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CAS No. : | 26250-84-0 | MDL No. : | MFCD00151904 |
Formula : | C11H19NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JQAOHGMPAAWWQO-QMMMGPOBSA-N |
M.W : | 229.27 | Pubchem ID : | 688617 |
Synonyms : |
Boc-L-pipecolic acid;Boc-Pip-OH
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.82 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 63.17 |
TPSA : | 66.84 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.41 cm/s |
Log Po/w (iLOGP) : | 1.6 |
Log Po/w (XLOGP3) : | 1.82 |
Log Po/w (WLOGP) : | 1.48 |
Log Po/w (MLOGP) : | 1.03 |
Log Po/w (SILICOS-IT) : | 0.5 |
Consensus Log Po/w : | 1.29 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.14 |
Solubility : | 1.65 mg/ml ; 0.00718 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.84 |
Solubility : | 0.329 mg/ml ; 0.00143 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -0.66 |
Solubility : | 50.7 mg/ml ; 0.221 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.73 |
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 |
---|---|---|
97% | With sodium hydrogencarbonate | |
97% | With sodium hydrogencarbonate Inert atmosphere; | |
90% | With tetra-(n-butyl)ammonium iodide; sodium hydrogencarbonate In dichloromethane at 25℃; for 24h; |
With sodium hydrogencarbonate In N,N-dimethyl-formamide | ||
With DBN In acetonitrile at 0 - 20℃; | M.2 Step 2: Synthesis of (S)-Piperidine-l,2-dicarboxylic acid 2-benzyl ester l-tør/-butyl esterTo a suspension of (S)-piperidine-2-carboxylic acid (5.159g; 22.5mmol) in acetonitrile (5OmL) at 0 oC is added benzyl bromide (2.5mL; 21.019mmol), followed by 1,5- diazabicyclo[4.3.0]non-5-ene (2.6mL; 21.04mmol). The reaction mixture is left stirring and slowly warm to room temperature overnight. The reaction mixture is diluted with ethyl acetate and washed with water, saturated NH4C1 aqueous solution then brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound, m/z 320 [M+H+] . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 4-pyrrolidin-1-ylpyridine; dicyclohexyl-carbodiimide In dichloromethane at -20℃; for 19h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.6% | With 4-pyrrolidin-1-ylpyridine; diisopropyl-carbodiimide In dichloromethane at -20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 4-pyrrolidin-1-ylpyridine; N-ethyl-N,N-diisopropylamine; diisopropyl-carbodiimide In dichloromethane at 0℃; for 4h; | |
85% | With 4-pyrrolidin-1-ylpyridine; N-ethyl-N,N-diisopropylamine; diisopropyl-carbodiimide In dichloromethane at -20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With borane-THF; In tetrahydrofuran; at 0℃; for 3h;Inert atmosphere; | Compound 13-1 (10.68 g, 46.6 mmol) was dissolved in THF (100 mL) and borane (100mL, 1 M in THF) was added dropwise slowly under nitrogen at 0 C. After the reactionwas completed, the reaction was quenched with methanol (80 mL). The reaction mixture wasconcentrated and purified by column chromatography (eluent: PE / EtOAc (v / v) = 4/1) togive 7.52 g of a colorless oil. Rate: 75%. |
EXAMPLE 50(a); Starting Material for Examples 52 Et Seq; Step 1; (S)-2-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester; To a solution of(S)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5 g, 21.8 mmol) in anhydrous THF (32 mL) at 0-5 C. was added borane-tetrahydrofuran complex (1M solution in THF) (3.6 g, 41.84 mmol) over a period of 15 min. The mixture was stirred at 0-5 C. for 2 h and then at rt for 2 h. The mixture was added over a period of 10 min to cold water (75 mL) and extracted with EtOAc (300 mL). The aqueous layer was re-extracted with EtOAc (2×150 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to obtain the title product as a colorless oil (4.72 g). | ||
With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 20℃; for 4h; | To a solution of BH3-Me2S (10 M, 44.49 mL) in THF (400 mL) was added a solution of compound 1 (51.00 g, 222.45 mmol) in THF (100 mL) at 0 C. The resultant solution was stirred for 1 hr. The reaction mixture was then warmed to 20 C and stirred for additional 3 hr. TLC showed most of the starting material was consumed. The resulting mixture were cooled to 0 C, and then sat. NaHCO3 aq. (500 mL) was added slowly to quench the reaction, and water (100 mL) was added, and then extracted with EtOAc (200 mL*3). The combined organic extracts were washed with sat. NaHCO3 aq. (1 L) and brine (300 mL), dried over Na2 SO4, filtered and concentrated to give compound 2 as a white solid (46.00 g, crude). The material was carried forward without additional purification. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.43. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; ammonia In DMF (N,N-dimethyl-formamide) for 5h; | A.43 [0353] (1-Methyl-piperidin-2S-yl)-methylamine [0354] Anhydrous ammonia gas was bubbled through a solution of (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidine carboxylic acid (500 mg, 2.18 mmol) in DMF (50 ml) for 15 minutes. PyBop (1.25 g, 2.40 mmol) was added. After 5 hours, solvent was evaporated under reduced pressure. A solution of the resultant residue in ethyl acetate was washed with 5% citric acid (50 ml×3), 1 N NaOH (50 ml×3), dried with MgSO4, filtered, and concentrated to give 450 mg of (S)-2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester as a clear oil in 95% yield, which was used without further purification. |
95.6% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; | 25.1 Step 1: tert-Butyl (2S) -2-carbamoylpiperidine-1-carboxylate (25A) (2S) -1-tert-butoxycarbonylpiperidine-2-carboxylic acid (2.10 g, 9.16 mmol)Was added 20 mL of dimethylformamide,2- (7-azobenzotriazole) -tetramethyluronium hexafluorophosphate (5.20 g, 13.7 mmol)And triethylamine (1.85 g, 18.3 mmol)Stir for 30 minutes.Add concentrated ammonia (10 mL, 28%).50 mL of water was added, extracted with dichloromethane (50 mL x 3)The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 49: 1 to 9: 1) to give the title compound (2S) -2- Carbamoylpiperidine-1-carboxylic acid tert-butyl ester (25A)White solid (2.0 g, yield 95.6%). |
93% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at -15℃; for 1h; Inert atmosphere; Stage #2: With ammonium hydroxide In tetrahydrofuran for 16h; Inert atmosphere; |
85% | With ammonium chloride; N-ethyl-N,N-diisopropylamine; HATU at 0 - 20℃; for 18h; | 1 General procedure for the preparation carboxylic acid amides 2 General procedure: Carboxylic acid 1 (1.0 eq.) was dissolved in dry THF (7 mL/mmol), then ammonium chloride (6.0 eq.) and DIPEA (3.0 eq.) were added. HATU (1.47 eq.) was added to the mixture at 0°C then the mixture was stirred for 18 h at room temperature. The reaction was monitored by LCMS and TLC. After completion, the reaction mixture was diluted with water (10 mL/mmol) and extracted with EtOAc (3x10 mL/mmol). The combined organic phases were washed with 10% Na2CO3 solution (2x3 mL/mmol), brine (2x3 mL/mmol) and dried over anhydrous Na2SO4. After filtration and concentration, the title compound was purified by flash chromatography (eluent: Heptane or Cyclohexane/EtOAc, 0-40 % EtOAc). tert-Butyl-(2S)-2-carbamoylpiperidine-1-carboxylate (2-1) The title compound was prepared according to Example 1 starting from tert-Butyl-(2S)- 2-piperidine carboxylic acid (1-1). White powder, Y: 85%. APCI MS, m/z 229 [M+H]+ , HPLC- MS (ELSD signal) 100% (AUC). 1H NMR (400 MHz, CDCl3) identical with WO2005115986 p105. |
With ammonium hydroxide; chloroformic acid ethyl ester; triethylamine 1.) THF, -10 deg C, 2.) THF, RT, 4 h; Yield given. Multistep reaction; | ||
With ammonium chloride; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) for 16h; | 79 To a solution of N-Boc-L-pipecolinic acid (200mg, 0. 87MMOL) in DMF (3. 5ML) was added TBTU (336mg, 1. 05mmol), ammonium chloride (93mg, 1. 74MMOL) then DIPEA (182µL, 1.05mmol) and the reaction stirred for 16h. The mixture was partitioned between ethyl acetate (2X30ML) and water (30mL), and the organics combined before being washed with 1M sodium hydroxide (3X30ML) and brine (3X30ML). The organic solution was dried (MGS04) and solvent removed in vacuo to give the title compound as a white solid. 8H (D6 DMSO): 7.23 (1H, s), 6.97 (1H, s), 4.56-4. 39 (1H, br m), 3.43-3. 74 (1H, d), 3.14-2. 90 (1H, br m), 2.09-2. 00 (1H, d), 1.63-1. 47 (3H, m), 1.30-1. 17 (2H, m). |
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 |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 23℃; for 3h; | ||
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 24h; | General procedure for the synthesis of compounds S-5a, b, n-y General procedure: According to a procedure of Choi et al.36 (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (1equiv) was dissolved in 20mL anhydrous CH2Cl2 and at 0°C the corresponding alcohol (1.0equiv), EDC·HCl (1.5equiv) and DMAP (0.2equiv) were added. After the reaction was completed (TLC control) the organic layer was washed twice with water and the solvent was evaporated in vacuo. The boc-protection group was cleaved with 2mL trifluoroacetic acid in 20mL CH2Cl2. After 24h the reaction was neutralized with saturated NaHCO3 extracted with 3×30mL CH2Cl2. The combined organic layers were dried over Na2SO4 and the solvent was evaporated to yield compound 8a, b, n-y which was used in the next step without further purification. Compound 8a, b, n-y (1equiv) was dissolved in 40mL of anhydrous CH2Cl2, and NMM or DIPEA (3equiv) was added at 0°C followed by corresponding sulfonyl chloride (1equiv), respectively. The mixture was stirred until completion (TLC) and subsequently the solvent removed in vacuo. After purification by means of flash-chromatography compounds S-5a, b, n-y were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at -30℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With TEA; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate In dichloromethane for 6h; | |
94% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; Stage #2: N,O-dimethylhydroxylamine*hydrochloride In dichloromethane at 20℃; for 17h; | 1.1 (S)-1-(tert-butoxycarbonyl)-2-(N-methyl-N-methoxy)-carbamoylpiperidine 2: Dissolve 20.0g (87.2mmol) (S)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid 1 in 400mL dichloromethane,slowly add 18.4g (113.5 mmol) N,N’-carbonyldiimidazole,stir at room temperature until no bubbles emerge,add 11.6g (113.4mmol) N,O-dimethylhydroxylamine hydrochloride,stir at room temperature for 17 hours.after the reaction mixture was diluted with 150 mL of water,extract with dichloromethane (60mL×3),Dry the organic phase with anhydrous sodium sulfate,filter,remove the solvent under reduced pressure,column chromatography separation,V (petroleum ether): V (ethyl acetate) = 4:1,22.3 g of colorless oily liquid was obtained, and the yield was 94%. |
87.55% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 14h; | 15.1 1. Preparation of compound 2. To a stirred solution of compound 1 (10.00 g, 43.62 mmol) and compound 1A (5.53g, 56.71 mmol) in DMF (100.00 mL) was added HOBt (7.66 g, 56.71 mmol), EDCI (10.87 g,56.71 mmol) and DIEA (11.27 g, 87.24 mmol) in the above order at 0 °C. The reaction mixturewas stirred for 2 hr at 0 °C, and then the mixture was stirred at 20 °C for another 12 hr. TLC andLCMS showed the starting material was consumed. The reaction was quenched with water (100mL) and extracted with EtOAc (100 mL*2), and the combined organic was washed with brine(200 mL*2), dried over Na2SO4, filtered and concentrated to get the crude. The residue waspurified by silica gel chromatography (petroleum ether/ethyl acetate =3:1) to get compound 2 asa yellow oil (10.40 g, 87.55%). ‘H NMR (400 IVIFIz, CDC13): = 4.91-5.05 (d, J= 8.0 Hz, 1H),3.89 (s, 1H), 3.75 (s, 3H), 3.47 (s, 1H), 3.17 (s, 3H), 1.96-1.99 (m, 1H), 1.57-1.68 (m, 3H), 1.43(s, 9H). LCMS: (M+Na): 295.1. TLC (Petroleum ether/Ethyl acetate = 3:1) Rf= 0.43. |
83% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; acetonitrile at 20℃; | 6 4.2.1. General method 1 General procedure: To a solution of appropriate amino protected carboxylic acidderivative (1 eq.) dissolved in a mixture of CH2Cl2 and CH3CN (1:1, 3.7 mL/mmol of carboxylic acid), EDC (1.3 eq.), HOBt (1.3 eq.), NMM (6.5 eq.) and HN(Me)OMe*HCl (2.1 eq.) were added. The mixture was stirred at room temperature over 24-72 h and then evaporated.The resulting crude product was dissolved in CH2Cl2, washed three times with saturated NaHCO3 solution, three times with 1 M HCl and once with brine. Organic layer was dried over MgSO4,filtered and concentrated in vacuo. Purification via flash chromatography was performed. 4.2.6 tert-Butyl (2S)-2-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (10a) According to general method 1, 10a was obtained as a yellow oil (0.986 g, 83%). 1H NMR (CDCl3, 300 MHz), δ (ppm): 5.18-4.87 (m, 1H); 4.10-3.84 (m, 1H); 3.76 (s, 3H); 3.58-3.39 (m, 1H); 3.18 (s, 3H); 2.01 (d, J = 15.0 Hz, 1H); 1.75-1.57 (m, 3H); 1.44 (s, 9H); 1.34-1.20 (m, 2H). 13C NMR (CDCl3, 75 MHz), δ (ppm): 173.5, 156.2, 79.7, 61.3, 50.8, 42.3, 32.2, 29.7, 28.5, 26.5, 19.6. MS (ESI+): m/z = 273.1 [M,H]+ found; C13H25N2O4 calculated m/z = 273.2 [M,H]+. |
72% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With pivaloyl chloride; triethylamine In dichloromethane at -10 - 0℃; for 1.5h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With triethylamine In dichloromethane for 18h; | |
61% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 18h; | Intermediate 3 : (5 -l-Boc-piperidine-2-carboxylic acid (25 g, 109 mmol, Sigma-Aldrich) in DMF (500 mL) was treated sequentially with MeNHOMe»HCl (1 1.2 g, 1 15 mmol), N-methylmorpholine (36 mL, 327 mmol), HOBt (16.2 g, 120 mmol), and EDCI (23 g, 120 mmol) and stirred for 18 h. The solution was diluted with EtOAc (1000 mL) and washed with H20 (2 500 mL) and saturated NaCl solution (500 mL). The solution was dried over MgS04, filtered andconcentrated. The residue was subjected to a 330 g Si02 Combiflash High Performance Gold column (0-100% EtOAc-hexanes gradient) to afford the Weinreb amide intermediate 3 (18.4 g, 61%) as a clear oil:1H NMR (CDC13, 300MHz): δ 5.06 (br m, 1H), 3.93 (br m, 1H), 3.77 (br s, 3H), 3.18 (s, 3H), 2.01 (app d, J= 13.5 Hz, 1H), 1.71 (m, 4H), 1.45 (s, 9H);LCMS (ESI) mlz 273 [M + H]+, tR = 2.31 min ;HPLC (RP: 6-98% MeCN-H20 gradient, 0.05% TFA modifier) tR = 4.423 min.R/= 0.60 (50% EtOAc-hexanes); |
61% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 18h; | 2 Example 2 Preparation of Intermediate 3 Example 2 Preparation of Intermediate 3 [0417] [0418] (S)-1-Boc-piperidine-2-carboxylic acid (25 g, 109 mmol, Sigma-Aldrich) in DMF (500 mL) was treated sequentially with MeNHOMe.HCl (11.2 g, 115 mmol), N-methylmorpholine (36 mL, 327 mmol), HOBt (16.2 g, 120 mmol), and EDCI (23 g, 120 mmol) and stirred for 18 h. The solution was diluted with EtOAc (1000 mL) and washed with H2O (twice with 500 mL) and saturated NaCl solution (500 mL). The solution was dried over MgSO4, filtered and concentrated. The residue was subjected to a 330 g SiO2 Combiflash High Performance Gold column (0-100% EtOAc-hexanes gradient) to afford the Weinreb amide intermediate 3 (18.4 g, 61%) as a clear oil: [0419] 1H NMR (CDCl3, 300 MHz): δ 5.06 (br m, 1H), 3.93 (br m, 1H), 3.77 (br s, 3H), 3.18 (s, 3H), 2.01 (app d, J=13.5 Hz, 1H), 1.71 (m, 4H), 1.45 (s, 9H); LCMS (ESI) m/z 273 [M+H]+, tR=2.31 min; [0420] HPLC (RP: 6-98% MeCN-H2O gradient, 0.05% TFA modifier) tR=4.423 min. Rf=0.60 (50% EtOAc-hexanes); |
With 4-methyl-morpholine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide at 0 - 20℃; | ||
76.8 g | With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; | |
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In chloroform at 0 - 20℃; | 1 Production Example 1 Synthesis of tert-butyl (2S) -2- ( (methoxy(methyl) amino) carbonyl)piperidine-1- carboxylate; Triethylamine (218 g) and N, O-dimethylhydroxyamine hydrochloride (84 g) were added to a chloroform solution (1200 ml) of (S) -l-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (165 g) . After ice cooling, a BOP reagent (334 g) was gradually added thereto . The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the concentrate was diluted with ethyl acetate and sequentially washed with 0.5 M hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, water, and saturated brine . The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=5: 1) to obtain the title compound (178 g) as a colorless oil. MS (ESI pos.) m/z : 273([M+H]+), (ESI pos.) m/z : 295([M+Na]+) IH NMR (200 MHz, CDC13) δ ppm 1.32 - 1.81 (m, 14 H), 1.93 - 2.06 (m, 1 H), 3.18 (s, 3 H), 3.30 - 3.61 (m, 1 H), 3.70 - 4 . 06 (m, 4 H) , 4 . 82 - 5 . 18 (m , 1 H) | |
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 18h; | 4 Intermediate 2: Intermediate 2: [0368] (S)-1-Boc-piperidine-2-carboxylic acid (25 g, 109 mmol, Sigma-Aldrich) in DMF (500 mL) was treated sequentially with MeNHOMe.HCl (11.2 g, 115 mmol), N-methylmorpholine (36 mL, 327 mmol), HOBt (16.2 g, 120 mmol), and EDCI (23 g, 120 mmol) and stirred for 18 h. The solution was diluted with EtOAc (1000 mL) and washed with H2O (2×500 mL) and saturated NaCl solution (500 mL). The solution was dried over MgSO4, filtered and concentrated. The residue was subjected to a 330 g SiO2 Combiflash High Performance Gold column (0-100% EtOAc-hexanes gradient) to afford the Weinreb amide intermediate 2: [0369] 1HNMR (CDCl3, 300 MHz): δ 5.06 (br m, 1H), 3.93 (br m, 1H), 3.77 (br s, 3H), 3.18 (s, 3H), 2.01 (app d, J=13.5 Hz, 1H), 1.71 (m, 4H), 1.45 (s, 9H). [0370] LCMS (ESI) m/z 273 [M+H]+, tR=2.31 min. [0371] HPLC(RP: 6-98% MeCN-H2O gradient, 0.05% TFA modifier) tR=4.423 min. [0372] Rf=0.60 (50% EtOAc-hexanes). | |
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 18h; | 4 Intermediate 2 (S)-i-l3oc-piperidine-2-carboxylic acid (25 g, 109 mmol, Sigma-Aldrich) in DMF (500 mE) was treated sequentially with MeNHOMe.HC1 (11.2 g, 115 mmol), N-methylmorpholine (36 mE, 327 mmol), HOSt (16.2 g, 120 mmol), and EDCI (23 g, 120 mmol) and stirred for 18 h. The solution was diluted with EtOAc (1000 mE) and washed with H20 (2x500 mE) and saturated NaC1 solution (500 mE). The solution was dried over MgSO4, filtered and concentrated. The residue was subjected to a 330 g Si02 Combiflash High Performance Gold column (0-100% EtOAc-hexanes gradient) to afford the Weinreb amide intermediate 2:‘H NMR (CDC13, 300 MHz): ö 5.06 (brm, 1H), 3.93 (brm, 1H), 3.77 (brs, 3H), 3.18 (s, 3H), 2.01 (app d, J=13.5 Hz, 1H),1.71 (m, 4H), 1.45 (s, 9H).ECMS (ESI) mlz 273 [M+H], tR=2.31 mm.HPEC (RP: 6-98% MeCN-H20 gradient, 0.05% TFAmodifier) tR-4.423 mm.R1rrrO.60 (50% EtOAc-hexanes). |
Yield | Reaction Conditions | Operation in experiment |
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87% | With hydrogen In methanol at 45℃; for 11h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 3h; | 16.1 (1) Preparation of compound 2b Compound 2a (5.0 g, 21.8 mmol, 1.0 eq), N, O-dimethylhydroxylamine hydrochloride (2.6 g, 26.2 mmol, 1.2 eq), DIPEA (7.6 mL, 43.6 mmol, 1.5 eq), EDCI ( 6.3 g, 32.7 mmol, 1.5 eq) and HOBT (5.3 g, 32.7 mmol, 1.5 eq) were dissolved in DCM (50 mL).Stir at room temperature for 3h.The reaction solution was washed with water, saturated brine, dried over Na2SO4, spin-dried, and passed through a column (PE / EA = 5/1) to obtain compound 2b (5.3 g, yield: 89%).TLC: PE / EA = 1/1, I2, Rf (compound 2a) = 0.2, Rf (compound 2b) = 0.4. |
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; dacarbazine; N-ethyl-N,N-diisopropylamine | ||
With triethylamine; isobutyl chloroformate In dichloromethane cooling; | ||
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 24h; | (S)-1-(Benzylsulfonyl)-N-isopropylpiperidine-2-carboxamide (S-5z) According to a procedure of Flynn et al.37 (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (1equiv) was dissolved in 20mL anhydrous CH2Cl2 and at 0°C isopropylamine (1.0equiv), EDC·HCl (1.3equiv), and HOBt (0.2equiv) were added. After the reaction was completed (TLC control) the organic layer was washed twice with water and the solvent was evaporated in vacuo. The boc protection group was cleaved with 2mL trifluoroacetic acid in 20mL CH2Cl2. After 24h the solution was neutralized with saturated NaHCO3 and extracted with 3×30mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and the solvent was evaporated to yield compound 8z which was used in the next step without further purification. Compound 8z (1equiv) was dissolved in 40mL of anhydrous CH2Cl2, and DIPEA (3equiv) was added at 0°C followed by phenylmethanesulfonyl chloride (1equiv), respectively. The mixture was stirred until completion (TLC control) and subsequently the solvent was removed in vacuo. After purification by means of flash chromatography compound S-5z was obtained as a colorless oil (0.20g, 53%); mp 75-77°C. 1H NMR (400MHz, CDCl3) δ 7.37-7.47 (m, 5H), 6.11 (d, J=6.8Hz), 4.29 (s, 2H), 4.22 (d, 1H, J=5.1Hz), 4.00-4.15 (m, 1H), 3.56-3.64 (m, 1H), 3.01 (ddd, 1H, J=13.6, 13.3, 2.9Hz), 2.18-2.26 (m, 1H), 1.20-1.65 (m, 5H), 1.14 (t, 6H, J=6.6Hz); 13C NMR (100MHz, CDCl3) δ 168.7, 130.7 (2C), 128.9, 128.8 (3C), 58.7, 56.4, 43.7, 41.7, 25.8, 24.5, 22.7, 22.5, 19.8; IR (ATR, vv [cm-1]): 3424, 3065, 2942, 2868, 1665, 1516, 1455, 1369, 1325, 1173, 1131, 741, 701 (m); HPLC purity: 97% (method II); ESI-MS: m/z 325.3 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0 - 70℃; for 20h; | |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 25℃; for 12h; | ||
With triethylamine; isobutyl chloroformate In dichloromethane cooling; |
With triethylamine; isobutyl chloroformate In dichloromethane cooling; | ||
With 1,2-dichloro-ethane; N-ethyl-N,N-diisopropylamine In dichloromethane; <i>tert</i>-butyl alcohol at 25℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at -5℃; for 24h; | |
84% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at -5℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at -5℃; for 24h; | |
99% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at -5℃; for 20h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In DMF (N,N-dimethyl-formamide) at 25℃; for 20h; | 11 Ester 11 To a DMF solution (2 mL) of the alcohol 9 (0.08 g, 0. 336 mmol) and N-Boc-pipecolinic acid 10 (0. 115 g, 0. 504 mmol, preparation described in International Publication No. WO 0140185) was added triethylamine (02 mL), EDC :(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (0. 097 g, 0.504 mmol) and HOBT (1-hydroxybenzotriazole hydrate) (0. 068 g, 0. 0504 mmol) at 25 C. After 20 h, the reaction mixture was diluted with EtOAc (50 mL), washed with brine (3X50 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (20-25% ETOAC in hexanes) affording 150 mg (100% yield) of the compound 11. 1H NMR (CDCl3) : (mixture of two rotamers) δ 8.48 (1H, d, J=8. 7 Hz), 7.11-6. 94 (1H, br s), 6.26 (1H, d, J=8.7 Hz), 4.85 (1H, br s), 4.36 (2H, m), 4.06-3. 86 (2H, m), 3. 67 (2H, m), 3. 12-2. 81 (1H, m), 2.26-2. 12 (3H, m), 1.46 (9H, s). |
100% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In DMF (N,N-dimethyl-formamide) at 25℃; for 20h; | 11 To a DMF solution (2 mL) of the alcohol 9 (0.08 g, 0.336 mmol) and N-Boc-pipecolinic acid 10 (0.115 g, 0.504 mmol, preparation described in International Publication No. WO 0140185) was added triethylamine (0.2 mL), EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (0.097 g, 0.504 mmol) and HOBT (1-hydroxybenzotriazole hydrate) (0.068 g, 0.0504 mmol) at 25° C. After 20 h, the reaction mixture was diluted with EtOAc (50 mL), washed with brine (3×50 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (20-25% EtOAc in hexanes) affording 150 mg (100% yield) of the compound 11. 1H NMR (CDCl3): (mixture of two rotamers) δ 8.48 (1H, d, J=8.7 Hz), 7.11-6.94 (1H, br s), 6.26 (1H, d, J=8.7 Hz), 4.85 (1H, br s), 4.36 (2H, m), 4.06-3.86 (2H, m), 3.67 (2H, m), 3.12-2.81 (1H, m), 2.26-2.12 (3H, m), 1.46 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With 4-methyl-morpholine; ammonium hydroxide; isobutyl chloroformate In tetrahydrofuran at 0 - 15℃; for 2h; Stage #2: With hydrogenchloride In 1,4-dioxane for 1h; | 11 (S)-1-(TERT-BUTOXYCARBONYL)-PIPERIDINE-2-CARBOXYLIC acid (1.0 g, 4.36 mmol) and N-METHYLMORPHOLINE (0.53 ml, 4.79 mmol) in tetrahydrofuran (15 ml) were cooled to- 15°C. Isobutyl CHLOROFORMATE (0.44 ML, 4.79 mmol) was added drop wise and then concentrated ammonium hydroxide (1.5 ml). The mixture was stirred at 0 to 5°C for 2 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with saturated sodium hydrogen carbonate solution, dried (MGS04) and concentrated under reduced pressure to give an oil which crystallised on standing (550 mg, 55%). This was used without further purification. The solid was stirred in 4M hydrogen chloride in dioxane (10 ml) for 1 hour and then concentrated under reduced pressure. The residue was dissolved in methanol, absorbed onto an ISOLUTE (3 SCX column, washed with methanol and eluted with 7N ammonia in methanol to give (2S)-piperidine-2-carboxamide (291 mg, 96%) as a white, crystalline solid ; 1H NMR spectrum: (DMSO d6) 1.31 (m, 3H), 1.45 (m, 1H), 1.71 (m, 2H), 2.12 (s, 1H), 2.45 (m, 1H), 2.93 (m, 2H), 6.86 (brs, 1H), 7.04 (brs, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.5% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 8.A A solution of (S)-(-)-1-Boc-2-piperidine carboxylic acid 1 g (4.27 mmol), 1-benzylpiperazine 0.77 g (4.27 mmol), EDC 1.64 g (8.54 mmol) and catalytic amount of 4-(dimethylamino) pyridine in methylene chloride (50 ml) was stirred at room temperature overnight. The reaction mixture was concentrated and applied to flash column chromatography using methylene chloride and methanol (100:5) as eluents to give 1.23 g of desired product in 74.5% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium carbonate In 1,4-dioxane; water; ethyl acetate | 4.A A. A. 2S-N-(t-Butoxycarbonyl) piperidine-2-carboxylic acid A solution of 1.64 g of sodium carbonate in 15 ml of water was added to a cold (0° C.) solution of 2.0 g (15.5 mol) of 2S-piperidinecarboxylic acid in 50 mL of dioxane. After approximately ten minutes, 3.7 g (17.0 mol) of di-t-butyl dicarbonate was added to the mixture. The resultant reaction mixture was reacted for approximately six hours, concentrated to one fourth of the original volume and then acidified to pH 2 using 1M sodiumhydrogen sulfate and ethyl acetate. The resulting layers were separated, and the organic layers were washed with a saturated brine solution, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide 2.67 g of a white crystalline solid. Yield: 75%. [α]D -55.26° (c=0.23, MeOH). 1 H NMR (CDCl3): δ 1.20-1.80 (m, 15H), 2.15-2.30 (m, 1H), 2.85-3.10 (m, 1H), 3.90-4.10 (m, 2H), 4.70-5.00 (m, 1H). IR (CHCl3): 3700-1800 (br.), 3025, 3018, 3011, 2980, 2947, 2865, 1716, 1685, 1449, 1394, 1368, 1280, 1252, 1162, 1147, 1129 cm-1. MS(FD): m/e 229 (M+, 100). |
75% | With sodium carbonate In 1,4-dioxane; water; ethyl acetate | 4.A A. A. 2S-N-(t-Butoxycarbonyl)piperidine-2-carboxylic acid A solution of 1.64 g of sodium carbonate in 15 ml of water was added to a cold (0° C.) solution of 2.0 g (15.5 mol) of 2S-piperidinecarboxylic acid in 50 mL of dioxane. After approximately ten minutes, 3.7 g (17.0 mol) of di-t-butyl dicarbonate was added to the mixture. The resultant reaction mixture was reacted for approximately six hours, concentrated to one fourth of the original volume and then acidified to pH 2 using 1M sodiumhydrogen sulfate and ethyl acetate. The resulting layers were separated, and the organic layers were washed with a saturated brine solution, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide 2.67 g of a white crystalline solid. Yield: 75%. [α]D -55.26° (c=0.23, MeOH). 1 H NMR (CDCl3): δ1.20-1.80 (m, 15H), 2.15-2.30 (m, 1H), 2.85-3.10 (m, 1H), 3.90-4.10 (m, 2H), 4.70-5.00 (m, 1H). IR (CHCl3): 3700-1800 (br.), 3025, 3018, 3011, 2980, 2947, 2865, 1716, 1685, 1449, 1394, 1368, 1280, 1252, 1162, 1147, 1129 cm-1. MS(FD): m/e 229 (M+, 100). Analysis for C27 H37 N3 O4: Calcd: C, 57.63; H, 8.35; N, 6.11; Found: C, 57.90; H, 8.35; N, 6.19. |
75% | With sodium carbonate In 1,4-dioxane; water; ethyl acetate | 4.A A. A. 2S-N-(t-Butoxycarbonyl) piperidine-2-carboxylic acid A solution of 1.64 g of sodium carbonate in 15 ml of water was added to a cold (0° C.) solution of 2.0 g (15.5 mol) of 2S-piperidinecarboxylic acid in 50 mL of dioxane. After approximately ten minutes, 3.7 g (17.0 mol) of di-t-butyl dicarbonate was added to the mixture. The resultant reaction mixture was reacted for approximately six hours, concentrated to one fourth of the original volume and then acidified to pH 2 using 1M sodiumhydrogen sulfate and ethyl acetate. The resulting layers were separated, and the organic layers were washed with a saturated brine solution, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide 2.67 g of a white crystalline solid. Yield: 75%. [α]D -55.26° (c=0.23, MeOH). 1 H NMR (CDCl3): δ1.20-1.80 (m, 15H), 2.15-2.30 (m, 1H), 2.85-3.10 (m, 1H), 3.90-4.10 (m, 2H), 4.70-5.00 (m, 1H). IR (CHCl3): 3700-1800 (br.), 3025, 3018, 3011, 2980, 2947, 2865, 1716, 1685, 1449, 1394, 1368, 1280, 1252, 1162, 1147, 1129 cm-1. MS(FD): m/e 229 (M+, 100). Analysis for C27 H37 N3 O4: Calcd: C, 57.63; H, 8.35; N, 6.11; Found: C, 57.90; H, 8.35; N, 6.19. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With caesium carbonate In N,N-dimethyl-formamide at 25℃; for 4h; Inert atmosphere; Schlenk technique; | |
96% | With caesium carbonate In N,N-dimethyl-formamide for 4h; | |
90.47% | With caesium carbonate In N,N-dimethyl-formamide at 15℃; for 16h; | 61.2 2. Preparation of compound 4. To a solution of compound 3 (50.00 g, 218.08 mmol) in DMF (400 mL) was added Mel (46.43 g, 327.12 mmol) and Cs2CO3 (35.53 g, 109.04 mmol). The mixture was stirred at 15 °C for 16 hr. TLC showed the starting material was consumed and one new spot with lower polarity was detected. The mixture was diluted with H20 (400 mL) and extracted with EtOAc (400 mL*3). The combined organic layers were washed with H20 (400 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (Si02, Petroleum ether: EtOAc = 100/1 to 10:1) to give compound 4 as a colorless oil (48.00 g, 90.47%). ‘H NIVIR (400 IVIHz, CHLOROFORM-d) = 4.94-4.61 (m, 1H), 4.10 -3.82 (m, 1H), 3.71 (s, 3H), 3.03 -2.70 (m, 1H), 2.17 (d, J=10.4 Hz, 1H), 1.77 - 1.51 (m, 4H), 1.47 - 1.30 (m, 11H), 1.28 - 1.08 (m, 1H). TLC (Petroleum ether:EtOAc = 5:1)Rf= 0.61. |
85% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 1 Step 1: Synthesis of (S)-1-tert-butvl 2-methyl piperidine-1 ,2-dicarboxylate 2 Potassium carbonate (108.50 g, 785.09 mmol) was added to a solution of(S)-1-(tert- butoxycarbonyl)piperidine-2-carboxylic acid 1 (90 g, 392.55 mmol) in DMF (900 ml). lodomethane (83.58 g, 588.82 mmol) was added to the mixture. The mixture was stirred atroom temperature overnight. Ethyl acetate was added to the reaction mixture. The resulting mixture was washed with water and brine. The organic layer was dried over Na2504, filtered and concentrated under vacuum to give intermediate 2 (90 g, yield: 85 %).m/z = 244 (M+H). |
85% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | A.1 Step 1: Synthesis of (S)-1-tert-butyl 2-methyl piperidine-1,2-dicarboxylate 2 Potasium carbonate (108.50 g, 785.09 mmol) was added to a solution of(S)-1-(tert- butoxycarbonyl)piperidine-2-carboxylic acid 1 (90 g, 392.55 mmol) in DMF (900 ml).lodomethane (83.58 g, 588.82 mmol) was added to the mixture. The mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture. The resulting mixture was washed with water and brine. The organic layer was dried over Na2504, filtered and concentrated under vacuum to give intermediate 2 (90 g, yield: 85 %).m/z = 244 (M+H). |
With sodium hydrogencarbonate In water; N,N-dimethyl-formamide | 61.a a a Synthesis of tert-butyl (S)-2-(methoxycarbonyl)piperidine carboxylate: In a 100 ml flask, 5 g of 1-((tert-butyl)oxycarbonyl)piperidine-(S)-2-carboxylic acid and 3.2 g of NaHCO3 were dissolved in 50 ml of N,N-dimethylformamide, and 1.8 ml of iodomethane was added thereto. The reaction solution was stirred for 8 hours at room temperature. After adding water, the reaction solution was extracted two times with ethyl acetate. The extracts were combined, dried over MgSO4 and evaporated to obtain 4.5 g of the title compound as a pale yellow oil. 1H NMR(CDCl3, ppm): δ4.94-4.73(brs, 1H), 3.97(br, 1H), 3.73(s, 3H), 2.95-2.88(br, 1H), 2.21(m, 1H), 1.65(m, 3H), 1.45(br, 9H), 1.25(m, 2H) | |
With caesium carbonate In N,N-dimethyl-formamide for 4h; | Intermediate 2 :N-Boc-(S)-piperidine-2-carboxylic acid (5.0 g, 22 mmol) in DMF (100 mL) was treated with Cs2C03 (3.5 g, 10.9 mmol) and Mel (1.5 mL, 24 mmol). The mixture was stirred for 4 hours and diluted with MTBE (250 mL). The mixture was washed with water (2 100 mL) and saturated sodium chloride solution (1 100 mL). The solution was dried over anhydrous sodium sulfate and concentrated to afford the ester intermediate 2 (5.1 g crude, 96%) as an oil which was used without further purification1H NMR (CDCI3, 300MHz): δ 4.80 (m, 1H), 3.97 (m, 1H), 3.73 (s, 3H), 2.93 (m, 1H), 2.18 (app d, J= 13.2 Hz, 1H), 1.67 (m, 2H), 1.45 (br s, 10H), 1.20 (app t, J= 13.5 Hz, 1H). | |
With caesium carbonate In N,N-dimethyl-formamide for 4h; | 4 Intermediate 1: Intermediate 1: [0365] N-Boc-(S)-piperidine-2-carboxylic acid (5.0 g, 22 mmol) in DMF (100 mL) was treated with Cs2CO3 (3.5 g, 10.9 mmol) and MeI (1.5 mL, 24 mmol). The mixture was stirred for 4 hours and diluted with MTBE (250 mL). The mixture was washed with water (2×100 mL) and saturated sodium chloride solution (1×100 mL). The solution was dried over anhydrous sodium sulfate and concentrated to afford the ester intermediate 1 which was used without further purification. [0366] 1H NMR (CDCl3, 300 MHz): δ 4.80 (m, 1H), 3.97 (m, 1H), 3.73 (s, 3H), 2.93 (m, 1H), 2.18 (app d, J=13.2 Hz, 1H), 1.67 (m, 2H), 1.45 (br s, 10H), 1.20 (app t, J=13.5 Hz, 1H). Rf=0.90 (30% EtOAc-hexanes). | |
With caesium carbonate In N,N-dimethyl-formamide for 4h; | 1.b Example 1b Preparation of Intermediate 2 Example 1b Preparation of Intermediate 2 [0414] [0415] N-Boc-(S)-piperidine-2-carboxylic acid (5.0 g, 22 mmol) in DMF (100 mL) was treated with Cs2CO3 (3.5 g, 10.9 mmol) and MeI (1.5 mL, 24 mmol). The mixture was stirred for 4 hours and diluted with MTBE (250 mL). The mixture was washed with water (twice with 100 mL) and saturated sodium chloride solution (100 mL). The solution was dried over anhydrous sodium sulfate and concentrated to afford the ester intermediate 2 (5.1 g crude, 96%) as an oil which was used without further purification [0416] 1H NMR (CDCl3, 300 MHz): δ 4.80 (m, 1H), 3.97 (m, 1H), 3.73 (s, 3H), 2.93 (m, 1H), 2.18 (app d, J=13.2 Hz, 1H), 1.67 (m, 2H), 1.45 (br s, 10H), 1.20 (app t, J=13.5 Hz, 1H). Rf=0.90 (30% EtOAc-hexanes); | |
With caesium carbonate In N,N-dimethyl-formamide for 4h; | 4 Procedure for the Preparation of Intermediate Al Intermediate 1 N-l3oc-(S)-piperidine-2-carboxylic acid (5.0 g, 22 mmol) in DMF (100 mE) was treated with Cs2CO3 (3.5 g, 10.9mmol) and Mel (1.5 mE, 24 mmol). The mixture was stirred for 4 hours and diluted with MTI3E (250 mE) The mixture was washed with water (2x100 mE) and saturated sodium chloride solution (lxi 00 mE) The solution was dried over anhydrous sodium sulfate and concentrated to afford the esterintermediate 1 which was used without further purification.‘H NMR (CDC13, 300 MHz): ö 4.80 (m, 1H), 3.97 (m, 1H), 3.73 (s, 3H), 2.93 (m, 1H), 2.18 (app d, J=13.2 Hz, 1H), 1.67 (m, 2H), 1.45 (br s, 1OH), 1.20 (app t, J=13.5 Hz, 1H).R1=0.90 (30% EtOAc-hexanes). | |
9.8 g | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4h; | 1.1 Step 1: Preparation 1b To a stirred solution of N-Boc-L-Homoproline (compound la) (10.0 g, 43.6 mmol) in dry DMF (100.0 mL) was added K2CO3 (6.80 g, 49.2 mmol) followed by methyl iodide (18.0 g, 126.7 mmol) and the resultant mixture was stirred at ambient temperature for 4 h. When TLC-analysis has indicated the completion of the reaction, the reaction mixture was then partitioned between water and EtOAc (ca. 200 mL each), the organic layer was separated and washed with water and brine, dried over Na2S04 and the solvents were removed under reduced pressure to furnish the ester lb (9.80 g). LCMS: 244.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.2% | Stage #1: 2-[4-(4-amino-phenylethynyl)-1H-pyrazol-3-yl]-4-chloro-phenol; (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With diisopropyl-carbodiimide In dichloromethane at 20℃; Stage #2: With lithium hydroxide In tetrahydrofuran; methanol; water at 20℃; for 3h; | 38 To a solution of compound 24A (520 mg, 1.7 mmol) and N-Boc-2(S)- piperidinecarboxylic acid (8A) (584 mg, 2.55 mmol) in anhydrous dichloromethane (30 mL) was added λζiV'-diisopropylcarbodiimide (DIPC, 0.4 mL, 2.55 mmol). The reaction mixture was stirred at rt overnight. The solvent was removed. To the residua were added THF (40 mL) and methanol (40 mL) and a solution of LiOH H2O (2.0 g, 47.68 mmol) in water (20 mL). The mixture was stirred at rt for 3 h. It was then neutralized with acetic acid (3 mL, 52.41 mmol). The mixture was diluted with ethyl acetate (~ 100 mL), washed with brine, and dried over sodium sulfate. It was filtered, concentrated and filtered again to remove diisopropylurea. The filtrate was purified with silica column chromatography eluting with hexanes/ethyl acetate (v/v 2/1, 3/2, 1/1) to provide the title compound (25A, 500 mg) as a yellowish solid in 57.2% yield. 1H NMR (CDCl3, 500 MHz) δ 10.62 (br s, IH), 8.71 (d, IH, J = 2.0 Hz), 8.35 (br s, IH), 7.84 (s, IH), 7.55 (s, 4H), 7.22 (dd, IH, J= 9.0, 2.0 Hz), 6.99 (d, IH, J= 9.0 Hz), 4.90 (s, IH), 4.05 (m, IH), 2.90 (t, IH, J= 11.5 Hz), 2.35 (m, IH), 1.80-1.30 (m, 16H). LCMS (ESI) m/z 587.15 (MNa+), 521.05 (MH+), 421.06; HPLC: tR = 5.32 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: N-hydroxycyclobutanecarboxamidine In N,N-dimethyl-formamide at 120℃; for 18h; | 2.1 [247] 200 mg (0.872 mmol) of (2S)-l-(tbutoxycarbonyl)piperidine-2-carboxylic acid was dissolved in 10 mL of N,N-dimethylformaide, and 170 mg (1.05 mmol) of 1,1-carbodimide was added thereto at room temperature. After stirring for 30 minutes, 100 mg (0.872 mmol) of N'-hydroxycyclobutanecarboximide was added thereto, and the reaction solution was heated to 12O0C, followed by stirring for 18 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was isolated and purified with column chromatography to give 204 mg of the title compound in a yield of 76%.[248] H NMR (CDCl3) δ 5.57-5.44 (IH, m), 4.03 (IH, brs), 3.65-3.58 (IH, m), 2.93 (IH, brs), 2.39-2.26 (6H, m), 2.10-1.94 (2H, m), 1.90-1.80 (2H, m), 1.71-1.60 (2H, m), 1.43 (9H, s)[249] Mass (m/e) 308 (M+l) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane | |
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In acetonitrile at 20℃; | 1 To a stirred suspension of (S)-(-)- l-Boc-2-piperidinecarboxylic acid (750 mg, 3.2 mmol), BOP reagent (benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate) (2.16 g, 4.9 mmol), and dimethylamine hydrochloride (399 mg, 4.9 mmol) in acetonitrile (50 mL) was added triethylamine (0.9 mL, 6.5 mmol) The reaction mixture was stirred at room temperature overnight then concentrated in vacuo. The resulting residue was taken up into ethyl acetate (150 mL) and washed with saturated potassium hydrogen sulfate (150 mL), saturated sodium bicarbonate (150 mL) and brine (150 mL). The organics were dried with sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (10 g) eluting with ethyl acetate/hexanes (2: 1) to give (5)-tert-butyl-2-(dimethoxycarbamoyl)piperidine-l-carboxylate (700 mg) as a clear viscous oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With triethylamine; isobutyl chloroformate In dichloromethane at 0 - 20℃; | |
With triethylamine; isobutyl chloroformate In tetrahydrofuran at 0 - 20℃; | ||
Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With triethylamine; isobutyl chloroformate In dichloromethane at 0℃; for 0.5h; Stage #2: 2,6-diisopropylbenzenamine In dichloromethane at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane | 4 1,5-Diphenyl-3-pentylmercaptyl N-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylateA mixture of N-(tert-butyloxycarbonyl)-(S)-pipecolic acid (2.11 g; 9.29 mmol), 1,5-diphenyl-3-pentylmercaptan (2.58 g; 10.22 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.96 g; 10.22 mmol) and 4-dimethylaminopyridine (catalytic) in dry methylene chloride (50 mL) was stirred overnight. the reaction mixture was diluted with methylene chloride (50 mL) and water (100 mL), and the layers were separated. The organic phase was washed with water (3×100 mL), dried over magnesium sulfate, and concentrated to provide 870 mg (20%) of the product as a thick oil, which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; | 1.c c) (S)-tert-Buty{ 2-((5)-l-amino-3-(4-iodophenyl)-l-oxopropan-2-ylcarbamoyl)piperidine-l- carboxylate4-Iodo-(L)-phenylalaninamide (2 g), (25)-l-(fert-butoxycarbonyl)piperidine-2-carboxylic acid (2.4 g) and diisopropylethylamine (3 mL) were dissolved in DMF (10 mL) and to the solution was added 2-(l-/-f-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (3.3 g). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether (200 mL) then washed with water (250 rnL) and brine (4x 250 mL). The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Crude product was purified by flash silica chromatography eluting with ethyl acetate to give the subtitle compound (2.88 g) as an oil.1H NMR (299.946 MHz, CDCl3) δ 7.63 (dd, J= 6.4, 1.8 Hz, 2H), 6.98 (dd, J= 8.6, 2.0 Hz, 2H), 6.49 (d, J= 7.9 Hz, IH), 6.18 - 6.04 (m, IH), 5.48 (s, IH), 4.77 - 4.62 (m, 2H), 3.90 - 3.78 (m, IH), 3.15 - 3.00 (m, 2H), 2.43 - 2.31 (m, IH), 2.24 - 2.14 (m, IH), 1.68 - 1.43 (m, 14H). m/z 401 [M-BOC+H]+ | |
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; | 1.iii iii) (S)-tert-Butyl 2-((S)-l-amino-3-(4-iodophenyl)-l-oxopropan-2- ylcarbamoyl)piperidine-l-carboxylate(S)-2-Amino-3-(4-iodophenyl)propanamide (Example 1, step (ii), 2 g), (2S)-l-(tert- butoxycarbonyl)piperidine-2-carboxylic acid (2.4 g) and diopropylethylamine (3 niL) were dissolved in DMF (10 mL) and to the solution was added 2-(l-H-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium tetrafluoroborate (3.3 g). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether (200 mL) then washed with water (250 mL) and brine (4x 250 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Crude product was purified by flash silica chromatography eluting with ethyl acetate to give the sub-titled compound (2.88 g) as an oil.1H NMR (299.946 MHz, CDCl3) δ 7.63 (dd, 2H), 6.98 (dd, 2H), 6.49 (d, IH), 6.18 - 6.04 (m, IH), 5.48 (s, IH), 4.77 - 4.62 (m, 2H), 3.90 - 3.78 (m, IH), 3.15 - 3.00 (m, 2H), 2.43 - 2.31 (m, IH), 2.24 - 2.14 (m, IH), 1.68 - 1.43 (m, 14H).m/e (APCI+) 401 [M+H-BOC]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 14-O-[5-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin In N,N-dimethyl-formamide at 20℃; | 18.A Step A. 14-O-[(1S,2S,5R)-5-[((S)-N-tert-Butoxycarbonyl-piperidine-2-carbonyl)-amino]-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin + (1R,2R,5S) diastereomer To a solution of (S)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (Boc-L-pipecolinic acid, Boc-L-homoproline, 903 mg, 3.94 mmol) in 20 mL of DMF is added HOBT (532 mg, 3.94 mmol) and EDC (755 mg, 3.94 mmol) and stirred for 30 min at RT. Then 14-O-[(1R,2R,5S)-5-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin + (1S,2S,5R) diastereomer (2 g, 3.94 mmol) from Example 2 is added and the resulting mixture is stirred at RT until completion of the reaction (typically overnight). The reaction mixture is charged with brine and extracted with CH2Cl2. The organic layers are dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and subjected to chromatography (silica, cHex / EtOAc = 1/4) yielding 14-O-[(1S,2S,5R)-5-[((S)-N-tert-butoxycarbonyl-piperidine-2-carbonyl)-amino]-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin + (1R,2R,5S) diastereomer (yield: 2.29 g, 81 %th) as a colorless foam. 1H NMR (200MHz, DMSO-d6, δ, ppm, inter alia): 7.6 (m, 1H, NHCO), 6.14 (dd, 1H, 19-H, J = 11Hz and 18Hz), 5.55 (d, 1H, 14-H, J = 7Hz), 5.06 (m, 2H, 20-H), 4.90 (m, 2H, 2'-OH), 4.52 (m, 1H, 11-OH), 4.4 (bs, 1H, Pip-CHNH), 3.85 - 2.90 (m, 8H, Pip-H, 5'-H, 2'-H, 11-H, 22-H, Pip-H, 1'-H), 2.40 (bs, 1H, 4-H), 1.36 (bs, 12H, tert-butyl, 15-CH3), 1.06 (s, 3H, 18-CH3), 0.82 (d, 3H, 17-CH3, J = 7Hz), 0.63 (d, 3H, 16-CH3, J = 6Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 48h; | 19 Preparation 19(S)-tert-Butyl 2-(( 1 -(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3 -yl)piperidin-4- yl)(methyl)carbamoyl)piperidine- 1 -carboxylate; Sequentially treat a solution of l-(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3-yl)- N-methylpiperidin-4-amine (100 mg, 0.318 mmol) in CH2Cl2 (3.2 mL) with (S)-I -(tert- butoxycarbonyl)piperidine-2-carboxylic acid (109 mg, 0.477 mmol), triethylamine (0.067 mL, 0.477 mmol) and EDCI (92 mg, 0.477 mmol). Stir the resulting mixture at ambient temperature for 2 d. Pour the reaction mixture into H2O containing ΝaHCθ3. Separate the layers, and extract the aqueous layer with CH2Cl2. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 2% 2 M NH3MeOH in CH2Cl2) to afford the title compound as a white solid (82 mg, 49%). ES/MS m/z 526.2 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Amide coupling procedure 4: Synthesis of (S)-2-(5-t°r/-Butyl-l,3,4-thiadiazol-2- ylcarbamoyl)-piperidine-l-carboxylic acid tert-bxty esterTo a suspension of (S)-piperidine-2-carboxylic acid (0.4g; 1.745mmol) in THF (5mL) is added N,N-diisopropylethylamine (0.608mL; 3.49mmol) and 3-(diethoxyphosphoryloxy)- l,2,3-benzotrizin-4(3H)-one (1.044g; 3.49mmol) at room temperature. After 30 minutes of stirring, 2-amino-5-t-butyl-l,3,4-thiadiazole (0.274g; 1.745mmol) is added and the reaction is stirred at room temperature for 18 hours. The reaction is quenched with saturated NEta4C1 aqueous solution and extracted with ethyl acetate 3 times. The organics are combined and washed with water, then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/Hexanes provides the title compound, m/z 369 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In toluene; at 20℃; for 18h; | Amide coupling procedure 2: Synthesis of (S)-2-(3-toer/-Butyl-isoxazol-5-ylcarbamoyl)- piperidine-1-carboxylic acid tert-b\\xiy\\ ester2-Ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline (445mg; l.deltammol) is added to a solution of (S)-piperidine-2-carboxylic acid (300mg; 1.308mmol) and 5-amino-3-t-butylisoxazole (183.4mg; 1.308mmol) in toluene (4.2mL) at room temperature and the mixture is stirred for 18 hours. After this time, the mixture is concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 352 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With triethylamine; isobutyl chloroformate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: diazomethane In diethyl ether Inert atmosphere; | |
Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -30℃; for 1h; Stage #2: diazomethane In tetrahydrofuran; diethyl ether at 20℃; Stage #3: With acetic acid In tetrahydrofuran; diethyl ether | I Example ITHE SYNTHESIS OF (S)-LAC-34 HYDROCHLORIDE FROM CHIRAL STARTING MATERIAL [0177] Isobutyl chloroformate (5.65 ml) was added dropwise to a solution of 9 g of Boc-L- pipecolic acid [1] and 4.97 ml of N-methylmorpholine in 150 ml of anhydrous tetrahydrofuran (THF) at -30 0C, and the reaction mixture was kept at -30 0C for 1 hour. Then 250 ml of a solution of diazomethane (prepared from 43 g of diazogen) in diethyl ether was added, and the mixture was stirred at room temperature overnight. Acetic acid (5 ml) was added dropwise to destroy excess diazomethane, and the reaction mixture was evaporated to dryness. The residue was dissolved in diethyl ether, washed with water, brine, and dried over Na2SO4. After evaporation, 8.9 g of crude diazomethyl ketone [2] was obtained, and used directly in the next step. [0178] Compound [2] (8.9 g) was dissolved in 100 ml anhydrous methanol, and 1.0 g of silver benzoate was added with stirring at room temperature. After 3 hours, 50 ml of brine was added, and the mixture was filtered through Celite. The filtrate was evaporated to remove methanol, and the resulting aqueous solution was extracted with ethyl acetate three times, the EPO combined organic extract washed with brine, and dried over Na2SO4. The dried organic layer was evaporated, and the residue was purified by column chromatography (silica gel) to give 7.64 g of N-Boc β-amino acid ester [3]. [0179] Lithium aluminum hydride (0.453 g) was added to a solution of 4.0 g of compound [3] in 100 ml of anhydrous diethyl ether at 0 0C. The suspension was stirred at 0 0C for 1 hour, and then poured onto ice-water. The mixture was filtered, and the filtrate was extracted with diethyl ether three times. The combined organic extract was washed with brine and dried over Na2SO4. After evaporation, 3.48 g of crude alcohol [4] was obtained and used in the next step without purification. [4] [5][0180] Compound [4] (3.48 g) was dissolved in 15 ml of dichloromethane, and 30 ml of 40% trifluoroacetic acid in dichloromethane was added at 00C. After 2 hours, excess trifluoroacetic acid and solvent were removed in vacuo, and the residual salt [5] was dried under high vacuum overnight. EPO [0181] A mixture of compound [5], 2.3 ml of benzyl bromide, 5 g of potassium carbonate in 00 ml of acetonitrile was refluxed overnight. The solvent was removed in vacuo, and 2N hydrochloric acid was added until the pH was ~4. The mixture was extracted with diethyl ether to remove neutral impurities. The aqueous layer was neutralized with 2N sodium hydroxide to pH~8, extracted with ethyl acetate three times, the combined organic extract washed with water, brine, and dried over Na2SO4. The organic layer was evaporated to dryness to give 2.5 g of N-benzyl protected alcohol [6]. [0182] A solution of compound [6] (2.5 g), 3ml of thionyl chloride, two drops of concentrated hydrochloric acid in 50ml of chloroform was heated at reflux overnight. The mixture was evaporated to dryness, and 50 ml of saturated aqueous sodium bicarbonate was added. The aqueous layer was extracted with ethyl acetate three times, and the combined organic extract was washed with water, brine, and dried over Na2SO4. After evaporation, the residue was purified by column chromatography (silica gel) to give 1.7 g of the corresponding alkyl chloride [7]. EPO [0183] A suspension of 2-aminophenylindane (1.7 g) and 0.4g of sodium amide in 40 ml of anhydrous toluene was stirred at room temperature for 3 hours. A solution of 1.7 g of compound [7] in 5 ml of anhydrous toluene was added. The reaction mixture was refluxed overnight and poured onto ice- water after cooling. The mixture was extracted with ethyl acetate three times, and the combined organic layer was washed and dried over Na2SO4. After evaporation, 1.1 g of pure N-benzyl (S)-LAC-34 [8] was obtained by column chromatography (silica gel). [9] S-LAC-34 . HCl[0184] A mixture of 1.1 g of compound [8] and 200 mg of 10% Pd-C in 50 ml of ethyl acetate was stirred under 30 psi of hydrogen gas at room temperature for 5 hours. The reaction mixture was filtered through Celite, and the filtrate was evaporated to dryness. The residue EPO was dissolved in 10 ml of anhydrous diethyl ether, and 10 ml of 2N hydrogen chloride in diethyl ether was added. The 650 mg of desired (S)-LAC-34 hydrochloride [9] was obtained by filtration.1H NMR (CDCl3) δ: 7.15-7.27 ( m, 6H, H-Ph), 6.74-6.86 ( m, 3H, H-Ph), 4.51~4.68(m, IH, PhNCH), 2.42-3.40(m, 1OH, C6H4(CH2)2-, PhNCH2-, -CHNCH2-), 1.25-1.77 (m, 8H, -NCH2CH2CHaCH2-, -NCH2CH2-). | |
Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -30℃; for 1h; Stage #2: diazomethane In tetrahydrofuran; diethyl ether at -30 - 20℃; for 16h; | 1.A A. (S)-2-(Methoxycarbonylmethyl)piperidine-1-carboxylic acid tert-butyl ester (Compound 2) To a stirred solution of boc-L-pipecolic acid (1; 15g, 68.10 mmol) in tetrahydrofuran (THF; 175 mL) was added N-methyl morpholine (9.4 mL, 85.12 mmol) at -30° C., followed by the addition of isobutyl chloroformate (9.8 mL, 74.90 mmol) dropwise at -30° C. The resulting mixture was stirred at that temperature for 1 hour. A solution of diazomethane in diethyl ether was then added to the reaction mixture and the mixture was stirred at room temperature (rt) for 16 hours. The reaction mixture was quenched by adding glacial acetic acid (10 mL) and was then concentrated. The residue was dissolved in diethyl ether (500 mL), washed with water (100 mL) and brine (25 mL). The combined organic layers were dried, filtered and concentrated. The crude material was dissolved in methanol (130 mL), silver benzoate (4 g) was added portion-wise at ice cold conditions and the mixture was stirred at rt for 16 hours. Brine solution (50 mL) was added to the reaction mixture and filtered through the Celite reagent and washed with methanol. The organic layer was evaporated in vacuo, the residue was diluted with ethyl acetate (EtOAc, 470 mL) and washed with water (50 mL) and brine (20 mL). The organic layer was dried, filtered and concentrated. The crude material was purified by chromatography using 230-400 mesh silica gel eluting with 3% EtOAc in hexane to provide compound 2 as a liquid. Yield: 10.2 g (58.28%); 1H-NMR (400 MHz, DMSO-d6): δ 4.51 (s, 1H), 3.81 (d, J=11 Hz, 1H), 3.57 (s, 3H), 2.77-2.74 (m, 1H), 2.55 (d, J=7 Hz, 2H), 1.58-1.52 (m, 6H), 1.37 (s, 9H);LCMS: [M+H]=258.2, RT=3.55 minutes, (Program R1, Column X). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: dimethyl amine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 16h; | |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide at 10 - 20℃; for 16h; | 5 (2S)-Piperidine-2-dimethylcarboxamide hydrochloride (WO 01/74775)20 g (87.2 mmol) of (S)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid and 13 g (96 mmol) of 1-hydroxybenzotriazole (HOBT) were dissolved in 300 ml of DMF. Addition of 150 ml (305 mmol) of a solution of 2 M dimethylamine in THF was followed by cooling the solution to 10° C. Then 18.4 (96 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDAC or EDCI) were added in portions. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was highly concentrated in vacuo, and the resulting residue was partitioned between ethyl acetate and water. The organic phase was washed 2× with water, 3× with 5% strength K2CO3 solution and again with water, dried and concentrated in vacuo. The resulting residue was dissolved in ether, and 100 ml of 5-6 M isopropanolic HCl were added. The reaction mixture was cautiously heated at 30° C. for 1 hour and then concentrated in vacuo. 14.6 g of the product were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; potassium iodide In acetone at 60℃; for 12h; | |
85% | With potassium carbonate; potassium iodide In acetone at 60℃; for 12h; | 4 Synthesis of (S)-1-tert-butyl 2-[2-(3,4-dimethoxyphenyl)ethyl] piperidine-1,2-dicarboxylate To a solution of 4-(2-bromoethyl)-1,2-dimethoxybenzene (385 mg, 1.57 mmol), in acetone (10ml) was added (S)-1-Boc-piperidine-2-carboxylic acid (300mg, 1.30 mmol), K2CO3 (217 mg, 1.57 mmol), and KI (catalytic amount). The reaction mixture was stirred at 60°C for 12h. The mixture was filtered and the solid residue washed with ethyl acetate (3 X 30 ml). The combined organic phases were washed with brine (30ml) and dried over MgS04. The solution was concentrated and then residue was purified by chromatography using Hexane: EtOAc 8:2 to afford (S)-1-tert-butyl 2-[2-(3,4-dimethoxyphenyl)ethyl] piperidine-1,2-dicarboxylate (440mg, 1.12 mmol, 85%). TLC (Hexane:EtOAc 8:2): RF = 0.46 1H NMR (300 MHz, CDCl3) δ= 1.46 (s,1H), 1.58-1.59 (m, 3H), 2.17 (d, 1H, j= 13.2 Hz), 2.91 (t, 2H, j= 6.9 Hz), 3.87 (s, 3H), 3.89 (s, 3H), 3.91-4.17 (m, 2H), 4.35 (t, 2H, J= 6.9 Hz), 4.71-4.88(m, 1 H), 6.75-6.83(m, 3H). 13C NMR (75 MHz, CDCl3) δ= 28.36, 34.75, 55.80, 55.94, 65.53, 79.89, 111.35, 112.11, 120.90, 147.78, 148.95. HRMS m/z 294.1694 [M - Boc + H] +, 394.2277 [M + H] +, 416.2083 [M + Na] +, calculated 294.1716 [M - Boc + H] +, 394.2151 [M + H] +, 416.2044 [M + Na] +. |
85% | With potassium carbonate; potassium iodide In acetone at 60℃; for 12h; | 4 Synthesis of (S)-l -tert-butyl 2-[2-(3,4-dimethoxyphenyl)ethyl] piperidine-1 ,2- dicarboxylate Example 4 Methods for the coupling of pipecolic acids A with building blocks B: Synthesis of (S)-l -tert-butyl 2-[2-(3,4-dimethoxyphenyl)ethyl] piperidine-1 ,2- dicarboxylate To a solution of 4-(2-bromoethyl)-1 ,2-dimethoxybenzene (385 mg, 1 .57 mmol), in acetone (10ml) was added (S)-1 -Boc-piperidine-2-carboxylic acid ( 300mg, 1 .30 mmol), K2CO3 (217 mg, 1 .57 mmol), and Kl (catalytic amount). The reaction mixture was stirred at 60°C for 12h. The mixture was filtered and the solid residue washed with ethyl acetate (3 X 30 ml). The combined organic phases were washed with brine (30ml) and dried over MgSO4. The solution was concentrated and then residue was purified by chromatography using Hexane: EtOAc 8:2 to afford (S)-l -tert-butyl 2-[2- (3,4-dimethoxyphenyl)ethyl] piperidine-1 ,2-dicarboxylate ( 440mg, 1 .12 mmol, 85%). TLC (Hexane:EtOAc 8:2): RF = 0.46 1 H NMR (300 MHz, CDCI3) δ= 1 .46 (s,1 H), 1 .58-1 .59 (m, 3H), 2.17 (d, 1 H, j= 13.2 Hz), 2.91 (t, 2H, j= 6.9 Hz), 3.87 (s, 3H), 3.89 (s, 3H), 3.91 -4.17 (m, 2H), 4.35 (t, 2H, J= 6.9 Hz), 4.71 -4.88(m, 1 H), 6.75-6.83(m, 3H). 13C NMR (75 MHz, CDCI3) δ= 28.36, 34.75, 55.80, 55.94, 65.53, 79.89, 1 1 1 .35, 1 12.1 1 , 120.90, 147.78, 148.95. HRMS m/z 294.1694 [M - Boc + H] 394.2277 [M + H] +, 416.2083 [M + Na] calculated 294.1716 [M - Boc + H] +, 394.2151 [M + H] +, 416.2044 [M + Na] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In acetone Inert atmosphere; Reflux; | |
77% | With potassium carbonate; potassium iodide In acetone at 60℃; for 12h; | |
77% | With potassium carbonate; potassium iodide In acetone at 60℃; for 12h; | 4 Synthesis of (S)-1-tert-butyl 2-(2-(3,4-dimethoxyphenoxy)ethyl)-piperidine-1,2-dicarboxylate To a solution of 4-(2-bromoethoxy)-1,2-dimethoxybenzene (200mg, 0.76 mmol), in acetone (10ml) was added (S)-1Boc-piperidine-2-carboxylic acid (150 mg, 0.65 mmol), K2CO3 (108 mg, 0.78 mmol), and KI (catalytic amount). The reaction mixture was stirred at 60°C for 12h. The mixture was filtered and the solid residue washed with ethyl acetate (3 X 30 ml). The combined organic phases were washed with brine (30ml) and dried over MgS04. The solution was concentrated and then residue was purified by chromatography using Hexane: EtOAc 7:3 to afford (S)-1-tert-butyl 2-(2-(3,4-dimethoxyphenoxy)ethyl)-piperidine-1,2-dicarboxylate (200mg, 0.50 mmol, 77%). TLC (Hexane:EtOAc 7:3): RF = 0.39 1H NMR (600 MHz, CDCl3) δ= 1.42 (d, 9H, J= 19.2 Hz), 1.57-1.65 (m, 4H), 2.17-2.23 (m, 1H), 2.86- 3.01 (m, 1H), 3.82 (s,3H), 3.83 (s,3H), 3.88-4.02 (m, 1H), 4.11 (t, 2H, J= 4.8 Hz), 4.45 (t, 2H, J= 4.8 Hz), 4.75 (s, 0.5H), 4.91 (s, 0.5H), 6.37 (dd, 1H, J= 3, 9 Hz), 6.51 (d, 1H, J= 1.2 Hz), 6.76 (d, 1H, J= 8.4 Hz). 13C NMR (150 MHz, CDCl3) δ= 26.79, 28.37, 41.03, 42.08, 53.79, 54.86, 55.81, 56.39, 63.17, 66.49, 101.08, 103.94, 111.68, 143.82, 149.84, 153.02, 171.89. MS (ESI) m/z 432.20[M + Na] +, 448.20[M + K] +, calculated 432.20 [M + Na] +, 448.17[M + K] +. |
77% | With potassium carbonate; potassium iodide In acetone at 60℃; for 12h; | 4 Synthesis of (S)-1 -tert-butyl 2-(2-(3,4-dimethoxyphenoxy)ethyl)-piperidine-1 ,2- dicarboxylate Synthesis of (S)-1 -tert-butyl 2-(2-(3,4-dimethoxyphenoxy)ethyl)-piperidine-1 ,2- dicarboxylate To a solution of 4-(2-bromoethoxy)-1 ,2-dimethoxybenzene (200mg, 0.76 mmol), in acetone (10ml) was added (S)-1 Boc-piperidine-2-carboxylic acid (1 50 mg, 0.65 mmol), K2CO3 (108 mg, 0.78 mmol), and Kl (catalytic amount). The reaction mixture was stirred at 60°C for 12h. The mixture was filtered and the solid residue washed with ethyl acetate (3 X 30 ml). The combined organic phases were washed with brine (30ml) and dried over MgSO4. The solution was concentrated and then residue was purified by chromatography using Hexane: EtOAc 7:3 to afford (S)-1 -tert-butyl 2-(2- (3,4-dimethoxyphenoxy)ethyl)-piperidine-1 ,2-dicarboxylate ( 200mg, 0.50 mmol, 77%). TLC (Hexane:EtOAc 7:3): RF = 0.39 1H NMR (600 MHz, CDCI3) δ= 1.42 (d, 9H, J= 19.2 Hz), 1.57-1.65 (m, 4H), 2.17-2.23 (m, 1H), 2.86- 3.01 (m, 1H), 3.82 (s,3H), 3.83 (s,3H), 3.88-4.02 (m, 1H), 4.11 (t, 2H, J= 4.8 Hz), 4.45 (t, 2H, J= 4.8 Hz), 4.75 (s, 0.5H), 4.91 (s, 0.5H), 6.37 (dd, 1H, J= 3, 9 Hz), 6.51 (d, 1H, J= 1.2 Hz), 6.76 (d, 1H, J= 8.4 Hz). 13C NMR (150 MHz, CDCI3) δ= 26.79, 28.37, 41.03, 42.08, 53.79, 54.86, 55.81, 56.39, 63.17, 66.49, 101.08, 103.94, 111.68, 143.82, 149.84, 153.02, 171.89. MS (ESI) m/z 432.20[M + Na] +, 448.20[M + K] +, calculated 432.20 [M + Na] +, 448.17[M + K]+. |
Yield | Reaction Conditions | Operation in experiment |
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80% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 15h; Inert atmosphere; | 1.1 Step 1: Preparation of tert-butyl (S)-2-((3-phenylpropyl)carbamoyl)piperidine-1- carboxylate of formula (II) N-Boc-L-pipecolinic acid (425 mg, 1.88 mmol), DIPEA (775 mg, 6 mmol) and HATU (684 mg, 1.8 mmol) were added to a solution of 3-phenylpropyl-1-amine (162 mg, 1.2 mmol) in 10 ml of anhydrous DMF. The additions are carried out at a constant temperature of 0°C, keeping the reaction flask under constant stirring in N2 atmosphere. When all the reagents had dissolved and the solution in the reaction flask was homogeneous, the temperature was allowed to rise to room temperature and maintained for 15 hours. The reaction solution was then mixed with 30 ml_ of ethyl acetate, and the phases were allowed to separate; the organic phase was washed several times with a saturated solution of NH4CI and brine and dried on anhydrous Na2SC>4. The aqueous solution was then filtered and evaporated by rotary evaporator until a yellow oil was obtained which was purified by flash chromatography column on silica gel using a mixture of DCM:EtOAc/8:1 as eluent. The expected derivative of the title was isolated as a colourless oil (330 g, 80% yield) and characterized as previously described. |
26% | With dmap; diisopropyl-carbodiimide In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In tetrahydrofuran at 20℃; for 20h; | Experimental Example: S-1-Boc-piperidine-2-carboxylic acid (500 g, 2.18 mol) was dissolved in tetrahydrofuranN, N'-Carbonyldiimidazole (353.7 g, 2.18 mol) was added portionwise with stirring at room temperature,Plus,The reaction was continued at room temperature for 20 hours until the reaction was completed.After the reaction was completed, the solvent was concentrated under reduced pressure.The remaining oil was dissolved in ethyl acetate (2 L), washed with water,Saturated sodium bicarbonate, saturated salt water.The organic phase is dried over anhydrous sodium sulphate,Concentration under reduced pressure gave Compound B as a white solid (602 g, 96% yield, purity 98%). |
In tetrahydrofuran at 20℃; for 18h; | 71 Example 71 Preparation of Intermediate 73 Example 71 Preparation of Intermediate 73 [0683] [0684] To a solution of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (30.0 g, 130 mmol) in tetrahydrofuran (260 mL) was added carbonyldiimidazole (21.2 g, 130 mmol) at room temperature. After 18 h, the reaction mixture was concentrated under reduced pressure and the crude residue was partitioned between ethyl acetate (600 mL) and water (200 mL). The phases were separated, and the organic layer was washed with water (200 mL), with saturated aqueous sodium bicarbonate solution (200 mL), and with saturated sodium chloride solution (200 mL). The organic layer was dried over Na2SO4, and was concentrated under reduced pressure to afford intermediate 73 (36 g, 99%) as a white crystalline solid. [0685] 1H NMR (CDCl3, 400 MHz): δ 8.21 (br s, 1H), 7.51 (br s, 1H), 7.08 (br s, 1H), 5.45-5.01 (m, 1H), 3.92 (br d, J=13.6 Hz, 1H), 3.39-3.05 (m, 1H), 2.13-1.98 (m, 1H), 1.96-1.82 (m, 1H), 1.78-1.56 (m, 2H), 1.55-1.30 (m, 11H). Rf=0.30 (50% ethyl acetate/hexanes). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; | |
With caesium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 1h; Inert atmosphere; | ||
Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: allyl bromide In N,N-dimethyl-formamide at 20℃; for 2h; | 1 2-allyl 1-(tert-butyl) (S)-piperidine-1,2-dicarboxylate (2). To a solution of N-Boc homoproline 1 (6.30 g) in DMF (40 mL), Cs2CO3 (2.90 g) was added. The resulting suspension was stirred at RT for 5 min before the addition of allyl bromide (6.3 g). After stirring at RT for 2 h, the suspension was filtered through a pad of celite, rinsed with EtOAc (50 mL), and washed with HCl (1M, 50 mL x3). The organic layer was dried over Na2SO4 and co-evaporated with toluene (30 mL×2). Crude product (8.10 g) was collected as a yellow oil and was pure enough for the next step without further purification. |
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
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74.6% | With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 0 - 20℃; for 2h; | 35.1 Step 1 ) the preparation of compound 35-2 To a solution of compound 35-1 (30.86 g, 134.7 mmol) and HATU (53.99 g. 141.46 mmol) in THF (300 mL) was added DIPEA (26.7 mL, 161.6 mmol) at 0 °C. the mixture was stirred at rt for 0.5 hr and then added a solution of compound 1-10-2 (27.71 g. 148.2 mmol) in THF (140 mL) at 0 °C. At the end of addition, the mixture was stirred at rt for 2 hrs. After the reaction was completed, the mixture was quenched with water (200 mL). and the solvent THF was removed. The resulting mixture was extracted with EtOAc (250 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was dissolved in acetic acid glacial (140 mL), and the mixture was stirred at 40 °C overnight. After the reaction was completed, the solvent acetic acid glacial was removed, and water (200 mL) was added. The resulting mixture was extracted with EtOAc (250 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1 ) to give the title compound as a brown solid (40 g. 74.6%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 380.5 [M+H] +; NMR (400 MHz. CDC13) 0 (ppm): 7.75-7.74 (m. 1 H), 7.36, 7.33 (d. d, 1H), 7.20. 7.19, 7.17 (s, s. s. 1 H), 5.12-5.06 (m. 1 H), 4.30-4.22 (m, l H), 2.96-2.87 (m, 1 H). 2.21 -2.13 (m, 1H), 1.93-1.80 (m, 1H), 1.70-1.63 (m, 1 H), 1.54-1.51 (m. 1 H), 1.50 (s, 9H). 1.24-1.06 (m, 2H). |
74.6% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: 4-Bromo-benzene-1,2-diamine In tetrahydrofuran at 0 - 20℃; for 2h; | 35.1 11639] Step 1) the Preparation of Compound 35-2 11640] To a solution of compound 35-1 (30.86 g, 134.7 mmol) and HATU (53.99 g, 141.46 mmol) in THF (300 mE) was added DIPEA (26.7 mE, 161.6 mmol) at 0° C., the mixture was stirred at rt for 0.5 hr and then added a solution ofcompound 1-10-2 (27.71 g, 148.2 mmol) in THF (140 mE) at 0°C. At the end of addition, the mixture was stirred at it for 2 hrs. Afier the reaction was completed, the mixture was quenched with water (200 mE), and the solvent THF was removed. The resulting mixture was extracted with EtOAc (250 mEx3). The combined organic layers were dried over anhydrous Na2504 and concentrated in vacuo. The residue was dissolved in acetic acid glacial (140 mE), and the mixture was stirred at 40° C. overnight. Afier the reaction was completed, the solvent acetic acid glacial was removed, and water (200 mE) was added. The resulting mixture was extracted with EtOAc (250 mEx3). The combined organic layers were washed with brine, dried over anhydrous Na2504 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound as a brown solid (40 g, 74.6%). The compound was characterized by the following spectroscopic data:11641] MS (ESI, pos. ion) mlz: 380.5 [M+H]11642] ‘H NMR (400 MHz, CDC13) ö (ppm): 7.75-7.74 (m,1H), 7.36, 7.33 (d, d, 1H), 7.20, 7.19, 7.17 (s, s, s, 1H),5.12-5.06 (m, 1H), 4.30-4.22 (m, 1H), 2.96-2.87 (m, 1H),2.21-2.13 (m, 1H), 1.93-1.80 (m, 1H), 1.70-1.63 (m, 1H),1.54-1.51 (m, 1H), 1.50 (s, 9H), 1.24-1.06 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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58.28% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -30℃; for 1h; Stage #2: diazomethane In tetrahydrofuran; diethyl ether at -30 - 20℃; for 16h; Stage #3: methanol With silver benzoate at 20℃; for 16h; Cooling with ice; | 1.A A. (S)-2-(Methoxycarbonylmethyl)piperidine-l-carboxylic acid tert-butyl ester (Compound 2) A. (S)-2-(Methoxycarbonylmethyl)piperidine-l-carboxylic acid tert-butyl ester (Compound 2) To a stirred solution of boc-L-pipecolic acid (1; 15 g, 68.10 mmol) in tetrahydrofuran (THF; 175 mL) was added N-methyl morpholine (9.4 mL, 85.12 mmol) at -30°C followed by the addition of isobutyl chloroformate (9.8 mL, 74.90 mmol) dropwise at -30°C. The resulting mixture was stirred at that temperature for 1 hour. A solution of diazomethane in diethyl ether was then added to the reaction mixture and the mixture was stirred at room temperature (rt) for 16 hours. The reaction mixture was quenched by adding glacial acetic acid (10 mL) and was then concentrated. The residue was dissolved in diethyl ether (500 mL), washed with water (100 mL) and brine (25 mL). The combined organic layers were dried, filtered and concentrated. The crude material was dissolved in methanol (130 mL), silver benzoate (4 g) was added portion- wise at ice cold conditions and the mixture was stirred at rt for 16 hours. Brine solution (50 mL) was added to the reaction mixture and filtered through the Celite reagent and washed with methanol. The organic layer was evaporated in vacuo, the residue was diluted with ethyl acetate (EtOAc, 470 mL) and washed with water (50 mL) and brine (20 mL). The organic layer was dried, filtered and concentrated. The crude material was purified by chromatography using 230-400 mesh silica gel eluting with 3% EtOAc in hexane to provide compound 2 as a liquid. Yield: 10.2 g (58.28%); 1H-NMR (400 MHz, DMSO- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; | 1 Step 1: Synthesis of Compound BB-6-2 Compound BB-6-1 (4.6 g, 20 mmol) was dissolved in acetonitrile (70 mL), compound BB-1-1 (5.56 g, 20 mmol) was added, and then DIPEA (2.58 g, 20 mmol) was added gradually. After addition, the reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to remove the solvent by a rotary evaporator, the resulting oil was diluted with H2O (100 mL) and extracted with ethyl acetate (60 mL×2), the organic phases obtained twice were combined and dried over anhydrous sodium sulfate, the filtrate obtained after filtration was concentrated under reduced pressure to remove the solvent thereby delivering the title compound BB-6-2 (8.4 g, 99%). LCMS m/z: 326.0 [M-100]+ |
61% | With N-ethyl-N,N-diisopropylamine In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran at 0 - 20℃; for 3h; Inert atmosphere; Sealed tube; | 13.1 the preparation of compound 13-2 To a solution of compound 13-1 (3.96 g, 17.28 mmol) and compound 1-12-2 (5.46 g, 19.81 mmol) in DCM (60 mL) was added DIPEA (3.4 mL, 20.67 mmol) dropwise at 0 °C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was quenched with ice water (50 mL). The aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a white solid (4.48 g, 61%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 426.3 [M+H]+; and ln NMR (400 MHz, CDC13) δ (ppm): 7.82-7.78 (m, 2H), 7.67-7.64 (m, 2H), 5.27 (m, 2H), 4.79-4.74 (m, 1H), 3.96-3.89 (m, 1H), 3.09-3.00 (m, 1H), 2.15-2.06 (m, 2H), 1.42 (s, 9H), 1.27-1.02 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | A solution of benzo[d]thiazol-2-amine(65 mg, 0.43 mmol), 1-(tert-butoxycarbonyl)-L-proline (138 mg, 0.64mmol), N1-hydroxy-7-azabenzotriazole(85 mg, 0.64 mmol) and N,N-diisopropylethylamine(83 mg, 0.64 mmol) in anhydrous DMF (2 mL) was treated with2-chloro-1-methylpyridinium iodide (163 mg, 0.64 mmol) and the mixture stirredat 20 oC for 18 h. The mixture was diluted with ethyl acetate (50ml) and washed with 1N HCl (50 ml), water (2 X 50 mL), saturated sodiumbicarbonate solution (50 mL) and brine (25 mL). The organic layer was driedwith Na2SO4 and evaporated. The residue was purified byreversed phase HPLC (method described in the general experimental section) andthe product fractions were evaporated under reduced pressure at <45 oC.The residue was dissolved in 4N HCl in 1,4-dioxane (2 mL) and stirred for 2 h.The solvents were evaporated under reduced pressure to provide 7 as a white solid HCl salt (65 mg,53%). 1H-NMR (CD3OD) d7.89 (d, J = 8.1 Hz, 1H), 7.75 (d, J =8.2 Hz, 1H), 7.48 (dd, J = 8.2 Hz, J = 8.1 Hz, 1H), 7.35 (dd, J = 8.2 Hz, J = 8.1 Hz, 1H), 4.58 (dd, J= 7.1 Hz, J = 6.8 Hz, 1H), 3.49(m, 2H), 2.58 (m, 1H), 2.17 (m, 3H). LC/MS M+H+ = 248, Rt = 2.77 mins, purity>95%. Exact mass calc?d for C12H13N3OS =247.0779, found = 247.0791. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In dichloromethane for 6h; Inert atmosphere; | Under a nitrogen atmosphere, the acid (1) (0.5 g, 2.13×10-3 mol) is dissolved in CH2Cl2. N-O-dimethylhydroxylamine hydrochloride (0.254 g, 2.55×10-3 mol) and triethylamine (7.51×10-3 mol) are added to this solution. Benzotriazol-1-yl-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) (1.06 g, 2.343×10-3 mol) is then added, and the reaction mixture is stirred for 6 h. The reaction mixture is then diluted in CH2Cl2 and transferred to a dropping funnel containing 1M HCl. The organic phase is washed with NaHCO3, then with saturated NaCl, and finally with water. It is dried over Na2SO4 and then, after filtration and evaporation of the solvent, the oil obtained is purified by flash chromatography (cyclohexane/ethyl acetate 8:2) to give the hydroxamate (2) (0.479 g, 83%). |
Yield | Reaction Conditions | Operation in experiment |
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72.2% | With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride In dichloromethane at 0 - 20℃; | 1 Synthesis of Compound PZ10348 To a solution of PZ1034-5 (0.5g, 2.2 mmol) in CH2Cl2 (30 mL) was added DMTMM (0.92g,3.3) and (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (0.47g,2.2mmol) at 0 °C. The mixture was stirred at ambient temperature overnight and then a mixture of water/CH2Cl2 (20mL/ 20mL) was added to quench the reaction. The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (20mL x 3). The combined organic phase were dried and concentrated. The residue was purified by flash columnchromatography on silica gel (EA/PE= 1:10) to give PZ1034-8 (0.7g, 72.2% yield) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
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42% | With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 20℃; for 2h; | 5 5.1.1.5. (2S,20S)-Di-tert-butyl 2,20-(([1,10-biphenyl]-4,40-diylbis(azanediyl))bis(carbonyl))bis(piperidine-1-carboxylate) (6). 5.1.1.5 (2S,2'S)-Di-tert-butyl 2,2'-(([1,1'-biphenyl]-4,4'-diylbis(azanediyl))bis(carbonyl))bis(piperidine-1-carboxylate) (6) A mixture of N-Boc-l-pipecolic acid (400 mg, 1.75 mmol), EDCI (363 mg, 1.9 mmol), and benzidine (134 mg, 0.73 mmol) in CH2Cl2 (7 mL) was stirred at ambient temperature for 2 h. The resulting residue was partitioned between CH2Cl2 and H2O. The organic layer was washed with 1.0 N aq HCl solution and brine, dried over MgSO4, filtered, and concentrated in vacuo. A silica gel mesh was prepared from the residue and submitted to flash chromatography (silica gel: EtOAc/hexane as eluent) to provide 20 as a solid (186 mg, 42%). 1H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): 9.99 (s, 2H), 7.67-7.58 (dd, 8H), 4.70 (m, 2H), 3.82 (d, 2H), 3.34 (m, 2H), 2.08 (app br s, 2H), 1.72-1.58 (m, 6H), 1.37 (app br s, 22H). 13C NMR (DMSO-d6, δ = 39.52 ppm, 100 MHz): 170.8, 155.3, 138.1, 134.5, 126.4, 119.7 78.9, 55.2, 53.9, 42.0, 28.0, 27.5, 24.2, 19.3. HRMS: Anal. calcd. for [M+H]+ C34H46N4O6: 607.3490; found 607.3491. |
42% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h; | 10 Example 10 Preparation of dimethyl((1R,1'R)-((2S,2'S)-2,2'-(([1,1'-biphenyl]-4,4'-diylbis(azandiyl))bis(carbonyl))bis(piperidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate N-Boc-L-pipecolic acid (400 mg, 1.75 mmol), EDC (363 mg, 1.9 mmol), and benzidine (134 mg, 0.73 mmol) were mixed in CH2Cl2 (7 mL), followed by stifling at room temperature for 2 hours. Then, the compound obtained above was fractionated with CH2Cl2 and H2O. The organic layer was washed with 1 N HCl aqueous solution and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue proceeded to silica gel mesh, followed by flash chromatography (eluent: EtOAc/hexane mixture) to give the target compound (2S,2'S)-di-tert-butyl 2,2'-(([1,1'-biphenyl]-4,4'-diylbis(azandiyl))bis(carbonyl))bis(piperidine-1-carboxylate) as a solid (186 mg, yield: 42%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: benzyl (1-(bis(4-(methylthio)phenoxy)phosphoryl)butyl)carbamate hydrobromide; (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With N-ethyl-N,N-diisopropylamine In acetonitrile for 0.2h; Stage #2: With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In acetonitrile at 20℃; for 12h; | 1.4 Stacie 4. Preparation of tert-butyl (S)-2-(((R)- 1-(bis(4-(methylthio) phenoxy) phosphoryl) butyl) carbamoyl) piperidine- 1 -carboxylate. 0.37g (0.77 mmol) of (1 -(bis(4-(methylthio) phenoxy) phosphoryl) butyl) carbamate hydrobromide is weighted into round-bottom flask and 0.20 g of Boc-Pip-OH (0.88 mmol) is added. The total is covered with acetonitrile (15 mL) and 0.32g of N,N-diisopropylethylamine (2.5 mmol) is added after 2 minutes. After 10 minutes, 0.43 g (0.82 mmol) of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate is added. The reaction is carried out at room temperature for 12 hours. Next, the volatile components of reaction mixture are evaporated and resultant oil is dissolved in 40 mL of ethyl acetate. Acetate layer is washed sequentially: twice with 5% of citric acid solution, brine, twice with sodium bicarbonate (5%) and brine. Acetate fractions are dried with anhydrous magnesium sulphate. Volatile solvents are evaporated and then the product is purified by column chromatography method using petroleum ether/ethyl acetate as the eluent at a volume ratio of 2:1. Once the fractions containing expected product are collected, volatile solvents are evaporated on the rotovap. 0.25 g of expected product is obtained (53% yield) as a colourless oil. Molecular formula: C29H4106N2PS2. Molecular weight:608.75g/mol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0℃; for 24h; | General procedure: According to a procedure of Choi et al.36 (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (1equiv) was dissolved in 20mL anhydrous CH2Cl2 and at 0C the corresponding alcohol (1.0equiv), EDC·HCl (1.5equiv) and DMAP (0.2equiv) were added. After the reaction was completed (TLC control) the organic layer was washed twice with water and the solvent was evaporated in vacuo. The boc-protection group was cleaved with 2mL trifluoroacetic acid in 20mL CH2Cl2. After 24h the reaction was neutralized with saturated NaHCO3 extracted with 3×30mL CH2Cl2. The combined organic layers were dried over Na2SO4 and the solvent was evaporated to yield compound 8a, b, n-y which was used in the next step without further purification. Compound 8a, b, n-y (1equiv) was dissolved in 40mL of anhydrous CH2Cl2, and NMM or DIPEA (3equiv) was added at 0C followed by corresponding sulfonyl chloride (1equiv), respectively. The mixture was stirred until completion (TLC) and subsequently the solvent removed in vacuo. After purification by means of flash-chromatography compounds S-5a, b, n-y were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 36h; | (-)-(S)-tert-Butyl 2-(quinolin-8-ylcarbamoyl)piperidine-1-carboxylate (2) To a solution of L-(-)-pipecolinic acid (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 |
---|---|---|
39% | To the reaction flask was added (2S) -1-tert-butoxycarbonylpiperidine-2-carboxylic acid (2.0 g, 8.70 mmol)Dichloromethane (10 mL) and triethylamine (2.4 mL, 17.4 mmol)Under ice bath, isobutyl chloroformate (2.2 mL, 17.4 mmol) was added dropwise to the nitrogen atmosphere,After stirring, the temperature was stirred for 1 hour, <strong>[31329-64-3]3,5-dimethylisoxazol-4-amine</strong> (1.46 g, 13.10 mol)Rose to room temperature stirring 6h,The reaction solution was washed successively with water (10 mL x 1), saturated brine (10 mL x 1), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether / ethyl acetate (v / v) 6: 1) to give a white solidTert-butyl (2S) -2 - [(3,5-dimethylisoxazol-4-yl) aminocarbonyl] piperidine-1-carboxylate (1B) (1.1 g, yield: 39 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.7% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With N-ethyl-N,N-diisopropylamine; isobutyl chloroformate In tetrahydrofuran for 0.5h; Cooling with ice; Stage #2: benzyl (5-methyloxazol-4-yl)carbamate With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Cooling with ice; Stage #3: In tetrahydrofuran at 20℃; for 1.66667h; | 24.2 Step 2: (S) -2 - ((benzyloxy) carbonyl) (5-methylyloxazol-4-yl) carbamoyl) piperidine-1-carboxylate (24C) (2S) -1-tert-butoxycarbonylpiperidine-2-carboxylic acid 24B (0.197 g, 0.861 mmol)Was added 10 mL of tetrahydrofuran,Under ice bath, isobutyl chloroformate (0.118 g, 0.861 mmol) was added under coolingDiisopropylethylamine (0.139 g, 1.08 mmol)And the mixture was stirred for 30 minutes to prepare a reaction solution.The (5-methyl-oxazol-4-yl) carbamate (0.200g,0.861 mmol)Was added 10 mL of tetrahydrofuran,Sodium hydride (0.0258 g, 1.08 mmol) was added under cooling with ice bath and allowed to react at room temperature for 30 minutes as reaction solution 2.The reaction solution 1 was added to the reaction solution 2, and the reaction was carried out at room temperature for 100 minutes. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 100: 2 to 10: 1) to give the title compound(S) -tert-butyl 2 - ((benzyloxy) carbonyl) (5-methyloxazol-4-yl) carbamoyl) piperidine-1-carboxylate (24C)Colorless liquid (0.600 g, yield 15.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | To the reaction flask was added (2S) -1-t-butoxycarbonylpiperidine-2-carboxylic acid (2.3 g, 10.0 mmol)Dichloromethane (10 mL) and1-ethyl- (3-dimethylaminopropyl) carbodiimide (i.e., EDCI) (2.3 g, 12.0 mmol)Add room temperature after 5min,<strong>[6646-51-1]1-methyl-2-aminoimidazole</strong> (1.07 g, 11.0 mol) was added,Stirred at room temperature for 5 hours,The reaction solution was washed successively with water (10 mL x 2), saturated brine (10 mL x 1), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated by column chromatography (dichloromethane / methanol (v / v) = 50 : 1) to give tert-butyl as a white solid(2-chloro-2-yl) aminocarbonyl] piperidine-1-carboxylate (4B) (308 mg, yield: 10%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.9% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With triethylamine; isobutyl chloroformate In tetrahydrofuran at 20℃; for 0.5h; Stage #2: benzyl (1,3-dimethyl-1H-pyrrol-2-yl)carbamate With sodium hydride In tetrahydrofuran at 20℃; for 2.5h; Inert atmosphere; Cooling with ice; | 17.4 Step 4: (S) -tert-Butyl 2 - (((benzyloxy) carbonyl) (1,3-dimethyl-1H-pyrrol-2-yl) carbamoyl) piperidine- Ester (17E) (S) -N-Boc-piperidine-2-carboxylic acid (16.89 g, 73.67 mmol)Was dissolved in tetrahydrofuran (105 mL)Triethylamine (9.94 g, 98.2 mmol) was added,A solution of isobutyl chloroformate (10.06 g, 73.67 mmol) was added dropwise at room temperature,Reaction for 30 minutes,The reaction solution is used.A solution of benzyl (1,3-dimethyl-1H-pyrrol-2-yl) carbamate (17D) (12 g, 49.12 mmol)Was dissolved in tetrahydrofuran (105 mL)Nitrogen protection,NaH (2.95 g, 73.8 mmol) was added under ice bath,Continue to react for 30 minutes.The above reaction solution was slowly added dropwise and reacted at room temperature for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (50 mL x 3).Dried over sodium sulfate, concentrated by filtration and purified by column chromatography (PET: ethyl acetate = 10: 1)(S) -tert-butyl 2 - ((benzyloxy) carbonyl) (1,3-dimethyl-1H-pyroglen-2-yl) carbamoyl) piperidine- )(2.0 g, yield 8.9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 2h; | 23.1 Step 1: (S) -1-tert-Butyl-2-methyl-4-oxopiperidine-1,2-dicarbonate (23A) To the reaction flask was added (S) -1- (tert-butoxycarbonyl) -4-oxopiperidine-2-carboxylic acid (1A) (5.0 g, 20.6 mmol)And N, N-dimethylformamide (70 mL),After stirring and dissolving,Cesium carbonate (8.1 g, 24.7 mmol) was added at room temperatureAnd methyl iodide (3.5 g, 24.7 mmol)The reaction was continued at room temperature for 2 hours.(30 mL x 3), the organic phases were combined, washed with water (50 mL x 4), and the organic phase was dried over anhydrous sodium sulfate (100 mL) and ethyl acetate (100 mL).The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5: 1-3: 1) to give the title compound as a colorless oil(S) -1-tert-butyl-2-methyl-4-oxopiperidine-1,2-dicarbonate (23A) (4.8 g, yield 91%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.9% | With 1,2-diamino-benzene at 200℃; for 2h; | 26.1 1st step: (S)-2 - (piperidine -2 - yl) - 1H - benzo [d] imidazole (26 a) (S)-2 - (piperidin - 2 - yl) - 1 H - benzo [d] imidazoleThe (S)-1 - (tert-butoxy carbonyl) piperidine -2 - formic acid (8.3 g, 0 . 0362 µM), O-phenylenediamine (3.9 g, 0 . 0362 µM) and poly phosphoric acid (20 ml) are added to a reaction in the bottle, is heated to 200 °C stirring 2 hours. Adding ice water (30 ml) and concentrated ammonia water (30 ml) to dissolve them and accent pH9 - 10, for 0 °C stirring for 30 minutes, filtering to obtain a yellow solid compound 26 a (4.0 g, yield 54.9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.5% | N-Boc-L-piperidine-2-carboxylic acid (7.56 g, 33 mmol) was added to the reaction flask,Triethylamine (3.64 g, 36, mmol)And dichloromethane (60 mL),A solution of isopropyl chloroformate (4.91 g, 36 mmol) was added dropwise under ice-0 C for 0.5 hour,Was added <strong>[74788-82-2]2,6-dimethylbenzylamine</strong> (2a) (4.06 g, 30 mmol)Plus finished recovery room temperature,React overnight.The system was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20: 1)A white solid was obtained(2S) -2 - [(2,6-dimethylphenyl) methylcarbamoyl] piperidine-1-carboxylate (2b)(2.65 g, 25.5%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine; isobutyl chloroformate; In dichloromethane; at 20℃; for 6.0h;Cooling with ice; | To the reaction flask was added (S) -1-t-butoxycarbonylpiperidine-2-carboxylic acid (3.1 g, 13.3 mmol) and dichloromethane (20 mL)Ice bath cooling,Triethylamine (1.5 g, 14.7 mmol) was added,A solution of isobutyl chloroformate (2.0 g, 14.7 mmol)In dichloromethane (10 mL),After incubation for 1 hour dropwise,A solution of 2,3,6-trimethylaniline 9e (1.5 g, 11.1 mmol)In dichloromethane (10 mL),The reaction was stirred at room temperature for 5 hours.(30 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the silica gel (10 mL) was added to the reaction mixture, and the reaction mixture was added with water and dichloromethane (50 mL).Column chromatography and purification (petroleum ether / ethyl acetate (v / v) = 20: 1-15: 1) gave a white solid (S) -tertButyl-2 - (2,3,6-trimethylphenyl) carbamoyl) piperidine-1-carbonate 9f (2.6 g, 68% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; for 3h; | Compound 13-1 (3.96 g, 17.28 mmol) and compound 13-7-0 (5.82 g, 19.81 mmol) weredissolved in CH 3CN (60 mL) and DIPEA (3.4 mL, 20.67 mmol) was slowly added dropwise at0 C. At the end of the addition, the mixture was stirred at rt for 3.0 hours. Afterthe reaction was completed, the reaction was quenched with ice water (50 mL) and theaqueous layer was extracted with DCM (50 mL x 3). The organic phases were combined,washed with saturated brine and dried over anhydrous Na 2SO 4Dried and concentrated. Theresidue was purified by column chromatography (eluent: PE / EtOAc (v / v) = 5/1) to give4.67 g of a white solid. Yield: 61%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane for 0.25h; Stage #2: 2-(1-(phenylsulfonyl)-4-(pyrazolo[1,5-b]pyridazin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethan-1-ol In dichloromethane for 24h; | b b. I -(tert-Butyl) 2-(2-(I -(phenylsulfonyl)-4-(pyrazololI ,5-blpyridazi n-3-yI)-I Hpyrrolol2,3-blpyridi n-2-yI)ethyl) (S)-pyrrol idi ne-I ,2-dicarboxylate HATU (942 mg, 2.48 mmol) was added to a solution of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (which can be prepared as described in Organic Letters, 2011, 13(2), 216-219) (533 mg, 2.48 mmol) and TEA (1.03 mL, 7.44 mmol) in DCM (2.5 mL) and the resultantmixture was stirred for 15 mm. The solution was then added to a solution of 2-(1-(phenylsulfonyl)-4-(pyrazolo[1 , 5-b]pyridazin-3-yl)- 1 H-pyrrolo[2, 3-b]pyridin-2-yl)ethan- 1 -ol(Intermediate 127a, 523 mg, 1.24 mmol) in DCM (2.5 mL) and the mixture was stirred for 24h. The reaction was quenched by addition of saturated aqueous solution of Na2003 andextracted with CHCI3. The combined organic layers were washed with a saturated aqueoussolution of Na2003, brine, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by FCC eluting with Petrol:EtOAc:MeOH (50:50:1 to 0:100:1) to give the title compound (739 mg, 97%) as a yellow oil.LCMS (Method 4): Rt 3.077 mi mlz 617.2 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane for 0.0833333h; Stage #2: 2-(1-(phenylsulfonyl)-4-(pyrazolo[1,5-b]pyridazin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethan-1-amine In dichloromethane for 0.5h; | Intermediate 47: tert-Butyl (S)-2-((2-(I -(phenylsulfonyl)-4-(pyrazolo[I ,5-b]pyridazi n-3- yI)-I H-pyrrolo[2,3-b]pyridi n-2-yI)ethyl)carbamoyl)piperidi ne-I -carboxylate HATU (380 mg, 1.00 mmol) was added to a solution of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (which can be prepared as described inUS2015/126500) (229 mg, 1.00 mmol) and TEA (0.55 mL, 4.00 mmol) in DM0 (2 mL) and the mixture was stirred for 5 mm. The solution was then added to a solution of 2-(1- (phenylsulfonyl)-4-(pyrazolo[1 , 5-b]pyridazin-3-yl)- 1 H-pyrrolo[2, 3-b]pyridin-2-yl)ethan- 1- amine (Intermediate 25, 313 mg, 0.75 mmol) in DM0 (5.0 mL) and the mixture was stirredfor 30 mm. The reaction was quenched with a saturated aqueous solution of Na2003 (20 mL) and extracted with CHCI3. The combined organic layers were washed with a saturated aqueous solution of Na2003, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by FCC eluting with 50-100% EtOAc in petrol to give the title compound (471 mg, 99%) as a yellow solid.LCMS (Method 4): Rt 2.97 mi mlz 630 [MH]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane for 0.0833333h; Stage #2: 2-(4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethan-1-amine In dichloromethane | Intermediate 42: tert-Butyl (S)-2-((2-(4-ch Ioro-1 -(phenylsulfonyl)-1 H-pyrrolo[2,3- b]pyridi n-2-yI)ethyl)carbamoyl)pyrrol idi ne-I -carboxylate HATU (1.33 g, 3.50 mmol) was added to a solution of (S)-1-(tert-butoxycarbonyl)piperidine- 2-carboxylic acid (which can be prepared as described in Organic Letters, 2011, 13(2), 216-219) (753 mg, 3.5 mmol) and TEA (1.56 mL, 11.25 mmol) in DCM (5 mL) and the resultant mixture was stirred for 5 mm. The solution was then added to a solution of 2-(4-chloro-1- (phenylsulfonyl)-1 H-pyrrolo[2,3-b]pyridin-2-yl)ethan-1 -amine (Intermediate 41, 989 mg, 2.95 mmol) in DCM (25.0 mL) and the mixture was then stirred overnight. The reaction was quenched with a saturated aqueous solution of Na2003 (25 mL) and extracted with DCMand the combined organic layers were washed with a saturated aqueous solution of Na2003, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC eluting with 33-100% EtOAc in petrol to give the title compound (871 mg, 66%) as a yellow solid.1H (400 MHz, CDCI3): 1.38 (9H, 5), 1.86 (2H, 5), 2.48-2.01 (2H, m), 3.54-3.20 (4H,m), 3.84 -3.64 (2H, m), 4.27 (1H, 5), 6.50 (1H, 5), 7.15 (1, d, J=5.3 Hz), 7.18 (1, 5),7.52-7.43 (2H, m), 7.61 -7.53 (1H, m), 8.15-8.07 (2H, m), 8.24 (1H, d, J=5.3 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 15h; | [0158] To a solution of 25-hydroxy cholesterol 1 (50 mg, 0.124 mmol) in DCM (5 mL) was added (S)-l-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (56 mg, 0.248 mmol), DMAP (45 mg, 0.372 mmol) and DCC (76 mg, 0.372 mmol). The resulting reaction mass was stirred at RT for 15h. After completion of reaction (TLC monitoring), the reaction mixture was filtered through Celite pad and washed with 50% EtOAc in hexane. The filtrate was washed with 5% citric acid (20 mL), saturated solution of NaHC03 (20 mL) and water (20 mL) sequentially. The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to get crude. The crude was purified over flash column (Silica l2g, redisep), eluted with 20% EtOAc in hexane to give pure compound 1.29 (40 mg, Yield: 55%) as off white solid. 1H- NMR (400 MHz, CDCl3): d 5.3 (s, 1H), 4.5-4.8 (m, 2H), 3.98 (br s, 1H), 2.22-2.35 (m, 2H), 1.85-2.02 (m, 4H), 1.37-1.64 (m, 22H), 0.67-1.25 (m, 28H), 0.68 (s, 3H). LCMS: 614.6 (M+H)+, 91.66% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; | 4.3 General procedure for the synthesis of compound 3a-3q General procedure: 2 (100mg, 0.14mmol) in 5mL of DCM was mixed with N-Boc-L-amino acid (0.28mmol), DCC (29mg, 0.14mmol) and DMAP (2mg, 0.016mmol) by stirring at room temperature for 2-4 h. After completion of the reaction as indicated by TLC, the reaction mixture was poured into DCM (30mL), and washed with water, brine, dried over anhydrous Na2SO4 and concentrated under vacuum, and then purified by column chromatography (PE/EA=3:1, v/v) to afford 3a-3q in 35%-65%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: methylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 3h; | 46.A Step A: Preparation of 1- (tert-butyl) -2- (1-ethoxy-3- (4- (ethoxycarbonyl) phenyl) -1, 3-dioxopropan-2-yl) (2S) -piperidine-1, 2-dicarboxylate To the solution of 256 g (746 mmol) of the product of Step C of example 1 in acetonitrile (2 L) , the diisopropylethylamine (141 mL, 821 mmol) and (S) -1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid (179 g, 781 mmol) were added and stirred at room temperature for 3 h before all volatile were evaporated. The residue was diluted with water (1000 mL) and extracted with ethyl acetate (3000 mL) . The organic phase was separated, dried over anhydrous Na2SO4and concentrated. The residue was purified by flash column chromatography with petroleum ether and ethyl acetate (8 : 1) to give 1- (tert-butyl) -2- (1-ethoxy-3- (4- (ethoxycarbonyl) phenyl) -1, 3-dioxopropan-2-yl) (2S) -piperidine-1, 2-dicarboxylate as a light yellow oil (260 g, 71%) .1H NMR (CDCl3, 600 MHz) δ: 8.13 (d, J = 7.3 Hz, 2H) , 8.01 (d, J = 7.5 Hz, 2H) , 6.29 (d, J = 19.2 Hz, 1H) , 5.05-4.86 (m, 1H) , 4.39 (q, J = 7.1 Hz, 2H) , 4.23 (q, J = 6.9 Hz, 2H) , 4.04-3.88 (m, 1H) , 3.10-2.88 (m, 1H) , 2.34-2.19 (m, 1H) , 1.70-1.67 (m, 3H) , 1.44-1.32 (m, 14H) , 1.20 (t, J = 7.1 Hz, 3H) . MS (ESI, m/z) : 492.2 [M+H]+. |
71% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 0 - 20℃; for 0.333333h; Stage #2: N,N-dimethylethylenediamine In dichloromethane at 20℃; | 15.1 Step 1: tert-Butyl (2S)-2-(2-Dimethylaminoethylcarbamoyl)piperidine-1-formate (2S)-1-tert-Butoxycarbonylpiperidine-2-carboxylic acid (3.7 g, 16 mmol) was dissolved in dichloromethane (50 mL) at room temperature, then the mixture was cooled to 0 °C. HATU (7.2 g, 19 mmol) and N,N-diisopropylethylamine (8.4 mL, 48 mmol) was added and the resulting mixture was stirred for 20 minutes. N,N-Dimethyl-1,2-ethylenediamine (2.1 g, 24 mmol) was added, and the resulting mixture was warmed to room temperature and stirred overnight. The resulting mixture was washed with water (30 mL), dried over anhydrous sodium sulfate, and filtered with suction. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/anhydrous MeOH (v/v) = 20/1) to give the title compound (2.7 g, yellow oil) in 56% yield. MS (ESI, pos. ion) m/z: 300.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 5 - 20℃; for 0.5h; Stage #2: 2-amino-4'-methylacetophenone hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 64a Example 64a: tert-butyl (S)-2-((2-oxo-2-(p-tolyl)ethyl)carbamoyl)piperidine-1- carboxylate: A solution of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (3.8g, 16.57 mmol) in Dichloromethane (20 mL) was cooled to 5°C. HOBt (3.05 g, 19.89 mmol)) and EDC.HCl (3.81 g, 19.89 mmol) were added and the reaction mixture was stirred for 30min at ambient temperature.2-amino-1-(p-tolyl)ethan-1-one hydrochloride (3.08 g, 16.57 mmol) and N,N-diisopropylethylamine (2.89 mL, 16.57 mmol) was added and the reaction mixture was stirred overnight at ambient temperature. The red reaction mixture was poured into iced 1M HCl (100 mL) solution, twice extratced with CH2Cl2 (50 mL), washed with water (50 mL), dried over MgSO4 and concentrated under reduced pressure. The crude was purified by silica gel column chromatography eluting with a gradient of EtOAc in Heptane to give tert-butyl (S)-2-((2-oxo-2-(p- 31040 PCT-2/13.10.20tolyl)ethyl)carbamoyl)piperidine-1-carboxylate (4.1 g, 11.37 mmol, 69% yield) as a yellow liquid.1H NMR (DMSO-d6, 400MHz): δ = 8.07 (br s, 1H), 7.90 (d, J=8.3 Hz, 2H), 7.35 (d, J=7.8 Hz, 2H), 4.45-4.77 (m, 3H), 3.85 (br d, J=12.7 Hz, 1H), 2.91-3.24 (m, 1H), 2.39 (s, 3H), 2.09-2.22 (m, 1H), 1.55 (range, 3H), 1.40 (br s, 9H), 1.19-1.35 ppm (m, 2H). MS (EI, 70 eV): 360 (1, [M]+•), 287 (2), 259 (2), 184 (23), 128 (100), 84 (81), 57 (39) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.9% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 8h; Inert atmosphere; | 4.1.15. (R)-N-((2S, 3R)-3-hydroxy-4-((N-isobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)-1-methylpiperidine-3-carboxamide (3m) General procedure: To a stirred solution of 10e (18.0 mg, 0.10 mmol) and 7a(44.7 mg, 0.11 mmol) in anhydrous DMF (1 mL) was added EDCI(28.8 mg, 0.15 mmol), HOBt (14.9 mg, 0.11 mmol) and DMAP (2.40 mg, 0.02 mmol) at 0 C under argon atmosphere. The reactionmixture was warmed to 25 C and stirred for 8 h. After this period,the reaction was diluted with 5 mL ethyl acetate, washed with H2Oand saturated aqueous NaCl and dried over anhydrous Na2SO4, andthen concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography to furnish 3m as ayellow powder: yield 30.2 mg (56.8%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.8% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 8h; Inert atmosphere; | 4.1.15. (R)-N-((2S, 3R)-3-hydroxy-4-((N-isobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)-1-methylpiperidine-3-carboxamide (3m) General procedure: To a stirred solution of 10e (18.0 mg, 0.10 mmol) and 7a(44.7 mg, 0.11 mmol) in anhydrous DMF (1 mL) was added EDCI(28.8 mg, 0.15 mmol), HOBt (14.9 mg, 0.11 mmol) and DMAP (2.40 mg, 0.02 mmol) at 0 C under argon atmosphere. The reactionmixture was warmed to 25 C and stirred for 8 h. After this period,the reaction was diluted with 5 mL ethyl acetate, washed with H2Oand saturated aqueous NaCl and dried over anhydrous Na2SO4, andthen concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography to furnish 3m as ayellow powder: yield 30.2 mg (56.8%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.6% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 8h; Inert atmosphere; | 4.1.15. (R)-N-((2S, 3R)-3-hydroxy-4-((N-isobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)-1-methylpiperidine-3-carboxamide (3m) General procedure: To a stirred solution of 10e (18.0 mg, 0.10 mmol) and 7a(44.7 mg, 0.11 mmol) in anhydrous DMF (1 mL) was added EDCI(28.8 mg, 0.15 mmol), HOBt (14.9 mg, 0.11 mmol) and DMAP (2.40 mg, 0.02 mmol) at 0 C under argon atmosphere. The reactionmixture was warmed to 25 C and stirred for 8 h. After this period,the reaction was diluted with 5 mL ethyl acetate, washed with H2Oand saturated aqueous NaCl and dried over anhydrous Na2SO4, andthen concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography to furnish 3m as ayellow powder: yield 30.2 mg (56.8%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 0.25h; Stage #2: 7-fluoronaphtho[2,1-d]thiazol-2-amine In N,N-dimethyl-formamide at 65℃; for 5h; | 20 Tert-butyl (S)-2-((7-fluoronaphtho[2,1-d]thiazol-2-yl)carbamoyl)piperidine-1-carboxylate (27-2) [0102] To a stirred solution of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (27-1, 0.32 g, 1.37 mmol) in DMF (2 mL), DIPEA (0.5 mL, 2.75 mmol) was added followed by HATU (0.52 g, 1.37 mmol) at 0°C and the reaction mixture was stirred at RT for 15 min. To the resulting reaction mixture, compound 4-3 (0.20 g, 0.92 mmol) was added and the reaction mixture was stirred at 65°C for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was triturated with diethyl ether followed by hexane and dried well to afford 27-2 (0.145 g, 37.0%) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.14 (dd, J=5.62, 9.05 Hz, 1H), 7.85-7.97 (m, 3H), 7.50-7.59 (m, 1H), 4.75-4.94 (m, 1H), 3.84 (d, J=12.23 Hz, 1H), 3.18-3.29 (m, 1H), 2.01-2.23 (m, 1H), 1.56-1.87 (m, 3H), 1.28-1.46 (m, 9H), 1.10-1.27 (m, 2H); LC-MS: m/z 428.15 [M-H]+; HPLC: 98.91%; SOR: -76.84, Solvent: Methanol, Path length: 100 mm, Concentration: 0.25 w/v%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In N,N-dimethyl-formamide at 0℃; for 0.333333h; Stage #2: (3S)-3-amino-N-benzyl-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide In N,N-dimethyl-formamide at 0 - 20℃; for 1h; | 2 COMPOUND 1 To a stirred mixture of (S)-l-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (260 mg, 1.13 mmol, 1.1 eq.) in N.N-diniethylforniamide was added o-(7- azabenzotriazobl-yl)-N,N.NNMetrameihyluronmm hexafluorophosphate (509 mg, 1.33 mmol, 1.3 eq.) and N,N-diisopropylethylamine (532 mg, 4.12 mmol, 4.0 eq.) at 0 °C. The mixture was stirred for 20 min at 0 °C. (3S)-3-amino-N-benzyl-2-hydroxy-4-((S)-2- oxopyrroiidin--3--yl)butanamide (300 mg, 1.03 mmol, 1.0 eq.) was added at 0 CC. The mixture was stirred for 1 h at rt, and the reaction was quenched with water (30 mL) at rt. The residue was extracted with EA (3 x 40 mL). The organic layers were combined, washed with brine (6 x 40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with diehloromefhaneunethanol (19: 1) to afford tert-butyl (2S)-2-(((2S)-4-(benzylamino)-3- hydroxy-4-oxo-l-((S)-2-oxopyrrolidin-3-y)butan-2-y)carbamoy)piperidine-i-carboxyate (380 mg, 66%) as a yellow solid. LCMS (ESI, m/z): 503 [M+Hf. |
66% | Stage #1: (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In N,N-dimethyl-formamide at 0℃; for 0.333333h; Stage #2: (3S)-3-amino-N-benzyl-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide In N,N-dimethyl-formamide at 0 - 20℃; for 1h; | 2 COMPOUND 1 To a stirred mixture of (S)-l-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (260 mg, 1.13 mmol, 1.1 eq.) in N.N-diniethylforniamide was added o-(7- azabenzotriazobl-yl)-N,N.NNMetrameihyluronmm hexafluorophosphate (509 mg, 1.33 mmol, 1.3 eq.) and N,N-diisopropylethylamine (532 mg, 4.12 mmol, 4.0 eq.) at 0 °C. The mixture was stirred for 20 min at 0 °C. (3S)-3-amino-N-benzyl-2-hydroxy-4-((S)-2- oxopyrroiidin--3--yl)butanamide (300 mg, 1.03 mmol, 1.0 eq.) was added at 0 CC. The mixture was stirred for 1 h at rt, and the reaction was quenched with water (30 mL) at rt. The residue was extracted with EA (3 x 40 mL). The organic layers were combined, washed with brine (6 x 40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with diehloromefhaneunethanol (19: 1) to afford tert-butyl (2S)-2-(((2S)-4-(benzylamino)-3- hydroxy-4-oxo-l-((S)-2-oxopyrrolidin-3-y)butan-2-y)carbamoy)piperidine-i-carboxyate (380 mg, 66%) as a yellow solid. LCMS (ESI, m/z): 503 [M+Hf. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With dmap; diisopropyl-carbodiimide In dichloromethane at 0 - 20℃; for 22h; Inert atmosphere; | General Procedure for the synthesis of diastereomeric esters from 1 by Steglich esterification: General procedure: To a solution of 1 in dry CH2Cl2 (roughly 0.03-0.04 M), the enantiopure acid 7(1.2 eq), DMAP (0.1 eq) and DIC (1-1.2 eq) were added at 0 C. The solution was stirred atroom temperature under a nitrogen atmosphere for 2-29 h, then was diluted with CH2Cl2(60 mL), washed with a saturated solution of NH4Cl (2 x 40 mL), with a saturated solutionof NaHCO3 (3 x 40) then with NH4Cl (3 x 40 mL). The organic layer was dried overNa2SO4, filtered and evaporated under reduced pressure. The crude was purified by flashchromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; diisopropyl-carbodiimide In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; | General Procedure for the synthesis of diastereomeric esters from 1 by Steglich esterification: General procedure: To a solution of 1 in dry CH2Cl2 (roughly 0.03-0.04 M), the enantiopure acid 7(1.2 eq), DMAP (0.1 eq) and DIC (1-1.2 eq) were added at 0 C. The solution was stirred atroom temperature under a nitrogen atmosphere for 2-29 h, then was diluted with CH2Cl2(60 mL), washed with a saturated solution of NH4Cl (2 x 40 mL), with a saturated solutionof NaHCO3 (3 x 40) then with NH4Cl (3 x 40 mL). The organic layer was dried overNa2SO4, filtered and evaporated under reduced pressure. The crude was purified by flashchromatography on silica gel. |
Tags: 26250-84-0 synthesis path| 26250-84-0 SDS| 26250-84-0 COA| 26250-84-0 purity| 26250-84-0 application| 26250-84-0 NMR| 26250-84-0 COA| 26250-84-0 structure
[ 917835-93-9 ]
1-(tert-Butoxycarbonyl)-4-hydroxypiperidine-2-carboxylic acid
Similarity: 0.97
[ 334769-80-1 ]
(2S,5S)-1-(tert-Butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid
Similarity: 0.97
[ 15761-39-4 ]
(S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxylic acid
Similarity: 0.97
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