5 g, 0.018 mol). Dry ether (100 mL) was added and to the stirred solution, nBuLi (9.2 mL, 0.018 mol) was added dropwise via airtight syringe through a rubber septum. The resulting pale orange colored solution was stirred at -78 C. for 30 min. 5-chloropicolinenitrile (2.5 g, 0.018 mol) was then added as a thick slurry in dry ether (approx 10 mL) via wide neck funnel. The resulting solution turned dark red in color and was stirred at -78 C. for 1 hr. LCMS indicated that the reaction was complete and, at -78 C. the reaction mixture was quenched with 1.0M HCl (approx 50 mL). The cooling bath was removed and as the reaction mixture reaction reached ambient temperature, (22 C.), the organic solution turned pale green in color. The solution was transferred to a separation funnel and the organic layer separated. The aqueous phase was washed with EtOAc (20 mL) and the combined organic portions dried over anhydrous Na2SO4, decanted and concentrated yielding a pale brown oil. This was dissolved in hexane (ca 15 mL) and loaded directly onto a silica gel ISCO cartridge (330 g, previously equilibrated with hexanes) and elution at 100 mL/min gradient 0 to 70% EtOAc in hexanes over 45 min. Elution time of the product was 17 to 20 mins and (5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methanone (4.1 g, 75% yield) was isolated as a pale yellow oil which crystallized on standing. Rf0.74 (Hexane:EtOAc 4:1) LCMS: 2.03 min [M+1] 304.2 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.98 min (4 min gradient, MeOH/H2O 0.2% PPA Purity 98%; NMR: 400 MHz 1H (CDCl3) 8.69 ppm, 1H, d, J=2.64 Hz; 8.22 ppm, 1H, s; 8.13 ppm, 1H, d, J=8.36 Hz; 8.07 ppm, 1H, brd, J=8.4 Hz; 7.93 ppm, 1H, dd, J=2.2 and J=8.36 Hz; 7.57 ppm, 1H, brd, J=8.4 Hz. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 90℃; for 16h;Inert atmosphere; | Reference Example 71 1-[3-fluoro-5-(trifluoromethyl)phenyl]pyrrolidin-3-ol; A solution of <strong>[130723-13-6]1-bromo-3-fluoro-5-(trifluoromethyl)benzene</strong> (10.0 g), 3-hydroxypyrrolidine (3.58 g), palladium(II) acetate (461 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.56 g) and cesium carbonate (26.7 g) in toluene (222 mL) was stirred under an argon gas atmosphere at 90C for 16 hr. After cooling to room temperature, the reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The filtrate and washing were combined and the solution was washed with water and saturated brine. This was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 98:2 - 20:80) to give the title compound (10.65 g, yield quant.) as a brown oil. 1H-NMR (300 MHz, CDCl3)delta:1.73 (br. s, 1 H), 2.05 - 2.28 (m, 2 H), 3.27 (d, J = 10.6 Hz, 1 H), 3.38 (td, J = 8.9, 3.4 Hz, 1 H), 3.45 - 3.59 (m, 2 H), 4.55 - 4.70 (m, 1 H), 6.35 (dt, J = 11.7, 2.3 Hz, 1 H), 6.52 (s, 1 H), 6.60 (d, J=8.7 Hz, 1 H). |
100% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 90℃; for 16h;Inert atmosphere; | A solution of <strong>[130723-13-6]1-bromo-3-fluoro-5-(trifluoromethyl)benzene</strong> (10.0 g), 3-hydroxypyrrolidine (3.58 g), palladium(II) acetate (461 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.56 g) and cesium carbonate (26.7 g) in toluene (222 ml) was stirred under an argon gas atmosphere at 90 C. for 16 hr. After cooling to room temperature, the reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The filtrate and washing were combined and the solution was washed with water and saturated brine. This was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 98:2-20:80) to give the title compound (10.65 g, yield quant.) as a brown oil.1H-NMR (300 MHz, CDCl3) delta: 1.73 (br. s, 1H), 2.05-2.28 (m, 2H), 3.27 (d, J=10.6 Hz, 1H), 3.38 (td, J=8.9, 3.4 Hz, 1H), 3.45-3.59 (m, 2H), 4.55-4.70 (m, 1H), 6.35 (dt, J=11.7, 2.3 Hz, 1 H), 6.52 (s, 1H), 6.60 (d, J=8.7 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; copper(l) iodide; L-proline; In dimethyl sulfoxide;Microwave irradiation; | Compound IIf-1 was obtained by the copper catalyzed cross-coupling of XXX and 3-trifluoromethyl-5-fluoro-bromobenzene. 1H NMR (<¾- MeOD, 400MHz), 6.73 (s, 1H), 6.56 (d, 1H, J= 12.0 Hz), 6.48 (d, 1H, J = 8.8 Hz), 3.60-3.56 (m, 1H), 3.38 (s, 3H), 2.90 (s, 2H), 1.90-1.82 (m, 2H), 1.35-1.23 (m, 2H), 1.13 (s, 3H), 1.09 (s, 3H), 1.07-0.98 (m, 5H). MS(ESI): calc'd (M+H)+ 348.2, exp (M+H)+ 348.1. | |
With potassium phosphate; copper(l) iodide; L-proline; In dimethyl sulfoxide;Microwave irradiation; | Compound IIf-1 was obtained by the copper catalyzed cross-coupling of XXX and 3-trifluoromethyl-5-fluoro-bromobenzene. 1H NMR (<£ - MeOD, 400MHz), 6.73 (s, 1H), 6.56 (d, 1H, J= 12.0 Hz), 6.48 (d, 1H, J = 8.8 Hz), 3.60-3.56 (m, 1H), 3.38 (s, 3H), 2.90 (s, 2H), 1.90-1.82 (m, 2H), 1.35-1.23 (m, 2H), 1.13 (s, 3H), 1.09 (s, 3H), 1.07-0.98 (m, 5H). MS(ESI): calc'd (M+H)+ 348.2, exp (M+H)+ 348.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; copper(l) iodide; L-proline; In dimethyl sulfoxide;Microwave irradiation; | Compound IIf-1 was obtained by the copper catalyzed cross-coupling of XXX and 3-trifluoromethyl-5-fluoro-bromobenzene. 1H NMR (d4-MeOD, 400 MHz), 6.73 (s, 1H), 6.56 (d, 1H, J=12.0 Hz), 6.48 (d, 1H, J=8.8 Hz), 3.60-3.56 (m, 1H), 3.38 (s, 3H), 2.90 (s, 2H), 1.90-1.82 (m, 2H), 1.35-1.23 (m, 2H), 1.13 (s, 3H), 1.09 (s, 3H), 1.07-0.98 (m, 5H). MS (ESI): calc'd (M+H)+ 348.2, exp (M+H)+ 348.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.9% | 5.00 g (20.57 mmol) of <strong>[130723-13-6]3-bromo-5-fluorobenzotrifluoride</strong> were stirred in 60 ml of dry ether and admixed dropwise at -78 C. under a protective gas atmosphere (argon) with 1.33 ml (20.75 mmol) of tert-butyllithium solution [cf. also trifluoroacylation: H. K. Nair, D. M. Quinn Bioorganic & Medicinal Chemistry Letters 3(12), 2619-22 (1993); G. J. Pork et al., J. Org. Chem. 22, 993 (1957)]. Subsequently, the reaction mixture was stirred at -78 C. for 45 minutes and then added dropwise, with the aid of a syringe, in portions at -78 C., to a solution of 3.71 g (26.17 mmol) of ethyl trifluoroacetate in 40 ml of dry ether. Thereafter, the entire reaction mixture was stirred first at -78 C. for 10 minutes and then at room temperature for one hour. For workup, the entire reaction mixture was added to water and extracted with ether. The organic phase was removed and dried at 40 C. under reduced pressure (not less than 10 mbar owing to the high volatility of the compound). This gave 4.06 g (75.9% of theory) of 2,2,2-trifluoro-1-[3-fluoro-5-(trifluoromethyl)phenyl]-ethanone, which was isolated as the hydrate.HPLC-MS: logP=2.54, mass (m/z): 261.1 (M+H)+ |
A170065 [40161-54-4]
1-Bromo-2-fluoro-4-(trifluoromethyl)benzene
Similarity: 0.94
A693258 [393-37-3]
5-Bromo-2-fluorobenzotrifluoride
Similarity: 0.92
A267091 [351003-21-9]
2-Bromo-4-fluorobenzotrifluoride
Similarity: 0.90
A100698 [68322-84-9]
2-Bromo-1-fluoro-4-(trifluoromethyl)benzene
Similarity: 0.90
A215906 [142808-15-9]
4-Bromo-2-fluorobenzotrifluoride
Similarity: 0.90
A170065 [40161-54-4]
1-Bromo-2-fluoro-4-(trifluoromethyl)benzene
Similarity: 0.94
A693258 [393-37-3]
5-Bromo-2-fluorobenzotrifluoride
Similarity: 0.92
A267091 [351003-21-9]
2-Bromo-4-fluorobenzotrifluoride
Similarity: 0.90
A100698 [68322-84-9]
2-Bromo-1-fluoro-4-(trifluoromethyl)benzene
Similarity: 0.90
A215906 [142808-15-9]
4-Bromo-2-fluorobenzotrifluoride
Similarity: 0.90
A170065 [40161-54-4]
1-Bromo-2-fluoro-4-(trifluoromethyl)benzene
Similarity: 0.94
A693258 [393-37-3]
5-Bromo-2-fluorobenzotrifluoride
Similarity: 0.92
A267091 [351003-21-9]
2-Bromo-4-fluorobenzotrifluoride
Similarity: 0.90
A100698 [68322-84-9]
2-Bromo-1-fluoro-4-(trifluoromethyl)benzene
Similarity: 0.90
A215906 [142808-15-9]
4-Bromo-2-fluorobenzotrifluoride
Similarity: 0.90
A170065 [40161-54-4]
1-Bromo-2-fluoro-4-(trifluoromethyl)benzene
Similarity: 0.94
A693258 [393-37-3]
5-Bromo-2-fluorobenzotrifluoride
Similarity: 0.92
A267091 [351003-21-9]
2-Bromo-4-fluorobenzotrifluoride
Similarity: 0.90
A100698 [68322-84-9]
2-Bromo-1-fluoro-4-(trifluoromethyl)benzene
Similarity: 0.90
A215906 [142808-15-9]
4-Bromo-2-fluorobenzotrifluoride
Similarity: 0.90