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Structure of 88675-24-5
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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.
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CAS No. : | 88675-24-5 |
Formula : | C4H9NO |
M.W : | 87.12 |
SMILES Code : | NC1COCC1 |
MDL No. : | MFCD07778394 |
InChI Key : | MIPHRQMEIYLZFZ-UHFFFAOYSA-N |
Pubchem ID : | 3365553 |
GHS Pictogram: |
![]() ![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H225-H302-H315-H318 |
Precautionary Statements: | P280-P305+P351+P338 |
Class: | 3(8) |
UN#: | 2924 |
Packing Group: | Ⅲ |
Num. heavy atoms | 6 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 23.02 |
TPSA ? Topological Polar Surface Area: Calculated from |
35.25 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.24 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.66 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.27 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.57 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.6 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.07 |
Log S (ESOL):? ESOL: Topological method implemented from |
0.04 |
Solubility | 94.6 mg/ml ; 1.09 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (Ali)? Ali: Topological method implemented from |
0.39 |
Solubility | 216.0 mg/ml ; 2.47 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.04 |
Solubility | 80.2 mg/ml ; 0.92 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 |
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) |
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 |
-7.3 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) |
1.45 |
* 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 hydrogen;palladium 10% on activated carbon; In methanol; hydrogen chloride; water; at 20℃; under 760.051 Torr; for 18h; | [0152] 2) The N-benzyloxycarbonyl-3-aminotetrahydrofuran thus prepared (3.4 gm, 15 mmol) was dissolved in methanol (50 ml) and concentrated hydrochloric acid. Pd-C (10percent, 300 mg) was added, and the mixture was hydrogenated at 1 atmosphere for 18 hours at room temperature. The mixture was filtered through a pad of celite, and the filtrate concentrated under reduced pressure. The residue was co-evaporated twice with a mixture of ethyl acetate and methanol, and then recrystallized from a mixture of ethyl acetate and methanol to give 1.9 g of 3-aminotetrahydrofuran as a yellow solid.[0153] If the starting 3-tetrahydrofuroic acid is chiral, then the product (3-aminotetrahydrofuran) is also chiral, i.e., the synthesis is stereospecific. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In methanol; at 80℃; for 40h; | [0154] 3. A mixture of 6-chloropurine riboside (0.5 gm, 1.74 mmol), <strong>[88675-24-5]3-aminotetrahydrofuran</strong> (0.325 gm, 2.6 mmol) and triethylamine (0.73 ml, 5.22 mmol) in methanol (10 ml) was heated to 80° C. for 40 hours. The mixture was cooled and concentrated under reduced pressure. The residue was chromatographed on a short column of silica gel, eluting with methylene chloride/methanol/propylamine (90/10/1). The fractions containing the product were combined and concentrated under reduced pressure. The residue was chromatographed on a chromatotron (2 mm plate, 92.5/7.5/1, methylene chloride/methanol/propylamine). The resulting white solid was recrystallized from methanol/ethyl acetate to give 0.27 gm of (4S,2R,3R,5R)-2-hydroxymethyl-5-[6-(tetrahydrofuran-3-ylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol as white crystals (mp 128° C.-130° C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With sodium acetate; sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; methanol; at 20℃; for 4.05h; | a) A solution of TETRAHYDROFURAN-3-AMINE (see W098/08855, 0.500 g, 4.04 mmol) and sodium acetate (0.331 g, 4.04 mmol) in a 1: 3 mixture of methanol and tetrahydrofuran (60 ml) was stirred at room temperature. To this was added (tert-butyl- dimethylsilanyloxy) acetaldehyde (2.112 g, 12.12 mmol) followed by glacial acetic acid (1.456 g, 24.24 mmol) and then sodium triacetoxyborohydride (2.568 g, 12. 12 mmol) was then added in 5 portions over 3 minutes (CAUTION: vigorous effervescence) and the resulting suspension was left to stir at room temperature for 4 hours. The mixture was evaporated under reduced pressure to leave a thick brown paste which was dissolved in dichloromethane (20 ml) and to this was added a solution of ammonia in methanol (7M solution, 25 ml). The mixture was stirred for 10 minutes and then evaporated under reduced pressure to leave an orange paste which was triturated with dichloromethane (50 ml) and filtered through Celite. The mixture was evaporated under reduced pressure to leave a brown gum which was dissolved in methyl tert-butyl ether (3 ML) and then purified by silica gel chromatography using methyl tert-butyl ether as eluent to give N-(2-{ [TERT- butyl (dimethyl) silyl] oxy} ethyl) tetrahydrofuran-3-amine (0.446 g, 48percent yield) as a brown oil: 1H-NMR (CDC13) : 3. 68 (8H, m), 2. 68 (2H, m), 2.04 (1H, m), 1.73 (1H, m), 0. 82 (9H, s), 0.00 (6H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 180℃; for 0.333333h;Microwave irradiation; | Step A. (+/-)-N-(2-Nitrophenyl)tetrahvdrofuran-3 -amineA solution of N, jV-diisopropylethylamine (3.20 mL, 18.4mmol), l-fluoro-2- nitrobenzene (0.484 mL, 4.59 mmol), and (+/-)-tetrahydrofuran-3 -amine (400 mg, 4.59 mmol) in rc-butanol (10 mL) was heated to 180 0C in a microwave reactor. After 20 min, the reaction was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography, eluting with a gradient of hexane: EtOAc - 100:0 to 0:100, gave the title compound. MS: mlz = 209 (M + 1). | |
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 180℃; for 0.333333h;microwave reactor; | A solution of N, N-diisopropylethylamine (3.20 mL, 18.4mmol), l-fluoro-2-nitrobenzene (0.484 mL, 4.59 mmol), and (+)-tetrahydrofuran-3 -amine (400 nig, 4.59 mmol) in 7z-butanol (10 mL) was heated to 180 0C in a microwave reactor. After 20 min, the reaction was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography, eluting with a gradient of hexane:EtOAc - 100:0 to 0:100, gave the title compound. MS: mlz = 209 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In methanol; | Preparation of 6-(<strong>[88675-24-5]3-aminotetrahydrofuran</strong>yl)purine Riboside A mixture of 6-chloropurine riboside (0.5 gm, 1.74 mmol), <strong>[88675-24-5]3-aminotetrahydrofuran</strong> (0.325 gm, 2.6 mmol) and triethylamine (0.73 ml, 5.22 mmol) in methanol (10 ml) was heated to 80° C. for 40 hours. The mixture was cooled, and concentrated. The residue was filtered through a short column of silica gel eluding with 90/10/1 (CH2 Cl2 /MeOH/PrNH2) the fractions containing the product were combined and concentrated. The residue was chromatorgraphed on the chromatotron (2 mm plate, 92.5/7.5/1, CH2 CL2 /MeOH/Pr NH2). The resulting white solid was recrystallized from MeOH/EtOAc to give 0.27 gm of white crystals (mp 128°-130° C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | N-(Tetrahydrofuran-3-yl)propionamide A solution of 50 g of <strong>[88675-24-5]3-aminotetrahydrofuran</strong> in 200 ml of dichloromethane was mixed with 63.8 g (0.63 mol) of triethylamine. 58.4 g (0.63 mol) of propionyl chloride were added dropwise with ice-cooling. The mixture was stirred at room temperature for 2 days, resulting in a white precipitate. The solution was filtered and the filtrate was distilled. B.p. 145° C. (12 mm), yield 81 g. 1H NMR (270 MHz, in CDCl3): delta=1.14 (t, 3 H), 1.83 (m, 1H), 2.22 (q, 2H), 2.31 (m, 1H), 3.64 (dd, 1H), 3.72-3.98 (m, 3H), 4.50 (m, 1H), 6.57 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | trans-di(mu-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II); tri tert-butylphosphoniumtetrafluoroborate; In tetrahydrofuran; at 125℃; for 0.166667h; | To N-[(7i?, 2S)- 1 - { [ 1 -(3-bromophenyl)- 1 eta-indazol-5-yl]oxy } - 1 -(6-methoxypyridin-3- yl)propan-2-yl]-2,2-difluoropropanamide (37 mg, 68mumol), <strong>[88675-24-5]3-aminotetrahydrofuran</strong> (18 mg, 204mumol), tri-t-butylphosphoniumtetrafluoroborat (8.8 mg, 31 mumol) and trans- bis(acetato)bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(II) (10.3 mg, 14mumol) in 1.5 mL THF was added molybdaenhexacarbonyl (12.5 mg, 47 mumol). The microwave vessel was closed and radiated in a microwave reactor (CEM discover) at 150 W and 125°C for 10 minutes (5 minutes ramp time. Then the solvent was removed i.vac, and the product purified by preparative thin layer chromatography on silica gel (ethyl acetate 100percent) to <n="57"/>yield 11 mg (30percent) 3-(5-[(7i?,25)-2-[(2,2-difluoropropanoyl)amino]-l-(6- methoxypyridin-3 -yl)propyl]oxy } - 1 H-indazol- 1 -y l)-N-(tetrahydrofuran-3 -yl)benzamide . ES+MS: m/z 580 [MH+]1H-NMR (300 MHz, CDCl3); delta = 8.20 (d, IH), 8.08 (dd, IH), 8.02 (s, IH), 7.83 (m, IH), 5 7.71 (m, IH), 7.67 (d, IH), 7.60 (dd, IH), 7.58 (t, IH), 7.16 (dd, IH), 6.99 (d, IH), 6.76 (d, IH), 6.66 (br, IH), 6.43 (br, IH), 5.36 (d, IH), 4.75 (m, IH), 4.40 (dq, IH), 4.01 (m,lH), 3.92 (s, 3H), 3.91 (m, IH), 3.83 (m, 2H), 2.38 (m, IH), 1.95 (m, IH), 1.77 (t, 3H), 1.29 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine; In toluene; at 50℃;Inert atmosphere; | Example 4 3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (tetrahydro-furan-3-yl)-amide To a solution of 3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (298 mg, 0.95 mmol) and <strong>[88675-24-5]tetrahydrofuran-3-ylamine</strong> (99 mg, 1.14 mmol) in toluene (1.5 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (40 mg, 0.28 mmol) and the reaction stirred under argon overnight at 50° C. Then the mixture was evaporated and the residue purified by chromatography (silica, heptane:ethyl acetate=4:1 to 1:1) to afford the title compound (87 mg, 25percent) which was obtained as a colourless gum. MS: m/e=370.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Example 456-(5-Hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(tetrahydrofuran-3-yl)-nicotinamide; To a solution of 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.21 mmol) in DMF (5 mL) was added <strong>[88675-24-5]3-aminotetrahydrofuran</strong> (26 mg, 0.30 mmol), N,N,N',N'-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (96 mg, 0.30 mmol) and N,N-diisopropyl ethylamine (0.15 mL, 0.84 mmol). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was partitioned (ethyl acetate/aqueous saturated sodium bicarbonate solution) and the organic phase was dried (Na2SO4) and concentrated. Chromatography (silica, dichloromethane:methanol=100:0 to 97:3) afforded the title compound (58 mg, 68percent) as a colorless oil. MS: m/e=397.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; water; at 20℃; | Example 97Rac-5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole- 3-carboxylic acid (tetrahydro-furan-3-yl)-amideTo a solution of 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H- pyrazole-3-carboxylic acid (100 mg, 0.29 mmol) in THF (10 mL) was added 1 -hydro xybenzotriazo Ie hydrate (45.0 mg, 0.29 mmol), N-ethyldiisopropylamine (126 muL, 0.76 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimidazole hydrochloride (56.3 mg, 0.29 mmol) and rac-<strong>[88675-24-5]3-aminotetrahydrofuran</strong> (25.1 mg, 0.29 mmol) and the resulting mixture stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by chromatography (silica, dichloromethane:methanol = 99:1 to 95:5) afforded the title compound (60 mg, 50percent) as a white solid. MS: m/e = 415.1 [M-H]". |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.3% | With dmap; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 25℃; for 4h; | EXAMPLE 44: (2i?)-2-(6-fluoro-3-oxopyrrolo[4,3,2-Je][2,6]naphthyridin- 4(l/f,3/f,5H)-yl)-3-methyl-Lambda/-(tetrahydrofuran-3-yl)butanamide[0410] To an 8 mL scintillation vial equipped for stirring was added (i?)-2-(6-fluoro-3- oxopyrrolo[4,3,2-(ie][2,6]naphthyridin-4(lH,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol). DMF (0.5 mL), tetrahydrofuran-3 -amine (0.077, 6.7mg), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25°C for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50percent). The fractions were collected and lyophilized to afford the title compound as a white solid (7.3mg, 39.3percent). 1H NMR (400 MHz, CD3OD) delta 0.93 (d, J=6.57 Hz, 3 H) 1.04 (dd, J=6.57, 2.78 Hz, 3 H) 1.74 -1.95 (m, 1 H) 2.21 (d, J=7.83 Hz, 1 H) 2.42 - 2.54 (m, 1 H) 3.50 - 3.67 (m, 1 H) 3.69 - 3.97 (m, 3 H) 4.37(td, J=3.85, 1.89 Hz, 1 H) 4.96 - 5.12 (m, 2 H) 5.36 - 5.52 (m, 1 H) 7.86 (s, 1 H) 8.17 (d, J=3.28 Hz, 1 H). [M+H] calc'd for Ci8H2IFN4O3, 361; found, 361.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of 4-chloropyrrolo[l,2-b]pyridazine-3-carbonitrile (15g) (0.15 g, 0.84 mmol) in DMF (2 mL) was added at room temperature tetrahydrofuran-3-amine (53a) (0.22 mgs, 2.52 mmol), DIPEA (0.87 mL, 5 mmol) and stirred at room temperature overnight. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL). The aqueous layer was separated and extracted with ethyl acetate (2 x 10 mL). The organic layers were combined washed with water (2 x 10 ml), brine (10 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel 12g, eluting with 0-100% ethyl acetate in hexanes) to furnish 4-(tetrahydrofuran-3- ylamino)pyrrolo[l,2-b]pyridazine-3-carbonitrile (53b) (0.175 g, 91%) as a tan solid; 1H NMR (300 MHz, DMSO) d 7.95 (s, IH), 7.89 (d, J = 7.0, IH), 7.71 (dd, J = 1.6, 2.6, IH), 7.24 (dd, J = 1.6, 4.5, IH), 6.69 (dd, J = 2.7, 4.4, IH), 4.86 (dt, J = 3.6, 11.1, IH), 4.01 - 3.83 (m, 3H), 3.76 (td, J = 5.8, 8.3, IH), 2.39 - 2.23 (m, IH), 2.15 (m, IH); IR (KBr) 2194 cm-1; MS (ES-) 227.0(M-I) 262.9 (M+Cl); Analysis: Calcd for C12H12N4O? 0.25 H2O: C, 61.92; H, 5.41; N, 24.07; Found: C, 62.05; H, 5.23; N, 24.01. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | b) Preparation of the intermediate compound l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-iV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide l-(5,6-Dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (1.0 g, 3.7 mmol), tetrahydrofuran-3 -amine hydrochloride (0.54 g, 4.4 mmol), 2-(7-aza-lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (EtaATU, 2.8 g, 7.4 mmol), N,N- diisopropylethylamine (Etaunig's base, DIEA, 0.96 g, 7.4 mmol) and N,N-dimethylformamide (25 mL) were stirred at room temperature for 1 hour. After an extractive work-up, the crude was chrystallized from dichloromethane/petroleum ether to give 1.0 g (83percent yield) of l-(5,6- dimethyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 5h; | Example 31: l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-iV-(tetrahydrofuran-3- yl)piperidine-4-carboxamide(a) Preparation of the intermediary compound l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide To a solution of l-(5,6-dichloro-lH-benzoimidazol-2-yl)-piperidine-4-carboxylic acid (0.3 g, 0.95 mmol) in N,Lambda/-dimethylformamide (5 niL) was added 2-(7-aza-lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (EtaATU, 0.544 g, 1.4 mmol) followed by N,N- diisopropylethylamine (Etaunig's base, DIEA, 0.33 mL, 1.9 mmol) and tetrahydrofuran-3 -amine (0.1 g, 1.1 mmol). The reaction mixture was stirred at room temperature for 5 hours,concentrated in vacuo and extracted with ethyl acetate (2 x50 mL). The combined organic phases were dried over anhydrous sodium sulphate and subjected to column chromatography(chloroform/methanol 95:5) to give 0.135 g (37 percent yield) of l-(5,6-dichloro-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 383.2 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h; | A suspension of (+/-)-tetrahydro~3-furanamine (1.1 g, 8.90 mmol, Small Molecules Inc., NJ, USA), 1 ,1-dimethyIethyl (2-bromoethy.)carbamate (1.995 g, 8.90 mmol), and potassium carbonate (3.69 g, 26.7 mmol) in N.N-dimethylformannide (15 mL) was maintained at 50 °C in a sealed pressure vessel for 16 hours. The mixture was cooled, diluted with ethyi acetate, and poured into water. The organic layer was washed twice with 5percent LiCI (aqueous), dried over sodium sulfate, and taken to a residue under reduced pressure to afford 1 ,1-dimethylethyl [2-(tetrahydro-3- furanylamino)ethyl]carbamate (1.33 g, 5.77 mmol, 65percent yield, roughly 50percent purity) as a clear oil used immediately in the subsequent transformation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine; In tetrahydrofuran; at 20℃; for 0.5h;Inert atmosphere; | <strong>[88675-24-5]3-aminotetrahydrofuran</strong> (33 mg, 0.38 mmol) was dissolved in 2 mL THF then Et3N (0.26 mL, 1.9 mmol) was added followed by dropwise addition of benzoyl chloride (53 L, 0.46 mmol) under N2. The mixture stirred at rt for 30 min. LCMS indicated complete conversion with formation of the desired product 22 with expected mass [M+H]+ = 192. Water (0.5 mL) was added then THF was removed under reduced pressure, the product extracted with ethyl acetate, dried over Na2SO4, filtered, concentrated under reduced presure then purified by column chromatography (EtOAc:Hexanes 1:1) to give 63.2 mg of white solid in 87percent yield.1H NMR (400 MHz, CDCl3) delta 7.90 (d, J = 8.3 Hz, 2H), 7.45 (m, 1H), 7.33 (t, J =8.0 Hz, 2H), 6.58 (br, 1H), 4.75 (m, 1H), 4.00 (m, 1H), 3.9 (m, 1H), 3.8 (m, 2H), 2.35 (m, 1H), 1.95 (m, 1H) (consistent with the spectral data in the following reference: Desai, V.L.; Sanford, M.S. Angew. Chem. Int. Ed. 2007, 46, 5737-5740. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 24h; | Example 26 1-(6-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-N-(tetrahydrofuran-3-yl)-2,3-dihydro-1H-indole-5-carboxamide; [Show Image] To a mixture of 1-(6-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-2,3-dihydro-1H-indole-5-carboxylic acid (150 mg) obtained in the below-mentioned Example 75, <strong>[88675-24-5]3-aminotetrahydrofuran</strong> (42.9 muL), and N,N-dimethylformamide (10 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (192 mg) and N-ethyldiisopropylamine (87.8 muL), and the mixture was stirred at room temperature for 1 day. Water was added to the reaction mixture, and the mixture was extracted with a mixed solution of ethyl acetate and tetrahydrofuran. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with 50percent ethyl acetate/hexane to give the title compound (150 mg,87percent) as a white solid. 1H-NMR (300 MHz, CDCl3)delta:1.20 (t, J=7.6 Hz, 3 H), 1.72 - 2.00 (m, 3 H), 2.04 - 2.16 (m, 2 H), 2.29 - 2.43 (m, 1 H), 2.47 (q, J=7.6 Hz, 2 H), 3.27 (t, J=8.5 Hz, 2 H), 3.50 - 3.64 (m, 2 H), 3.76 - 3.96 (m, 3 H), 3.97 - 4.07 (m, 3 H), 4.23 - 4.35 (m, 2 H), 4.67 - 4.80 (m, 1 H), 5.34 - 5.46 (m, 1 H), 5.97 (s, 1 H), 6.19 (d, J=7.2 Hz, 1 H), 7.58 (dd, J=8.5, 1.5 Hz, 1 H), 7.65 (d, J=1.5 Hz, 1 H), 8.19 (s, 2 H), 8.41 (d, J=8.5 Hz, 1 H), 8.51 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In methanol; at 30℃; for 16h;Inert atmosphere; | General procedure: All reactions were carried out in vials under nitrogen atmosphere. Step 1: A solution of compound 15 (125 mumol, 1.0 equiv) and compound 16 (125 mumol, 1.0 equiv) in MeOH (0.3 M) was treated with NaHCO3 (250 mumol, 2.0 equiv) and stirred for 16 h at 30 °C. The reaction was then treated with NaBH4 (125 mumol, 1.0 equiv) and stirred for 3 h (LCMS check). The reaction mixture was filtered and concentrated. The crude amine was suspended in 1 N NaOH (1 mL) and extracted with dichloromethane (3 × 1 mL). The organics were pooled, dried (Na2SO4) and evacuated to afford 18. Step 2: A solution of 17 (75 mumol, 0.60 equiv) in DMF (0.1 M) was treated with HATU (75 mumol, 0.60 equiv) followed by the crude amine 18 (125 mumol, 1.0 equiv) and iPr2NEt (225 mumol, 1.8 equiv). The reactions were concentrated and purified directly by reversed phase preparative HPLC using a C18 column and eluting with acetonitrile?water (0.225percent formic acid or pH = 10 NH4OH) gradient. All compounds were deemed greater than 95percent purity by LCMS and HPLC. #10; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.41 g | In ethanol; at 20℃; for 1h; | To a solution of tetrahydrofuran-3-amine (2.94 g) in ethanol (20 mL) was added 4-thioxo-l, 3-thiazolidin-2-one (3.0 g) , and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration and washed with ethanol to give the title compound (2.41 g).XH NMR (300 MHz, DMSO-d6) delta 1.80-1.92 (1H, m) , 2.18 (1H, dq, J = 13.0, 7.6 Hz), 3.60-3.88 (4H, m) , 4.22 (2H, s) , 4.32-4.43(1H, m) , 9.29 (1H, d, J = 5.3 Hz) .MS (ESI+) : [M+H]+187.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1.08333h;Inert atmosphere; Microwave irradiation; | Example A30 To a solution of Example A3 (2.0 g, 5.7 mmol) in NMP (10 mL) was added <strong>[88675-24-5]tetrahydro-furan-3-ylamine</strong> (1.5 g, 17.2 mmol) and DBU (1.7 g, 11.4 mmol). Nitrogen was bubbled through the mixture for 5 min and then it was heated in the microwave at 180° C. for 1 h. The reaction mixture was cooled to RT, poured into water and extracted with EtOAc (3*). The combined organics were washed with brine, dried over Na2SO4, concentrated under reduced pressure and purified by silica gel chromatography to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(tetrahydrofuran-3-ylamino)-1,6-naphthyridin-2(1H)-one (0.57 g, 25percent yield). 1H NMR (400 MHz, DMSO-d6): delta 8.39 (s, 1H), 7.66 (s, 1H), 7.27 (d, J=6.4 Hz, 1H), 7.18 (d, J=11.2 Hz, 1H), 6.72 (d, J=9.6 Hz, 1H), 6.33 (s, 1H), 5.31 (s, 2H), 4.46-4.42 (m, 1H), 4.08 (q, J=6.8 Hz, 2H), 3.89-3.81 (m, 2H), 3.75-3.69 (m, 1H), 3.55-3.52 (m, 1H), 2.22-2.17 (m, 1H), 1.83-1.79 (m, 1H), 1.20 (t, J=6.8 Hz, 3H). |
25% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1h;Inert atmosphere; Microwave irradiation; | Example A30: To a solution of Example A3 (2.0 g, 5.7 mmol) in NMP (10 mL)was added <strong>[88675-24-5]tetrahydro-furan-3-ylamine</strong> (1.5 g, 17.2 mmol) and DBU (1.7 g, 11.4 mmol).Nitrogen was bubbled through the mixture for 5 min and then it was heated in the microwaveat 180°C for 1 h. The reaction mixture was cooled to RT, poured into water and extractedwith EtOAc (3x). The combined organics were washed with brine, dried over Na2S04,concentrated under reduced pressure and purified by silica gel chromatography to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7 -(tetrahydrofuran-3-ylamino )-1 ,6-naphthyridin-2(1H)-one (0.57 g, 25percent yield). 1H NMR (400 MHz, DMSO-d6): b 8.39 (s, 1 H), 7.66 (s, 1H), 7.27 (d, J = 6.4 Hz, 1 H), 7.18 (d, J = 11.2 Hz, 1 H), 6.72 (d, J = 9.6 Hz, 1 H), 6.33 (s, 1H), 5.31 (s, 2 H), 4.46-4.42 (m, 1 H), 4.08 (q, J = 6.8 Hz, 2 H), 3.89-3.81 (m, 2 H), 3.75-3.69(m, 1 H), 3.55-3.52 (m, 1 H), 2.22-2.17 (m, 1 H), 1.83-1.79 (m, 1 H), 1.20 (t, J = 6.8 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With triethylamine; In dichloromethane; at 0℃; for 0.166667h; | a) 7-bromo-4-chloro-N-(tetrahydrofuran-3-yl)quinoline-3-sulfonamide. To a solution of 7-bromo-4-chloro-3-quinolinesulfonyl chloride (530 mg, 1 .56 mmol) and triethylamine (313 mg, 3.1 mmol) in dry dichloromethane (8 mL) was added a solution of tetrahydrofuran-3-amine (149 mg, 1 .7 mmol) in dichloromethane (2 mL) dropwise at 0 °C. The mixture was stirred for 10 minutes. TLC showed the starting material was consumed completely. Water (10 mL) was added and the mixture extracted with dichloromethane (20 mL x 3). The combined organic phases were concentrated and purified by silica gel chromatography (25percent ethyl acetate/petroleum ether) to afford the title compound (420 mg, 69percent) as a solid. 1 H NMR (300 MHz, DMSO-d6) delta ppm 1.67-1.75 (m, 1 H), 1.87-1.98 (m, 1 H), 3.41 - 3.46 (m, 1 H), 3.54-3.76 (m, 3 H), 3.86-3.92 (m, 1 H), 8.05 (dd, J=2.1 , 9.0 Hz, 1 H), 8.37 (d, J=9.0 Hz, 1 H), 8.45 (d, J=2A Hz, 1 H), 8.73 (d, J=7.5 Hz, 1 H), 9.27 (s, 1 H). LCMS (ES+) m/e 391 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
240 mg | With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 22 - 26℃; for 10h;Inert atmosphere; | Step-a: Synthesis of 3-Nitro-N-(tetrahydrofuran-3-yl)benzamide Tetrahydrofuran-3-amine (0.1 g, 1.148 mmol) and 3-nitrobenzoic acid (0.192 g, 1.148 mmol) were taken in pyridine (2 ml), to the mixture EDC.HCl (0.220 g, 1.148 mmol) was added, the reaction mixture was stirred under nitrogen for 10 hrs at room temperature. The reaction mixture was diluted with cold water (15 ml), extracted with ethyl acetate (2*10 ml). Combined organic layer was washed with satd. aq. sod bicarbonate and dil HCl, the organic layer was dried over sodium sulfate and concentrated under vacuum to afford the title product (240 mg). 1HNMR (400 MHz, CDCl3): delta 8.62-8.61 (m, 1H), 8.39-8.36 (m, 1H), 8.19-8.17 (m, 1H), 7.67 (t, 1H, J=8 Hz), 6.62 (d, 1H, J=6 Hz), 4.79-4.75 (m, 1H), 4.08-4.00 (m, 1H), 3.93-3.83 (m, 3H), 2.44-2.37 (m, 1H), 2.01-1.98 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 6h; | A mixture of (6-(4-((6-chloropyridazin-3-yl)methoxy)-2-oxopyridin-l (2H)-yl)-7,8- dihydronaphthalen-2-yl)methyl methanesulfonate (350 mg, 0.739 mmol), tetrahydrofuran-3- amine (77 mg, 0.886 mmol) and K2CO3 (306 mg, 2.216 mmol) in N, N-dimethylformamide (DMF) (15 mL) was stirred at 80 °C for 6 hr, then solvent was removed to give the residue which was purified by prep HPLC and chiral prep HPLC to give 4-[(6-chloropyridazin-3- yl)methoxy]-l - {6-[(tetrahydrofuran-3-ylamino)methyl]-3,4-dihydronaphthalen-2-yl}pyridin- 2(lH)-one hydrochloride as a yellow solid (peak 1 , 65 mg, 1 1.2percent yield): 1H NMR (400 MHz, CD3OD) delta ppm 8.05 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.41-7.38 (m, 2H), 7.30-7.28 (m, 1H), 6.89-6.87 (m, 1H), 6.80 (s, 1H), 6.63 (d, J = 2.4 Hz, 1H), 5.64 (s, 2H), 4.23-4.21 (m, 2H), 4.06-3.95 (m, 3H), 3.86-3.82 (m, 1H), 3.75-3.72 (m, 1H), 3.1 1 -3.09 (m, 2H), 2.76-2.68 (m, 2H), 2.43-2.41 (m, 1H), 2.15-2.10 (m, 1H); ES- LCMS m/z 465 (M+H), and 4-[(6-chloropyridazin-3-yl)methoxy]-l - {6-[(tetrahydrofuran-3- ylamino)methyl]-3,4-dihydronaphthalen-2-yl}pyridin-2(lH)-one hydrochloride as a yellow solid (peak 2, 49.3 mg, 8.5percent yield): 1H NMR (400 MHz, CD3OD) delta ppm 7.98-7.93 (m, 3H), 7.41-7.38 (m, 2H), 7.30-7.28 (m, 1H), 6.85-6.79 (m, 2H), 6.61 -6.60 (m, 1H), 5.64 (s, 2H), 4.23-4.22 (m, 2H), 4.05-4.00 (m, 3H), 3.87-3.83 (m, 1H), 3.73-3.71 (m, 1H), 3.13-3.09 (m, 2H), 2.73-2.67 (m, 2H), 2.41-2.39 (m, 1H), 2.12-2.10 (m, 1H); ES-LCMS m/z 465 ( +H)+. Chiral HPLC method Instrument: Thar 80 Column: AS 250mm*20mm, 20um Mobile phase: A: Supercritical C02, B: MeOH, A: B =55:45 at 80mL/min Column Temp: 38°C Nozzle Pressure: lOOBar Nozzle Temp: 60°C Evaporator Temp: 20°C Trimmer Temp: 25°C Wavelength: 220nm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Example 6B (0.018 g, 0.05 mmol) was dissolved in acetonitrile (0.5 ml), and treated with potassium carbonate (0.021 g, 0.15 mmol) and 1 -(2-chloroethyl)pyrrolidine (0.017 g, 0.1 mmol). The reaction mixture was heated via microwave at 180 °C for 30 minutes, concentrated in vacuo, and submitted to reverse-phase HPLC (as described in Example 6C) to provide the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1-methyl-pyrrolidin-2-one; at 110℃; for 48h; | General procedure: Step 2 A mixture of 76 (80 mg, 0.195 mmol), (S)-(+)-2-amino-1-propanol (75 mg, 0.977 mmol), and NMP (0.551 mL, 5.86 mmol) was mixed and heated at 110° C. for 48 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC purification eluting with a MeCN/H2O (containing 0.1percent NH4OH) gradient (5 to 85percent MeCN) over 14 min to afford I-24 as a yellow solid. The title compounds were prepared as a racemate in accord with the procedure in example 2 except in step 2, (S)-(+)-2-amino-1-propanol was replaced with tetrahydrofuran-3-amine and subsequently resolved via chiral supercritical fluid chromatography (diastereomers are arbitrarily assigned). [0340] Diastereomer 1: 1H NMR (400 MHz, DMSO) delta 9.21 (d, J=8.7 Hz, 1H), 9.03 (s, 1H), 8.40 (d, J=8.3 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.61 (s, 1H), 7.39 (s, 1H), 7.32 (dd, J=12.6, 1.9 Hz, 1H), 7.21 (m, 2H), 7.13 (t, J=8.6 Hz, 1H), 6.76 (s, 1H), 6.23 (d, J=8.6 Hz, 1H), 4.33 (m, 1H), 3.94 (dd, J=8.8, 5.9 Hz, 1H), 3.87 (dd, J=15.4, 7.4 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.78-3.71 (m, 1H), 3.64 (dd, J=8.8, 3.8 Hz, 1H), 2.24 (m, 1H), 1.90 (m, 1H). LCMS (Method G): RT=9.82 min, M+H+=477.2. ERK IC50 1.27 nM. [0341] Diastereomer 2: 1H NMR (400 MHz, DMSO) delta 9.21 (d, J=8.7 Hz, 1H), 9.03 (s, 1H), 8.40 (d, J=8.3 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.61 (s, 1H), 7.39 (s, 1H), 7.32 (dd, J=12.6, 1.9 Hz, 1H), 7.24-7.18 (m, 2H), 7.13 (t, J=8.6 Hz, 1H), 6.76 (s, 1H), 6.23 (d, J=8.6 Hz, 1H), 4.32 (m, 1H), 3.94 (dd, J=8.8, 5.9 Hz, 1H), 3.87 (dd, J=15.3, 7.4 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.76 (m, 1H), 3.64 (dd, J=8.8, 3.8 Hz, 1H), 2.24 (m, 1H), 1.90 (m, 1H). LCMS (Method G): RT=9.77 min, M+H+=477.2. ERK IC50 2.75 nM. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1-methyl-pyrrolidin-2-one; at 140℃; for 24h; | The following Examples were prepared according to Method 5 (Example 54) above using 8-chloro-A/-(2-methoxy-4-(1 -methyl-1 H-pyrazol-4-yl)phenyl)pyrido[3,4- d]pyrimidin-2-amine (Example 94) and the appropriate amine as described. Where the amine hydrochloride was used, triethylamine (190uL, 0.373 mmol) was also added to the reaction. The crude reaction residues were purified as above or according to one of the following methods: Method A: Silica gel column chromatography eluting with 0-5percent or 0-10percent MeOH in DCM. Method B: Silica gel column chromatography eluting with 0-5percent MeOH in EtOAc. Method C: Silica gel column chromatography eluting with 0-70percent EtOAc in cyclohexane followed by reverse phase preparative HPLC eluting with 10-90percent MeOH in water (0.1percent formic acid). N2-(2-methoxy-4-(1 -methyl- NMR (500 MHz, DMSO-d6): delta 9.20 (s, 0.008 1 H-pyrazol-4-yl)phenyl)-N8- 1H), 8.51 (s, 1H), 8.16 (s, 1H), 8.14 (d, J = (tetrahydrofuran-3- 8.3 Hz, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.81 (d, yl)pyrido[3,4-d]pyrimidine-2,8- J = 5.7 Hz, 1 H), 7.27 (d, J = 1.9 Hz, 1 H), 7.21 diamine (dd, J =8.2, 1.9 Hz, 1H), 6.93 (d, J = 5.7 Hz, 1 H), 6.78 (br d, J = 6.8 Hz, 1 H), 4.68 - 4.58 (m, 1 H), 3.98 - 3.85 (m, 8H), 3.82 - 3.75 (m, HN'^ ^ OMe 1H), 3.68 (dd, J = 8.9, 3.9 Hz, 1H), 2.36 - FontWeight="Bold" FontSize="10" UpsilonUpsilonUpsilonIota 2.25 (m, 1 H), 2.03 - 1.93 (m, 1 H). T -N~~ HRMS (ESI) MS m/z calcd for C22H24N702 [M+H]+ 418.1986, found 418.1983. Using tetrahydrofuran-3-amine at 140°C for 24 hours and purification method B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | Example 60 8-(4-Chlorophenyl)-N-(tetrahydrofuran-3-yl)-l,6-naphthyridine-2-carboxamide A mixture of 8-(4-chlorophenyl)-l,6-naphthyridine-2-carboxylic acid (0.08 g, 0.28 mmol), N, N- diisopropylethylamine (0.04 g, 0.06 ml, 0.34 mmol) and 0-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU, 0.13 g, 0.35 mmol) in dimethylformamide (1 ml) was stirred at room temperature for 1 hour. Tetrahydrofuran-3-amine (0.03 g, 0.31 mmol) was added and stirring was continued for 5 hours. Removal of the solvent by distillation and chromatography (C18 reverse phase, methanol / water (0.1percent formic acid) = 20:80 to 95:5) yielded the title compound as a solid (0.002 g, 2percent). MS: m/e = 354.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In tetrahydrofuran; for 2h; | To a solution of 2,4-dichloro-5-nitropyridine (386 mg, 2.0 mmol), and triethylamine (417 \L, 3.0 mmol) in THF (6 mL) was added dropwise <strong>[88675-24-5]tetrahydrofuran-3-ylamine</strong> (208 mg, 2.4 mmol) and the reaction mixture was stirred for 1 h. An additional amount of <strong>[88675-24-5]tetrahydrofuran-3-ylamine</strong> (50 mg) was added and the reaction mixture was stirred for 1 h. The volatiles were removed in vacuo and the resulting residue was partitioned between water and EtOAc. The organic phase was dried (MgS04) and concentrated in vacuo to afford the title compound as a yellow solid (490 mg, quantitative). LCMS (ESI): [M+H]+ 244.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 4h; | DIPEA (1 .93ml, 1 1 .1 mmol) was added to a solution of Tricyclo[3.3.1.13,7]decane-1 - carbonyl chloride (1 ) (2g, 10.1 mmol) and <strong>[88675-24-5]3-aminotetrahydrofuran</strong>; (29)(1 .0ml, 1 1 mmol) in DCM (20ml) and the solution stirred at room temperature for 4 hours. The solution was washed with 0.1 N HCI (30ml), saturated NaHC03 (30ml), dried (Na2S04), filtered and the solvents removed to give crude product which was further purified via crystallization from 15percent EA in hexanes to give as a white solid | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 4h; | DIPEA (1 .93ml, 1 1 .1 mmol) was added to a solution of Tricyclo[3.3.1.13,7]decane-1 - carbonyl chloride (1 ) (2g, 10.1 mmol) and <strong>[88675-24-5]3-aminotetrahydrofuran</strong>; (29)(1 .0ml, 1 1 mmol) in DCM (20ml) and the solution stirred at room temperature for 4 hours. The solution was washed with 0.1 N HCI (30ml), saturated NaHC03 (30ml), dried (Na2S04), filtered and the solvents removed to give crude product which was further purified via crystallization from 15percent EA in hexanes to give as a white solid | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 4h; | DIPEA (1.93 ml, 11.1 mmol) was added to a solution of Tricyclo[3.3.1.13,7]decane-1-carbonyl chloride (1) (2 g, 10.1 mmol) and <strong>[88675-24-5]3-aminotetrahydrofuran</strong>; (29)(1.0 ml, 11 mmol) in DCM (20 ml) and the solution stirred at room temperature for 4 hours. The solution was washed with 0.1N HCl (30 ml), saturated NaHCO3 (30 ml), dried (Na2SO4), filtered and the solvents removed to give crude product which was further purified via crystallization from 15percent EA in hexanes to give as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 0.0833333h;Flow reactor; | The synthesis was conducted in flow. Reagent solution A contained 4-(4-chlorophenyl)isoquinoline-6-carboxylic acid (8 mg, 28.2 11mol), 0-(benzotriazol-1-yl)- N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 10.9 mg, 33.8 11mol) and N,N diisopropylethylamine (10.9 mg, 14.8 111, 84.6 11mol) in dimethylformamide (230 Ill) and reagent solution B contained <strong>[88675-24-5]tetrahydrofuran-3-ylamine</strong> (106 111 of a 0.4 M stock solution in dimethylformamide, 42.3 11mol) in dimethylformamide (144 Ill). The two reagent solutions were injected (0.250 mL of each solution) by means of Gilson LH 215 auto-sampler into the reactor sample loops (Gilson 819). Then, both reagent streams were combined at aT-piece connectorand the reagent mixture heated at 120 °C for 5 min in a 10 ml PFA tube reactor coil. The crude product stream was purified in-line by preparative HPLC (C18 reverse phase, acetonitrile I water (0.05 percenttriethylamine)= 2:98 to 98:2) to yield the title compound as a colorless oil (2.2 mg,16 percent). MS: m/e = 353.4 [M+Ht. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | at 130℃; for 4h; | Tetrahydrofuran amine (198mg, 1.92mmol) was dropwise added to (4S,5R)-5-[3,5- bis(trifluoromethyl)phenyl]-4-methyl-3-[(2-chloro-5-trifluoromethylpyridin-3-yl)met^ oxazolidin-2-one obtained in step 3. This reaction mixture was refluxed at 130°C for 4 hrs with stirring, cooled to room temperature, diluted with ethyl acetate, and then extracted with water. The organic layer thus formed was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography to afford the title compound (130 mg, 36percent). 1 H NMR (400MHz, CDCI3) 8.36 (s, 1 H), 7.89 (s, 1 H), 7.71 (d, J = 2.8Hz, 2H), 7.36 (s, 1 H), 5.71 (d, J = 8.0Hz, 1 H), 4.68 (m, 2H), 4.13-3.97 (m, 4H), 3.90 (m, 2H), 3.76 (m, 2H), 2.33 (m, 1 H), 1.99 (m, 1 H), 0.88 (t, 3H), 0.80 (m, 3H). |
A188717 [204512-95-8]
(S)-Tetrahydrofuran-3-amine hydrochloride
Similarity: 0.96
A213685 [204512-94-7]
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