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CAS No. : | 3105-95-1 | MDL No. : | MFCD00005981 |
Formula : | C6H11NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HXEACLLIILLPRG-YFKPBYRVSA-N |
M.W : | 129.16 | Pubchem ID : | 439227 |
Synonyms : |
H-HoPro-OH
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.83 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 37.33 |
TPSA : | 49.33 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.73 cm/s |
Log Po/w (iLOGP) : | 1.16 |
Log Po/w (XLOGP3) : | -2.31 |
Log Po/w (WLOGP) : | -0.17 |
Log Po/w (MLOGP) : | -2.21 |
Log Po/w (SILICOS-IT) : | 0.46 |
Consensus Log Po/w : | -0.61 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.88 |
Solubility : | 981.0 mg/ml ; 7.59 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 1.81 |
Solubility : | 8340.0 mg/ml ; 64.6 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.42 |
Solubility : | 48.5 mg/ml ; 0.376 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.69 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | at 0 - 20℃; | (S)-Piperidme-2-carboxylic acid (10.00 g, 77.46 mmol) in methanol (200ml) at 0°Cwas added thionyl chloride (15.0 ml, 205.61 mmol) under Ar. The mixture was stirred at 0°C for 30 min, then RT overnight, evaporated and crystallized with EtOH to afford the title product (9.90 g, 92percent yield). EIMS m/z 144.1 ( | M ]++I I ). |
79.1% | at 0 - 70℃; for 4 h; | To a solution of (i)-piperidine-2-carboxylic acid ( 10.0 g. 77.4 mmol) in MeOH (50 mL) was added thionyl chloride (8.5 mL, 1 17.2 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 hr and at 70 °C for another 3 hrs. After the reaction was completed, the mixture was concentrated in vacuo to give the title compound as a white solid (11.0 g, 79.1percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 144.1 [M+H] +; NMR (400 MHz, CDC13) δ (ppm): 5.02 (br, 1 H), 4.00 (br, 1 H), 3.85 (s, 3H), 3.63 (br, 1 H), 3.15 (br, 1 H), 2.28 (m, 1 H), 2.08 (m, 2H), 1.86 (m. 2H), 1.63 (br, 1H). |
79.1% | at 0 - 70℃; for 4 h; | To a solution of L(-)-pipecolinic acid (10.0 g.77.4 mmol) in MeOH (50 mL) was added thionyl chloride (8.5 mL 117.2 mmol) dropwise at 0 °C. At the end of the addition, the mixture was stirred at 0 °C for 1.0 hr and then at 70 °C for another 3.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo to give the title compound as a white solid (11.0 g.79.1percent). The compound was characterized by the following spectroscopic data:MS (LSI. pos.ion) w r: 144.1 [M+H] : and NMR (400 MHz. CDCl;,)i)(ppm): 5.02 (br. lH).4.00(br.1 H).3.85 (s.3H).3.63 (br. lH).3.15(br. lH). 2.28 (m.1H).2.08 (m.2H).1.86 (m.2H).1.63 (br.1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate In 1,4-dioxane at 20℃; | Synthesis of building blocks A Synthesis of (S)-1 -(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-2-carboxylic acid A solution of the L-pipecolic acid (3.6g, 38.7 mmol) in 40ml of 10percent sodium carbonate was dissolved in round bottom flask and allowed to stir for 5 min at rt. To this solution was added F-moc succinamide (8.5g, 34.8 mmol) dissolved in 35 ml dioxane and the reaction was stirred overnight. After overnight stirring water was added and the aqueous layer was extracted with ethyl acetate. The aqueous layer was made acidic (pH-2) by addition of concentrated HCI. The acidic layer was extracted with ethyl acetate (3x 40ml). The organic phase was washed with 1 N HCI followed by brine, dried over MgSO4 and concentrated under vacuo to yield a oily colorless liquid. The oily liquid was dissolved in ether and cooled to get fluffy white solid which was washed with hexane and dried to yield (S)-1 -(((9H-fluoren-9- yl)methoxy)carbonyl)piperidine-2-carboxylic acid ( 8.2g, 38.7mmol, 83percent). TLC (Hexane:EtOAc: TFA 1 : 1 : 0.2): RF = 0.60 HPLC (Gradient A) retention time= 24.6-24.8 min 1 H NMR (300 MHz, CDCI3) 5=1 .28-1 .53 (m, 2H), 1 .69-1 .82 (m, 3H), 2.19-2.37 (m, 1 H), 3.15 (t, 1 H, J= 13.2Hz), 4.05-4.33 (m, 2H), 4.37-4.49 (m, 2H), 4.76-5.05(m, 1 H), 7.28-7.41 (m, 4H), 7.55-7.62 (m, 2H), 1 .77 (s, 2H). 13C NMR (75 MHz, CDCI3) δ= 20.72, 24.70, 26.55, 41 .94, 47.25, 54.19, 67.86, 1 19.97, 125.08, 127.07, 127.68, 141 .33, 143.89, 156.65, 177.36 MS (ESI) m/z 352.66 [M + H] \ calculated 352.40 [M + H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.41 g | With sodium carbonate In 1,4-dioxane; water at 0 - 20℃; for 16 h; | To a stirred mixture of (S)-piperidine-2-carboxylic acid (1.0 g, 7.75 mmol) and Na2C03 (1.65 g, 15.50 mmol) in water (10 mL) was added a solution of FMOC-C1 (3.0 g, 11.63 mmol) in 1,4-dioxane (10 mL) dropwise at 0°C and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 mL) and washed with MTBE (25 mL). The aqueous layer was acidified with 1M aqueous HC1 (10 mL) to pH 2 and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous a2S04, filtered and concentrated to afford the title compound (1.41 g) as an off-white solid. The crude product was used in the next step without purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: With dimethylsulfide borane complex; boron trifluoride diethyl etherate In tetrahydrofuran at 0℃; Reflux Stage #2: With hydrogenchloride; methanol In water at 0℃; Reflux |
Amino alcohol B-12: (S)-Piperidin-2-ylmethanolBH3-DMS (62.0 mmol, 4.0 equiv.) and BF3-Et2O (15.5 mmol, 1.0 equiv.) were added at 0° C. to a solution of (2S)-piperidine-2-carboxylic acid (15.5 mmol, 1.0 equiv.) in THF (50 ml), and the mixture was refluxed for 14 hours. The solvent was concentrated under reduced pressure, and then MeOH (40 ml) was added dropwise at 0° C. Concentrated HCl (5 ml) was added to the reaction mixture, and refluxing was carried out for a further 2 hours. The solvent was concentrated, and the residue was stirred for 15 minutes in 10percent isopropanol in DCM and filtered. The filtrate was concentrated to dryness, and a white solid was obtained. Yield: 80percent. |
44% | With dimethylsulfide borane complex; boron trifluoride diethyl etherate In tetrahydrofuranReflux | (S)-Piperidine-2-carboxylic acid (2 g, 15.5 mmol) was initially introduced into tetrahydrofuran (20 ml) and boron trifluoride etherate (2.1 ml, 117.1 mmol) was added, followed by boron dimethylsulfide in tetrahydrofuran (dropwise, 3 ml, 30.9 mmol). The reaction mixture was then refluxed for 16 h. The mixture was quenched with ice-cooled methanol (10 ml), hydrogen chloride solution (conc. aq., 3 ml) was added dropwise and the mixture was refluxed for 30 min. After cooling, the mixture was rendered alkaline with dilute sodium hydroxide solution (4percent) and extracted with methylene chloride (3.x.50 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was employed in the next stage without further purification. |
44% | Stage #1: With dimethylsulfide borane complex; boron trifluoride diethyl etherate In tetrahydrofuranReflux Stage #2: With hydrogenchloride; water In tetrahydrofuranCooling with ice; Reflux |
Synthesis of Carboxylic Acid 1 (Acid Structural Unit)(S)-2-((1-(4-Methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acidUsed in the Synthesis of Examples 25, 80 and 81 (i): (S)-Piperidine-2-carboxylic acid (2 g, 15.5 mmol) was placed in tetrahydrofuran (20 ml); boron trifluoride etherate (2.1 ml, 117.1 mmol) was added, followed by boron dimethylsulfide in tetrahydrofuran (dropwise, 3 ml, 30.9 mmol). The reaction mixture was then refluxed for 16 h. Quenching was carried out with ice-cold methanol (10 ml); hydrogen chloride solution (conc. aq., 3 ml) was added dropwise, and refluxing was carried out for 30 min. After cooling, the mixture was rendered alkaline with dilute sodium hydroxide solution (4percent) and extracted with dichloromethane (3.x.50 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was used in the next stage without being purified further. Yield: 44percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With thionyl chloride; at 0 - 20℃; | (S)-Piperidme-2-carboxylic acid (10.00 g, 77.46 mmol) in methanol (200ml) at 0°Cwas added thionyl chloride (15.0 ml, 205.61 mmol) under Ar. The mixture was stirred at 0°C for 30 min, then RT overnight, evaporated and crystallized with EtOH to afford the title product (9.90 g, 92percent yield). EIMS m/z 144.1 ( | M ]++I I ). |
79.1% | With thionyl chloride; at 0 - 70℃; for 4h; | To a solution of (i)-piperidine-2-carboxylic acid ( 10.0 g. 77.4 mmol) in MeOH (50 mL) was added thionyl chloride (8.5 mL, 1 17.2 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 hr and at 70 °C for another 3 hrs. After the reaction was completed, the mixture was concentrated in vacuo to give the title compound as a white solid (11.0 g, 79.1percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 144.1 [M+H] +; NMR (400 MHz, CDC13) delta (ppm): 5.02 (br, 1 H), 4.00 (br, 1 H), 3.85 (s, 3H), 3.63 (br, 1 H), 3.15 (br, 1 H), 2.28 (m, 1 H), 2.08 (m, 2H), 1.86 (m. 2H), 1.63 (br, 1H). |
79.1% | With thionyl chloride; at 0 - 70℃; for 4h; | To a solution of L(-)-pipecolinic acid (10.0 g.77.4 mmol) in MeOH (50 mL) was added thionyl chloride (8.5 mL 117.2 mmol) dropwise at 0 °C. At the end of the addition, the mixture was stirred at 0 °C for 1.0 hr and then at 70 °C for another 3.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo to give the title compound as a white solid (11.0 g.79.1percent). The compound was characterized by the following spectroscopic data:MS (LSI. pos.ion) w r: 144.1 [M+H] : and NMR (400 MHz. CDCl;,)i)(ppm): 5.02 (br. lH).4.00(br.1 H).3.85 (s.3H).3.63 (br. lH).3.15(br. lH). 2.28 (m.1H).2.08 (m.2H).1.86 (m.2H).1.63 (br.1H). |
With thionyl chloride; at 0 - 70℃; for 4h; | 11655] To a solution of (s)-piperidine-2-carboxylic acid (10.0 g, 77.4 mmol) in MeOH (50 mE) was added thionyl chloride (8.5 mE, 117.2 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 1 hr and at 70° C. for another 3 hrs. Afier the reaction was completed, the mixture was concentrated in vacuo to give the title compound as a white solid (11.0 g, 79.1percent). The compound was characterized by the following spectroscopic data:11656] MS (ESI, pos.ion) mlz: 144.1 [M+H]11657] ?H NMR (400 MHz, CDC13) oe (ppm): 5.02 (br, 1H),4.00 (br, 1H), 3.85 (s, 3H), 3.63 (br, 1H), 3.15 (br, 1H), 2.28 (m, 1H), 2.08 (m, 2H), 1.86 (m, 2H), 1.63 (br, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In 1,4-dioxane; water; | Step A N-(t-Butoxycarbonyl)piperidine-2(S)-carboxylic acid 2(S)-Piperidinecarboxylic acid (3.0 g, 0.023 mol) was dissolved in dioxane (30 mL) water (30 mL) with stirring and cooling in an ice-water bath, and the solution brought to pH 8 with diisopropylethylamine. The resulting solution was treated alternately with di-tert-butyl dicarbonate (11 mL, 0.048 mol) and diisopropylethylamine (total of 15 mL, 0.086 mol) then stirred at ambient temperature for 16 h. The reaction mixture was treated with 0.1N NaOH solution (200 mL) and extracted with EtOAc (3*100 mL). The organics were combined, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was used without further purification. | |
With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; | To a solution of L-(-)-<strong>[3105-95-1]pipecolinic acid</strong> (1.55 g, 12 mmol) in aqueous solution of NaOH (1M, 24 mL) and dioxane (6 mL) was added Boc2O (3.3 ml, 14.4 mmol) dropwise over 10 min at 0 C. The resulting mixture was stirred at 0 C for 30 min and then allowed to warm to room temperature overnight. The reaction mixture was acidified to pH = 2 with a 1 M aqueous solution of HCl and extracted with CH2Cl2 (3 * 100 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, and concentrated by rotary evaporation to afford a white solid, which was sufficiently pure to be used for the next step. To a solution of the above acid in 20 mL anhydrous CH2Cl2 were added 8-aminoquinoline (2.1 g, 1.2 equiv), EDCI (2.8 g, 1.2 equiv) and DMAP (293 mg, 0.2 equiv). The resulting mixture was stirred at room temperature for 36 h, then quenched with aqueous solution of HCl (1M, 80 mL) and diluted with EtOAc (100 mL). The organic layers were separated and the aqueous layer was extracted with EtOAc (3 * 70 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. Flash column chromatography (silica gel, Petroleum ether: EtOAc 20: 1) afforded a known compound (-)-2 1 (3.07 g, 72%, 91.8% ee) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium carbonate; In 1,4-dioxane; water; | To a 100 mL roundbottom containing a stir bar was added (<S)-piperidine-2- carboxylic acid (0.500 g, 3.8 mmol) followed by a 1 : 1 mixture of water: dioxane (20 mL). Stirring commenced and sodium carbonate was added (0.525 g, 5.0 mmol). Gas evolved; once the evolution had ceased most of the solid had dissolved. To this stirring mixture was added Cbz-Cl (0.325 mL, 0.391 g, 2.3 mmol) dropwise. The reaction mixture was allowed to stir overnight. The following day, the reaction mixture was concentrated to approximately half-volume on a rotary evaporator. This mixture was transferred to a separatory funnel and extracted with DCM (50 mL). This extract was discarded. In the separatory funnel, the aqueous layer was acidified by addition of concentrated HC1 until the aqueous layer was acidic (pH ~ 2 by pH paper). The acidified aqueous layer was extracted with DCM (3 x 50 mL). The organic layers were combined and dried over sodium sulfate and concentrated in vacuo to yield the pure product as a clear oil (0.904 g, 89 %). Spectroscopic data matches that reported for this compound. 'H NMR (500 MHz) (CDCb) (amide rotamers) d: 10.08 (1H, br s), 7.37 -7.31 (5H, m), 5.16 (2H, m), 5.01 - 4.90 (1H, app d), 4.10 (1H, app d), 3.10 - 2.97 (1H, m), 2.25 (1H, dd, J= 27.5, 12.5 Hz), 1.73 - 1.63 (3H, m), 1.47 - 1.23 (2H, m). 13C NMR (125 MHz) (CDCb) (amide rotamers) d: 177.6, 177.5, 156.7, 155.9, 136.4, 128.4, (0412) 128.0, 127.8, 67.5, 67.4, 54.3, 54.1, 41.9, 41.7, 26.6, 26.5, 24.6, 24.4, 20.7, 20.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; at 24.84℃; for 2h;Inert atmosphere; UV-irradiation;Kinetics; | 2.6. Photocatalytic reaction | |
With Cp*Ir(biot-p-L)Cl; D-amino acidoxidase from porcine kidney; L-amino acid oxidase from Crotalus atrox; streptavidin S112A mutant; oxygen; sodium formate; catalase from bovine liver; In aq. buffer; at 37℃;pH 7.8;Enzymatic reaction; | General procedure: The following stock solutions were prepared. Catalase from bovine liver (50 kU ml-1) was dissolved in MOPS/sodium formate buffer (0.6 M in MOPS, 3.0 M in sodium formate, pH adjusted with aq. KOH to pH 7.8). Sav S112T (16.4 mg ml-1, 0.75 mM free binding sites, assuming three free binding sites per tetramer) was dissolved in the catalase containing buffer. [IrCp*(biot-p-L)Cl] was dissolved in DMF (37.5 mM). Affinity purified MAO-N-9 (buffer exchange with MOPS, 0.6 M, pH adjusted with KOH to 7.8) was diluted in MOPS buffer (0.6 M, pH adjusted with KOH to 7.8) to a concentration of 0.38 mg ml-1. Substrate stock was prepared by dissolving the hydrochloride of 1-ox in H2O (1 M). The ATHase was prepared by adding [IrCp*(biot-p-L)Cl]-stock (10 mul ml-1) to the Sav-stock solution. MAO-N-stock was placed in 1.5 ml PP-tubes (100 mul) and ATHase was added (100 mul). The reactions were initiated by addition of substrate stock solution (7.5 mul) and incubated at 37 C and 250 r.p.m. in a lying position. For work-up aq. NaOH solution was added (50 mul of a 10 M solution) and the mixture extracted with CH2Cl2 (1 × 1 ml). The organic phase was dried over Na2SO4 and analysed by HPLC (Supplementary Sections S2.3.1 and S2.4.1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; hydrogen In methanol for 15h; Ambient temperature; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 95%Chromat. | With hydrogenchloride; alpha-ketoglutaric acid; ammonium iron (II) sulfate; L-proline cis-3-hydroxylase type I; sodium L-ascorbate; In aq. buffer; at 21℃; for 14h;pH 6.5;Enzymatic reaction; | General procedure: Analytical scale proline hydroxylase (PH) incubations were performed by sequential addition of the reagents in Table S1 to a 1.5 mL Eppendorf tube (100 muL final volume): The incubation mixture was kept at 21 C for 14 h (unless otherwise stated). To quench the reaction, an equal volume of methanol was added and the mixture cooled on ice for 10 min before centrifugation (13,000g for 3 min); the quenching methanol contained 0.25 mM p-aminosalicylic acid (pASA) as an internal standard. The supernatant was decanted and analysed by an LC/MS. ?Negative controls? were performed in parallel, but with substitution of 50 mM MES-NaOH, pH 6.5 for the enzyme solution. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 95%Chromat. | With hydrogenchloride; alpha-ketoglutaric acid; ammonium iron (II) sulfate; L-proline trans-4-hydroxylase; sodium L-ascorbate; In aq. buffer; at 21℃; for 14h;pH 6.5;Enzymatic reaction; | General procedure: Analytical scale proline hydroxylase (PH) incubations were performed by sequential addition of the reagents in Table S1 to a 1.5 mL Eppendorf tube (100 muL final volume): The incubation mixture was kept at 21 C for 14 h (unless otherwise stated). To quench the reaction, an equal volume of methanol was added and the mixture cooled on ice for 10 min before centrifugation (13,000g for 3 min); the quenching methanol contained 0.25 mM p-aminosalicylic acid (pASA) as an internal standard. The supernatant was decanted and analysed by an LC/MS. ?Negative controls? were performed in parallel, but with substitution of 50 mM MES-NaOH, pH 6.5 for the enzyme solution. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium hydroxide; In water; | To a 50 mL roundbottom flask containing a stir bar was added (<S)-pipecolic acid (0.250 g, 1.9 mmol) and water (5 mL) followed by 2N aqueous sodium hydroxide (0.200 g, 5.0 mmol in 5 mL water). Stirring commenced and methyl chloroformate was added (0.160 mL, 0.198 g, 2.1 mmol). The reaction mixture was allowed to stir overnight. The following day the reaction was quenched with the addition of concentrated HC1 (until pH ~ 2 by pH paper) and extracted twice with ethyl acetate (30 mL per extraction). The organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to yield the crude product as a clear oil. The crude material was purified by silica gel chromatography (1 :1 ethyl acetate: hexanes) to yield the pure produce as a clear oil (0.238 g, 66 %). Spectroscopic data matches that reported for this compound. NMR (500 MHz) (CDCb) (amide rotamers) d: 9.65 (1H, br s), 4.90 (1H, app d), 4.04 (1H, app dd), 3.72 (3H, app d), 3.06 - 2.94 (1H, m), 2.25 (1H, br t, J = 15.0 Hz), 1.73 - 1.64 (3H, m), 1.44 - 1.27 (2H, m). 13C NMR (125 MHz) (CDCb) (amide rotamers): 177.5, 177.4, 157.3, 156.6, 54.3, 54.0, 53.0, 41.8, 41.6, 26.7, 26.5, 24.6, 24.4, 20.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.1% | With thionyl chloride; at 0 - 70℃; for 2h; | To a solution of L-<strong>[3105-95-1]pipecolinic acid</strong> (10 g, 77.4 mmol) in MeOH (50 mL) was added dropwise thionyl chloride(8.5 mL, 117.2 mmol) slowly in an ice bath. The mixture was stirred at 0 C for 1 hour, then stirred at 70 C for another1 hour and concentrated in vacuo to give the title compound 45-1 as a white solid (11.0 g, 79.1%, HPLC: 65%). Thecompound was characterized by the following spectroscopic data:MS-ESI: m/z 144.1 [M-HCl+H]+; and1H NMR (400 MHz, CDCl3): delta 5.02 (br, 1H), 4.00 (br, 1H), 3.85 (s, 3H), 3.63 (br, 1H), 3.15 (br, 1H), 2.28 (m, 1H),2.08 (m, 2H), 1.86 (m, 2H), 1.63 (br, 1H). |
56% | With thionyl chloride; at 20℃; for 2h; | Example 47-7: (S)-Piperidine-2-carboxylic acid methyl ester; To a mixture of (S)-piotape?diotane-2-carboxyliotac acid (10 mmol, 1 29 g) in MeOH (20 mL) is dropwise added thionyl chloride (30 mmol, 2 17 mL) at room temperature The mixture is stirred at 2 hours, and then concentrated under reduced pressure To the residue is added water (5 mL) and basified with potassium carbonate The mixture is extracted with CH2CI2 The combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure to give (S)-piotaperiotadiotane-2-carboxyliotac acid methyl ester as a pale brown oil (800 mg, 56%)1 H NMR (400 MHz, CHLOROFORM-c/) delta ppm 1 40 - 1 61 (m, 4 H) 1 74 - 1 85 (m, 1 H) 1 92 - 2 01 (m, 1 H) 2 62 - 2 71 (m, 1 H) 3 05 - 3 1 1 (m, 1 H) 3 37 (dd, J=9 73, 3 16 Hz, 1 H) 3 64 (s, 1 H) 3 72 (s, 3 H) |
With thionyl chloride; at -5 - 40℃; for 7h;Neat (no solvent); | To a suspension of (S)-(-)-2-piperidinecarboxylic acid in methanol (30 mL) at -5 C. under a positive pressure of dry argon, thionyl chloride (1.25 mL, 17.1 mmol) was added in dropwise manner. Thereafter the suspension was slowly warmed to 40 C. and further stirred at 40 C. for 7 hours. The solvent was then evaporated to yield 2.7 g of white powder, whose structure was confirmed as that of piperidine-2-carboxylic acid methyl ester by 1H NMR (D2O, 300 MHz): delta 1.61-1.94 (m, 5H), 2.29-2.35 (dd, J=2.6 Hz & 13.2 Hz, 1H), 3.02-3.12 (dt, J=2.5 Hz, 9.0 Hz, 1H), 3.45-3.52 (m, 1H), 3.85 (s, 3H, Me), 4.04-4.10 (dd, J=3.3 Hz, 11.4 Hz, 1H). 13C NMR (D2O, 75 MHz): delta 21.21, 21.37, 25.61, 44.15, 53.63, 56.80, 170.21. |
With thionyl chloride; at 0 - 70℃; for 2h;Cooling with ice; | To a solution of L-<strong>[3105-95-1]pipecolinic acid</strong> (10 g, 77.4 mmol) in MeOH (50 mL) was added dropwise thionyl chloride (8.5 mL, 117.2 mmol) slowly in an ice bath. The mixture was stirred at 0 C for 1 hour, then stirred at 70 C for another 1 hour and concentrated in vacuo to give the title compound 45-1 as a white solid (11.0 g, 79.1%, HPLC: 65%). The compound was characterized by the following spectroscopic data: MS-ESI: m/z 144.1 [M-HCl+H]+; and1H NMR (400 MHz, CDCl3): delta 5.02 (br, 1H), 4.00 (br, 1H), 3.85 (s, 3H), 3.63 (br, 1H), 3.15 (br, 1H), 2.28 (m, 1H), 2.08 (m, 2H), 1.86 (m, 2H), 1.63 (br, 1H). | |
With thionyl chloride; In dichloromethane; at -10 - 20℃; for 18h;Inert atmosphere; | Methyl (2S)-piperidine-2-carboxylate (S)-(L)-Pipecolic acid (6.1 g, 47.2 mmol) was added to methanol (47.2 mL) under an N2 atmosphere. To this solution thionyl chloride (6.9 mL, 94.3 mmol) was slowly added at -10 C. The reaction mixture was allowed to warm to rt and was stirred for 18 hours. Reaction mixture was evaporated and co-evaporated with toluene and dried under vacuum. The crude methyl (2S)-piperidine-2-carboxylate was used in next step without further purification or characterization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 45% 2: 12% | With hydrogen; trifluoroacetic acid In methanol for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With porcine kidney D-amino acid oxidase; Pseudomonas putida N-methyl-L-amino acid dehydrogenase; Tris buffer In various solvent(s) at 30℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; for 0.333333h;Heating / reflux; | L-Pipecolinic acid (0.9g, 6.97 mmol) is dissolved in 40 mL of absolute EtOH. HCl gas is bubbled for -1 minute. The reaction mixture is refluxed for 20 min, cooled and the solvents removed by rotary evaporation to give 1.34g of the title compound, a wax that is used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.41 g | With sodium carbonate; In 1,4-dioxane; water; at 0 - 20℃; for 16h; | To a stirred mixture of (S)-piperidine-2-carboxylic acid (1.0 g, 7.75 mmol) and Na2C03 (1.65 g, 15.50 mmol) in water (10 mL) was added a solution of FMOC-C1 (3.0 g, 11.63 mmol) in 1,4-dioxane (10 mL) dropwise at 0°C and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 mL) and washed with MTBE (25 mL). The aqueous layer was acidified with 1M aqueous HC1 (10 mL) to pH 2 and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous a2S04, filtered and concentrated to afford the title compound (1.41 g) as an off-white solid. The crude product was used in the next step without purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: kinetic resolution through transesterification using acylase I from Aspergillus sp. and vinyl butyrate 2: 1.) DMSO, (COCl)2, 2.) Et3N / 1.) CH2Cl2, -70 deg C, 90 min, 2.) CH2Cl2, from -70 deg C to RT 3: 76 percent / KMnO4, MgSO4 / acetone / 0.5 h / Ambient temperature 4: 94 percent / H2 / 10percent Pd/C / methanol / 6 h / 2327.2 Torr / Ambient temperature | ||
Multi-step reaction with 3 steps 1: kinetic resolution through transesterification using acylase I from Aspergillus sp. and vinyl butyrate 2: 77 percent / CrO3, aq.H2SO4 / acetone / 0.25 h / 0 °C 3: 94 percent / H2 / 10percent Pd/C / methanol / 6 h / 2327.2 Torr / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In dichloromethane; at 20℃; | A mixture of L-(-)-<strong>[3105-95-1]pipecolinic acid</strong> (129.2 mg, 1 mmol) and SOCl2 (0.22 mL, 3 mmol, 3.0 equiv) in anhydrous CH2Cl2 (2 mL) was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo to give the crude acyl chloride, which was used for the next step without further purification. The crude acyl chloride and triethylamine (151.8 mg, 1.5 mmol) were dissolved in 10 mL of anhydrous CH2Cl2 and then cooled down to 0 C. 8-Aminoquinoline (144.2 mg, 1.0 mmol) in 5 mL of anhydrous CH2Cl2 was added to the reaction mixture dropwise by syringe at 0 C. The reaction mixture was allowed to warm to room temperature for 1 h, concentrated in vacuo to give the mixture, which was used for the next step without further purification. To the mixture in 10 mL of anhydrous CH3CN were added K2CO3 (414.6 mg, 3.0 mmol) and n-PrI (169.0 mg, 1.0 mmol). The reaction mixture was stirred at 80 C for 7 h, then cooled down to room temperature, concentrated under vacuum. After the reaction mixture was basified by addition of NaOH aqueous solution (0.1 M), the mixture was extracted with CH2Cl2 (4 * 20 mL). The combined extracts were dried over Na2SO4 and concentrated. Flash column chromatography (silica gel, Petroleum ether: EtOAc 20: 1) afforded compound (-)-1 (148,7 mg, 50%) as brown solid, mp 70-71 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | A 100 mg quantity of (free) <strong>[3105-95-1]L-pipecolic acid</strong> was suspended in 1.5 mL (a 15-fold quantity) of toluene, 284 mu L (2.0 equivalents) of 4 mol/L hydrochloric acid/dioxane were added, and the mixture was stirred for one hour. Subsequently, 145 mu L (2.0 equivalents) of phosphoryl chloride were added. A 282 mu L (3.0 equivalents), quantity of 2,6-dimethylaniline was then gradually added and the mixture was stirred overnight at room temperature. 10 mL of water was added to the reaction solution and the mixture was adjusted to pH 6 with 2 mol/L of sodium hydroxide. The mixture was washed twice with 10 mL of toluene. The aqueous phase was further adjusted to pH 11 and extracted twice with 10 mL of toluene. The organic phase was dried with sodium sulfate anhydride, filtered, and evaporated under reduced pressure, yielding 108 mg (60 % yield) of pipecolic acid-2,6-xylidide. | |
42% | A 100 mg quantity of (free) <strong>[3105-95-1]L-pipecolic acid</strong> was suspended in 1 mL of tetrahydrofuran, 62 mu L (1.05 equivalents) of methanesulfonyl chloride were added, and the mixture was stirred for 20 min. at 50C. A 192 mu L (2 equivalents) quantity of 2,6-dimethylaniline was added, the mixture was stirred overnight, 62 muL of methanesulfonyl chloride and 192 muL of 2,6-dimethylaniline were similarly added, and the mixture was again stirred overnight. A 2 mL quantity of water was added to the reaction mixture, the aqueous phase was adjusted to pH 4 with 2 mol/L of sodium hydroxide, and the organic phase was discarded. The remaining aqueous phase was then adjusted to pH 7 with 2 mol/L of sodium hydroxide and washed with 2 mL of toluene. Subsequently, the product was adjusted to pH 9 with 2 mol/L of sodium hydroxide and the product of interest was extracted with toluene. The toluene phase was dried with sodium sulfate anhydride, concentrated under reduced pressure, and dried under vacuum, yielding 67 mg (a crude yield of 42 %) of crude extract. The purity was estimated about 80 % by NMR. | |
10 parts by weight of 2-piperidinecarboxylic acid and120 parts by volume volume ratio of 2: 1 mixture of toluene and chloroform was added conical flask,Stir, HCl gas was introduced to pH2;The conical flask was placed in a sonicator (sonicator power set to 300 W)1.5 parts by volume of N, N-dimethylformamide was added,Dropping 13 parts by weight of thionyl chloride and 20 parts by volume of toluene mixture, dropping completed, 40 ultrasonic 1.5h, nitrogen 1.5h;Dropping 20 parts by weight of 2,6-dimethylaniline and 30 parts by volume of toluene mixture, sonicating at 45 C for 1.2 hours, filtering to obtain brown wet product,Dry to a gray solid, the solid was added to 240The cumulative purified water, the reaction solution was stirred solution;The 10% NaOH solution was added dropwise to the reaction solution, pH was adjusted to 5.1 ~ 6.0, with 60 bodiesContinue to use 10% NaOH solution to adjust the pH to 6.1 ~ 7.0, with 60 parts by volume of toluene extraction, retain the water layer; continue to use 10% NaOH solution to adjust the pH to 7.1 ~ 8.0, with 60 parts by volume Toluene extraction, retaining the water layer; continue to use 10% NaOH solution to adjust the pH to 9 to 10, extraction and extraction with 80 parts by volume of methylene chloride, the organic layer was extracted, the aqueous layer was further extracted with 50 parts by volume of dichloromethane, Anhydrous sodium sulfate dehydration, concentrated under reduced pressure at 40 C, intermediate (I) N- (2,6-dimethyl benzene) -2- piperidinecarboxamide; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In 30 ml of dichloromethane was suspended 1.00 g (7.74 mmol) of (S)-homoproline, and to this suspension was added 1.08 ml (7.74 mmol) of triethylamine. To the mixture was added dropwise under ice cooling and stirring 0.83 ml (7.74 mmol) of methylmalonyl chloride, and the mixture was stirred at the same temperature for 15 minutes. The mixture was further stirred at room temperature for 30 minutes, and saturated aqueous sodium hydrogencarbonate solution was added to this reaction mixture to separate the mixture. The aqueous layer was made pH 2 by the addition of concentrated hydrochloric acid and extracted with a mixture of dichloromethane:isopropanol = 4:1. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was washed with diisopropyl ether to give 1.42 g of the title compound as a pale yellow powder (yield: 80%). Melting Point: 142-144C 1H-NMR Spectrum (500 MHz, CDCl3) delta ppm: 4.40-4.38 (0.8H, m), 4.35-4.29 (0.2H, m), 3.76 (2.4H, s), 3.57-3.43 (3H, m), 3.42 (1.6H, s), 3.00 (0.8H, dd, J = 16Hz, 4Hz), 2.65 (0.2H, dd, J = 16Hz, 4Hz), 2.52 (0.2H, dd, J = 16Hz, 8Hz), 2.46 (0.8H, dd, J = 16Hz, 8Hz), 2.20-2.08 (1H, m), 2.07-1.92 (2H, m), 1.90-1.83 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.3 g (69%) | With thionyl chloride; potassium iodide; potassium carbonate; In diethyl ether; ethanol; n-heptane; water; ethyl acetate; butanone; | Example 27 (S)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-2-piperidinecarboxylic acid hydrochloride STR30 Crude (S)-(-)-2-piperidinecarboxylic acid (19.5 g, prepared as described in example 26) was suspended in ethanol (250 ml), and thionyl chloride (40 ml, 0.46 mol) was added dropwise. After addition was complete, the suspension was heated at reflux temperature for 2 h. The mixture was filtered hot, and the filtrate was cooled to room temperature. Filtration and evaporation in vacuo afforded an oil, which was crystallized by rubbing. Ethanol (10 ml) was added, followed by slow addition of diethyl ether (150 ml). The precipitated solid was filtered off, washed with diethyl ether and dried by suction to give 13.8 g (35% calculated from 2-piperidinecarboxylic acid) <strong>[123495-48-7](S)-(-)-2-piperidinecarboxylic acid ethyl ester hydrochloride</strong>. [alpha]25D =-10.7 (c=4.5% in water) Gas Chromatography (run as described in example 26) of N-acetyl derivative: Rt =47.2 minutes. Enantiomeric excess=96%. 5-(3-Bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.7 g, 8.6 mmol, prepared as described in WO 9518793), potassium carbonate (7.14 g, 52 mmol), potassium iodide (1.4 g, 8.6 mmol), and <strong>[123495-48-7](S)-(-)-2-piperidinecarboxylic acid ethyl ester hydrochloride</strong> (3.3 g, 17 mmol) were mixed in methyl ethyl ketone (50 ml) and heated at reflux temperature for 3 days. After cooling to room temperature, ethyl acetate (100 ml) was added and the mixture was washed with water (2*100 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica gel (600 ml), using a mixture of ethyl acetate and heptane (1:4) as eluent. This afforded 2.3 g (69%) of (S)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-2-piperidinecarboxylicacid ethyl ester as an oil. TLC: Rf =0.22 (SiO2: ethyl acetate/heptane=1:4) |
2.3 g (69%) | With thionyl chloride; potassium iodide; potassium carbonate; In diethyl ether; ethanol; n-heptane; water; ethyl acetate; butanone; | Example 27 (S)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-2-piperidinecarboxylic acid hydrochloride Crude (S)-(-)-2-piperidinecarboxylic acid (19.5 g, prepared as described in example 26) was suspended in ethanol (250 ml), and thionyl chloride (40 ml, 0.46 mol) was added dropwise. After addition was complete, the suspension was heated at reflux temperature for 2 h. The mixture was filtered hot, and the filtrate was cooled to room temperature. Filtration and evaporation in vacuo afforded an oil, which was crystallized by rubbing. Ethanol (10 ml) was added, followed by slow addition of diethyl ether (150 ml). The precipitated solid was filtered off, washed with diethyl ether and dried by suction to give 13.8 g (35% calculated from 2-piperidinecarboxylic acid) <strong>[123495-48-7](S)-(-)-2-piperidinecarboxylic acid ethyl ester hydrochloride</strong>. [alpha]25D=-10.7 (c=4.5% in water) Gas Chromatography (run as described in example 26) of N-acetyl derivative: Rt=47.2 minutes. Enantiomeric excess=96% 5-(3-Bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.7 g, 8.6 mmol, prepared as described in WO 9518793), potassium carbonate (7.14 g, 52 mmol), potassium iodide (1.4 g,8.6 mmol), and <strong>[123495-48-7](S)-(-)-2-piperidinecarboxylic acid ethyl ester hydrochloride</strong> (3.3 g, 17 mmol) were mixed in methyl ethyl ketone (50 ml) and heated at reflux temperature for 3 days. After cooling to room temperature, ethyl acetate (100 ml) was added and the mixture was washed with water (2*100 ml), dried. (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica gel (600 ml), using a mixture of ethyl acetate and heptane (1:4) as eluent. This afforded 2.3 g (69%) of (S)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-2-piperidinecarboxylicacid ethyl ester as an oil. TLC: Rf=0.22 (SiO2: ethyl acetate/heptane=1:4) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.3 g (69%) | With thionyl chloride; potassium iodide; potassium carbonate; In diethyl ether; ethanol; n-heptane; water; ethyl acetate; butanone; | STR30 Crude (S)-(-)-2-piperidinecarboxylic acid (19.5 g, prepared as described in example 26) was suspended in ethanol (250 ml), and thionyl chloride (40 ml, 0.46 mol) was added dropwise. After addition was complete, the suspension was heated at reflux temperature for 2 h. The mixture was filtered hot, and the filtrate was cooled to room temperature. Filtration and evaporation in vacuo afforded an oil, which was crystallized by rubbing. Ethanol (10 ml) was added, followed by slow addition of diethyl ether (150 ml). The precipitated solid was filtered off, washed with diethyl ether and dried by suction to give 13.8 g (35% calculated from 2-piperidinecarboxylic acid) <strong>[123495-48-7](S)-(-)-2-piperidinecarboxylic acid ethyl ester hydrochloride</strong>. [alpha]25D =-10.7 (c=4.5% in water) Gas Chromatography (run as described in example 26) of N-acetyl derivative: Rt =47.2 minutes. Enantiomeric excess=96%. 5-(3-Bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.7 g, 8.6 mmol, prepared as described in WO 9518793), potassium carbonate (7.14 g, 52 mmol), potassium iodide (1.4 g, 8.6 mmol), and <strong>[123495-48-7](S)-(-)-2-piperidinecarboxylic acid ethyl ester hydrochloride</strong> (3.3 g, 17 mmol) were mixed in methyl ethyl ketone (50 ml) and heated at reflux temperature for 3 days. After cooling to room temperature, ethyl acetate (100 ml) was added and the mixture was washed with water (2*100 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica gel (600 ml), using a mixture of ethyl acetate and heptane (1:4) as eluent. This afforded 2.3 g (69%) of (S)-1-(3-(10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5-ylidene)-1-propyl)-2-piperidinecarboxylicacid ethyl ester as an oil. TLC: Rf =0.22 (SiO2:ethyl acetate/heptane=1:4) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In methanol; at 20℃; for 0.333333 - 0.5h; | A solution of 150 g of L-pipecolinic acid (1170 mmol) in methanol (3000 ml) was stirred at room temperature for 10 to 15 min, after which was added 900 mL of saturated methanolic HCl slowly over a period of 20 to 30 min; stirring continued until a clear solution was formed (after about 20 to 30 min). The methanol was then removed by vacuum distillation and the solid obtained was dried to give pure L-pipecolic acid hydrochloride (192.3 g) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;palladium 10% on activated carbon; In methanol; under 760.051 Torr; for 16h; | To mixtures of Pd/C (10 % by wt., dry 30 mg) and methanol (5 mL) is added L- <strong>[3105-95-1]pipecolinic acid</strong> 4a (2.3 mmol, 300 mg) and acetone (1 mL). The reaction mixtures are stirred under 1 atm of H2 for 16 hours. The reaction flask is then purged with N2 and filtered through celite. Removal of the methanol under reduced pressure gave the desired product 4b (310 mg). Found m/z ES+ = 171. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Amino alcohol B-12: (S)-Piperidin-2-ylmethanolBH3-DMS (62.0 mmol, 4.0 equiv.) and BF3-Et2O (15.5 mmol, 1.0 equiv.) were added at 0° C. to a solution of (2S)-piperidine-2-carboxylic acid (15.5 mmol, 1.0 equiv.) in THF (50 ml), and the mixture was refluxed for 14 hours. The solvent was concentrated under reduced pressure, and then MeOH (40 ml) was added dropwise at 0° C. Concentrated HCl (5 ml) was added to the reaction mixture, and refluxing was carried out for a further 2 hours. The solvent was concentrated, and the residue was stirred for 15 minutes in 10percent isopropanol in DCM and filtered. The filtrate was concentrated to dryness, and a white solid was obtained. Yield: 80percent. | |
44% | With dimethylsulfide borane complex; boron trifluoride diethyl etherate; In tetrahydrofuran;Reflux; | (S)-Piperidine-2-carboxylic acid (2 g, 15.5 mmol) was initially introduced into tetrahydrofuran (20 ml) and boron trifluoride etherate (2.1 ml, 117.1 mmol) was added, followed by boron dimethylsulfide in tetrahydrofuran (dropwise, 3 ml, 30.9 mmol). The reaction mixture was then refluxed for 16 h. The mixture was quenched with ice-cooled methanol (10 ml), hydrogen chloride solution (conc. aq., 3 ml) was added dropwise and the mixture was refluxed for 30 min. After cooling, the mixture was rendered alkaline with dilute sodium hydroxide solution (4percent) and extracted with methylene chloride (3.x.50 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was employed in the next stage without further purification. |
44% | Synthesis of Carboxylic Acid 1 (Acid Structural Unit)(S)-2-((1-(4-Methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acidUsed in the Synthesis of Examples 25, 80 and 81 (i): (S)-Piperidine-2-carboxylic acid (2 g, 15.5 mmol) was placed in tetrahydrofuran (20 ml); boron trifluoride etherate (2.1 ml, 117.1 mmol) was added, followed by boron dimethylsulfide in tetrahydrofuran (dropwise, 3 ml, 30.9 mmol). The reaction mixture was then refluxed for 16 h. Quenching was carried out with ice-cold methanol (10 ml); hydrogen chloride solution (conc. aq., 3 ml) was added dropwise, and refluxing was carried out for 30 min. After cooling, the mixture was rendered alkaline with dilute sodium hydroxide solution (4percent) and extracted with dichloromethane (3.x.50 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was used in the next stage without being purified further. Yield: 44percent |
(S)-2-((1-(4-Methoxy-2,6-dimethylphenysulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D]Employed in the Synthesis to give Examples 46, 54-57, 59-61 (i): (S)-Piperidine-2-carboxylic acid (2 g, 15.5 mmol) was initially introduced into tetrahydrofuran (20 ml), and boron trifluoride etherate (2.1 ml, 117.1 mmol) was added, followed by boron dimethyl sulfide in tetrahydrofuran (dropwise, 3 ml, 30.9 mmol). The reaction mixture was then refluxed for 16 h. The mixture was quenched with ice-cooled methanol (10 ml), hydrogen chloride solution (conc. aq., 3 ml) was added dropwise and the mixture was refluxed for 30 min. After cooling, the mixture was rendered alkaline with dilute sodium hydroxide solution (4percent aq.) and extracted with methylene chloride (3.x.50 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was employed in the next stage without further purification. Yield: 44percent. | ||
Synthesis of (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (S2); Stage 1: (S)-Piperidin-2-ylmethanol; (S)-Piperidine-2-carboxylic acid (2 g, 15.5 mmol) was introduced into tetrahydrofuran (20 ml), boron trifluoride etherate (2.1 ml, 117.1 mmol) was added, followed by boron dimethyl sulfide in tetrahydrofuran (dropwise, 3 ml, 30.9 mmol). The reaction mixture was then refluxed for 16 h. The mixture was quenched with ice-cold methanol (10 ml), hydrogen chloride solution was added dropwise (conc. eq, 3 ml), and the mixture was refluxed for 30 min. After cooling, the mixture was alkalised with dilute sodium hydroxide solution (4percent) and extracted with dichloromethane (3.x.50 ml). The combined organic phases were dried over sodium sulfate and concentrated to small volume under vacuum. The crude product was used in the next stage with no further purification. Yield: 44percent | ||
Synthesis of (S)-2-((1 -(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2- yl)methoxy)acetic acid (AC28)Step (i): (S)-Piperidin-2-ylmethanol(S)-Piperidine-2-carboxylic acid (2 g, 15.5 mmol) was placed in tetrahydrofuran (20 ml); boron trifluoride etherate (2.1 ml, 117.1 mmol) was added, followed by boron dimethylsulfide in tetrahydrofuran (dropwise, 3 ml, 30.9 mmol). The reaction mixture was then refluxed for 16 h. Quenching was carried out with ice-cold methanol (10 ml); hydrogen chloride solution (cone, aq., 3 ml) was added dropwise, and refluxing was carried out for 30 min. After cooling, the mixture was rendered alkaline with dilute <n="102"/>sodium hydroxide solution (4percent) and extracted with dichloromethane (3 x 50 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was used in the next stage without being purified further. Yield: 44percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With potassium carbonate In tetrahydrofuran Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: pipecolinic acid With thionyl chloride at 20 - 23℃; for 16h; Inert atmosphere; Stage #2: ethanol for 6h; Inert atmosphere; | |
90% | With thionyl chloride for 4h; Reflux; | |
With thionyl chloride at 70℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: benzyl bromide; pipecolinic acid With potassium hydroxide In isopropyl alcohol at 40℃; for 8h; Inert atmosphere; Stage #2: With hydrogenchloride In water; isopropyl alcohol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium phosphate; copper(l) chloride; N,N`-dimethylethylenediamine In dimethyl sulfoxide at 110℃; for 24h; Inert atmosphere; Sealed tube; | |
81% | With potassium phosphate; copper(l) chloride; N,N`-dimethylethylenediamine In dimethyl sulfoxide at 110℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | A solution of the L-pipecolic acid (3.6g, 38.7 mmol) in 40ml of 10percent sodium carbonate was dissolved in round bottom flask and allowed to stir for 5 min at rt. To this solution was added F-moc succinamide (8.5g, 34.8 mmol) dissolved in 35 ml dioxane and the reaction was stirred overnight. After overnight stirring water was added and the aqueous layer was extracted with ethyl acetate. The aqueous layer was made acidic (pH-2) by addition of concentrated HCl. The acidic layer was extracted with ethyl acetate (3x 40ml). The organic phase was washed with 1 N HCl followed by brine, dried over MgSO4 and concentrated under vacuo to yield a oily colorless liquid. The oily liquid was dissolved in ether and cooled to get fluffy white solid which was washed with hexane and dried to yield (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-2-carboxylic acid (8.2g, 38.7mmol, 83percent). TLC (Hexane:EtOAc: TFA 1:1: 0.2): RF = 0.60 HPLC (Gradient A) retention time= 24.6-24.8 min 1H NMR (300 MHz, CDCl3) delta=1.28-1.53 (m, 2H), 1.69-1.82 (m, 3H), 2.19-2.37 (m, 1 H), 3.15 (t, 1H, J= 13.2Hz), 4.05-4.33 (m, 2H), 4.37-4.49 (m, 2H), 4.76-5.05(m, 1 H), 7.28-7.41 (m, 4H), 7.55-7.62 (m, 2H), 1.77 (s, 2H). 13C NMR (75 MHz, CDCl3) delta= 20.72, 24.70, 26.55, 41.94, 47.25, 54.19, 67.86, 119.97, 125.08, 127.07, 127.68, 141.33, 143.89, 156.65, 177.36 MS (ESI) m/z 352.66 [M + H]+, calculated 352.40 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; In 1,4-dioxane; at 20℃; | Synthesis of building blocks A Synthesis of (S)-1 -(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-2-carboxylic acid A solution of the L-pipecolic acid (3.6g, 38.7 mmol) in 40ml of 10percent sodium carbonate was dissolved in round bottom flask and allowed to stir for 5 min at rt. To this solution was added F-moc succinamide (8.5g, 34.8 mmol) dissolved in 35 ml dioxane and the reaction was stirred overnight. After overnight stirring water was added and the aqueous layer was extracted with ethyl acetate. The aqueous layer was made acidic (pH-2) by addition of concentrated HCI. The acidic layer was extracted with ethyl acetate (3x 40ml). The organic phase was washed with 1 N HCI followed by brine, dried over MgSO4 and concentrated under vacuo to yield a oily colorless liquid. The oily liquid was dissolved in ether and cooled to get fluffy white solid which was washed with hexane and dried to yield (S)-1 -(((9H-fluoren-9- yl)methoxy)carbonyl)piperidine-2-carboxylic acid ( 8.2g, 38.7mmol, 83percent). TLC (Hexane:EtOAc: TFA 1 : 1 : 0.2): RF = 0.60 HPLC (Gradient A) retention time= 24.6-24.8 min 1 H NMR (300 MHz, CDCI3) 5=1 .28-1 .53 (m, 2H), 1 .69-1 .82 (m, 3H), 2.19-2.37 (m, 1 H), 3.15 (t, 1 H, J= 13.2Hz), 4.05-4.33 (m, 2H), 4.37-4.49 (m, 2H), 4.76-5.05(m, 1 H), 7.28-7.41 (m, 4H), 7.55-7.62 (m, 2H), 1 .77 (s, 2H). 13C NMR (75 MHz, CDCI3) delta= 20.72, 24.70, 26.55, 41 .94, 47.25, 54.19, 67.86, 1 19.97, 125.08, 127.07, 127.68, 141 .33, 143.89, 156.65, 177.36 MS (ESI) m/z 352.66 [M + H] \ calculated 352.40 [M + H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With amidase from Cupriavidus necator JMP134; water; In aq. phosphate buffer; at 30℃;pH 7.0;Enzymatic reaction; | General procedure: During the purification and characterization of amidase from Cupriavidus sp. KNK-J915, an enzyme assay was performed with (R,S)-BNPD as a substrate. The standard reaction mixture (0.2 mL) contained 100 mM potassium phosphate buffer (pH 7.0), 45.8 mM BNPD, and an appropriate amount of the enzyme. After the reaction was performed at 30C for 0.5-1 h, the amount of BNPA was determined using HPLC. One unit of the enzyme was defined as the amount catalyzing the formation of 1 mol of BNPA per minute under the aforementioned condition. Protein content was determined by the Bradford method [11] with BSA as a standard using a kit from Bio-Rad Laboratories Ltd. (Tokyo, Japan). |
Yield | Reaction Conditions | Operation in experiment |
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40%; 14% | With iron(III) chloride; In methanol; at 20℃; for 24h; | General procedure: FeCl3 (for 1a-c) or TiCl4 (for 1d-g) (5 mol%) and isocyanide (1.0 eq.) were added to a stirred solution of appropriate alpha-amino acid (1.2 eq.) and carbonyl component (1.0 eq.) in MeOH (100 mL).The mixture was stirred at rt for 24 h (72 h for 1d-g) and the volatiles were removed under reduced pressure. The resulting crude products were purified by FC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With triethylamine; In 1,4-dioxane; water; at 20℃; for 12h; | To a stirred solution of(S)-piperidine-2-carboxylic acid (500 mg, 3.4 mmol)in dioxane (6 mL) and water (2 mL) was added triethylamine (0.8 mL, 10.3 mmol)followed by isobutyryl chloride (0.41 g, 4.1 mmol) and the reaction mass was stirred at room temperature for 12 h. The reaction mixture was partitioned between ethyl acetate (5 mL) and water (3 mL). Organic layer was separated, dried with sodium sulfate and concentrated under reduced pressure to afford (5)-i -isobutyrylpiperidine2-carboxylic acid (285 mg, 42% yield). LCMS (ESI) m/e 200.2 [(M+H), calcd for C,0H,8N03, 200.1]; LC/MS retention time (method B): tR =1.09 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | General procedure: To the dipeptide salt (7 or 11, 1 mmol) in Schemes 2 and 3 wasadded a solution of 7 N NH3 in CH3OH (10 mL) and reaction mixturewas stirred for 10 min at 0 C. The solvent was evaporatedunder reduced pressure to afford free peptides, which was dissolvedin DMF (4 mL) and cooled to 4 C. To this reaction mixturerequisite carboxylic acid (1 mmol), DIC (1.1 mmol) and HOBt(1.1 mmol) was added and stirring continued at 4 C for 36 h. Thesolvent was removed under reduced pressure and the resultingresidue purified by column chromatography over neutral alumina using CHCl3/CH3OH (4:1) as eluant to afford desired peptides.The peptides were checked for their homogeneity on aShimadzu SPD-M20A HPLC system using a Supelcosil LC-8(25 cm 4.6 mm ID) column. The peptides were analyzed by usingan isocratic solvent system of CH3CN-H2O-TFA (70:30:0.8%) usinga SUPELCOSIL C-18 column with a flow rate of 1 mL/min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | General procedure: To the dipeptide salt (7 or 11, 1 mmol) in Schemes 2 and 3 wasadded a solution of 7 N NH3 in CH3OH (10 mL) and reaction mixturewas stirred for 10 min at 0 C. The solvent was evaporatedunder reduced pressure to afford free peptides, which was dissolvedin DMF (4 mL) and cooled to 4 C. To this reaction mixturerequisite carboxylic acid (1 mmol), DIC (1.1 mmol) and HOBt(1.1 mmol) was added and stirring continued at 4 C for 36 h. Thesolvent was removed under reduced pressure and the resultingresidue purified by column chromatography over neutral alumina using CHCl3/CH3OH (4:1) as eluant to afford desired peptides.The peptides were checked for their homogeneity on aShimadzu SPD-M20A HPLC system using a Supelcosil LC-8(25 cm 4.6 mm ID) column. The peptides were analyzed by usingan isocratic solvent system of CH3CN-H2O-TFA (70:30:0.8%) usinga SUPELCOSIL C-18 column with a flow rate of 1 mL/min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Into a 100-mL round-bottom flask, was placed a solution of (S)-N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide (350 mg, 0.56 mmol, 1.00 equiv) in ethanol (20 mL), (S)-piperidine-2-carboxylic acid (216 mg, 1.67 mmol, 2.00 equiv). This was followed by the addition of acetic acid (2 mL). The mixture was stirred for overnight at room temperature. To this was added NaBH3CN (77 mg, 1.22 mmol, 2.20 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of ethyl acetate. The resulting mixture was washed with 1*20 mL of water. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with methanol:dichloromethane (1:5). This resulted in 300 mg (73%) of (S)-1-(2-(N-methyl-3-(4-(piperidin-1-yl)-2-(4-((S)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)benzamido)ethyl)piperidine-2-carboxylic acid as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: thionyl chloride / 3 h / Reflux 1.2: 90 - 100 °C 2.1: sodium methylate / 50 - 60 °C 3.1: sodium tetrahydroborate; methanol / 6 h / 20 - 30 °C 3.2: 35 - 40 °C 4.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 20 °C / Cooling with ice 5.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 20 °C 5.2: 45 - 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With triethylamine; In tetrahydrofuran; water; at 0 - 20℃; for 4h; | General procedure: To a solution of L-proline (4.61 g, 40.0 mmol) and Et3N (14.0 mL, 100.0 mmol) in a mixture of THF (20 mL) and H2O (40 mL) was added 2-nitrobenzoyl chloride (8.91g, 48.0 mmol) at 0 C. The resulting mixture was allowed to stir at room temperature for 4 h. The reaction mixture was cooled to 0 C, acidified (pH ca. 2) with conc. HCl and extracted with10% MeOH/CHCl3. The organic extract was washed with brine solution, dried with anhydrous MgSO4 and concentrated. The crude compound was purified by trituration using CHCl3 and n-pentane to obtain the carboxylic acid 9a (8.25 g, 78%) as off-white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.5 g | In ethanol; ethyl acetate; for 0.5h;Reflux; | To a round bottom flask equipped with reflux condenser, <strong>[842133-18-0]Canagliflozin</strong> (5 gm), ethanol (10ml) and ethyl acetate (50 ml) were added and the reaction mass was stined for 10 mm at 25-30C. L-Pipecolic acid (1.74 gm) was added, the reaction mass was allowed to rise to reflux and stined for 30 mm. Then the reaction mass was cooled to 25-30C and the solid was filtered. To the resulting wet solid, ethanol (10 ml) and ethyl acetate (50 ml) was added and raised the temperature of the reaction mass to reflux. The reaction mass was further cooled to25-30C and the solids were filtered to get <strong>[842133-18-0]Canagliflozin</strong> L-pipecolic acid co-crystal (3.5 gms). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.9% | With palladium 10% on activated carbon; hydrogen; In methanol; under 1810.07 Torr; for 32h; | (S) -piperidine-2-carboxylic acid (40 g, 0.910 mol)Methanol (500 mL),Propanal (150 mL),Palladium on carbon (20 g, 10%) was added to the hydrogenation reaction flask for H2 replacement three times,Plus H2 (35PSI) swing hydrogenation for 32 hours.LC-MS detection reaction completed,The filter was washed with anhydrous methanol (50 mL x 2), the organic phases were combined and evaporated to dryness. The residue was washed with ethyl acetate (100 mL) with stirring, filtered and the cake was dried to give a white solid (S ) -1-propylpiperidine-2-carboxylic acid (3D) (44.5 g, yield 83.9%) was used directly in the next step. |
83.9% | With palladium 10% on activated carbon; hydrogen; In methanol; under 1810.07 Torr; for 32h; | (S)- 1 - propylpiperidine - 2 - carboxylic acidThe (S)- piperidine -2 - carboxylic acid (40 g, 0.910 muM), methanol (500 ml), propionaldehyde (150 ml) and palladium (20 g, wt=10%) added to the hydrogenation reaction bottle, hydrogen replacement three times, adds the hydrogen (35 PSI) swing hydrogenation 32 hours. Liquid chromatography - mass spectrometry detection said technological, diatomaceous earth for filtering, the filter cake is water-free methanol (50 ml × 2) washing, and combined with the organic phase to dryness, the residue is ethyl acetate (100 ml) washing, filtering, the filter cake drying, to obtain white solid intermediate 1 (44.5 g, yield 83.9%). |
83.9% | With palladium 10% on activated carbon; hydrogen; under 1810.07 Torr; for 32h; | (S) -piperidine-2-carboxylic acid (26a) (40 g, 0.910 mol)Methanol (500 mL),Propionaldehyde (150mL)Pd / c (20 g, 10%)Add hydrogenation reaction bottle,H2 replacement in three times,Hydrogenation,35PSI swing hydrogenation for 32 hours.The residue was washed with ethyl acetate (100 mL) with stirring, filtered, and the filter cake was filtered and the residue was washed with ethyl acetate (100 mL). The residue was washed with ethyl acetate (100 mL) Dry to obtain a white solid(S) -1-propylpiperidine-2-carboxylic acid (26b)(44.5 g, yield 83.9% |
83.9% | With palladium 10% on activated carbon; hydrogen; In methanol; under 1810.07 Torr; for 32h; | (S)-piperidine-2-carboxylic acid (40 g, 0.910 mol),Methanol (500mL),Propionaldehyde (150mL) Pd/c (20g, 10%)Add the hydrogenation reaction bottle,Replace H2 three times,H2 (35 PSI) was added to shake hydrogenation for 32 hours.LC-MS detection reaction,Filtered with diatomaceous earth,The filter cake was washed with anhydrous methanol (50 ml x 2).Combine the organic phases and evaporate to dryness.The residue was washed with ethyl acetate (100 mL).Filter and dry the filter cake to give a white solid(S)-1-propylpiperidine-2-carboxylic acid (1D) (44.5 g,The yield was 83.9%) and was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.8% | With 5%-palladium/activated carbon; hydrogen; In ethanol; at 20℃; | 20 g (0.155 mol) of S-type 2-piperidine carboxylic acid and 16.8 g (0.233 mol) of n-butyraldehyde were added to 200 ml of an ethanol solvent,Stirring for about 1 hour, weighed 2g of 5% mass fraction of palladium carbon added to the reaction solution,Through the hydrogen and 3 times the gas exchange, followed by continuous access to hydrogen, room temperature reaction at atmospheric pressure 8 ~ 10 hours, after the completion of the reaction to complete the reaction. The reaction solution was filtered and the filtrate was collected. After the filtrate was spin dried, 200 ml of petroleum ether was added to beat, filtered and the filter cake was collected and dried to give 27.8 g of 1-butylidene-2-carboxylic acid. Yield 96.8%. |
65% | 5 g (38.7 mmol) of S configuration pipecolic acid,8.37 g (116.1 mmol) of n-butyraldehyde,Trifluoroacetic acid (878 mg, 7.7 mmol) was added to methanol (50 ml)After stirring at room temperature for about 1 h, 7.3 g (116.1 mmol) of sodium cyanoborohydride were added,30 ~ 40 temperature conditions continue stirring reaction 6h;With 1mol / L sodium hydroxide solution to adjust the pH of the reaction solution to 7 to 8,Add 100ml ethyl acetate extract, the organic phase evaporated and concentrated,The crude product obtained after purification by column chromatography4.6gS configuration 1-butylpiperidine-2-carboxylic acid in 65% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: trifluoroacetic acid / methanol / 1 h / 20 °C 1.2: 6 h / 30 - 40 °C 2.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 1 h / 20 °C 2.2: 15 h / 110 - 120 °C | ||
Multi-step reaction with 3 steps 1.1: hydrogenchloride / toluene / 20 °C 1.2: 55 °C 2.1: 55 °C 3.1: potassium carbonate / N,N-dimethyl-formamide / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 100℃;Inert atmosphere; | Step 2: Synthesis of (S)-1-(3-((8-(tert-butoxycarbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)- 5-(trifluoromethyl)phenyl)piperidine-2-carbox lic acid A flask was charged with tert-butyl 1-(3-bromo-5-(trifluoromethyl)benzyl)-1,8- diazaspiro[4.5]decane-8-carboxylate (600 mg, 1.26 mmol, 1.00 equiv), DMF (10 mL), (2S)- piperidine-2-carboxylic acid (325 mg, 2.52 mmol, 2.00 equiv), potassium carbonate (696 mg, 5.04 mmol, 4.00 equiv), and copper(I) iodide (48.0 mg, 0.252 mmol, 0.20 equiv) under nitrogen. The reaction mixture was stirred overnight at 100 C and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column to provide 450 mg (68% yield) of (S)-1-(3-((8-(tert- butoxycarbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-5-(trifluoromethyl)phenyl)piperidine-2- carboxylic acid. LCMS (ESI, m/z): 526 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hydrogenchloride; thionyl chloride / toluene; chloroform; N,N-dimethyl-formamide; water / 3 h / 40 °C / pH 2 / Sonication; Inert atmosphere 1.2: 1.2 h / 45 °C / Sonication 2.1: potassium carbonate / N,N-dimethyl-formamide / 1.5 h / 40 °C / Sonication 3.1: hydrogenchloride / water; isopropyl alcohol / 0.8 h / 40 °C / pH 1 - 2 / Sonication | ||
Multi-step reaction with 4 steps 1: sodium cyanoborohydride / dichloromethane / 10 h / 35 °C / Inert atmosphere 2: thionyl chloride / dichloromethane; N,N-dimethyl-formamide / 4 h / 5 - 40 °C 3: potassium hydroxide / N,N-dimethyl-formamide / 3 h / 20 - 45 °C 4: hydrogenchloride / isopropyl alcohol; water / 2 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In chloroform; at 50℃; for 1h; | To a solution of solid-supported methoxypiperidine 5(0.80 g, 0.80 mmol/g, 0.640 mmol) in THF-CH2Cl2 (1:1, 10mL) at -78C, TMSCN (0.150 mL, 1.184 mmol) was addedfollowed by the addition of TMSOTf (0.495 mL, 2.74mmol). The mixture was stirred at -78C by 5 min. Then, themixture was filtered and washed with CH2Cl2 (3 x 10 mL),transferred to a flask, followed by the addition of 10 mL ofCHCl3 and a solution of HCl in CHCl3 (10.0 mL, 1.0 M).The mixture was stirred at 50C by 1 h. Then, the organic layer was filtered, extracted with H2O (3 x 5.0 mL),basified with NH4OH, and extracted with CH2Cl2 (3 x 5.0mL mL). The organic layer was dried with MgSO4 and thesolvent was removed in vacuum to give a white solid in 50%overall yield. White solid; mp 270-271 oC; [alpha]D +27.0 (c =0.15, H2O); 1H NMR (300 MHz, D2O), delta: 1.40-1.58 (3H,m), 1.69-1.75 (2H, m), 2.06 (1H, d, J 12.8), 2.85 (1H, t, J12.5), 3.26 (1H, d, J 12.5), 3.43 (1H, d, J 7.7). 13C NMR (75MHz, D2O), delta: 21.4, 21.7, 26.3, 43.4, 58.8, 174.1. HRMS(MALDI): m/z Calcd. for [C6H11NO2 + H]+ 130.0868, found130.0864. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With sodium cyanoborohydride; acetic acid; In N,N-dimethyl-formamide; at 5 - 20℃; for 4h; | To a solution of 43 (1.0 g, 4.1 mmol) in MeOH (30 mL) was added H2SO4 (5 mL)dropwise. The reaction was heated at reflux overnight before concentrated. The residue wastreated with water and extracted with EtOAc twice. The combined organic layers were washedwith brine, dried over Na2SO4 and evaporated under reduced pressure to give 44 (1.1 g, 100%)as an off-white solid. A suspension of 44 (900 mg, 3.46 mmol), 1 (853 mg, 10.4 mmol), K2CO3(955 mg, 6.92 mmol), CuI (198 mg, 1.04 mmol) and 8-hydroxyquinoline (100 mg, 0.69 mmol)in DMSO (9 mL) was heated at 110C overnight under nitrogen. After cooling, water wasadded and the mixture was acidified by aqueous KHSO4 and extracted with EtOAc 3 times.The product was in the water phase. The water layer was directly purified by reverse prep-HPLC to give 45 (310 mg, 36%) as a white solid. LCMS (m/z: m+1): 248.1. To a mixture of 45 (310 mg, 1.26 mmol) in MeOH (30 mL) was added dropwise H2SO4 (2 mL). The reactionwas heated at reflux overnight before being concentrated. The residue was treated with water,basified by 2N NaOH under ice-water bath and extracted with CH2Cl2 3 times. The combinedorganic layers were washed with brine, dried over Na2SO4, and evaporated under reducedpressure to give 46 (260 mg, 79%) as a slightly yellow solid. LCMS (m/z: m+1): 262.1. Amixture of 46 (260 mg, 1.0 mmol) and Pd/C (80 mg) in THF (10 mL) was stirred at roomtemperature under hydrogen atmosphere overnight. The reaction mixture was filtered and thefiltrate was concentrated under reduced pressure to give 47 (231 mg, 100%) as a slightly yellowoil. LCMS (m/z: m+1): 232.3. A mixture of 47 (231 mg, 1.0 mmol), 41 (323 mg, 1.0 mmol),HATU (760 mg, 2.0 mmol) and DIEA (646 mg, 5.0 mmol) in DMF (3 mL) was heated at 70Covernight. After cooling, the reaction was directly purified by reverse prep-HPLC and thensilica gel prep-TLC to give 48 (148 mg, 28%) as a slightly yellow solid. LCMS (m/z: m+1):537.3. To a solution of 48 (148 mg, 0.28 mmol) in THF (5 mL) was added LAH (42 mg, 1.10mmol). The mixture was stirred at room temperature overnight before being quenched withwater (100 mg). The resulting mixture was filtered through Celite and washed withCH2Cl2/MeOH (10/1). The filtrate was evaporated under reduced pressure to give the fullyreduced benzylic alcohol (145 mg, 100%) as a slightly yellow solid which was used in nextstep without purification. A mixture of this material (125 mg, 0.25 mmol) and MnO2 (427 mg,4.9 mmol) in CH2Cl2/MeOH (20/1, 30 mL) was heated at reflux overnight. The reactionmixture was filtered and washed with CH2Cl2/MeOH (20/1, 60 mL). The filtrate wasevaporated under reduced pressure to give aldehyde 49 (123 mg, 99%) as a slightly yellowsolid. This material was also used in the next step without intermediate purification. To asolution of 49 (103 mg, 0.20 mmol) and (S)-piperidine-2-carboxylic acid (129 mg, 1.0 mmol)in DMF (2 mL) was added AcOH (2 drops) and then NaBH3CN (63 mg, 1.0 mmol) at 5C.The mixture was stirred at room temperature for 4 h. The reaction mixture was directly purifiedby reverse prep-HPLC to give crude product (48 mg, ~60% purity). 23 mg of the crude productwas further purified by silica gel prep-TLC to give pure 2b (12 mg, 20%) as a white solid. |
12 mg | With sodium cyanoborohydride; acetic acid; In N,N-dimethyl-formamide; at 5 - 20℃; for 4h; | To a solution of 65 (148 mg, 0.28 mmol) in THE (5 mL) was added LAH (42 mg, 1.10 mmol). The mixture was stirred at room temperature overnight before quenched with water (1 00 mg). The resulting mixture was filtered through Celite and washed with CH2CI2/MeOH (10/1). The filtrate was evaporated under reduced pressure to give thefully reduced benzylic alcohol (145 mg, 100%) as a slightly yellow solid which was used in next step without purification. A mixture of this material (125 mg, 0.25 mmol) and Mn02 (427 mg, 4.9 mmol) in CH2CI2/MeOH (20/1, 30 mL) was ref luxed overnight. The reaction mixture was filtered and washed with CH2CI2/MeOH (20/1, 60 mL). The filtrate was evaporated under reduced pressure to give aldehyde 66 (123 mg, 99%) as a slightly yellow solid. This material was also used in the next step without intermediatepurification. To a solution of 66 (103 mg, 0.20 mmol) and (S)-piperidine-2-carboxylicacid (129 mg, 1 .0 mmol) in DMF (2 mL) was added AcOH (2 drops) and then NaBH3CN(63 mg, 1 .0 mmol) at 5 C. The mixture was stirred at room temperature for 4 hours.The reaction mixture was directly purified by reverse prep-HPLC to give crude product(48 mg, -60% purity). 23 mg of the crude product was further purified by silica gel prep-TLC to give pure (S)-1-(3-(3-((4-(4-fluorophenyl)pyrimidin-2-yl)amino)-4-methylbenzamido)-5-(4-methyl-1 H-imidazol-1 -yl)benzyl)piperidine-2-carboxylic acid (12 mg, 20%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.8% | To a solution of 4-(4-hydroxybutoxy)-2-((2-methyl-[l,l'-biphenyl]-3- yl)methoxy)pyrimidine-5-carbaldehyde (0.24 g, 0.61 mmol) in MeOH (2 mL) and DMF (2 mL), (,S)-piperidine-2-carboxylic acid (79 mg, 0.61 mmol) and acetic acid (1 drop) were added simultaneously and the reaction mixture was stirred at room temperature for 2 h. To this reaction mixture, NaC BH3 (115 mg, 1.83 mmol) was added and continued stirring at room temperature for 16 h. The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with DCM (2 x 25 mL). The combined organic layer was washed with water (5 mL) and brine solution (5 mL), dried over sodium sulphate and concentrated to give crude product which was purified flash chromatography using 10% methanol in dichlorom ethane as eluent to afford (,S)-l-((4- (4-hydroxybutoxy)-2-((2-methyl-[l, l'-biphenyl]-3-yl)methoxy)pyrimidin-5- yl)methyl)piperidine-2-carboxylic acid as white solid (Yield: 250 mg, 80.8%). LCMS (ES) m/z = 506.43 [M+H]+; 1H MR (400 MHz, DMSO-d6): delta 1.33-1.54 (m, 7H), 1.74 (m, 4H), 2.20 (s, 3H), 2.30 (m, 1H), 2.91 (m, 1H), 3.17 (m, 1H), 3.43 (m, 2H), 3.55 (d, J= 14 Hz, 1H), 3.66 (d, J =14 Hz, 1H), 4.33 (m, 2H), 5.42 (s, 2H), 7.18 (m, 1H), 7.25- 7.32 (m, 3H), 7.37 (m, 1H), 7.43-7.47 (m, 3H), 8.23 (s, 1H). HPLC purity 214 nm, 97.43%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With sodium cyanoborohydride; acetic acid; In N,N-dimethyl-formamide; at 70℃; for 4h; | A solution of 5-(((4-formyl-7-((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)-2,3- dihydro-lH-inden-5-yl)oxy)methyl)nicotinonitrile (100 mg, 0.21 mmol), (S)- piperidine-2-carboxylic acid (40.8 mg, 0.32 mmol), sodium cyanoborohydride (66.4 mg, 1.06 mmol) and acetic acid (2 drops) in DMF (5 mL), the reaction mixture was stirred at 70 C for 4 h. After completion, the reaction mixture was poured on ice cold water (10 mL) and collected the white solid by filtration. A solution of white solid in DCM (20 mL) was dried over sodium sulfate and concentrated. The resulting crude was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent. The product was further purified by reverse phase HPLC using method-B to obtain (S)-l-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[l,l'- biphenyl]-3-yl)methoxy)-2,3-dihydro-lH-inden-4-yl)methyl)piperidine-2- carboxylic acid (Yield: 26 mg, 46%) as white solid. LCMS (ES) m/z = 588.38 [M+H]+; NMR (400 MHz, DMSO-d6) d ppm: 1.32-1.45 (m, 4H), 1.75 (m, 2H), 1.97 (m, 2H), 2.21 (s, 3H), 2.32 (m, 1H), 2.76 (m, 2H), 2.81-3.03 (m, 3H), 3.11 (m, 1H), 3.68 (d, J= 12.28 Hz, 1H), 3.88 (d, J= 12.4 Hz, 1H), 5.14 (s, 2H), 5.28 (m, 2H), 6.77 (s, 1H), 7.19 (d, J= 7.6 Hz, 1H), 7.25-7.33 (m, 3H), 7.39 (m, 1H), 7.44-7.47 (m, 3H), 8.48 (s, 1H), 9.01 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | To a solution of methyl 5-((4-formyl-7-((2-methyl-[l,l'-biphenyl]-3- yl)methoxy)-2, 3-dihydro- lH-inden-5-yl)oxy)pentanoate (340 mg, 0.71 mmol), in MeOH (4 mL) and DMF (4 mL), (S)-piperidine-2-carboxylic acid (102 mg, 0.79 mmol) and acetic acid (3 drops) were added and stirred for 2 h. To this mixture, sodium cyanoborohydride (134 mg, 2.1 mmol) was added and the mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with 10% MeOH in DCM (3 x 30 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated. The resulting crude was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to obtain (S)- 1 -((5-((5-methoxy-5 -oxopentyl)oxy)-7-((2-methyl- [1,1 '-biphenyl] -3- yl)methoxy)-2, 3-dihydro- lH-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 245 mg, 59%) as light yellow solid. LCMS (ES) m/z = 584.63 [M-H]; NMR (400 MHz, DMSO-de) d ppm: 1.45 (m, 4H), 1.74 (m, 7H), 1.96-2.00 (m, 2H), 2.21 (s, 3H), 2.39 (m, 2H), 2.75 (m, 2H), 2.80 (m, 1H), 2.95 (m, 1H), 3.05 (m, 1H), 3.11 (m, 1H), 3.59 (s, 3H), 3.75 (d, J= 12.0 Hz, 1H), 3.88 (d, J =12.0 Hz, 1H), 4.00 (m, 2H), 5.20 (s, 2H), 6.64 (s, 1H), 7.19 (d, J= 7.6 Hz, 1H), 7.27-7.40 (m, 4H), 7.44-7.49 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | A solution of 6-methyl-7-((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1 //-indcnc-4-carbaldchydc (100 mg, 0.28 mmol), (S)-piperidine-2-carboxylic acid (50 mg, 0.42 mmol) and acetic acid (1 drop) in DMF (2 mL) and MeOH (2 mL) was stirred at room temperature for 2 h. Sodium cyanoborohydride (50 mg, 0.84 mmol) was added and the mixture was stirred for 16 h. After completion, the reaction mixture was concentrated and the residue was diluted with water (10 mL). The aqueous mixture was extracted with 10% MeOH in DCM (3 x 10 mL). The combined organic layer was dried over sodium sulfate and concentrated. The resulting crude was purified by flash chromatography (silica gel, 4 g) using 0-20% MeOH in DCM as eluent to obtain (S)- l - ((6-methyl-7-((2-methyl-[ l,l'-biphenyl]-3-yl)methoxy)-2, 3-dihydro- l -inden-4- yl)methyl)piperidine-2-carboxylic acid (Yield: 62 mg, 46%) as white solid. LCMS (ES) m/z = 470.20 [M+H]+; NMR (400 MHz, DMSO-d6) d ppm: 1.22-1.34 (m, 2H), 1.48 (m, 3H), 1.78 (m, 2H), 1.99 (m, 2H), 2.19 (s, 3H), 2.23 (s, 3H), 2.83 (m, 1H), 2.88 (m, 4H), 3.09 (m, 1H), 3.41 (d, J = 12.8 Hz, 1H), 3.81 (d, j = 12.8 Hz, 1H), 4.94 (s, 2H), 6.97 (s, 1H), 7.19 (d, J= 7.2 Hz, 1H), 7.27-7.32 (m, 3H), 7.37 (m, 1H), 7.44- 7.49 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Asolution of 6-methyl-7-((2-methyl-[l,r-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1 /7-indene-4-carbaldehyde (120 mg, 0.30 mmol), (S)-piperidine-2-carboxylic acid (60 mg, 0.40 mmol) and acetic acid (1 drop) in DMF (2 mL) and MeOH (2 mL) was stirred at room temperature for 2 h. Sodium cyanoborohydride (54 mg, 0.90 mmol) was added and the reaction mixture was stirred further for 16 h. After completion of the reaction, the reaction mixture was concentrated and the residue was diluted with water (10 mL) and saturated sodium bicarbonate solution (2 mL). The aqueous mixture was extracted with EtOAc (3 x 10 mL). The combined organic layer was dried over sodium sulphate and concentrated. The resulting crude was purified by flash chromatography (silica gel, 4g ) using 0-20% MeOH in DCM as eluent to obtain (S)-l-((6-chloro-7-((2-methyl-[l,L- biphcnyl]-3-yl)mcthoxy)-2,3-di hydro- 1 //-indcn-4-yl)mcthyl)pipcridinc-2-carboxylic acid (Yield: 80 mg, 57%) as white solid. LCMS (ES) m/z = 490.14 [M+H]+; NMR (400 MHz, DMSO-de) d ppm: 1.22-1.34 (m, 2H), 1.48 (m, 3H), 1.75 (m, 2H), 2.01 (m, 2H), 2.26 (s, 3H), 2.82-2.88 (m, 5H), 3.08 (m, 1H), 3.36 (d, J= 13.6 Hz, 1H), 3.74 (d, J = 13.6 Hz, 1H), 5.04 (s, 2H), 7.20 (d, J= 7.6 Hz, 1H), 7.25 (d, J= 8.0 Hz, 1H), 7.27-7.32 (m, 3H), 7.37 (m, 1H), 7.44-7.49 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With sodium cyanoborohydride; acetic acid; In N,N-dimethyl-formamide; at 70℃; for 4h; | A solution of 3-(((4-formyl-7-((2-methyl-[l,r-biphenyl]-3-yl)methoxy)-2,3- dihydro- 17/-indcn-5-yl )oxy) methyl )bcnzonitrilc (100 mg, 0.21 mmol), (S)-pipcridinc-2- carboxylic acid (40.8 mg, 0.32 mmol), sodium cyanoborohydride (66.4 mg, 1.06 mmol) and acetic acid (2 drops) in DMF (5 mL) was stirred at 70 C for 4 h. After completion, the reaction mixture was poured on to ice-cold water (10 mL). The solid was filtered and dissolved in DCM. The organic solvent was dried over sodium sulfate and concentrated. The resulting crude was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to obtain (S)-l-((5-((3-cyanobenzyl)oxy)-7-((2-methyl- [l,l'-biphenyl]-3-yl)methoxy)-2, 3-dihydro- IH- inden-4-yl)methyl)piperidine-2- carboxylic acid (Yield: 26 mg, 46%) as white solid. LCMS (ES) m/z = 587.15 [M+H]+; NMR (400 MHz, DMSO-de) d ppm: 1.32-1.45 (m, 4H), 1.78 (m, 2H), 1.97 (m, 2H), 2.20 (s, 3H), 2.32 (m, 1H), 2.73 (m, 2H), 2.81 (m, 1H), 2.94-3.03 (m, 2H), 3.14 (m, 1H), 3.71 (d, j = 12.4 Hz, 1H), 3.88 (d, j = 12.4 Hz, 1H), 5.14 (s, 2H), 5.23 (s, 2H), 6.73 (s, 1H), 7.19 (d, J= 7.6 Hz, 1H), 7.25-7.33 (m, 3H), 7.37 (m, 1H), 7.44-7.49 (m, 3H), 7.61 (t, J = 7.6 Hz, 1H), 7.80 (d, j= 7.2 Hz, 1H), 7.86 (d, j= 7.2 Hz, 1H), 7.98 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With sodium cyanoborohydride; acetic acid; In methanol; N,N-dimethyl-formamide; at 20℃; for 8h; | To a solution of 5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[l,r- biphenyl]-3-yl)methoxy)-2, 3-dihydro- lH-indene-4-carbaldehyde (50 mg, 0.11 mmol), (S)-piperidine-2-carboxylic acid (52 mg, 0.32 mmol) in MeOH (3 mL) and DMF (3 mL), sodium cyanoborohydride (19 mg, 0.32 mmol) and acetic acid (2 drops) were added and the mixture was stirred at room temperature for 8 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (3 x 30 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated. The resulting crude was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to obtain (S)-l-((5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl- [l,l'-biphenyl]-3-yl)methoxy)-2, 3-dihydro- lH-inden-4-yl)methyl)piperidine-2- carboxylic acid (Yield: 30 mg, 48%) as white solid. LCMS (ES) m/z = 581.47 [M+H]+; NMR (400 MHz, DMSO-d6) d ppm: 1.32-1.45 (m, 4H), 1.75 (m, 2H), 1.97 (m, 2H), 2.32 (m, 3H), 2.49 (m, 1H), 2.74 (m, 2H), 2.81-3.05 (m, 3H), 3.14 (m, 1H), 3.68 (d, J = 12.8 Hz, 1H), 3.88 (d, j= 12.4 Hz, 1H), 5.16 (s, 2H), 5.26 (m, 2H), 6.78 (s, 1H), 7.19 (d, J= 7.6 Hz, 1H), 7.25-7.33 (m, 3H), 7.39 (m, 1H), 7.44-7.47 (m, 3H), 7.92 (d, J=9.6 Hz, 1H), 8.54 (s, 1H), 8.61 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45%Chromat. | With hydrogenchloride; alpha-ketoglutaric acid; ammonium iron (II) sulfate; l-proline cis-4-hydroxylase; sodium L-ascorbate; In aq. buffer; at 21℃; for 14h;pH 6.5;Enzymatic reaction; | General procedure: Analytical scale proline hydroxylase (PH) incubations were performed by sequential addition of the reagents in Table S1 to a 1.5 mL Eppendorf tube (100 muL final volume): The incubation mixture was kept at 21 C for 14 h (unless otherwise stated). To quench the reaction, an equal volume of methanol was added and the mixture cooled on ice for 10 min before centrifugation (13,000g for 3 min); the quenching methanol contained 0.25 mM p-aminosalicylic acid (pASA) as an internal standard. The supernatant was decanted and analysed by an LC/MS. ?Negative controls? were performed in parallel, but with substitution of 50 mM MES-NaOH, pH 6.5 for the enzyme solution. |
Tags: 3105-95-1 synthesis path| 3105-95-1 SDS| 3105-95-1 COA| 3105-95-1 purity| 3105-95-1 application| 3105-95-1 NMR| 3105-95-1 COA| 3105-95-1 structure
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