Structure of 496807-97-7
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CAS No. : | 496807-97-7 |
Formula : | C5H10ClF2N |
M.W : | 157.59 |
SMILES Code : | FC1(F)CNCCC1.[H]Cl |
MDL No. : | MFCD03452800 |
InChI Key : | LEHHIPIDKQVNEV-UHFFFAOYSA-N |
Pubchem ID : | 2758349 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 37.86 |
TPSA ? Topological Polar Surface Area: Calculated from |
12.03 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.76 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.27 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.49 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.98 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.5 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.93 |
Solubility | 1.87 mg/ml ; 0.0119 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.63 |
Solubility | 3.69 mg/ml ; 0.0234 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.82 |
Solubility | 2.39 mg/ml ; 0.0152 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
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) |
No |
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) |
No |
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 |
-6.01 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
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 |
2.0 |
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<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.41 |
* 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 |
---|---|---|
With hydrogenchloride; hydrogen;5% palladium-on-charcoal; In methanol; ethanol; for 22h; | To a solution of 1-benzyl-piperidin-3-one (1G) in CH2CI2 (LOML) is added [bis (2-methoxy- ethyl) amino] SULFER TRIFLUORIDE (1. 84mL) at 0C, and stirred for 1.5hr at room temperature. The reaction mixture is poured in aqueous NaHC03 and extracted with ethyl acetate. The organic layer is successively washed with H20 and aqueous NACI, dried over MgS04, and concentrated in vacuo. The residue is purified by column chromatography to give a colorless oil. The oil and Pd/C (5% w/w on activated carbon, 100MG) in HCI in ETOH/MEOH (50mL) is stirred for 22hr under H2 atmosphere. The reaction mixture is filtrated through celite pad. 4The filtrate is added HCI in EtOAc, then concentrated in vacuo to provide the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of E-4-(2-chloro-acetylamino)-adamantane-1-carboxylic acid methyl ester (0.075 g, 0.26 mmoles) from Example 25B, in MeOH (1.5 mL) and DIPEA (0.05 mL, 0.29 mmoles) was treated with <strong>[496807-97-7]3,3-difluoro-piperidine hydrochloride</strong> (0.062 g, 0.39 mmoles) and stirred for 2 hours at 80 C. The cooled reaction mixture was purified on reverse phase HPLC and hydrolyzed with 3N HCl at 60 C. over 6 hours. Drying of the reaction mixture under reduced pressure provided the hydrochloride salt of the title compound as a white solid (50 mg, 52%). 1H NMR (300 MHz, DMSO-d6) delta 8.45 (m, 1H), 3.97 (bs, 2H), 3.88 (m, 1H), 3.65 (m, 2H), 3.23 (m, 2H), 2.11 (m, 2H), 1.91 (m, 11H), 1.79 (m, 2H), 1.47 (m, 2H); MS (DCI+) m/z 357 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With N-ethyl-N,N-diisopropylamine; In methanol; at 70℃; | A solution of E-4-(2-bromo-propionylamino)-adamantane-1-carboxylic acid amide (33 mg, 0.1 mmoles) and the hydrochloride of 3,3-difluoropiperidine (19 mg, 0.12 mmol) from Example 31B in MeOH (0.5 mL) and DIPEA (0.1 mL) was stirred overnight at 70 C. The MeOH was removed under reduced pressure and the residue purified on reverse phase HPLC to provide the title compound as a white solid (18 mg, 48%). 1H NMR (400 MHz, Py-d5) delta 7.92 (d, J=7.7 Hz, 1H), 7.51 (s, 2H), 4.32 (d, J=7.7 Hz, 1H), 3.42 (q, J=7 Hz, 1H), 2.92 (q, J=10.7 Hz, 1H), 2.78 (q, J=11.6 Hz, 1H), 2.5 (m, 2H), 2.27-2.10 (m, 8H), 1.98-1.88 (m, 5H), 1.68 (m, 2H), 1.55 (m, 2H), 1.32 (d, 3H); MS (ESI+) m/z 370 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In methanol; at 70℃; | A solution of (E)-4-(2-bromo-propionylamino)-adamantane-1-carboxamide (33 mg, 0.1 mmoles) and the hydrochloride of 3,3-difluoropiperidine (19 mg, 0.12 mmol) from Example 31B in MeOH (0.5 mL) and DIPEA (0.1 mL) was stirred overnight at 70 C. The MeOH was removed under reduced pressure and the residue purified on reverse phase HPLC to provide the title compound as a white solid. 1H NMR (400 MHz, Py-d5) delta 7.92 (d, J=7.7 Hz, 11H), 7.51 (s, 2H), 4.32 (d, J=7.7 Hz, 1H), 3.42 (q, J=7 Hz, 1H), 2.92 (q, J=10.7 Hz, 1H), 2.78 (q, J=11.6 Hz, 1H), 2.5 (m, 2H), 2.27-2.10 (m, 8H), 1.98-1.88 (m, 5H), 1.68 (m, 2H), 1.55 (m, 2H), 1.32 (d, 3H); MS(ESI+) m/z 370 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Example 27; 8-[(3,3-Difluoropiperidin-1-yl)methyl]-3-(phenylsulfonyl)quinoline hydrochloride(E27); A suspension of 3-(phenylsulfonyl)quinoline-8-carbaldehyde (D3) (45 mg, 0.15 mmol) in anhydrous dichloromethane (1 ml) was treated with <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (26 mg, 0.165 mmol) and sodium triacetoxyborohydride (37 mg, 0.175 mmol) and the mixture was stirred under argon at room temperature for 18h. The reaction mixture was then diluted with dichloromethane (30 ml) and washed with aqueous sodium bicarbonate solution (2 x 20ml). The dichloromethane solution was dried by filtration through a hydrophobic cartridge and evaporated to a gum. This material was dissolved in a mixture of dimethylsulphoxide (0.45 ml) and acetonitrile (0.45 ml) and purified by mass-directed auto-preparative chromatography using a 10 minute gradient containing water and between 15% and 55% acetonitrile with 0.1% formic acid. Product fractions were collected and evaporated to a gum. This material was dissolved in ether (2 ml) and treated with 1M hydrogen chloride in ether (1 ml). The mixture was evaporated, dissolved in ether and re-evaporated to yield the title compound as a white solid (35 mg, 0.08 mmol, 53%). deltaH (CD3OD, 400MHz) 1.90-2.40 (4H, m), 3.20-3.90 (4H, m), 5.06 (2H, s), 7.61-7.72 (3H, m), 7.86 (IH, t, J = 7Hz), 8.06-8.16 (3H, m), 8.34 (1 H, dd, J = 1.2, 8.4Hz), 9.17 (1 H, d, J = 2Hz), 9.40 (1 H, d, J = 2Hz). Mass spectrum: C2IH20F2N2O2S requires 402; found 403 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | Example 37; 8-[1 -(3,3-Dif luoro-1 -piperidinyl)ethyl]-3-(phenylsulfonyl)quinoline (E37); A suspension of 1-[3-(phenylsulfonyl)quinolin-8-yl]ethanone (D8) (96 mg, 0.3 mmol) in anhydrous dichloromethane (2 ml) was treated with <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (52 mg, 0.33 mmol) and sodium triacetoxyborohydride (95 mg, 0.44 mmol) and the mixture was stirred under argon at room temperature for 3 days. The reaction mixture was then diluted with dichloromethane (75 ml) and washed with aqueous sodium bicarbonate solution (2 x 50ml). The dichloromethane solution was dried by filtration through a hydrophobic cartridge and evaporated to a gum. This material was dissolved in a mixture of dimethylsulphoxide (0.90 ml) and acetonitrile (0.90 ml) and purified by mass- directed auto-preparative chromatography using a 10 minute gradient containing water EPO <DP n="52"/>and between 15% and 55% acetonitrile with 0.1% formic acid. Product fractions were collected and evaporated to give the title compound as a colourless foam (14 mg, 11%). deltaH (CDCI3, 400MHz) 1.41 (3H, t, J = 7Hz), 1.70-1.89 (4H, m), 2.33-2.36 (1 H, m), 2.61- 2.78 (3H, m), 5.00 (1 H, q, J = 7Hz), 7.52-7.63 (3H, m), 7.70 (1 H, t, J = 8Hz), 7.86 (1 H, dd, J = 1.2Hz, 7Hz), 7.99-8.10 (3H, m), 8.81 (1 H, d, J = 2Hz), 9.24 (1 H1 d, J = 2Hz) Mass spectrum: C22H22F2N2O2S requires 416; found 417 (MH+) | |
11% | With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 72h; | A suspension of l-[3-(phenylsulfonyl)quinolin-8-yl]ethanone (96 mg, 0.3 mmol) in anhydrous dichloromethane (2 ml) was treated with <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (52 mg, 0.33 mmol) and sodium triacetoxyborohydride (95 mg, 0.44 mmol) and the mixture was stirred under argon at room temperature for 3 days. The reaction mixture was then diluted with dichloromethane (75 ml) and washed with aqueous sodium bicarbonate solution (2 x 50ml). The dichloromethane solution was dried by filtration through a hydrophobic cartridge and evaporated to a gum. This material was dissolved in a mixture of dimethylsulphoxide (0.90 ml) and acetonitrile (0.90 ml) and purified by mass-directed auto -preparative chromatography using a 10 minute gradient containing water and between 15% and 55% acetonitrile with 0.1% formic acid. Product fractions were collected and evaporated to give the title compound as a colourless foam (14 mg, 11%). <n="211"/>deltaH (CDCl3, 400MHz) 1.41 (3H, t, J = 7Hz), 1.70-1.89 (4H, m), 2.33-2.36 (IH, m), 2.61-2.78 (3H, m), 5.00 (IH, q, J = 7Hz), 7.52-7.63 (3H, m), 7.70 (IH, t, J = 8Hz), 7.86 (IH, dd, J = 1.2Hz, 7Hz), 7.99-8.10 (3H, m), 8.81 (IH, d, J = 2Hz), 9.24 (IH, d, J = 2Hz) Mass spectrum: C22H22F2N2O2S requires 416; found 417 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Description 20; 8-[(3,3-Dif luoro-1 -piperidinyl)methyl]-3-iodoquinoline (D20); 3-lodo-delta-quinolinecarbaldehyde (D19) (2g, 7.06mmol) and <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (0.94g, 7.77mmol) were dissolved in dichloromethane (20ml). Sodium triacetoxyborohydride (2.25g, 10.6mmol) and acetic acid (0.44ml, 7.77mmol) were added and the reaction stirred at room temperature under argon overnight. The reaction was diluted with dichloromethane, cooled and basified with saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to yield a brown oil (2.89g). The residue was purified on the Jones Flashmaster Il with an IST SPE 7Og silica column eluting a gradient of 5-12% ethyl acetate/n-hexane over 40 minutes. This yielded the title compound as a pale yellow oil (2.27g).LC/MS [MH+] 389 consistent with molecular formula C15H15F2IN2. | ||
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; | 3-Iodo-8-quinolinecarbaldehyde (2g, 7.06mmol) and <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (0.94g, 7.77mmol) were dissolved in dichloromethane (20ml). Sodium triacetoxyborohydride (2.25g, 10.6mmol) and acetic acid (0.44ml, 7.77mmol) were added and the reaction stirred at room temperature under argon overnight. The reaction was diluted with dichloromethane, cooled and basified with saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to yield a brown oil (2.89g). The residue was purified on the Jones Flashmaster II with an 1ST SPE 7Og silica column eluting a gradient of 5-12% ethyl acetate/«-hexane over 40 minutes. This yielded the title compound as a pale yellow oil (1.2Ig).LC/MS [MH+] 389 consistent with molecular formula Ci5H15F2IN2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 18h; | A suspension of 3-(phenylsulfonyl)quinoline-8-carbaldehyde (45 mg, 0.15 mmol) in anhydrous dichloromethane (1 ml) was treated with <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (26 mg, 0.165 mmol) and sodium triacetoxyborohydride (37 mg, 0.175 mmol) and the mixture was stirred under argon at room temperature for 18h. The reaction mixture was then diluted with dichloromethane (30 ml) and washed with aqueous sodium bicarbonate solution (2 x 20ml). The dichloromethane solution was dried by filtration through a hydrophobic cartridge and evaporated to a gum. This material was dissolved in a mixture of dimethylsulphoxide (0.45 ml) and acetonitrile (0.45 ml) and purified by mass-directed auto -preparative chromatography using a 10 minute gradient containing water and between 15% and 55% acetonitrile with 0.1% formic acid. Product fractions were collected and evaporated to a gum. This material was dissolved in ether (2 ml) and treated with IM hydrogen chloride in ether (1 ml). The mixture was evaporated, dissolved in ether and re-evaporated to yield the title compound as a white solid (35 mg, 0.08 mmol, 53%). <n="206"/>deltaH (CD3OD, 400MHz) 1.90-2.40 (4H, m), 3.20-3.90 (4H, m), 5.06 (2H, s), 7.61-7.72 (3H, m), 7.86 (IH, t, J = 7Hz), 8.06-8.16 (3H, m), 8.34 (IH, dd, J = 1.2, 8.4Hz), 9.17 (IH, d, J = 2Hz), 9.40 (IH, d, J = 2Hz). Mass spectrum: C2IH20F2N2O2S requires 402; found 403 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine; In dichloromethane; at 20℃; for 2h; | Intermediate 7; 6-[(3,3-Difluoro-1 -piperidinyl)sulfonyl]-1 -[1 -(trifluoroacetyl)-4-piperidinyl]-2,3- dihydro-1H-indoleTo a solution of 1-[1-(trifluoroacetyl)-4-piperidinyl]-2,3-dihydro-1 H-indole-6-sulfonyl chloride (which may be prepared as described for Intermediate 4, 150mg, 0.38mmol) in DCM (1 OmL) was added triethylamine (132mul_, 0.95mmol) followed by 3,3- difluoropiperidine hydrochloride (71 mg, 0.45mmol). The mixture was stirred at room temperature under argon for 2 hours. It was then shaken with 1 M aqueous HCI (1OmL); the DCM layer was isolated and concentrated in vacuo. The resultant yellow oil was purified by flash chromatography on silica gel (25+S, SP4) eluting with a solvent gradient of 0 to 50% ethyl acetate/hexane to afford the title compound as a yellow oil (157mg, 86%).1H NMR (CDCI3, 400MHz): delta 1.59-1.73 (2H, m, partially obscured by H2O), 1.77-1.98 (6H, m), 2.88 (1 H, t, J=13.0), 3.01-3.12 (4H, m), 3.22-3.34 (3H, m), 3.41-3.51 (2H, m), 3.73 (1 H, tt, J=12.0, 4.0), 4.11-4.19 (1 H, m, partially obscured by EtOAc), 4.71 (1 H, m), 6.70 (1 H, d, J=1.5), 6.02 (1 H, dd, J=7.5, 1.5), 7.15 (1 H, m). Mass spectrum (ESI): C20H24F5N3O3S requires 481 ; found 482 (MH+). |
86% | With triethylamine; In dichloromethane; at 20℃; for 2h; | Intermediate 6; 6-[(3,3-Difluoro-1 -piperidinyl)sulfonyl]-1 -[1 -(trifluoroacetyl)-4-piperidinyl]-2,3- dihydro-1H-indoleTo a solution of 1-[1-(trifluoroacetyl)-4-piperidinyl]-2,3-dihydro-1 H-indole-6-sulfonyl chloride (which may be prepared as described for Intermediate 4, 150mg, 0.38mmol) in DCM (1 OmL) was added triethylamine (132mul_, 0.95mmol) followed by 3,3- difluoropiperidine hydrochloride (71 mg, 0.45mmol). The mixture was stirred at room temperature under argon for 2 hours. It was then shaken with 1 M aqueous HCI (1OmL); the DCM layer was isolated and concentrated in vacuo. The resultant yellow oil was purified by flash chromatography on silica gel (25+S, SP4) eluting with a solvent gradient of 0 to 50% ethyl acetate/hexane to afford the title compound as a yellow oil (157mg, 86%).1H NMR (CDCI3, 400MHz): delta 1.59-1.73 (2H, m, partially obscured by H2O), 1.77-1.98 (6H, m), 2.88 (1 H, t, J=13.0), 3.01-3.12 (4H, m), 3.22-3.34 (3H, m), 3.41-3.51 (2H, m), 3.73 (1 H, tt, J=12.0, 4.0), 4.11-4.19 (1 H, m, partially obscured by EtOAc), 4.71 (1 H, m), 6.70 (1 H, d, J=1.5), 6.02 (1 H, dd, J=7.5, 1.5), 7.15 (1 H, m). Mass spectrum (ESI): C20H24F5N3O3S requires 481 ; found 482 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 18h; | To a mixture of aldehyde 33a1 (40 mg, 0.07 mmol) and <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (47 mg, 0.30 mmol) in DCM (1 mL) is added NaHB(OAc)3 (31 mg, 0.15 mmol). The mixture is stirred at RT for about 18 hours. Tetrahydrofuran (2 mL), MeOH (1 mL), NaOH (1 N, 1 mL, 1.0 mmol) and LiOH-H2O (15 mg, 0.35 mmol) are added and the mixture is stirred for 3 hours. The mixture is concentrated, taken-up in AcOH (2.5 mL), filtered then injected onto a preparative HPLC to isolate compound 1117. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Step C/lntermediate B41 : 3,3-difluoro-1 '-[3-(methyloxy)-4-nitrophenyl]-1 ,4'- bipiperidine; A mixture of 1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinone (600 mg, 2.4 mmol), commercially available <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (753 mg, 4.8 mmol), acetic acid (0.20 ml_, 3.6 mmol) and triethylamine (0.33 ml_, 3.6 mmol) in 1 ,2- dichloroethane was stirred for 30 minutes. Sodium triacetoxyborohydride (615 mg, 2.9 mmol) was added. When LC/MS indicated the absence of starting material, the reaction was quenched with the addition of sat'd NaHCO3. The reaction was diluted with dichloromethane and the layers were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with water, dried over MgSO4 and concentrated onto silica gel. The crude material was purified by flash column chromatography to give 3,3-difluoro-1'-[3-(methyloxy)-4- nitrophenyl]-1 ,4'-bipiperidine (584 mg, 68%). 1H NMR (400 MHz, d6-DMSO) delta 7.84 (d, J = 9.6 Hz, 1 H), 6.55 (dd, J = 9.6 and 2.0 Hz, 1 H), 6.46 (d, J = 2.0 Hz, 1 H), 4.04 (d, J = 12.8 Hz, 1 H), 3.87 (s, 3H), 2.90 (t, J = 12.0 Hz, 2H), 2.72-2.60 (m, 3H), 2.47 (m under DMSO peak, 2H), 1.87-1.74 (m, 4H), 1.61-1.58 (m,. 2H), 1.48-1.38 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | Example 8a (101 mg, 0.21 mmol) was reacted with <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (2.5 eq.) as described under General Procedure K to afford the title compound (37 mg, 33%) as a clear oil. 1H NMR (300 MHz, CDCI3) delta 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.07 (t, J = 5.4 Hz, 2H), 3.97 (td, J = 6.9, 1.5 Hz, 2H), 3.83 (s, 3H), 3.05-2.83 (m, 1 H), 2.75-2.68 (m, 4H), 2.50-2.46 (m, 5H), 2.18 (s, 3H), 2.13-1.94 (m, 2H), 1.90-1.74 (m, 4H), 1.29 (d, J = 6.9 Hz, 3H). MS (ES+) m/z 528 (M + H+).; General Procedure K: Alkylation of lambda/-heterocyclesTo a solution of the lambda/-heterocycle hydrochloride salt (2.5 eq.) in anhydrous DMF (1 M) was added NaH (60% dispersion in oil, 3.0 eq.) and the reaction was stirred at room temperature for 2-3 h. To this was added the bromide (1.0 eq.) in anhydrous DMF (0.2-0.5 M) and the reaction was stirred at 50-60 0C under a N2 atmosphere until the reaction was complete by TLC (~ 16 h). The reaction was quenched with NH4CI(aq ) (sat.) and extracted with EtOAc. The organic phase was washed with water then brine, dried over MgSO4 and concentrated under vacuum.The crude residue was purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 4h; | A mixture of ethyl 4-fluoro-3-nitrobenzoate (Chontech 01072; 500 mg; 2.35 mmol; 1 eq.), 3,3- difluoropiperidine hydrochloride (Aldrich 665517; 554.47 mg; 3.52 mmol; 1.5 eq.) and triethylamine (712.07 mg; 7.04 mmol; 3 eq.) in DMF (3 rmL) was stirred at 600C for 4 hours. The reaction mixture was then partitioned between ethyl acetate and aq. NH4CI. The organic layer was washed three times with aq. NH4CI then brine, dried over magnesium sulfate and <n="59"/>concentrated in vacuo to give a yellow oil. The oil was taken up in THF (15 ml_) and lithium hydroxide (280.86 mg; 1 1.73 mmol; 5 eq.) then water (15 ml_) were added. The reaction mixture was stirred at room temperature for 4 hours and the THF was evaporated under vaccum. The resulting solution was washed with Et2O, acidified with acetic acid and extracted twice with Et2O. The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to give a yellow oil which was crystallized from water. Filtration and drying under high vaccum afforded the title compound (630 mg, 94%) as a yellow solid. HPLC (Method A) : Rt 3.61 min (purity 99.4%). LC/MS : 286.9 (M+H)+, 284.9 (M-H)". |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 5:; To the crude aldehyde 5a4 (2 g, 9.5 mmol) in 45 mL of DCE is added difluoropiperidine-HCI salt (1.6 g, 10.5 mmol) and triacetoxy sodium borohydride (2.8 g, 13.4 mmol). This reaction is stirred overnight at RT. The mixture is diluted with EtOAc (300 mL) and washed with water (100 mL) and brine (10OmL). The organic phase is then dried over MgSO4, filtered and concentrated. The residue is purified by flash chromatography (Combiflash, 15-40% EtOAc/Hex.) to afford 5a6 as an orange <n="65"/>oil. | ||
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; | To aldehyde 3a1 (2.0 g, 9.5 mmol) in 45 mL of DCE is added 3,3-difluoropiperidine- HCI salt (1.6 g, 10.5 mmol) and Na(AcO)3BH (2.8 g, 13.4 mmol). The mixture is stirred overnight at RT. The mixture is diluted with EtOAc (300 mL) and washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgS04, filtered and concentrated. The residue is purified by flash chromatography (Combiflash, 15- 40% EtOAc/Hex) to afford pyridyl chloride 3a2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; | Step 2:; To a solution of 37a2 (100 mg, 0.18 mmol) and <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (31 mg, 0.20 mmol) in DCE (1.5 ml.) is added NaBH(OAc)3 (52 mg, 0.25 mmol). The mixture is stirred at RT overnight, then water is added. The mixture is extracted with DCM (3x), the organics are dried and concentrated under reduced pressure. Purification by combiflash (15% EtOAc in hex) gives 37a3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium hydride;sodium iodide; In N,N-dimethyl-formamide; at 65℃; | 5-Acetyl-7-r3-(4-fluorophenvnbutoxyl-6-(2-(3,3-difluoropiperidin-1-yl)- ethoxy)-4-methyl-2-difluoromethyl-benzord1oxazoleA solution of Example 31a) (56 mg, 109 mmol), NaH (13 mg, 0.327 mmol), 3,3- difluoropiperidine hydrochloride (52 mg, 0.327 mmol) and NaI (cat.) in DMF was <n="88"/>heated to 65 0C overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed twice with water and brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, Et2O / hexane, 2:3) to give the title compound as a clear colourless oil (36 mg, 60 %). 1H NMR (300 MHz, CDCI3) 7.22-7.17 (m, 2H), 7.00-6.93 (m, 2H), 6.75 (t, J = 52 Hz, 1 H), 4.34-4.19 (m, 2H), 4.15 (t, J = 5.4 Hz, 2H), 3.12-3.01 (m, 1 H), 2.80-2.73 (m, 4H), 2.54-2.48 (m, 5H), 2.41 (s, 3H), 2.20-1.74 (m, 6H), 1.33 (d, J = 7.2 Hz, 3H), ESIMS m/z [M+H]+ 555.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium carbonate;sodium iodide; In N,N-dimethyl-formamide; at 65℃; for 96h; | 5-Acetyl-beta-r2-(3,3-difluoropiperidin-1-yl)ethoxy1-7-r3-(4- fluorophenyl)butoxy1-2-isopropyl-4-methylbenzord1oxazole:A solution of Example 33a) (109 mg, 0.215 mmol), sodium carbonate (160 mg, 1.51 mmol), <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (250 mg, 1.58 mmol) and NaI (cat.) in DMF was heated to 65 0C for 4 d. The reaction mixture was cooled to room temperature, diluted with water and extracted with ether. The pooled organics were dried over MgSO4 and concentrated in vacuo. The crude product was purified by preparative thin layer chromatography (silica gel, EtOAc / hexane, 2:8) to give the title compound as a clear colourless oil (87 mg, 74%). 1H NMR (300 MHz, CDCI3) delta 7.21-7.16 (m, 2H), 7.00-6.95 (m, 2H), 4.29-4.17 (m, 2H), 4.10 (t, J 5.5 Hz, 2H), 3.18 (hep, J = 7 Hz, 1 H), 3.16-2.98 (m, 1 H), 2.82-2.74 (m, 4H), 2.54-2.51 (m, 2H), 2.52 (s, 3H), 2.38 (s, 3H), 2.16-1.74 (m, 6H), 1.39 (d, J = 7.0 Hz, 6H), 1.32 (d, J = 7.0 Hz, 3H), ESIMS m/z [M+H]+ 547.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium hydride;sodium iodide; In N,N-dimethyl-formamide; at 65℃; | 5-Acetyl-6-r2-f3.3-difluoropiperidin-1-yl)ethoxy1-7-r3-(4- fluorophenyl)butoxy1-2-isopropyl-4-methylbenzord1oxazole:A solution of Example 36a) (54 mg, 106 mmol), NaH (12 mg, 0.319 mmol), 3,3- difluoropiperidine hydrochloride (50 mg, 0.319 mmol) and NaI (cat.) in DMF was heated to 65 0C overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed twice with water and brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, Et2O / hexane, 1 :1) to give the title compound as a clear, colourless oil (39 mg, 68%).1H NMR (300 MHz, CDCI3) 7.20-7.16 (m, 2H), 7.02-6.96 (m, 2H), 4.24-4.11 (m, 2H), 4.08 (t, J = 5.4 Hz, 2H), 3.09-2.98 (m, 1 H), 2.81-2.74 (m, 4H), 2.55-2.48 (m, 5H), 2.35 (s, 3H), 2.19-1.73 (m, 7H), 1.32 (d, J = 6.9 Hz, 3H), 1.16- 1.13 (m, 4H), ESIMS m/z [M+H]+ 545.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | 5-Acetyl-4-chloro-7-(3-(4-fluorophenyl)butoxy)-6-(2-(3,3-difluoropiperidin-1- yl)ethoxy)-2-methyl-benzord1oxazole:To a stirred solution of Example 38g) (97 mg, 0.21 mmol) in dry acetone (3 ml_) under N2 was added NaI (352 mg, 2.35 mmol). The solution was heated to reflux for 3 days. After this time the reaction was cooled to room temperature and diluted with Et2O (10 ml_). The etheral layer was washed with water (3 x 5 mL), brine (5 ml_), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was dissolved in dry DMF (2 mL) and this solution was added to a stirred suspension of <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (155 mg, 0.98 mmol), NaH (60% dispersion in oil, 38 mg, 0.93 mmol) and NaI (33 mg, 0.22 mmol) in dry DMF (5 mL). The solution was heated to 6O0C for 24 hours. After this time the reaction was cooled, diluted with sat. NH4CI(aq) and the product extracted with Et2O (3 x 5 mL). The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, methanol / ethyl acetate / petroleum spirit 2:18:80) to give the title compound (53 mg, 47%). NMR (300 MHz, CDCI3) delta 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.33- 4.19 (m, 2H), 4.12-4.09 (m, 2H), 3.74-3.71 (m, 4H), 3.09-2.98 (m, 1 H), 2.70-2.66 (m, 2H), 2.61 (s, 3H), 2.58 (s, 3H) 2.54-2.50 (m, 4H), 2.16-1.94 (m, 2H), 1.33-1.31 (d, J = 7.0 Hz, 3H), ESIMS m/z [M+H]+ 539.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With sodium hydride; In N,N-dimethyl-formamide; at 65℃; | 5-Acetyl-7-r3-(4-fluorophenyl)butoxyl-6-r2-(3,3-difluoropiperidin-1-yl)- ethoxyl-2,4-dimethyl-benzooxazole:A solution of Example 10a) (102 mg, 0.21 mmol), NaH (26 mg, 0.64 mmpl) and <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (85 mg, 0.54 mmol) in DMF was heated to 65 0C overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed twice with water and brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, Et2O / DCM, 1 :9) to give the title compound as a clear, colourless oil (55 mg, 51%).1H NMR (300 MHz, CDCI3) delta 7.21-7.16 (m, 2H), 7.01-6.95 (m, 2H), 4.27- 4.19 (m, 2H), 4.09 (t, J = 5.6 Hz, 2H), 3.05 (m, 1 H), 2.81-2.70 (m, 4H), 2.58 (s, 3H), 2.53 (s, 3H), 2.57-2.50 (m, 2H), 2.37 (s, 3H), 2.17-1.77 (m, 6H), 1.32 (d, J = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 519.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 40℃; for 2h; | Solid <strong>[496807-97-7]3,3-difluoro-piperidine hydrochloride</strong> (34 mg, 0.22 mmol) was added to a THF solution (1 mL) of diisopropylethyl amine (0.10 mL, 0.56 mmol) and 6-bromomethyl-2-(5-chloro- furan-2-yl)-thieno[2,3-d]pyrimidin-4-ylamine (50 mg, 0.14 mmol) and the mixture was heated to 40 0C. After 2 h the mixture was diluted with EtOAc then washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to give 31 mg of the title compound. 1H NMR (CHLOROFORM-d ,300MHz): delta = 7.23 (d, J=3.4 Hz, 1 H), 6.99 (s, 1 H), 6.34 (d, J=3.4 Hz, 1 H), 5.31 (br. s., 2 H), 3.86 (s, 2 H), 2.75 (t, J=I L l Hz, 2 H), 2.57 (t, J=5.1 Hz, 2 H), 1.73 - 1.99 ppm (m, 4 H); MS m/e 385 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With triethylamine; In dimethyl sulfoxide; at 20℃; for 22h;Heating; | C. N-(3-Methyl-benzo[b]thiophen-2-yl)-2-(3,3-difluoropiperidin-1-yl)-ethylsulfonamide (9c). Compound 9b (1.16 g, 3.47 mmol) was added to a solution of <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (1.48 g, 9.39 mmol) and triethylamine (1.21 mL, 8.68 mmol) in DMSO (10 mL) and stirred at room temperature for 4 hours, then heated for 18 hours. Water (1 mL) was added. The solution was applied to pHPLC column (C18 ABZ+) and eluted with a gradient of acetonitrile (10% to 90%) in water (0.1% TFA). The solvent was removed by lypholization, and the residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to give compound 9c (0.77 g, 59%). 1H NMR (DMSO-d6) delta 1.81-2.01 (m, 4H), 2.43 (s, 3H), 2.68 (br. s., 2H), 2.87 (m, 2H), 3.06 (t, J=5.99 Hz, 2H), 3.36 (t, J=5.99 Hz, 2H), 7.26 (br. s., 1H), 7.33-7.43 (m, 2H), 7.66-7.76 (m, 2H); MS: m/z 375.0 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; water; | Example 31 2-({(2-(4-Chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-6-(3,3-difluoropiperidin-1-yl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile At RT, 150 mg (0.20 mmol, purity about 74%) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), 64 mg (0.41 mmol) of <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> and 57 mul (0.41 mmol) of triethylamine were stirred in 3 ml of THF for 2 h. The reaction mixture was then diluted with about 1 ml of water and about 3 ml of THF and purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 90 mg (71% of theory) of the target compound. 1H-NMR (400 MHz, DMSO-d6): delta=7.95 (d, 2H), 7.69 (s, 1H), 7.56 (d, 4H), 7.12 (d, 2H), 4.90 (br s, 1H), 4.71 (s, 2H), 4.17 (t, 2H), 4.09 (t, 2H), 3.92-3.85 (m, 2H), 3.74 (t, 2H), 2.20-2.07 (m, 2H), 1.86-1.78 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With diisopropylethylamine; In ethanol; at 130℃; for 1h;Microwave irradiation; | Example 56 3,3-Difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine A mixture of 5-chloro-1-methyl-4-nitro-1H-pyrazole (0.1 g, 4.5 mmol), <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (0.14 g, 0.93 mmol) and DIPEA (0.5 mL, 2.8 mmol) in EtOH (3 mL) was heated at 130 C. in a microwave for 1 hr. Additional DIPEA (0.5 mL, 2.8 mmol) and <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (0.29 g, 1.8 mmol) were added and the mixture was heated at 130 C. in a microwave for 2 hr. The solvent was removed under reduced pressure and the crude product was purified via silica gel column chromatography (0-60% EtOAc/isohexane) to yield 3,3-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a yellow oil (127 mg, 83%). 1H NMR (400 MHz, CDCl3) delta 8.04 (s, 1H), 3.80 (s, 3H), 3.41-3.29 (m, 2H), 3.26-3.04 (m, 2H), 2.17-2.03 (m, 2H), 1.97-1.88 (m, 2H). |
83% | With N-ethyl-N,N-diisopropylamine; In ethanol; at 130℃; for 3h;Microwave irradiation; | Example 56 3,3-Difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine A mixture of 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (0.1 g, 4.5 mmol), <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (0.14 g, 0.93 mmol) and DIPEA (0.5 mL, 2.8 mmol) in EtOH (3 mL) was heated at 130 C. in a microwave for 1 hr. Additional DIPEA (0.5 mL, 2.8 mmol) and <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (0.29 g, 1.8 mmol) were added and the mixture was heated at 130 C. in a microwave for 2 hr. The solvent was removed under reduced pressure and the crude product was purified via silica gel column chromatography (0-60% EtOAc/isohexane) to yield 3,3-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a yellow oil (127 mg, 83%). 1H NMR (400 MHz, CDCl3) delta 8.04 (s, 1H), 3.80 (s, 3H), 3.41-3.29 (m, 2H), 3.26-3.04 (m, 2H), 2.17-2.03 (m, 2H), 1.97-1.88 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In 1,4-dioxane; at 90℃; for 14h;Inert atmosphere; | A mixture of 1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1- phenyl-lH-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.5 mmol) , 3, 3-difluoropiperidine hydrochloride (94.6 mg, 0.6 mmol), NaO-t- Bu (125 mg, 1.3 mmol), Xantphos (46.3 mg, 0.08 mmol) and Pd2(dba)3 (18.3 mg, 0.02 mmol) in 1,4-dioxane (2.5 mL) was heated to 90C for 14 hr under Ar. The mixture was diluted with NaHC03 aqueous solution, extracted with AcOEt, dried over Na2S04, filtered, concentrated under reduced pressure, purified by column chromatography on basic silica gel (hexane/AcOEt = 50/50 to 0/100) and recrystallized with AcOEt/hexane to yield the title compound (132 mg, 55% yield) as a yellow solid: mp 182- 187C. 1H NMR (DMSO-d6, 300 MHz): delta ppm 1.68-1.81 (2H, m) , 1.97- 2.16 (2H, m) , 3.34-3.43 (2H, m) , 3.67 (2H, t, J = 11.9 Hz), 3.76 (3H, s), 6.73-7.10 (4H, m) , 7.24-7.50 (5H, m) , 7.78 (1H, d, J = 1.9 Hz), 8.39 (1H, d, J = 1.9 Hz). Anal. Calcd for C2SH22F3 5O2 : C, 62.36; H, 4.61; N, 14.55. Found: C, 62.60; H, 4.60; N, 14.31. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of 1 -benzyl-1 H-pyrazole-4-carboxylic acid [5-(3-formyl-phenyl)-1 - (toluene-4-sulfonyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl]-amide (100mg, 0.17mmol) in MeOH (1 ml_) was added 4A molecular sieves followed by dimethylamine, 2.0M solution in THF (4ml_, 8mmol) and the reaction stirred for 3 hours at RT. Sodium triacetoxyborohydride (72.1 mg, 0.34mmol) was added and the reaction stirred 18 hours at RT. The inorganic material was separated via filtration and the filtrate was diluted with DCM. The solution was washed with aqueous saturated sodium bicarbonate solution, dried (MgSO4) and concentrated in vacuo. The residue was purified using automated column chromatography eluting with DCM to 10% MeOH/DCM. Fractions containing pure compound were combined and concentrated in vacuo to give the desired compound as a colourless glass, 61 mg, 58.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
612 mg | With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1.5h; | 1-(3-[tert-butyl(dimethyl)silyl]oxy}propyl)-3 FontWeight="Bold" FontSize="10" 3-difluoropiperidine To a solution of <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (518 mg) in DMF (15 mL) was added cesium carbonate (3.21 g) and (3-bromopropoxy)-tert-butyldimethylsilane (0.838 mL). The resulting reaction mixture was heated to 50C for 1.5 hours before cooling back to room temperature. Water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate (2x). The combined organics were washed with water (2x), brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO, 0 to 40% ethyl acetate in hexanes with 1% triethylamine) gave the desired product (612 mg). NMR (400 MHz, CDC13): delta (ppm) 4.20 (t, 1H), 3.71-3.64 (m, 2H), 3.46 (t, 1H), 2.62 (t, 1H), 2.50-2.47 (m, 1H), 2.44-2.42 (m, 1H), 2.05-1.98 (m, 1H), 1.91-1.82 (m, 2H), 1.77-1.67 (m, 4H), 0.89 (d, 9H), 0.05 (s, 3H), 0.04 (s, 3H). |
612 mg | With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1.5h; | To a solution of <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (518 mg) in DMF (15 mL) was added cesium carbonate (3.21 g) and (3-bromopropoxy)-tert-butyldimethylsilane (0.838 mL). The resulting reaction mixture was heated to 50 C. for 1.5 hours before cooling back to room temperature. Water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate (2×). The combined organics were washed with water (2×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO, 0 to 40% ethyl acetate in hexanes with 1% triethylamine) gave the desired product (612 mg). 1H NMR (400 MHz, CDCl3): delta (ppm) 4.20 (t, 1H), 3.71-3.64 (m, 2H), 3.46 (t, 1H), 2.62 (t, 1H), 2.50-2.47 (m, 1H), 2.44-2.42 (m, 1H), 2.05-1.98 (m, 1H), 1.91-1.82 (m, 2H), 1.77-1.67 (m, 4H), 0.89 (d, 9H), 0.05 (s, 3H), 0.04 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 23 - 95℃; for 19h;Inert atmosphere; | Under nitrogen, to <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (552 mg, 3.50 mmol, 1.00 equiv) in toluene (10 mL) at 23 C was added BetaIotaNuAlphaRho (327 mg, 0.530 mmol, 0.150 equiv), 4- iodonitrobenzene (853 mg, 4.20 mmol, 1.20 equiv), Pd(OAc)2 (79 mg, 0.35 mmol, 0.10 equiv), and cesium carbonate (2.90 g, 8.80 mmol, 2.50 equiv). After stirring for 19 hr at 95 C, the reaction mixture was warmed to 23 C and 0 (10 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (30 mL) and dried (MgS04). The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel eluting with hexanes/EtOAc to afford 628 mg of the title compound as a yellow solid (74% yield). R/= 0.14 (hexanes/EtOAc 9: 1 (v/v)). NMR Spectroscopy: *H NMR (300 MHz, CDC13, 23 C, delta): 8.13 (d, / = 7.2 Hz, 2H), 6.85 (d, J = 1.2 Hz, 2H), 3.65 (t, / = 11.4 Hz, 2H), 3.52-3.42 (m, 2H), 2.21-2.01 (m, 2H), 1.97-1.85 (m, 2H). iyF NMR (281 MHz, CDC13, 23 C, delta) 101.69 (m, 2F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.8% | 3,3-Difluoropiperidine hydrochloride (319 mg, 2.02 mmol) was added to a stirred solution of 7- bromo-5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carbaldehyde (Intermediate 3) (500 mg, 1.84 mmol) in MeOH (9 mL) and glacial acetic acid (1 mL). The mixture was stirred at room temperature for 15 minutes then 2-picolineborane complex (216 mg, 2.02 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated. Saturated sodium bicarbonate solution (15 mL) was added. The mixture was extracted with DCM (3x15 mL). The combined extracts were dried and evaporated. The residue was purified by column chromatography on silica gel (2-4% MeOH/DCM) to give the title compound (442 mg, 1 .172 mmol, 63.8 % yield) as a yellow solid. LCMS (2 min, Formic Acid): Rt = 0.85 min, MH+ = 377/379 Intermediate 96: 7-bromo-2-((3-fluoropiperidin-1 -yl)methyl)-5-methylthienor3,2-c1pyridin- 4(5H)-one The title compound was prepared using a method similar to that described for Intermediate 95. Yellow solid (346 mg, 0.963 mmol, 52.4 % yield). LCMS (2 min, Formic Acid): Rt = 0.49 min, MH+ = 359/361. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; acetic acid; triethylamine; In 1,2-dichloro-ethane; at 20℃; for 12h; | To a dichloroethane (10 mL) solution of methyl (lS)-3- oxocyclopentanecarboxylate (0.28 mL, 2.2 mmol, step A), <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (420 mg, 2.7 mmol, 1.2 equiv.), and triethylamine (0.43 mL, 3.1 mmol, 1.4 equiv.) were added sodium triacetoxyborohydride (940 mg, 4.4 mmol, 2.0 equiv.) and acetic acid (0.25 mL, 4.4 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 12 hours and quenched with IN aqueous sodium hydroxide. It was extracted with dichloroethane, dried (sodium sulfate), and concentrated in vacuo to afford a crude product. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound as a diastereomeric mixture. LC/MS = 248 [M+l]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14 mg | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; | To a solution of Example W-44 (50 mg, 0.060 mmol), 3,3-difluoropiperidine/HCl (39.0 mg, 0.247 mmol), HATU (71.1 mg, 0.187 mmol) in DCM (2 mL) was added DIEA (0.105 mL, 0.603 mmol). The reaction mixture was stirred at rt overnight. Then 2 M ammonia in MeOH (2 mL) was added and the reaction mixture was stirred at rt for 3 h. The volatile component was removed in vacuo and the residue was purified by a preparatory HPLC (CH3CN/H2O/NH4OAc) system to yield Example W-46A (14 mg), LC/MS (Cond. W-1): [M+H]+ 807.6, Rt=1.535 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 5℃; | Compound 31 (1 equivalent) was dissolved in dichloromethane, cooled to 5 C. and trifluoroacetic acid (2-3 w/v) was added and stirred at room temperature for 4 h. The reaction mixture was concentrated and the residue dissolved in dimethylformamide and cooled to 5 C. before addition of diisopropylethyl amine (10 equivalents). TBTU (1.8 equivalents) was added followed by <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (1.2 equivalents). The reaction was stirred until completion and added to 1M citric acid and solid collected by filtration. The solid was crystallized from ethylacetate/heptane to give ACH-0142684 (1 purity>98%). ACH-0142684 was suspended in methanol and aqueous sodium hydroxide (1.05 equivalents) was added at about 5 C. to give a clear solution. The reaction mixture was concentrated to dryness and the residue crystallized from IPA to give crystalline ACH-0142684·Na. The crystalline ACH-0142684.Na was dissolved in a mixture of methanol/ethyl acetate and the solution was added to pentane. The solid was collected by filtration and dried to give ACH-0142684·Na in the amorphous form (purity>98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14 mg | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; | To a solution of Example W-44 (50 mg, 0.060 mmol), 3,3- difluoropiperidine/HC1 (39.0 mg, 0.247 mmol), HATU (71.1 mg, 0.187 mmol) in DCM (2 mL) was added DIEA (0.105 mL, 0.603 mmol). The reaction mixture was stirred at rt overnight. Then 2 M ammonia in MeOH (2 mL) was added and thereaction mixture was stirred at rt for 3 h. The volatile component was removed invacuo and the residue was purified by a preparatory HPLC (CH3CN/H20/NH4OAc)system to yield Example W-46A (14 mg), LC/MS (Cond. W-1): [M+H] 807.6, R =1.535 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With sodium tris(acetoxy)borohydride; triethylamine; In 1,2-dichloro-ethane; at 20℃; | 3,3-Difluoropiperidine hydrochloride [CAS RN: 496807-97-7] (531 mg, 3.37 mmol,1.6 eq), 5-chloropyrazine-2-carbaldehyde [CAS RN: 88625-24-5] (300 mg,2.11 mmol, 1.0 eq) and sodium triacetoxyborohydride (1.43 g, 6.74 mmol,3.2 eq) were suspended in 20 mL 1,2-dichloroethane. Then, triethylamine (0.59 mL, 4.21 mmol, 2.0 eq) was added and the reaction mixture was stirred at rt overnight. Then, water was added. After stirring for 10 mm, the resulting phases were separated by the use of a Whatman filter. The volatile components of theorganic phase were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 9/1 -> hexane/ethyl acetate 1/1) to give 340 mg (58% yield of theory) of the title compound.UPLC-MS (Method 2): R = 1.09 mm; MS (EI0): m/z = 248 [M+H].1H-NMR (400 MHz, DMSO-d6): oe [ppm] = 1.64 (m, 2H), 1.86 (m, 2H), 2.73 (t, 2H),3.78 (5, 2H), 8.49 (d, 1H), 8.74 (d, 1H), 2H?s obscured by solvent signal. |
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