* 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.
With hydrogenchloride; sodium hydroxide In methanol; water
A. 1-Piperazinecarboxylic acid, phenylmethyl ester A mixture of 17.2 g (0.2 mole) of anhydrous piperazine, 40 ml of water and 60 ml (0.36 mole) of 6N hydrochloric acid in 300 ml of methanol was heated to boiling. Small portions of benzylchloroformate (total 48 g, 0.28 mole) and 4N sodium hydroxide (total 100 ml) were added alternately to maintain a pH of 4.5-5.5. The mixture was heated under reflux for 3 hr, allowed to cool overnight, concentrated in vacuo to remove the methanol, made alkaline with sodium hydroxide and extracted with dichloromethane. The dichloromethane extract was washed with water and then extracted with 400 ml of 1N hydrochloric acid. The acid extract was washed with dichloromethane, made alkaline with sodium hydroxide, and extracted with dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness in vacuo to give 25 g of crude product. Distillation under vacuum afforded 21.3 g (48percent) of the product, bp 140°-143° (0.1 torr). VPC indicated the material consisted of 97percent of a single component and the NMR was consistent with the assigned structure.
Reference：
[1] Patent: US4659708, 1987, A,
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[ 1448041-81-3 ]
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[ 75462-61-2 ]
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[1] Chemical Communications, 2013, vol. 49, # 61, p. 6867 - 6869
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[ 110-85-0 ]
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[ 31166-44-6 ]
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[ 102181-95-3 ]
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[1] Synthesis, 1997, # 7, p. 759 - 763
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[1] Chemistry and Biology, 2015, vol. 22, # 10, p. 1347 - 1361
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[ 110-85-0 ]
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[ 31166-44-6 ]
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[1] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 8, p. 2719 - 2723
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[ 142-64-3 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2007, vol. 349, # 4-5, p. 535 - 538
With sodium hydrogencarbonate In ethanol for 2h; Heating / reflux;
37
EXAMPLE 37 Preparation of 4-(6-Nitrobenzothiazol-2-yl)piperazine-1-carboxylic acid benzyl ester A mixture of 2-chloro-6-nitrobenzothiazole (1.00 g, 4.66 mmol), benzyl 1-piperazinecarboxylate (1.03g, 4.66 mmol), and NaHCO3 (0.783 g, 9.32 mmol) in EtOH was heated at reflux temperature for 2 h, concentrated, and extracted with EtOAc. The combined extracts were dried over Na2SO4 and concentrated in vacuo to provide the title compound (1.13 g, 61%), characterized by NMR and mass spectral analyses.
With potassium phosphate;palladium diacetate; johnphos; In 1,2-dimethoxyethane; for 20h;Heating / reflux;
(3-bromo-phenyl)-acetonitrile (5.1g, 25.5mMol) is dissolved in dimethoxyethane (54ml). After addition of piperazine-1-carboxylic acid benzylester (11.4g, 5I mMoI), potassium phosphate (10.8g, 5I mMoI), (2-biphenyl)di-tert butylphosphine (2.28g, 7.6mMol) and palladium-ll- acetate (573mg, 2.55mMol) the mixture is refluxed for 20 hours. After cooling to room temperature the mixture is filtered and the brown filtrate is evaporated in vacuo to give a brown oil. The crude mixture is separated by flash chromatography (gradient of ethyl acetate/hexane 1 :9 to 1 :1) yielding the pure product as a dark yellow oil (M+H+ 336.2).
With potassium carbonate; In toluene; at 150℃; for 0.5h;Microwave;
Step 1: Heat a mixture <strong>[369-33-5]3,4-difluoroacetophenone</strong> (0.25 g), piperazine-1-carboxylic acid benzyl ester (1.84 ml), and K2CO3 (1.32 g) in toluene (4 ml) by microwave at 150 C. 0.5 h. Allow to cool and partition with EtOAc and water. Dry (K2CO3), concentrate and chromatograph on silica to obtain the aryl-piperazine
With potassium carbonate; In toluene; at 150℃; for 0.5h;Microwave;
Heat a mixture <strong>[369-33-5]3',4'-difluoroacetophenone</strong> (0.25 g), piperazine-1-carboxylic acid benzyl ester (1.84 ml), and K2CO3 (1.32 g) in toluene (4 ml) by microwave at 150 C. 0.5 h. Allow to cool and partition with EtOAc and water. Dry (K2CO3), concentrate and chromatograph on silica to obtain the aryl-piperazine.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h;
EDAC.HCl (0.65 g, 3.37 mmol) was added to a stirred solution of compound 71 (0.62 g, 2.81 mmol), compound 72 (0.40 g, 2.81 mmol), HOBt (0.46 g, 3.37 mmol), and DIPEA (0.69 mL, 3.93 mmol) in CH2Cl2 (12 mL) at room temp. After 3 hr the reaction mixture was conc. and the residue was partitioned between EtOAc and 1N HCl. The organic phase was isolated, washed with 1N HCl, H2O, sat. NaHCO3, sat. NaCl, dried (MgSO4), and conc. to give 0.97 g (100%) of compound 73.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 3h;
1.1 Referential Example 1-1, Benzyl 4-(cyclopropylcarbonyl)piperazin-1-carboxylate
In 35 mL of N,N-dimethylformamide were dissolved benzyl 1-piperazinecarboxylate (5.00 g, 22.7 mmol) and cyclopropanecarboxylic acid (2.54 g, 29.5 mmol), and 1-ethyl-3-(3-(N,N-dimethylamino)propyl)-carbodiimide hydrochloride (6.53 g, 34.1 mmol), 1-hydroxybenzotriazole (4.52 g, 29.5 mmol) and triethylamine (3.60 g, 35.9 mmol) were added thereto at room temperature, followed by stirring at the same temperature for three hours. The reaction mixture was mixed with water, and extracted twice with ethyl acetate. The organic layer was sequentially washed with water twice, with a saturated aqueous solution of sodium bicarbonate once and with brine once, and then dried over anhydrous sodium sulfate. The organic layer was passed through a silica gel column (Fuji Silysia, NH Silica gel) and evaporated to give the title compound (6.10 g, 93.1%) as a white amorphous.1H-NMR Spectrum (CDCl3,400MHz) δ(ppm): 0.75-0.83(2H,m), 0.95-1.03(2H,m),1.65-1.75(1H,m),3.40-3.80(8H,m),5.16(2H,s), 7.30-7.40(5H,m).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; for 7h;
Benzyl piperazine-1-carbamate (2.203 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 ml); 2-hydroxy-2-methylpropionic acid (1.25 g, 12.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g, 12.0 mmol), 1-hydroxy-1H-benzotriazole monohydrate (1.84 g, 12.0 mmol) and triethylamine (3.35 ml, 24.0 mmol) were added; and the reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and dried under reduced pressure to yield the title compound (2.823 g, 9.21 mmol, 92.1%) as a colorless oil. 1H-NMR Spectrum (CDCl3) delta (ppm): 1.50 (6H, s), 3.52-3.55 (4H, m), 3.60-3.70 (4H, m), 3.93 (1H, s), 5.16 (2H, s), 7.34-7.38 (5H, m).
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃;
Step 1:; Preparation of 1-(benzyloxycarbonyl)-4-(2,3,6-trifluoro-4- nitrophenyl) piperazine; A solution of <strong>[5580-79-0]2,3,4,5-tetrafluoronitrobenzene</strong> (10.0 g, 51.2 mmol) in DMSO (200 mL) is treated with N, N-diisopropylethylamine (6.95 g, 8.8 mL, 53.8 mmol) and then N-(benzyloxycarbonyl)piperazine (Aldrich, 11.8 g, 53.8 mmol) is added over 30 min at room temperature. The mixture is stirred overnight at ambient temperature. The mixture is diluted with H20 and the extracted with EtOAc. The combined organic extracts are washed with H20, brine, dried over Mg2S04, filtered and concentrated under reduced pressure. The residue is triturated with Et20 / hexanes. The solid is collected by filtration and dried under vacuum to give 18.70 g (92%) of the title compound as a light yellow solid. HRMS calc'd. for C18H16F3N3O4: 396.1171; Found: 396.1190. Analytical calc'd. for C18H16F3N3O4: C, 54.69; H, 4.08; N, 10.63; Found: C, 54.56; H, 4.12; N, 10.62.
With caesium carbonate In benzene at 20 - 70℃; for 14h;
177.A
N-Cbz piperazine (8.24 g, 37.4 mmol), 3-iodobenzyl alcohol 265 (7g, 29.9 mmol), 2-bis(tert-butyl)phosphinobiphenyl (1.8 g, 6.0 mmol), palladium acetate (1.34 g, 6.0 mmol) and cesium carbonate (14.6 g, 44.9 mmol) were combined with benzene (72 mL) at ambient temperature. This mixture was purged with argon and heated to 70° C. for 14 h. The reaction mixture was cooled to ambient and diluted with EtOAc (40 mL); the resulting mixture was stirred vigorously for 10 min Solids were removed by filtration, washed with EtOAc (2×20 mL) and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromotography (4:1 Hex/EtOAc) to afford 255 (2.29 g, 24%) as a light-yellow semi-solid.
4-[2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-2-oxoethyl]-1-piperazinecarboxylic acid, phenylmethyl ester A solution is prepared of 10 g (87.5 mM) of N-methylhomopiperazine in 200 ml of dichloromethane, to which 36.6 ml of triethylamine are added. The mixture is cooled to -78 C. and 6.97 ml of chloroacetyl chloride are added dropwise. The reaction mixture is agitated for 1.5 hours at -78 C., and a solution of 19.3 g (87.6 mM) of the benzyl ester of 1-piperazinecarboxylic acid in 10 ml of dichloromethane is then added. The mixture is then left to come back to ambient temperature, and agitation is carried out for 15 hours. The medium is then hydrolyzed with a solution of sodium carbonate. The mixture is decanted, the organic phase is washed once with water and then dried over magnesium sulphate and concentrated under reduced pressure. The crude product is purified by silica gel chromatography in eluding with the aid of a dichloromethane/methanol/aqueous ammonia mixture (90/10/5; v/v/v). The product sought after is thus obtained as a yellow oil (yield=43%). 1H NMR (250 MHz, DMSO) delta: 7.36 (m, 5H); 5.07 (s, 2H); 3.55 (m, 2H); 3.44 (m, 2H); 3.38 (m, 4H); 3.16 (d, 2H); 2.60 (m, 2H); 2.44 (m, 6H); 2.24 and 2.22 (2s, 3H); 1.76 (m, 2H).
4-{4-Methoxy-2[(5-methyl-thiophene-2-carbonyl)-amino]-benzothiazol-7-yl}-piperazine-1-carboxylic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
EXAMPLE 64 4-{4-Methoxy-2[(5-methyl-thiophene-2-carbonyl)-amino]-benzothiazol-7-yl}-piperazine-1-carboxylic acid benzyl ester The title compound was synthesised starting from N-benzyloxycarbonylpiperazine and <strong>[33696-00-3]4-bromo-2-nitroanisole</strong> as described for 5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide and obtained as a white solid in 12% overall yield, MS: m/e=523 (M+H+).
piperazine-1-(2-hydroxy-2-cyclohexyl)carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With NMM; 1,2-dichloro-ethane;palladium-carbon; benzotriazol-1-ol; In ethanol; N,N-dimethyl-formamide;
Step 1 Piperazine-1-(2-hydroxy-2-cyclohexyl)carboxamide Benzyl 1-piperazine carboxylate (3.12 mmol) was reacted with commercially available 1-hydroxy cyclohexane carboxylic acid (2.08 mmol) in DMF in the presence of HOBt (3.33 mmol), EDC (3.54 mmol) and NMM (6.24 mmol) for 18 hour at 25 C. After an aqueous work up and purification on a silica column this material was dissolved in absolute ethanol and treated with 10% Pd/C catalyst under a hydrogen atmosphere for 1.5 hour. The catalyst was removed via filtration and the title compound was isolated after rotary evaporation. FAB-MS: calc: 212.5 found: 213.2.1H-NMR (CD3OD): 3.3 ppm (m, 4H); 2.8 ppm (m, 4H); 1.5-1.9 ppm (m, 9H); 1.3 ppm (m, 1H).
benzyl 4-(2-cyanomethoxyethyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonium hydroxide; potassium iodide; sodium carbonate In methanol; dichloromethane; water; butanone
I.2 I.3.2.
I.3.2. Benzyl 4-(2-cyanomethoxyethyl)piperazine-1-carboxylate 6.4 g (0.029 mol) of benzyl piperazine-1-carboxylate, 3.8 g (0.0319 mol) of (2-chloroethoxy)acetonitrile, 6.8 g (0.0638 mol) of sodium carbonate, 20 mg of potassium iodide and 32 ml of methyl ethyl ketone are introduced into a 100 ml three-necked round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. This mixture is maintained at the reflux temperature (80° C.) for 20 hours. 1.7 g (0.0145 mol) of (2-chloroethoxy)acetonitrile are then added and the mixture is maintained at the reflux temperature for a further 24 hours. It is allowed to cool to room temperature and 75 ml of water are then added and the methyl ethyl ketone is eliminated on a rotary evaporator under reduced pressure. The aqueous phase is extracted with 75 and then 50 ml of dichloromethane. The organic phases are combined and are dried over sodium sulphate. The mixture is filtered and the filtrate is concentrated on a rotary evaporator under reduced pressure. 10.5 g of a dark brown liquid are obtained, which product is purified by preparative chromatography on silica gel (eluent: 99/1/0.1 (v/v/v) mixture of dichloromethane/methanol/28% aqueous ammonia solution gradually replaced by a 98/2/0.1 mixture of the same constituents 7.3 g (83%) of benzyl 4-(2-cyanomethoxyethyl)piperazine-1-carboxylate are obtained in the form of a yellow liquid. NMR: δ: 2.39 (4H, m); 2.54 (2H, t, 5.5 Hz); 3.39 (4H, m); 3.63 (2H, t, 5.3 Hz); 4.45 (2H, s); 5.07 (2H, s); 7.35 (5H, m). Mass spectrum: 304 (MH+).
With potassium carbonate; sodium iodide; In acetone; for 24h;Heating / reflux;
A solution of <strong>[164365-88-2](4-bromobutyl)carbamic acid tert-butyl ester</strong> (3.75 g, 90%, 13.38 mmol) in acetone (10 mL) was added to a mixture of piperazine-1-carboxylic acid benzyl ester 15 (2.68 g, 12.16 mmol), sodium iodide (1.82 g, 12.16 mmol), and potassium carbonate (5.04 g, 36.47 mmol) in acetone (100 mL). The reaction mixture was stirred at reflux for 24 h. The mixture was concentrated in vacuo, the resulting residue was diluted with dichloromethane and insoluble inorganics were filtered off. The filtrate was concentrated in vacuo and the resulting residue was purified by Biotage silica gel column chromatography using methanol/dichloromethane (gradient 0% to 5%) to give A-{A-tert-butoxycarbonylaminobutyl)piperazine-l-carboxylic acid benzyl ester (16) as a viscous, brown oil (3.26 g, 68%): lR NMR (300 MHz, CDC13) 5 1.40 (s, 9H), 1.51 (m, 4H), 2.49 (m, 6H), 3.10 (m, 2H), 3.51 (m, 4H), 5.10 (s, 2H), 5.25 (br, 1H), 7.32 (m, 5H); ESI MS m/z 392 [C21H33N3O4 + H]+.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 4h;
169
To (R)- 2-hydroxy-4-methyl-pentanoic acid (1.71 g, 12.9 mmol) in 48 mL ofDMF was added sequentially triethylamine (4.9 mL, 35. mmol), HOBt (1.75 g, 12.9 mmol), EDCTHC1 (2.48 g, 12.9 mmol) and piperazine-1-carboxylic acid benzyl ester (2.59 g, 11.8 mmol) at room temperature. The reaction mixture was stirred for 4 h and then diluted with EtOAc (50 mL) and extracted with 50 mL of water. The organic layer was separated and dried over Na2SC>4, and the solvent was removed under reduced pressure to give an oil. The residuewas subjected to purification by normal phase LC using 40-85% EtOAc-hexanes to give (1.92 g,49% yield) of 4-(2(i?)-hydroxy-4-methyl-pentanoyl)-piperazine-l-carboxylic acid benzyl esterthe desired product. LC/MS: m/z 335.4 (M+H)+ at 2.96 min (10%-99% CH3CN (0.035%TFA)/H20 (0.05% TFA)).
With potassium phosphate;bis(tri-tert-butylphosphine)palladium(0); In ISOPROPYLAMIDE; at 100℃;
A mixture of methyl -bromo-l-benzothiophene-^-carboxylate (60 mg, 0.21 mmol), Cbz- piperazine (0.100 mL, 0.52 mmol) and K3PO4 (220 mg) in DMAc (1 mL) was degassed by the freeze- pump-thaw method. Next, Pd[P(tert-butyl)3]2 (20 mg) was added and the mixture stirred at 100C overnight. The crude mixture was partitioned between EtOAc and sat'd NaCl, the organic layer dried (Na2SO4) and concentrated. Chromatography on SiO2 (EtOAc/CH2Cl2, 0:100 to 10:90) gave 42 mg (47%) of the ethyl ester coupled product. A mixture of this ester in 2: 1: 1 THF/MeOH/water (2 mL) was treated with LiOH (10 mg, 0.24 mmol) and stirred overnight, then partitioned between EtOAc and 1 M citric acid. The organic layer was dried (Na2SO4) and concentrated. The residue was dissolved in DMF (1 mL) and treated with EDC (25 mg, 0.13 mmol), HOBt (15 mg, 0.11 mmol), and 1,2-phenylenediamine (25 mg, 0.23 mmol), then stirred overnight. The reaction mixture was partitioned between CH2Cl2 and sat'd NaHCO3, dried (Na2SO4), concentrated and finally triturated with ether to provide the desired product: 1H NMR (600 MHz, DMSO-^6) delta 9.75 (s, 1 H), 8.13 (s, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 7.45 (d, J = 2.1 Hz, 1 H), 7.36 (m, 5 H), 7.32 (m, 1 H), 7.17 (dd, J = 9.1, 2.3 Hz, 1 H), 6.95 (t, J = 7.8 Hz, 1 H), 6.75 (dd, J = 9.4, 1.2 Hz, 1 H), 6.57 (t, J = 7.6 Hz, 1 H), 5.10 (s, 2 H), 4.93 (s, 2 H), 3.55 (br, 4 H), 3.25 (br, 4 H); MS cal'd 487 (MH+), exp 487 (MH+).
With 4-methyl-morpholine; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 20℃; for 20h;
6.a
To a solution of phenylmethyl 1 -piperazinecarboxylate (3.0 g, 13.62 mmol) in CH2CI2 (68 ml_) was added EDC (2.61 g, 13.62 mmol), HOOBt (44 mg, 0.27 mmol), λ/-[(1 ,1-dimethylethyl)oxy]carbonyl}-L-leucine (3.15 g, 13.62 mmol), and 4-methylmorpholine (4.51 ml_, 40.9 mmol). The reaction mixture was stirred at room temperature for 20 h whereupon the reaction was diluted with CH2CI2 and washed with 10% citric acid and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Column chromatography (10- 80% ethyl acetate:hexane) afforded 5.4 g (91 % yield) of the title compound as a white solid: LCMS (m/z): 434.2 (M+H).
benzyl 4-[4-(tert-butyloxycarbonylaminomethyl)benzylaminocarbonyl]piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
At 0 C., 25.0 g (106 mmol) of 4-(tert-butyloxycarbonylaminomethyl)benzylamine in 150 ml of dichloromethane are added dropwise to a solution of 22.4 g (111 mmol) of 4-nitrophenyl chloroformate in 200 ml of dichloromethane, and the mixture is stirred for 10 min. 15.6 ml (111 mmol) of triethylamine are then added dropwise, and the mixture is stirred at RT for 1.5 h. At 0 C., initially 24.5 g (111 mmol) of benzyl piperazine-1-carboxylate in 80 ml of dichloromethane and then 15.6 ml (111 mmol) of triethylamine are added dropwise. The mixture is stirred at RT for 16 h. The solvent is removed from the reaction mixture and the crude product is chromatographed over silica gel (toluene/ethyl acetate=1:1). Crystallization from diisopropyl ether gives 41.7 g of the title compound as a colorless solid of m.p. 108-112 C.
At 0 C., 25.0 g (106 mmol) of 4-(tert-butyloxycarbonylaminomethyl)benzylamine in 150 ml of dichloromethane are added dropwise to a solution of 22.4 g (111 mmol) of 4-nitrophenyl chloroformate in 200 ml of dichloromethane, and the mixture is stirred for 10 min. 15.6 ml (111 mmol) of triethylamine are then added dropwise, and the mixture is stirred at RT for 1.5 h. At 0 C., initially 24.5 g (111 mmol) of benzyl piperazine-1-carboxylate in 80 ml of dichloromethane and then 15.6 ml (111 mmol) of triethylamine are added dropwise. The mixture is stirred at RT for 16 h. The solvent is removed from the reaction mixture and the crude product is chromatographed over silica gel (toluene/ethyl acetate=1:1). Crystallization from diisopropyl ether gives 41.7 g of the title compound as a colorless solid of m.p. 108-112 C.
With potassium carbonate; In toluene; at 127℃; for 20h;
Example 48 rac-[(4S*,5R*)-2-(6-tert-Butyl-4-ethoxy-pyhdin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5- dimethyl-4,5-dihydro-imidazol-1 -yl]-[4-((S)-2,3-dihydroxy-propyl)-piperazin-1 -yl]- methanone <n="71"/>(S)-(+)-2,2-Dimethyl-1 ,3-dioxolan-4-ylmethyl p-toluenesulfonate (286 mg, 1.0 mmol, Aldrich) and piperazine-1-carboxylic acid benzyl ester (235 mg, 1.1 mmol, Aldhch) were combined with potassium carbonate (148 g, 1.1 mmol) in dry toluene (6 ml_) in a 10 mL pressure vessel. This was well stirred and heated to 127 0C for 20 h. The reaction was cooled, diluted with ethyl ether (20 mL) and 20 mL of water. The organics were washed with water, brine, dried (MgSO4) and evaporated to give 4-(S)-(-)-(2,2-dimethyl-[1 ,3]dioxolan-4-ylmethyl)- piperazine-1 -carboxylic acid benzyl ester as a heavy oil which was purified by flash column chromatography (silica gel, eluting with 3% thethylamine and 1 :1 ethyl acetate:hexane to ethyl acetate). LR-MS: 334 [(IvRH)+].4-(S)-(-)-(2,2- dimethyl-[1 ,3]dioxolan-4-ylmethyl)-piperazine-1 -carboxylic acid benzyl ester (220 mg, 0.65 mmol) was dissolved in 20 mL of ethanol and 10% palladium on carbon (50 mg, Aldrich). The mixture was hydrogenated in a Parr reactor at 40 psi for 18 h. The reaction mixture was filtered through Celite and evaporated to give an oil. The oil was mostly dissolved in hexane, treated with Norite, filtered and crystallized from cold hexane to give 1-(S)-(-)-(2,2-dimethyl-[1 ,3]dioxolan-4- ylmethyl)-piperazine. LR-MS: 200 [(M+H)+].
With potassium carbonate In acetonitrile Heating / reflux;
13.A
A mixture of benzyl 1-piperazinecarboxylate (1.2 mL, 6.2 mmol) and 5-chloromethyl-2- oxazolidinone (0.800 g, 5.9 mmol) in ACN 100% (5.9 mL, 5.9 mmol) was added potassium carbonate (1.2 g, 8.9 mmol) and the mixture was refluxed overnight. After cooling to RT, the heterogeneous mixture was quenched with water followed by IN HCl (1 mL) and the separated aqueous layer was extracted with EtOAc (2 x 5 mL) and the combined organic layers were washed with dried (Na2SO4), and concentrated. Purification of the crude concentrate by flash column chromatography afforded (DCM to 2% MeOH in DCM) benzyl 4-((2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate as a pale yellow oil. 318 (M+H)+
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃;
Step A: Preparation of 2a; According to general procedure C, 2a was obtained with 1a (0.25 mL, 5.18 mmol, 1.0 eq.), EDC (324 mg, 10.36 mmol, 2.0 eq.), DMAP (317 mg, 10.36 mmol, 2.0 eq.) and N-methylpyrrole-2-carboxylic acid (329 mg, 10.36 mmol, 2.0 eq.). The mixture was washed first with a saturated solution of ammonium chloride, then with 1 N HCl and at the end with a saturated solution of sodium carbonate. The residue was purified by flash chromatography on silica gel, eluting with cyclohexane-ethyl acetate (8:2 to 1:1) to afford 2a (420 mg, 98%) as a colorless oil.MS (ESI+) (+0.1% HCOOH): 328.12 [C18H21N3O3+H]+ (m/z); ?General method C? (peptide coupling) consists of adding 1.2 to 2.0 equivalents of EDCl and 1.2 to 2.0 equivalents of HOBt or DMAP and 1.2 to 2.0 equivalents of heteroaryl carboxylic acid, at 0 C., to a 0.2 to 0.6M solution within DMF of protected amino(piperidine) derivative N-Boc or N-CBz. The mixture is maintained under stirring at ambient temperature for 16 to 18 hours, then diluted with ethyl acetate and washed with water. The solution is then dried and concentrated to dryness under reduced pressure, then the residue is purified by chromatography over silica eluting with the cyclohexane-ethyl acetate mixture.
With N-ethyl-N,N-diisopropylamine In ethanol at 100℃; for 18h;
9.1
INTERMEDIATE 9; Ethyl [5-(3-piperazin-l-yIisoxazol-5-yl)-2//-tetrazol-2-yl]acetate; Step 1 : Benzyl 4-[5-(aminocarbonyl)-4,5-dihydroisoxazol-3-yl]piperazine-l -carboxylate; A mixture of 3-bromo-4,5-dihydroisoxazole-5-carboxamide (Intermediate 3, 6.0 g, 31.1 mmol), benzyl piperazine-1-carboxylate (1.4 g, 6.22 mmol) and DIPEA (2.3 mL, 12.95 mmol) in ethanol (60 mL) was heated at 100 °C for 18 h. The solvent was evaporated, the mixture diluted with 5% aqueous citric acid solution (50 mL), and the suspension was filtered through filter paper on a Hirsch funnel, washing the resulting solid with water and Et2O. The solid was dried under high vacuum to afford the title product. MS (ESI, Q+) m/z 333 (M + 1).
With N-ethyl-N,N-diisopropylamine In ethanol at 100℃; for 18h;
9.1
Step 1: Benzyl 4-[5-(aminocarbonyl)-4,5-dihydroisoxazol-3-yl]piperazine-1-carboxylate A mixture of 3-bromo-4,5-dihydroisoxazole-5-carboxamide (Intermediate 3, 6.0 g, 31.1 mmol), benzyl piperazine-1-carboxylate (1.4 g, 6.22 mmol) and DIPEA (2.3 mL, 12.95 mmol) in ethanol (60 mL) was heated at 100° C. for 18 h. The solvent was evaporated, the mixture diluted with 5% aqueous citric acid solution (50 mL), and the suspension was filtered through filter paper on a Hirsch funnel, washing the resulting solid with water and Et2O. The solid was dried under high vacuum to afford the title product. MS (ESI, Q+) m/z 333 (M+1).
Stage #1: phenylmethyl 1-piperazinecarboxylate; N-(tert-butoxycarbonyl)-4-aminocyclohexanone With acetic acid In methanol for 0.5h;
Stage #2: With 2-picoline borane complex In methanol for 12h;
1
To a solution of tert-butyl N-(4-oxocyclohexyl)carbamate (10 g, 46.89 mmol, 1 eq) in methanol (150 mL) was added acetic acid (15 mL) and benzyl piperazine-1-carboxylate (10.33 g, 46.89 mmol, 1 eq). The mixture was stirred at 30° C. for 0.5 hour. Then 2-methylpyridine borane complex (10.03 g, 93.78 mmol, 2 eq) was added and the mixture was stirred at 30° C. for 12 hours. LCMS analysis of an aliquot indicated completion of the reaction. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (200 mL×3). The combined organic phase was washed with a saturated aqueous solution of sodium bicarbonate (200 mL) and saturated brine (300 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with petroleum ether:ethyl acetate (V/V=5:1, 150 mL) to give benzyl 4-[4-(tert-butoxycarbonylamino)cyclohexyl]piperazine-1-carboxylate (13 g, 31.1 mmol, 66.4% yield) obtained as a white solid. MS (ESI) m/z: 418.2[M+H]+.
With methanol; sodium tris(acetoxy)borohydride at 20℃;
9.v
Example 9:; Synthesis of 4-{4-[(1 H-Benzotriazole-δ-carbonylJ-aminoJ-cyclohexy^-piperazine-i carboxylic acid; 3-chloro-5-trifluoromethyl-benzyl esterv. Compound 36 (1.20 g, 5.63 mmol) and compound 37 (1.50 g, 6.81 mmol) were dissolved in methanol (100 ml.) and sodium triacetoxyborohydride (1.50 g, 7.07 mmol) was added at RT slowly. The mixture was stirred for 18 h at RT. The solvent was evaporated and the residue redissolved in dichloromethane. The organic phase was washed with saturated sodium hydrogencarbonate solution. This aqueous solution was extracted with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated to dryness. The crude solid compound 38 (1.90 g, 4.55 mmol, 81%) was used without further purification.In analogy to the general procedures d, c, b. and e compound 39 was synthesized.
With sodium t-butanolate In toluene at 100℃; for 4h; Inert atmosphere; Sealed tube;
A1.C
Step C: A microwave vial charged with Intermediate Ale (900 mg, 2.73 mmol), tris(dibenzylideneacetone)dipalladium (75 mg, 0.08 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (142 mg, 0.24 mmol), sodium terbutoxide (394 mg, 4.1 mmol) and benzyl piperazine-l-carboxylate (723 mg, 3.28 mmol) is sealed, evacuated, set under nitrogen and treated with toluene (7 mL). The resulting mixture is heated to 100 °C for 4 hours. The mixture is diluted with ethyl acetate and washed with water. The aqueous phase is then re-extracted with ethyl acetate. The combined organics are dried over sodium sulfate, concentrated in vacuo and the crude material is purified by flash chromatography (ethyl acetate/hexanes gradient) to afford benzyl 4-(5-(l-(tert- butoxycarbonyl)azetidin-3-yloxy)pyridin-2-yl)piperazine-l-carboxylate Aid as a light yellow solid: 1H-NMR (400 MHz, CDC13) δ = 7.76 (d, J = 3.2 Hz, 1H), 7.40-7.32 (m, 5H), 7.08 (dd, J = 9.2, 3.2 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 5.19 (s, 2H), 4.86-4.81 (m, 1H), 4.28 (dd, J = 10.4, 6.4 Hz, 2H), 4.00 (dd, J = 10.4, 4.0 Hz, 2H), 3.66-3.63 (m, 4H), 3.46-3.43 (m, 4H), 1.47 (s, 9H); MS calcd. for C25H33N4O5 ([M+H]+): 469.2, found: 469.2.
With sodium t-butanolate; ruphos;bis(dibenzylideneacetone)-palladium(0); In toluene; at 100℃; for 1h;Inert atmosphere;
Step 1 Preparation of Compound 132To a suspension of NaOt-Bu (3.73 g, 38.9 mmol), Pd(dba)2 (0.298 g, 0.518 mmol), RuPhos (0.484 g, 1.036 mmol) and 2-bromo-l,4-difluorobenzene (5 g, 25.9 mmol) in Toluene (50 ml) was added benzyl piperazine-l-carboxylate (6.00 ml, 31.1 mmol) at r.t. under N2.The mixture was stirred at 100C under N2 for 1 hr. The reaction mixture was diluted with H20 and AcOEt at r.t., then the resulting solid was filtered, rinsed with AcOEt and H2O.The filtrate was extracted with AcOEt x 2. The organic layers were combined and washed with brine. The organic layer was dried over MgS04, filt and cone. The crude product was added to a silica gel column and was eluted with AcOEt-Hexane. Collected fractions were evaporated. The residual oil was triturated with CH2C12-Hexane, then filtered, rinsed with Hexane to afford compound 132 (3.7 g, 43.0 %) as a white solid.1H-NMR (CDC13) delta: 7.40-7.29 (5H, m), 7.01-6.89 (1H, m), 6.66-6.56 (2H, m), 5.16 (2H, s), 3.67 (4H, t, J= 5.1 Hz), 3.11-2.97 (4H, m).
With triethylamine; In N,N-dimethyl-formamide; at 80℃; for 15h;
Cbz lnt-1 a A mixture of 5-fjiioro-2-nitrobenzaldehyde (20 g, 118 mmol) in DMF (150 mL), benzyl 1-piperazine carboxylate (31.2 g, 142 mmol), and triethylamine (14.3 g,142 mmol) was heated to 80 C for 15 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (300 mL), washed with brine (3 x 150 mL), dried over Na2S04, filtered, and concentrated. The resulting thick oil was purified by a flash column, eiuting with 20% EtOAc/hexanes to yield 36.2 g (86%) of Int-la as a yellow solid.
With sodium tris(acetoxy)borohydride; In tetrahydrofuran; at 22 - 32℃;Cooling with ice;
Benzyl piperazine-l-carboxylate 23 (27.3 mL, 142.2 mmol) was dissolved in dry THF (313.1 mL) and <strong>[6704-31-0]oxetan-3-one</strong> (12.29 g, 10.93 mL, 170.6 mmol) was added. The resulting solution was cooled in an ice-bath. NaBH(OAc)3 (59.99 g, 284.4 mmol) was added portionwise over 30 mins, about a quarter was added. Mixture removed from ice bath, allowed to warm to room temperature then continued adding the NaBH(OAc)3 portionwise over 30 mins. On complete addition, an exotherm from 22C slowly to 32C was observed, whereby the mixture was subsequently cooled on an ice bath until an internal of 22C was reached. The ice bath was removed and the reaction mixture's internal temp was steady at 22C. The mixture was stirred at room temperature overnight. [00442] The resulting white suspension was quenched by addition of 2M sodium carbonate solution (approx 150 mL) (pH = 8) and concentrated under reduced pressure to remove THF. Product was then extracted with EtOAc (3 x 250 mL). Organics were combined, dried over MgS04, filtered and concentrated under reduced pressure to leave product 24 as a white solid (32.7g 83% yield). XH NMR (500 MHz, DMSO-d6) delta 7.39 - 7.30 (m, 5H), 5.07 (s, 2H), 4.52 (t, 2H), 4.42 (t, 2H), 3.43 - 3.39 (m, 5H) and 2.22 (t, 4H). MS (ES+) 276.8.
83%
With sodium tris(acetoxy)borohydride; In tetrahydrofuran; at 0 - 20℃;
[0512] Benzyl piperazine-1-carboxylate 23 (27 .3 mL,142.2 mmol) was dissolved in dry THF (313.1 mL) and<strong>[6704-31-0]oxetan-3-one</strong> (12.29 g, 10.93 mL, 170.6 mmol) was added.The resulting solution was cooled in an ice-bath. NaBH(Oac )3 (59.99 g, 284.4 mmol) was added portionwise over 30mins, about a quarter was added. Mixture removed from icebath, allowed to warm to room temperature then continuedadding the NaBH(Oac )3 portionwise over 30 mins. On completeaddition, an exotherm from 22 C. slowly to 32 C. wasobserved, whereby the mixture was subsequently cooled onan ice bath until an internal of 22 C. was reached. The icebath was removed and the reaction mixture's internal tempwas steady at 22 C. The mixture was stirred at room temperatureovernight. [0513] The resulting white suspension was quenched byaddition of 2M sodium carbonate solution (approx 150 mL)(pH=8) and concentrated under reduced pressure to removeTHF. Product was then extracted with EtOAc (3x250 mL).Organics were combined, dried over MgS04 , filtered andconcentrated under reduced pressure to leave product 24 as awhite solid (32.7 g 83% yield). 1H NMR (500 MHz, DMSOd6)o 7.39-7.30 (m, 5H), 5.07 (s, 2H), 4.52 (t, 2H), 4.42 (t,2H), 3.43-3.39 (m, 5H) and 2.22 (t, 4H). MS (ES+) 276.8.
With sodium cyanoborohydride; acetic acid; In acetonitrile; at 20℃; for 16h;
2.6 g of 3-oxetanone, 1.0 g of sodium cyanoborohydride and 0.16 ml of acetic acid are added to a solution of 2.0 g of benzyl piperazine-1-carboxylate in 20 ml of acetonitrile and then stirred for 16 hours at RT. The reaction mixture is diluted with water and filtered through a Chem Elut cartridge, eluting with DCM. The combined organic phases are dried over MgSO4 and the solvent is evaporated under vacuum. The residue is purified by preparative HPLC and 1.7 g of a white solid is obtained.
With sodium cyanoborohydride; acetic acid; In acetonitrile; at 20℃; for 16h;
Preparation 7.2Oxetan-3-ylpiperazine.2.6 g of 3-oxetanone, 1 .0 g of sodium cyanoborohydride and 0.16 ml of acetic acid are added to a solution of 2.0 g of benzyl piperazine-1 -carboxylate in 20 ml of acetonitrile and then stirred for 16 hours at RT. The reaction mixture is diluted with water and filtered through a Chem Elut cartridge, eluting with DCM. The combined organic phases are dried over MgSO4 and the solvent is evaporated under vacuum. The residue is purified by preparative HPLC and1 .7 g of a white solid is obtained. 0.5 g of this solid is dissolved in 20 ml of EtOH, 0.2 g of Pd/C at 10% is added and the mixture is stirred under a hydrogen atmosphere (4 bar) for 3 hours. The reaction mixture is filtered on Celite and the filtrate is concentrated under vacuum. The expected compound is obtained.
Intermediate 19 (2.6 g, 8.8 mmol) was added to a stirring solution of benzyl piperazine-1-carboxylate (1.1 mL, 5.87 mmol) in CH3CN (80 mL). The reaction mixture was refluxed over night, cooled, and quenched with satd. NaHCO3 (100 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated to give the crude (3.8 g) as opaque oil. The chromatography (1:3, hexanes/EtOAc) afforded the title compound (1.78 g, 70%) as clear oil. ES/MS calcd. for C24H43N2O3Si+ 435.3. Found m/z=435.2 (M+H)+.
With 4-methyl-morpholine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 20℃; for 12h; Inert atmosphere;
C.a (a) benzyl 4-[2-(tert-butoxycarbonylamino)acetyl]piperazine-1-carboxylate (3a)
General procedure: General method for the peptide coupling step (C) Under inert atmosphere and at room temperature, to a solution of the previously obtained piperazine (1 .85 mmol, 1 eq.) in dichloromethane (DCM, 15 ml) were successively added: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide (EDC, 1.85 mmol, 1 eq.), 1- hydroxybenzotriazole (0.37 mmol, 0.2 eq.), the corresponding Boc-protected aminoacid (1.85 mmol, 1 eq.) and N-methylmorpholine (5.55 mmol, 3 eq.). After 12 hours of stirring, the reaction mixture was diluted by addition of 75 ml of DCM and washed with citric acid (aq soln. 10%, 3 x 50 ml) and then with brine. The organic phase was subsequently dried over magnesium sulfate, filtered and the solvent evaporated under vacuum. The crude product was purified by flash-chromatography to give the desired coupling product. (a) benzyl 4-[2-(tert-butoxycarbonylamino)acetyl]piperazine-1-carboxylate (3a) The crude derivative obtained following the general protocol described before was purified by flash-chromatography (eluent: EtOAc/PE 5/5). C19H27N3O5; yield 95%; white solid; m.p. 66-67 °C; M = 377.43 g/mol; IR (ATR): v = 3329 (w), 2971 (w), 1691 (s), 1627 (m), 1527 (m), 1420 (m), 1223 (s), 1153 (m), 756 (m), 695 (m) cm ; H NMR (250 MHz, CDCI 3) δ 7.40-7.32 (m, 5H), 5.48 (as, 1 H), 5.14 (s, 2H), 3.96 (d, J = 4.4 Hz, 2H), 3.69-3.60 (m, 2H), 3.53-3.49 (m, 4H), 3.45-3.47 (m, 2H), 1.44 (s, 9H); C NMR (63 MHz, CDCI 3) δ 167.2 (C q), 155.9 (Cq), 155.2 (C q), 136.4 (C q), 128.7 (2CH), 128.4 (CH), 128.2 (2CH), 79.9 (C q), 67.7 (CH 2), 44.3 (CH 2), 43.7 (CH 2), 43.6 (CH 2), 42.4 (CH 2), 41.8 (CH 2), 28.5 (3CH 3); MS: m/z = 400 [M + Na] ;
93%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere;
89%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h;
Synthesis of 3.48 and 3.18 - Figure 18
Benzyl 4-(2-((tert-butoxycarbonyl)amino)acetyl)piperazine-l-carboxylate. To a mixture of N-Cbz-piperazine (2.2 mL, 11.4 mmol) and Boc-Gly-OH (1.8 g, 10.4 mmol) in DMF (20 mL) was added BOP (6.0 g, 13.6 mmol) and diisopropylethylamine (5.4 mL, 31.2 mmol). After stirring for 16h at rt, the resulting mixture was treated with saturated brine and then extracted with EtOAc. The combined organic layers were washed with 5% aqueous NaHCCte and saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue as purified by flash column chromatography eluting with Hexane:EtOAc (1 :2) to obtain benzyl 4-(2-((tert- butoxycarbonyl)amino)acetyl)piperazine-l-carboxylate (3.5 g, 89 % yield) as a viscous oil. ESI-MS [M+Na]= 400.2; 1H NMR (600 MHz, CDCb) δ 7.39-7.2691 (m, 5H), 5.47 (br s, 1H), 5.15 (s, 2H), 3.96 (d, 2H, J=4.2), 3.62 (br s, 2H), 3.55-3.50 (m, 4H), 3.38 (br s, 2H), 1.45 (s, 9H).
79%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h;
1
Combined 2-(tert-butoxycarbonylamino)acetic acid (1.314 g, 7.5 mmol) and benzyl piperazine-l-carboxylate (1.652 g, 7.50 mmol) in DCM (20 mL) then added l-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.582 g, 8.25 mmol). Stirred at RT for 16 h then removed DCM. Partitioned between water and ethyl acetate, washed org. with water, brine, dried (MgSC^), filtered and concentrated. Obtained benzyl 4-(2-(tert- butoxycarbonylamino)acetyl)piperazine-l-carboxylate (2.24 g, 5.93 mmol, 79 % yield) as a colorless oil.
With 4-methyl-morpholine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 20℃; for 12h;
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 70℃; for 16h;
[00199] To a suspension of Intermediate 33 A (50 mg, 0.167 mmol) and Pd2(dba)3 (15.25 mg, 0.017 mmol) in toluene (2 mL) was added xantphos (28.9 mg, 0.050 mmol), benzyl piperazine-l-carboxylate (36.7 mg, 0.167 mmol), followed by sodium tert-butoxide (48.0 mg, 0.500 mmol). The reaction mixture was stirred at 70 C for 16 h, and then filtered. The filtrate was concentrated and purified on ISCO using a 15 min gradient from 0 to 100% EtOAc in hexane to give Intermediate 33B (70 mg,0.159 mmol, 96 % yield). LC-MS (ESI) m/z 440.1 (M+H), RT = 2.27 min (Method B).
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 70℃; for 16h;
To a suspension of Intermediate 10A (50 mg, 0.17 mmol) and Pd2(dba)3 (15 mg, 0.017 mmol) in toluene (2 mL) was added Xantphos (29 mg, 0.050 mmol), benzyl piperazine-l-carboxylate (37 mg, 0.17 mmol), followed by sodium tert-butoxide (48 mg, 0.50 mmol). The reaction mixture was stirred at 70 C for 16 h, and then filtered. The filtrate was concentrated and purified by flash chromatography using a 15 min gradient from 0 to 100% EtOAc in hexanes to give Intermediate 10B (70 mg, 0.16 mmol, 96% yield). LC-MS (ESI) m/z 440.1 (M+H), RT = 2.27 min (Method B).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 5h;
benzyl4-(biphenylcarbonyl)piperazine-1-carboxylate (37)
To a mixture of 4-biphenylcarboxylic acid(198 mg, 1 mmol), benzyl piperazine-1-carboxylate(0.23 mL, 1.2 mmol), and HOBt (0.27 g,2 mmol) in DCM was added EDCI (0.38 g,2 mmol) at 0 thereaction mixture was stirred for 5 h at rt. The mixture was extracted with ethylacetate; the organic layer waswashed with saturated aqueous NH4Cl solution and brine, dried overanhydrous Na2SO4, filtered and concentrated under reducedpressure. The resulting mixturewas purified by silica gel column chromatography to give 37 (0.33 g,82%) as a colorless oil. 1HNMR (400 MHz, CDCl3): δ7.65-7.33 (m, 14H), 5.17 (s, 2H), 3.89-3.42 (m, 8H) ppm. 13C NMR (125 MHz, CDCl3):δ 170.4, 155.1, 142.9, 140.0, 136.3,133.9, 128.8, 128.5, 128.1, 127.9, 127.8, 127.6, 127.1, 67.4, 47.5, 43.9, 42.1ppm. MS (ESI, m/z): 401 (M++1).
With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; Cooling with ice;
28 Preparation Example 28
Preparation Example 28 A mixture of benzyl piperazine-1-carboxylate (10 g), 2,2,6,6-tetramethylpiperidin-4-one (7.05 g), and dichloromethane (100 mL) was ice cooled, and sodium triacetoxy borohydride (11.5 g) was added thereto followed by stirring at room temperature overnight. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution was added followed by extraction with chloroform. An organic layer obtained was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. After the filtrate was concentrated under reduced pressure, the resulting residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to give benzyl 4-(2,2,6,6-tetramethylpiperidin-4-yl)piperazine-1-carboxylate (7.18 g).
With triethylamine In acetonitrile at 0 - 0.25℃; for 0.5h; Inert atmosphere;
Intermediate AB: Preparation of (S)-2-Hydroxy-l-piperazin-l-yl-propan-l-one (AB) To a solution of AB-1 (1.0 g, 4.5 mmol) and TEA (1.3 mL, 9.1 mmol) in MeCN (25 mL) at 0 °C is added AB-2 (0.7 g, 4.5 mmol). The resultant mixture is warmed to ambient temperature, stirred for 30 min, poured into ice water, and extracted with EtOAc. The organic layer is extracted with saturated aqueous NaHCC>3 and brine, dried over Na2S04, filtered and concentrated to afford AB-3. To a solution of AB-3 (1.3 g, 3.8 mmol) in a mixture of dioxane (10 mL) and water (10 mL) is added LiOH (0.40 g, 9.7 mmol). The resultant mixture is stirred for 2 h, neutralized with concentrated HCl, and extracted with EtOAc .The organic layer is dried over Na2S04, filtered and concentrated to give AB-4. To a solution of AB-4 (1.3 g, 4.4 mmol) in EtOH (25 mL) is added 10% Pd/C (0.3 g). The mixture is stirred for 4 h under an atmosphere of H2, filtered through a pad of diatomaceous earth, and concentrated to give the title product (AB).
benzyl 4-(1H-pyrrole-2-carbonyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 20h; Inert atmosphere;
General procedure for synthesis of compounds 9c-g
General procedure: N-Cbz piperazine (0.55 g, 2.48 mmol, 1 eq) and carboxylic acid 8c-g (2.48 mmol, 1 eq) were dissolved in dry DMF (10 mL), the reaction mixture flushed with argon and cooled to 0 °C. N-methyl morpholine (NMM; 7.44 mmol,3 eq), hydroxybenzotriazole hydrate (HOBt; 2.98 mmol,1.2 eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride HCl salt (EDC; 3.22 mmol, 1.3 eq) were slowly added. The reaction mixture was stirred under argon atmosphere for 5 h at 0 °C and an additional 15 h at room temperature. DMF was evaporated under reduced pressure and the residue redissolved in dichloromethane (10 mL).The dichloromethane phase was washed with H2O (1 x 10 mL), a 1 M HCl solution (3 x 10 mL), saturated aqueous NaHCO3 solution (3 9 10 mL), brine (1 x 20 mL), dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/hexane solvents as eluents to afford compounds 9c-g.
benzyl 4-(1H-indole-2-carbonyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 20h; Inert atmosphere;
General procedure for synthesis of compounds 9c-g
General procedure: N-Cbz piperazine (0.55 g, 2.48 mmol, 1 eq) and carboxylic acid 8c-g (2.48 mmol, 1 eq) were dissolved in dry DMF (10 mL), the reaction mixture flushed with argon and cooled to 0 °C. N-methyl morpholine (NMM; 7.44 mmol,3 eq), hydroxybenzotriazole hydrate (HOBt; 2.98 mmol,1.2 eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride HCl salt (EDC; 3.22 mmol, 1.3 eq) were slowly added. The reaction mixture was stirred under argon atmosphere for 5 h at 0 °C and an additional 15 h at room temperature. DMF was evaporated under reduced pressure and the residue redissolved in dichloromethane (10 mL).The dichloromethane phase was washed with H2O (1 x 10 mL), a 1 M HCl solution (3 x 10 mL), saturated aqueous NaHCO3 solution (3 9 10 mL), brine (1 x 20 mL), dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/hexane solvents as eluents to afford compounds 9c-g.
benzyl 4-((tert-butoxycarbonyl)-L-prolyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 20h;Inert atmosphere;
General procedure: N-Cbz piperazine (0.55 g, 2.48 mmol, 1 eq) and carboxylic acid 8c-g (2.48 mmol, 1 eq) were dissolved in dry DMF (10 mL), the reaction mixture flushed with argon and cooled to 0 C. N-methyl morpholine (NMM; 7.44 mmol,3 eq), hydroxybenzotriazole hydrate (HOBt; 2.98 mmol,1.2 eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride HCl salt (EDC; 3.22 mmol, 1.3 eq) were slowly added. The reaction mixture was stirred under argon atmosphere for 5 h at 0 C and an additional 15 h at room temperature. DMF was evaporated under reduced pressure and the residue redissolved in dichloromethane (10 mL).The dichloromethane phase was washed with H2O (1 x 10 mL), a 1 M HCl solution (3 x 10 mL), saturated aqueous NaHCO3 solution (3 9 10 mL), brine (1 x 20 mL), dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/hexane solvents as eluents to afford compounds 9c-g.
With sodium tris(acetoxy)borohydride In dichloromethane at 20℃;
30.a Benzyl 4-[I -(tert-butoxycarbonyl)pi peridi n-4-yI]methyl}pi perazi ne-I - carboxylate
A mixture of tert-butyl 4-formylpiperidine-1-carboxylate (0.98 g, 4.60 mmol), benzyl piperazine-1-carboxylate (1.02 g, 4.61 mmol) and sodium triacetoxyborohydride (1.01 g, 4.76 mmol) in dichloromethane (30 mL) was stirred overnight at room temperature. The crude was washed with 2N aqueous solution of sodium hydroxide and 2N aqueoussolution of hydrogen chloride, dried over magnesium sulfate and the solvent was evaporated to yield the title compound (1 .68 g, 87%) as a white solid.LRMS (mlz): 418 (M+1).1H-NMR (300 MHz, CDCI3): 1.20- 1.35 (m, 3H), 1.45 (s, 9H), 1.80-2.20 (m, 3H), 2.60 - 2.90 (m, 6H), 3.50 (s, 2H), 3.77 - 4.58 (m, 6H), 5.15 (s, 2H), 7.32 -7.40 (m, 5H).
83.77%
With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;
1D.1 Step 1: Synthesis of benzyl 4-[[l-(tert-butoxycarbonyl)piperidin-4-yl]methyl]iperazine-l- carboxylate
To a stirred solution of tert-butyl 4-formylpiperidine-l-carboxylate (2.00 g, 9.38 mol, 1.00 equiv) and benzyl piperazine- 1-carboxylate (2065.60 mg, 9.38 mmol, 1.00 equiv) in THF (50.00 mL) was added NaBH(OAc)3 (1987.47 mg, 9.387 mmol, 1.00 equiv). The resulting mixture was stirred for 24 h at room temperature. After reaction, the reaction was quenched with sat.NELCl (20 mL) at 0 degrees C. The resulting mixture was extracted with EA (3x30 mL). The combined organic layers were washed with water (3x10 mL), dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EA = 1: 1 to afford benzyl 4-[[l-(tert-butoxycarbonyl)piperidin-4-yl]methyl]piperazine-l-carboxylate (3.28 g, 83.77%) as light yellow oil. LC/MS: mass calcd. For C23H35N3O4: 417.26, found: 418.30 [M+H]+.
76%
Stage #1: phenylmethyl 1-piperazinecarboxylate; tert butyl 4-formylpiperidine-1-carboxylate In methanol at 25℃; for 10h;
Stage #2: With methanol; sodium cyanoborohydride at 25℃; for 2h;
3.1 Step 1: Preparation of benzyl 4-((l-(tert-butoxycarbonyl)pipendin-4- yl)methyi)piperazine-l -carboxylate
To a solution of tert-butyl 4-formylpiperidine-l -carboxylate (10.00 g, 46.89 mmol, 1.00 eq) in methanol (20 mL) was added benzyl piperazine- 1 -carboxylate (10.33 g, 46.89 mmol, 9.06 mL, 1.00 eq) at 25 °C and stirred for 10 h. Then the mixture ws added sodium cyanoborohydride (4.42 g, 70.33 mmol, 1.50 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3/1) to give benzyl 4-[(l-tert-butoxycarbonyl-4- piperidyI)methyl]piperazine-l-carboxylate (15.00 g, 35.92 mmol, 76% yield) as a colorless oil. ' i-NXR (400MHz, CD Of)) 67.22 - 7.43 (m, 5H), 5.09 - 5.14 (m, 2H), 4.03 - 4.13 (m, 2H), 3.49 (s, 4H), 2.75 (s, 2.H), 2.39 (s, 4H), 2.20 (d, 7 6.4 Hz, 2H), 1.63 - 1.82. (m, 3H), 1.44 (s, 9H), 0.97 - 1.13 (m, 2.H).
53%
With sodium triacetoxyborohydride; acetic acid In dichloromethane Molecular sieve;
4.1; 15.1 first step:4-[(1-tert-Butoxycarbonyl-4-piperidinyl)methyl]piperazine-1-carboxylic acid benzyl ester (4b)
Combine 1-tert-butoxycarbonylpiperidine-4-carbaldehyde (4a) (2.5g, 12mmol) andBenzyl 1-piperazinecarboxylate (2.8g, 13mmol) was dissolved in 60mL of dichloromethane,Add 5 grams of molecular sieves, acetic acid (1.1 g, 18 mmol), sodium triacetoxyborohydride (7.5 g, 35 mmol), and stir overnight.Add 30 mL of water, filter with diatomaceous earth, layer, dry,The residue is separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=50/1-20/1),4-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]piperazine-1-carboxylic acid benzyl ester (4b) (2.6g, yield: 53%) was obtained.
53%
With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane Molecular sieve;
17.1 The first step: 4-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]piperazine-1-carboxylic acid benzyl ester (17b)
Add 1-tert-Butoxycarbonylpiperidine-4-carbaldehyde (17a) (2.5g, 12mmol)And benzyl 1-piperazinecarboxylate (2.8g, 13mmol)Dissolve in 60mL dichloromethane,Add 5 grams of molecular sieve,Acetic acid (1.1g, 18mmol), sodium triacetoxyborohydride (7.5g, 35mmol),Stir overnight.Add 30mL water, Diatomaceous earth filtration, layering, drying, the residue is separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=50/1-20/1) to obtain 4-[(1-tert-butyl Oxycarbonyl-4-piperidinyl)methyl]piperazine-1-carboxylic acid benzyl ester (17b) (2.6 g, yield: 53%).
693 mg
Stage #1: phenylmethyl 1-piperazinecarboxylate; tert butyl 4-formylpiperidine-1-carboxylate With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃;
Stage #2: With water; sodium hydrogencarbonate In dichloromethane
1 Step 1 : benzyl 4-((l-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperazine-l-carboxylate
Step 1 : benzyl 4-((l-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperazine-l-carboxylate Sodium triacetoxyborohydride (1732 mg, 8.17 mmol) was added to a mixture of benzyl piperazine-l-carboxylate (600 mg, 2.72 mmol), tert-butyl 4-formylpiperidine-l-carboxylate (697 mg, 3.27 mmol) and acetic acid (156 uL, 2.72 mmol) in DCM (14 mL) at room temperature. After stirring at room temperature overnight, the mixture was quenched with sat. NaHCC , the aq. layer was CH2CI2 extraction (2X20 mL). The combined org. fractions were dried over Na2SC>4 and concentrated to dryness. The residue was purified by ISCO column chromatography (silica gel ISCO 24 g prepacked, eluting with 0-100% EtOAc/Hexane) to give the title compound (693 mg). LCMS m/z (M+H): Calc'd 418.2, found 418.4.
With potassium carbonate; In acetonitrile; at 80℃;
A mixture of 1-Cbz piperazine (1 g, 4.55 mmol),2-bromo-2-methylpropionamide (751 mg, 4.55 mmol),potassium carbonate (942 mg, 6.83 mmol) and acetonitrile (10 mE) was stirred at 80 C. overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel colunm chromatography to obtain 57-c (1.05 g, 76%). EC-MS (ESI): mlz 306.3 (M+H).
With triethylamine; sodium iodide In tetrahydrofuran at 50℃;
1.1 (Step 1) Synthesis of benzyl 4- (3-hydroxypropyl) piperazine-1-carboxylate
Benzyl Piperazine-1-carboxylate (10.50 g)In tetrahydrofuran (225 mL) were added triethylamine (5.51 g), sodium iodide (0.68 g) and 3-bromo-1-propanol (9.77 g). It was then stirred at 50 ° C. overnight. Thereafter, it was cooled to room temperature. The resulting solution was poured into water and extracted with ethyl acetate. The organic layers were combined and washed with saturated brine to give the title compound (11.62 g, yield 92%).
87%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 12h;
19.a
Cbz-Piperazine (3.5 g, 15.9 mmol), 3-bromo-1-propanol (2.7 g, 19.1 mmol), and triethylamine (1.9 g, 19.1 mmol) were stirred in DMF (15 mL) at room temperature for 12 hours. Half of the solvent was removed by rotary evaporator. DI water was added and the mixture was extracted with ethyl acetate (3 x 30mL). The combined organic extracts were washed with brine and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel chromatography (0% to 80% ethyl acetate and hexanes) to afford the product as a thick clear oil. Yield 87 %. LC/MS [M+H]+ = 279.2.
benzyl 4-(3-diethoxyphosphorylpropyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium carbonate; In acetonitrile; at 75℃;
To a solution of benzyl piperazine-1 -carboxylate (1 .10 g, 4.99 mmol) and 1 -bromo-3-diethoxyphosphoryl-propane (1 .29 g, 4.99 mmol) in CH3CN (40.00 mL) was added K2003 (1 .38 g, 9.98 mmol). The reaction mixture was stirred at 75 00 overnight and then EtOAc (50 mL) and water (30 mL) were added. The layers were separated, and the aqueous phase was extracted again with EtOAc (20 mLx2). The combined organic phases were washed with brine (40 mL), dried over anhydrous Mg504, filtered andconcentrated. The residue was purified by flash column chromatography on silica gel to afford Compound 15.la (EtOAc/MeOH=50:1) to afford (1.80 g, 4.52 mmol, 91% yield) as an oil. 1H NMR (400 M, ODd3), oe7.35 (m, 5H), 5.13 (s, 2H), 4.12 (m, 4H), 3.52 (m, 4H), 2.42 (m, 6H), 1.78 (m, 4H), 1.32 (m, 6H).
benzyl 4-(4-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With palladium diacetate; caesium carbonate; XPhos; In toluene; at 105℃;Inert atmosphere;
Into a 100-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was added <strong>[120157-97-3]tert-butyl (4-bromophenethyl)carbamate</strong> (4,00 g, 13.3 mmol) and anhydrous toluene (50 mL). To the resulting solution was added benzyl piperazine-1- carboxylate (3.53 g, 16.0 mmol), Pd(OAc)2 (300 mg, 1.34 mmol), XPhos (1.28 g, 2.69 mmol), and CsiCO, (13.1 g, 40.0 mmol). The reaction mixture was stirred overnight at 105 C in an oil bath and then cooled to RT and quenched by the addition of H20 (200 mL). The resulting mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by FCC eluting with ethyl acetate/petroleum ether (PE/EA=3 : 1) to afford benzyl 4-(4-(2-((fert-butoxycarbonyl)amino)ethyl)phenyl)piperazine-l- carboxylate as a yellow solid (5 g, 85%), LCMS (ESI, m/z) 440 [M+H]+
85%
With palladium diacetate; caesium carbonate; XPhos; In toluene; at 105℃;Inert atmosphere;
(0937) [00331] Into a 100-mL round-bottom flask, purged and maintained under an inert atmosphere of nitrogen, was added fe/t~buty (4~bromophenethyl)carbarnate (4.00 g, 13.3 mmol) dissolved in anhydrous toluene (50-mL). To the resulting solution was added benzyl piperazine-1- carboxylate (3.53 g, 16.0 mmol), Pd(OAc)2 (0.300 g, 1.34 mmol), XPhos (1.28 g, 2.69 mmol), and CS2CO3 (13.1 g, 40.0 mmol). The reaction mixture was stirred overnight at 105 C in an oil bath and then cooled to RT and quenched with H2O (200 mL). The resulting mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by FCC eluting with ethyl acetate/petroleum ether (PE/EA=3: 1) to afford benzyl 4-(4-(2-((feri-butoxycarbonyl)amino)ethyl)phenyl) piperazine-1- carboxylate as a yellow solid (5 g, 85%), LCMS (ESI, m/z): 440 [M+H]+.
benzyl 4-(4-bromo-3-methoxyphenyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 80℃; for 3h;Inert atmosphere;
(0957) [00336] Into a lOG-mL round-bottom flask, purged and maintained under an inert atmosphere of nitrogen, was added l,4-dibromo-2-methoxybenzene (2.60 g, 9.78 mmol), benzyl piperazine- 1-carboxylate (2.37 g, 10.8 mmol), Pd2(dba)3-CHCij (0.508 g, 0.490 mmol), XantPhos (0,583 g, 0.980 mmol), and NaOtBu (2.82 g, 29.3 mmol) followed by toluene (40 mL). The reaction mixture was stirred, for 3 h at 80 C and then concentrated in vacuo. The resulting crude product was purified by FCC eluting with ethyl acetate/petroleum ether (1 : 10) to afford benzyl 4-(4- (0958) 131 (0959) 144628010 vl bromo-3-methoxyphenyl)piperazine-l-carboxylate as a brown solid (2 g, 50%). LCMS (ESi, m/z): 405, 407 [M?H]+
benzyl 4-(4-nitro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With caesium carbonate; In dimethyl sulfoxide; at 120℃;
(0971) [00339] into a 100-mL round-bottom flask was added l-fiuoro-4-nitro-2- (trifluoromethyl)benzene (3.20 g, 15.3 mmol) followed by DMSO (20 n L). Benzyl piperazine- (0972) 1 - carboxylate (3.30 g, 15.0 mmol) and CS2CO3 (15.0 g, 46.0 mmol) were then added and the reaction mixture was stirred overnight at 120 °C. The reaction mixture was cooled to RT, quenched with water (100 mL), and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated in vacuo to afford a crude product that purified by FCC eluting with ethyl acetate/petroleum ether (1 : 10) to afford benzyl 4-(4-nitro-2- (trifluoromethyl)phenyl)piperazine-l -carboxylate as an orange oil (3.2 g, 51percent). LCMS (ESI, m/z . 410 M-H] .
benzyl 4-(2-methyl-4-nitrophenyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With caesium carbonate; In dimethyl sulfoxide; at 140℃; for 2h;
(0992) [00345] Into a 100-mL round-bottom flask was added l-fluoro-2-methyl-4-nitrobenzene (1.55 g, 9.99 mmol), benzyl piperazine-l-carboxylate (2,20 g, 9,99 mmol) and CS2CO3 (9.78 g, 30.0 mmol) followed by DMSO (15 rnL). The resulting suspension was stirred for 2 h at 140 °C and then quenched with water (50 rnL) and extracted with ethyl acetate (3 x 100-mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by FCC eluting with ethyl acetate/petroleum ether (1 : 10) to (0993) 135 (0994) 144628010 vl afford benzyl 4-(2-methyl-4-nitrophenyl)piperazine-l-carboxylate as an orange solid (2.1 g, 59percent). LCMS (ESI, m/z) 356 [M+Hf.
benzyl 4-(4-bromo-2-chlorophenyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 60℃; for 4h;Inert atmosphere;
(1019) (1020) intermediate 31-1 (1021) [00354] Into a 100-mL round-bottom flask that purged and maintained under an inert atmosphere of nitrogen was added 4-bromo-2-chloro-l-iodobenzene (1.20 g, 3.78 mmol), benzyl piperazine-l -carboxylate (0.924 g, 4, 19 mmol), NaOtBu (1.10 g, 1 1.4 mmol), XantPhos (0.695 g, 1.20 mmol), Pd2(dba)3 (0.393 g, 0.430 mmol), and toluene (10 mL). The reaction mixture was stirred for 4 h at 60 C and then concentrated in vacuo to provide a crude product that was purified by FCC eluting with ethyl acetate/petroleum ether (1 : 10) to afford benzyl 4-(4-bromo-2- chlorophenyl)piperazine-l -carboxylate as a colorless oil (713 mg, 46%). LCMS (ESI, m/z) 409, 41 1 [ M 1 [ j .
benzyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In toluene at 80℃; for 2h; Inert atmosphere;
44.1 Step 1. Benzyl 4-(4-bromo-2-fluorophenyl)piperazine~l-carboxylate
Step 1. Benzyl 4-(4-bromo-2-fluorophenyl)piperazine~l-carboxylate (1155) [00386] Into a 100-mL round-bottom flask, purged and maintained under an inert atmosphere of nitrogen, was added 4-bromo-2-fluoro-l-iodobenzene (3.00 g, 10.0 mmol), benzyl piperazine- 1-carboxylate (2.60 g, 11.8 mmol), Pd2(dba)3 (0.458 g, 0,500 mmol), XantPhos (0.595 g, 1.00 mmol), and NaOtBu (2.88 g, 30.0 mmol). Toluene (30 mL) was added and the reaction mixture was stirred for 2 h at 80 °C then concentrated in vacuo to a crude material that was purified by FCC eluting with ethyl acetate/petroleum ether (1 : 10) to afford benzyl 4-(4-bromo-2- fluorophenyl)piperazine-l-carboxylate as a brown oil (2.5 g, 64%). LCMS (ESI, m z): 393[ i i l
tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With triethylamine; In N,N-dimethyl acetamide; at 90℃; for 5h;Sealed tube;
In 2 mL of dimethyl acetamide were combined tert-butyl 4- chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.0 g, 3.7 mmol), triethylamine (1.0 mL, 7.4 mmol), and benzyl 1-piperazinecarboxylate (0.86 mL, 4.4 mmol). The reaction vessel was sealed and the reaction mixture was heated to 90 C with stirring. After 5 hours, the reaction was diluted with brine and extracted with methyl t-butyl ether. The combined organic layers were washed sequentially with saturated ammonium chloride and brine, dried over MgSC"4, and concentrated under reduced pressure to a thick oil. The oil was chromatographed (RediSep, 24 g) eluting withl : l ethyl acetate/Hexanes to give tert-butyl 4-(4- ((benzyloxy)carbonyl)piperazin-l-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.3 g, 2.9 mmol, 77 % yield). ES+APCI MS m/z 454.2 [M+H]+.
77%
With triethylamine; In N,N-dimethyl acetamide; at 90℃; for 5h;Sealed tube;
In 2 mL of dimethyl acetamide were combined <strong>[1053656-57-7]tert-butyl 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate</strong> (1.0 g, 3.7 mmol), triethylamine (1.0 mL, 7.4 mmol), and benzyl 1-piperazinecarboxylate (0.86 mL, 4.4 mmol). The reaction vessel was sealed and the reaction mixture was heated to 90° C. with stirring. After 5 hours, the reaction was diluted with brine and extracted with methyl t-butyl ether. The combined organic layers were washed sequentially with saturated ammonium chloride and brine, dried over MgSO 4, and concentrated under reduced pressure to a thick oil. The oil was chromatographed (RediSep , 24 g) eluting with 1:1 ethyl acetate/Hexanes to give tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5,8-dihydropyrido [3,4-d]pyrimidine-7(6H)-carboxylate (1.3 g, 2.9 mmol, 77% yield). ES+APCI MS m/z 454.2 [M+H] +.
tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 85℃; for 2.0h;
Benzyl 1-piperazinecarboxylate (1.268 mL, 6.575 mmol) and tert-Butyl 2,4-dichloro-5,6-dihydropyrido[3 4-d]pyrimidine-7(8H)- carboxylate (2 g, 6.575 mmol) were dissolved in dimethyl acetamide (10 mL) and treated with N-ethyl-N-isopropylpropan-2-amine (3.445 mL, 19.73 mmol). The reaction mixture was stirred at 85 C for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgS04, filtered and concentrated. The concentrate was purified by chromatography (CombiFlash, 0%-50% ethyl acetate:Hexanes as the eluent to provide the product (2.69g, 83%). ES+APCI MS m/z 488.2, 490.2 [M+H]+ .
83%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 85℃; for 2.0h;
Benzyl 1-piperazinecarboxylate (1.268 mL, 6.575 mmol) and tert-Butyl 2,4-dichloro-5,6-dihydropyrido[3 4-d]pyrimidine-7(8H)-carboxylate (2 g, 6.575 mmol) were dissolved in dimethyl acetamide (10 mL) and treated with N-ethyl-N-isopropylpropan-2-amine (3.445 mL, 19.73 mmol). The reaction mixture was stirred at 85° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgSO 4, filtered and concentrated. The concentrate was purified by chromatography (CombiFlash , 0%-50% ethyl acetate:Hexanes as the eluent to provide the product (2.69 g, 83%). ES+APCI MS m/z 488.2, 490.2 [M+H] +.
tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6.93%
To a solution of tert-butyl 4-hydroxy-6,8-dihydro-5H-pyrido[3,4- d] pyrimidine-7-carboxylate (16.0 g, 63.7 mmol, 1.00 eq) in DMF (4.00 mL) was added DBU (29.1 g, 191 mmol, 28.8 mL, 3.00 eq) and benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PYBOP) (39.8 g, 76.4 mmol, 1.20 eq). The mixture was stirred at 25 C for 1 hour. Benzyl piperazine-l-carboxylate (21.0 g, 95.5 mmol, 18.5 mL, 1.50 eq) was added and the reaction mixture was stirred at 25 C for 16 hours. The mixture was diluted with ethyl acetate (500 mL) and washed with water (3 chi 400 mL), dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by column chromatography (S1O2, diethyl ether/ethyl acetate = 1 : 1) to give tert-butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-6,8-dihydro- 5H- pyrido[3,4-d]pyrimidine-7-carboxylate (2.00 g, 4.41 mmol, 6.93 % yield) as a yellow oil. ESI MS m/z 454.3 [M+H]+.
6.93%
To a solution of tert-butyl 4-hydroxy-6,8-dihydro-5H-pyrido[3,4-d] pyrimidine-7-carboxylate (16.0 g, 63.7 mmol, 1.00 eq) in DMF (4.00 mL) was added DBU (29.1 g, 191 mmol, 28.8 mL, 3.00 eq) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PYBOP) (39.8 g, 76.4 mmol, 1.20 eq). The mixture was stirred at 25° C. for 1 hour. Benzyl piperazine-1-carboxylate (21.0 g, 95.5 mmol, 18.5 mL, 1.50 eq) was added and the reaction mixture was stirred at 25° C. for 16 hours. The mixture was diluted with ethyl acetate (500 mL) and washed with water (3 400 mL), dried over Na 2SO 4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO 2, diethyl ether/ethyl acetate=1:1) to give tert-butyl 4-(4-benzyloxycarbonylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimid- ine-7-carboxylate (2.00 g, 4.41 mmol, 6.93% yield) as a yellow oil. ESI MS m/z 454.3 [M+H] +.
To a cooled solution of imidazole at 000 (1.00 g, 14.7 mmol, 2equiv) in 0H2012 (18 mL),benzyl chloroformate (1.03 mL, 7.35 mmol, 1 equiv) was slowly added. After 1h45 ofstirring the white solid (imidazole hydrochloride) was filtered off. The obtained filtrate wasconcentrated, and then solubilised in ethanol (17.5 mL). In another flask the solution of<strong>[142-64-3]piperazine dihydrochloride</strong> (1.75 g, 11.03 mmol, 1.5 equiv) in water (17.5 mL) wasprepared, then added dropwisely to ethanolic solution of Cbz-imidazole. The resultedmixture was stirred for 4h30 at room temperature and then concentrated to 1h of itsvolume. Obtained aqueous phase was extracted with chloroform (4x) to remove the diacylated product, then NaOHsat was added to the previous aqueous phase (pH 9-10).The resulted aqueous phase was extracted again with chloroform (4x) to recover the monoacylated product. The organic phase with monoacylated product was washed with water (4x), dried over MgSO4 and concentrated to give (1) (0.809 g, 50% in two steps) asa colorless oil
benzyl 4-(2-bromo-6-cyanophenyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 140℃; for 16h;Sealed tube;
A mixture of <strong>[840481-82-5]3-bromo-2-fluorobenzonitrile</strong> (2.0 g, 10.1 mmol), benzyl piperazine-1- carboxylate (3.3 g, 15.1 mmol), and DIPEA (2.6 g, 20.2 mmol) in DMSO (15 mL) was stirred at 140 C in sealed tube for 16 h. H20 (20 mL) and EtOAc (20 mL) was then added and the organic layer was separated. The aqueous layer was further extracted with EtOAc (2 x 20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by chromatography (silica, PE/EtOAc = 10/1 to 3/1) to afford benzyl4-(2-bromo-6-cyanophenyl)piperazine-1-carboxylate (2.1 g, 5.26 mmol, 52%) as a yellow oil. ESI-MS (EI+, m/z): 400.1 [M+H]t
benzyl 4-(2-(2-hydroxyethoxy)ethyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;
To a solution of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (2.7 g, 10.4 mmol) and benzyl piperazine-1-carboxylate (2.3 g, 10.4 mmol) in DMF (10 mL) was added K2CO3 (2.86 g, 20.8 mmol). The solution was stirred at 80oC overnight. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed with water (10 mL) and brine (8 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to afford the crude Benzyl 4-(2-(2-hydroxyethoxy)ethyl)piperazine-1-carboxylate (4.5 g), which was used in the next reaction without further purification
benzyl 4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30.1%
With tris-(dibenzylideneacetone)dipalladium(0); lithium hexamethyldisilazane; DavePhos; In tetrahydrofuran; at 65℃; for 24h;Cooling with ice;
To an ice cold stirred solution of <strong>[121219-03-2]4-bromo-3-fluorophenol</strong> (1, 15 g, 0.079 mol), benzyl piperazine-l-carboxylate (20.76 g, 0.094 mol), DavePhos (3.704 g, 0.009 mol), Pd2(dba)3 (7.186 g, 0.008 mol) in THF (100 mL), LHMDS (100 mL) was added. After addition, the reaction was allowed to reach room temperature. Then it was heated to 65C for 24h. After the completion, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. Combined organic layer was washed with saturated brine solution, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude obtained was purified by column chromatography (230-400 silica gel (30% EA/ Pet ether as an eluent) to afford the product as off white solid (10.00 g, 30.1%). LCMS (ESI positive ion) m z: calculated: 330.36; observed: 331.1 (M+1).
benzyl 4-(4-fluoropyridin-2-yl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
With dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; [(2-di-cyclohexylphosphino-3,6-dimethoxy-2?,4?,6?-triisopropyl-1,1?-biphenyl)-2-(2?-amino-1,1?-biphenyl)]palladium(II) methanesulfonate; methanesulfonato(2-dicyclohexylphosphino-2?,6?-di-i-propoxy-1,1?-biphenyl)(2?-methylamino-1,1?-biphenyl-2-yl)palladium(II); caesium carbonate; In toluene; at 80℃; for 16h;Sealed tube;
A mixture of <strong>[357927-50-5]2-bromo-4-fluoropyridine</strong> (600 mg, 3.41 mmol, 1.00 eq.), benzyl piperazine- 1 -carboxylate (754 mg, 3.42 mmol, 1.00 eq.), CS2CO3 (3.3 g, 3.00 eq.), Brettphos (18 mg, 0.01 eq.), Brettphos Pd G3 catalyst (31 mg, 0.01 eq.) in toluene (10 mL) was stirred in a 30 mL sealed tube for 16 h at 80 C in an oil bath. The resulting mixture was cooled, diluted with water, and extracted with 2x30 mL EtOAc. The organic layers were combined and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / hexane (1/1) to afford 110 mg (10 %) of the title compound as an off-white solid. LC-MS: (ES, m/z) 316
benzyl 4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With potassium carbonate In acetonitrile at 70℃; Inert atmosphere;
25.1 Step 1 Synthesis of benzyl 4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazine-l-carboxylate
A mixture of benzyl piperazine- l-carboxylate (400 mg, 1.818 mmol), l-bromo-2-(2- (2-methoxyethoxy)ethoxy)ethane (620 mg, 2.727 mmol) and K2CO3 (501 mg, 3.636 mmol) in ACN (20 mL) was stirred at 70 °C overnight under a N2 atmosphere. The mixture was cooled to rt, then concentrated in vacuo, and water (10 mL) was added to the residue and the mixture was extracted with EtOAc (15 mL x 3), the combined organic phases were washed with brine (50 mL). The organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE:EtOAc = 10: 1 ~ 6: 1) to give a colorless oil (500 mg, 82%).
benzyl 4-[3-[2-(tert-butoxycarbonylamino)ethyl]phenyl]piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
600 mg
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In toluene at 90℃; for 18h; Inert atmosphere;
24.2 Step 2: preparation of benzyl 4-[3-[2-(terZ- butoxycarbonylamino)ethyl]phenyl]piperazine- 1-carboxylate (compound 24b)
To a solution of tert- butyl V-[2-(3-bromophenyl)ethyl]carbamate (compound 24a, 1.00 g, 3.33 mmol), benzyl piperazine- l-carboxylate (734 mg, 3.33 mmol), sodium ZerZ-butoxide (640 mg, 6.66 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (386 mg, 0.67 mmol) in toluene (28 mL) was added tris(dibenzylideneacetone)dipalladium (0) (305 mg, 0.33 mmol) and the mixture was stirred at 90 °C under N2 atmosphere for 18 hrs. Then the mixture was concentrated and purified by flash column (PE/EA = 5/1) to give compound 24b (600 mg) as a yellow oil. MS: calc’d 440 (MH+), measured 440 (MH+).
tert-butyl 2-(4-benzyloxycarbonylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50.79%
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; for 5h;Inert atmosphere;
[0402] No. Tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (C) (0.478 g, 2 mmol), No.57 benzyl-1-piperazine carbonate (440 mg, 2 mmol), No.35 acetic acid (120 mg, 2.0 mmol) and No.40 dichloroethane (7 mL) were added in a 50 mL reaction flask, and the system was stirred for half an hour. No.35 Sodium triacetoxyborohydride (0.636g, 3mmol) was added and the resultant reacted for 5h. The reaction system was quenched with No.5 water (10 mL), extracted with ethyl acetate (5 mL 3), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v)=4:1) to obtain No.57 tert-butyl 2-(4-benzyloxycarbonylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (36A) as light yellow oily substance (450 mg, yield 50.79%). MS m/z =444.2[M+H]+;
benzyl 4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35.71%
With methanol; sodium cyanoborohydride at 25℃;
49.1
To a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (4.02 g, 17.709 mmol, 1.00 equivalent) and benzyl piperazine-1-carboxylate (3.90 g, 17.727 mmol, 1.00 equivalent) in MeOH (40 mL) was added NaBH3CN (2.26 g, 35.313 mmol, 2 equivalent), the resulting solution was stirred at 25 oC for 1 hours. The resulting mixture was diluted with water (50 mL), extracted with EA (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 45% THF in petroleum ether. Pure fractions were evaporated to dryness to afford benzyl 4-(2-(1-(tert- butoxycarbonyl)piperidin-4-yl)ethyl)piperazine-1-carboxylate (2.76 g, 35.71%) as a colorless oil. LCMS (ESI) m/z: [M+H]+ = 432.
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In 1,4-dioxane; at 100.0℃; for 1.0h;
Combine <strong>[1340506-55-9]tert-butyl 6-chloropyridazine-3-carboxylate</strong> (7b) (0.4g, 1.86mmol), benzyl 1-piperazinecarboxylate (0.4g, 1.82mmol),Potassium carbonate (0.6g, 6mmol) and tetrabutylammonium iodide (0.08g, 0.2mmol) were sequentially added to 10mL 1,4-dioxane and heated to 100 degrees.The reaction was stirred for 1 h and then cooled to room temperature, the solvent was removed under reduced pressure, and 20 mL of DCM and 20 mL of water were added for extraction.After the organic layer was concentrated under reduced pressure, the residue was beaten with 30 mL of dichloromethane/petroleum ether (dichloromethane/petroleum ether (v/v) = 1/2) for 20 min.After filtration, tert-butyl 6-(4-benzyloxycarbonylpiperazin-1-yl)pyridazine-3-carboxylate (8a) (0.45 g, yield: 60%) was obtained.
benzyl 4-(3-hydroxybenzoyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; for 15h; Inert atmosphere;
145.a a) benzyl 4-(3- (piperazine- 1-carbowlate
To a mixture of 1 -Cbz-piperazine (7.97 g, 36.2 mmol, 1.0 eq) and 3-hydroxybenzoic acid (5 g, 36.2 mmol, 1.0 eq) in DCM (50 mL) were added HATU (16.52 g, 43.44 mmol, 1.2 eq) and triethylamine (6.05 mL, 43.4 mmol, 1.2 eq) at 25 °C. Then the mixture was stirred at 25 °C for 15 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica column (PE/EtOAc 0-50%) to afford the title compound (8 g, 23.5 mmol, 65% yield) as a white solid. MS (ESI): 341.1 ([M+H]+).
65%
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; for 1.5h; Inert atmosphere;
Intermediate 101a: benzyl 4-(3-hydroxybenzoyl)piperazine-1-carboxylate
To a mixture of 1-Cbz-piperazine (7.97 g, 36.2 mmol, 1.0 eq) and 3-hydroxybenzoic acid (5 g, 36.2 mmol, 1.0 eq) in DCM (50 mL) were added HATU (16.52 g, 43.44 mmol, 1.2 eq) and triethylamine (6.05 mL, 43.44 mmol, 1.2 eq) at 25 °C. Then the mixture was stirred at 25 °C for 15 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (PE/EtOAc 1:1) to afford the title compound (8 g, 23.5 mmol, 65% yield) as a white solid. MS (ESI): 341.1 ([M+H]+).
6-(4-benzyloxycarbonylpiperazin-1-yl)-2-chloropyrimidine-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 18h;
Method A - Step 1 - 6-(4-benzyloxycarbonylpiperazin-1-yl)-2-chloro-pyrimidine-4- carboxylic acid (Intermediate 5)
Intermediate 1 (1.73g, 8.98mmol) and K2CO3 (8.68g, 62.87mmol) were stirred in DMF (40ml_) and 1-Cbz-piperazine (1.38 L, 7.18mmol) added at 0°C and stirred. The reaction was warmed to room temperature and stirred for 18 hours. Solvent was then removed in vacuo. Water was added and the pH adjust to 1-2 by addition of 1M aq. HCI followed by extraction with EtOAc (3x300ml_). The combined organic phases were dried over Na2SC>4 and the solvent removed in vacuo. The residue was purified by column chromatography using an eluent of 0-20% MeOH in DCM reached via a gradient followed by reverse phase column chromatography using an eluent 5-100% of MeCN (+0.1% formic acid) in water (+0.1% formic acid) reached via a gradient to give 6-(4-benzyloxycarbonylpiperazin-1-yl)-2- chloro-pyrimidine-4-carboxylic acid (Intermediate 5) (1.36g, 3.61 mmol, 40% yield). UPLC-MS (ES+, Method 2): 1.53 min, m/z 377.1, 379.1 [M+H]+.1H-NMR (400MHz, DMSO-d6) d/ppm: 7.40-7.31 (5H, m), 7.30 (1 H, s), 5.12 (2H, s), 3.88- 3.61 (4H, m), 3.52 (4H, br s), exchangeable proton not seen.
benzyl 4-[2-chloro-6-(1-naphthylcarbamoyl)pyrimidin-4-yl]piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
Stage #1: 2,6-dichloro-4-pyrimidinecarboxylic acid; phenylmethyl 1-piperazinecarboxylate With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5h;
Stage #2: 1-amino-naphthalene With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; ethyl acetate at 65℃; for 1.5h;
1.1 Step 1 - benzyl 4-[2-chloro-6-(1-naphthylcarbamoyl)pyrimidin-4-yl]piperazine-1- carboxylate
Intermediate 1 (729mg, 3.78mmol) and K2CO3 (3.65g, 26.44mmol) were dissolved in DMF (20ml_) followed by the addition of 1-Cbz-piperazine (0.58ml_, 3.02mmol). The reaction was left stirring at room temperature for 5 hours and then solvent removed in vacuo. The residue was dissolved in THF (20ml_) followed by the addition of DIPEA (1.98ml_, 11.37mmol), T3P (3.37ml_, 5.66mmol, 50% volume in EtOAc) and 1-aminonaphthalene (1.62g, 11.33mmol). The reaction was stirred at 65°C for 1.5 hours and the solvent removed in vacuo. The residue was dissolved in DCM (200ml_) and washed with water (2x200ml_). The organic phase was dried over Na2SC>4 and the solvent removed in vacuo. The residue was purified by column chromatography using an eluent of 0-50% EtOAc in petroleum ether reached via a gradient to give benzyl 4-[2-chloro-6-(1-naphthylcarbamoyl)pyrimidin-4-yl]piperazine-1-carboxylate (352mg, 0.70mmol, 17% yield) as a yellow oil.UPLC-MS (ES+, Method 2): 2.16 min, m/z 502.2, 504.1 [M+H]+.1H-NMR (400MHz, CDC ) d/ppm: 10.30 (1H, s), 8.26 (1 H, d, J = 7.2Hz), 8.01 (1H, d, J = 8.8Hz), 7.91 (1H, d, J = 8.0Hz), 7.74 (1H, d, J = 8.0Hz), 7.64-7.59 (1 H, m), 7.57-7.51 (2H, m), 7.42 (1H, s), 7.41-7.33 (5H, m), 5.20 (2H, s), 3.81 (4H, br s), 3.69-3.59 (4H, m).
Stage #1: 7-fluoro-2,2-dimethylchroman-4-one With sulfuric acid; potassium nitrate at 0℃; for 2h;
Stage #2: phenylmethyl 1-piperazinecarboxylate In acetonitrile at 40℃;
Stage #1: BOC-glycine; phenylmethyl 1-piperazinecarboxylate With triethylamine; diisopropyl-carbodiimide In 1-methyl-pyrrolidin-2-one; dichloromethane at 20℃; for 2h; Inert atmosphere;
Stage #2: With palladium on activated charcoal; hydrogen In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; dichloromethane at 20℃;
6 Synthesis Example 2
General procedure: After dissolving the benzyl piperazine-1-carboxylate derivative in 5-fold volume of dichloromethane and 5-fold volume of N-methyl-2-pyrrolidone (NMP), 1.0 equivalent of amino acid in which the amine group was protected with t-butoxycarbonyl (Boc), 1.1 equivalent of diisopropylcarbodiimide (DIPC), and 1.2 equivalent of triethylamine were added. The mixture was stirred for 2 hours at room temperature under an argon gas environment, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran, 5% amount of palladium adsorbed on 10 wt % pure carbon was added thereto, followed by stirring at room temperature under hydrogen gas at normal pressure. After the reaction was completed, the reaction solution was filtered, and the filtrate was recovered and concentrated under reduced pressure. It was purified by column chromatography using silica gel (eluent: a mixture of dichloromethane and methanol) to obtain an acylated piperazine intermediate. A 10-fold volume of dichloromethane was added thereto, dissolved, and 1.5 equivalents of pyridine were added. The reaction solution was cooled to 0° C. or less under an argon gas environment, and then 1.2 equivalents of triphosgene diluted in 15-fold volume of dichloromethane were slowly added dropwise and stirred. After stirring at room temperature for 2 hours, it was washed with saturated brine and the organic layer was separated. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain a yellow oily substance. After 10-fold volume of acetonitrile was added thereto and completely dissolved, 1.0 equivalent of edaravone and 3.0 equivalent of cesium carbonate were added thereto. After stirring at room temperature to confirm the completion of the reaction, the reaction solution was filtered using Celite, and the filtrate was recovered and concentrated under reduced pressure. The residue was dissolved with 10-fold volume of ethyl acetate, washed with saturated brine, and the organic layer was separated, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrated residue was purified by column chromatography using silica gel (eluent: a mixture of ethyl acetate and normal hexane). To the obtained intermediate, 5 equivalents of a 1,4-dioxane solution in which 4N-hydrochloric acid was dissolved was added to completely dissolve, and the mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. After 10-fold volume of ethyl acetate was added thereto, it was concentrated under reduced pressure. (This was repeated 3 times) Finally, 10-fold volume of ethyl acetate was added, and the obtained suspension was filtered to obtain the target compound in a solid state.
benzyl 4-(3-hydroxy-3-methylbutyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52.7%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 60h;
To a mixture of benzyl piperazine-1-carboxylate (150 mg, 0.681 mmol) and potassium carbonate (188 mg, 1.362 mmol) in DMF (2 mL) at 0 C was added 4-bromo- 2-methylbutan-2-ol (143 mg, 0.858 mmol) in DMF (0.2 mL) in one portion. The mixture was stirred at room temperature for 60 h, diluted with ethyl acetate (10 mL), and filtered through Celite. The filtrate was diluted with ethyl acetate (60 mL), washed with water (2 x 20 mL) and brine (20 mL), and dried over anhydrous MgSO4. The title intermediate (110 mg, 0.359 mmol, 52.7 % yield) was isolated as a white solid by ISCO chromatography (24 g silica gel, solid loading, 1-8% ethyl acetate/hexane). LCMS(M+H)+= 307.4.1H NMR (400 MHz, chloroform-d) δ 7.39-7.29 (m, 5H), 5.13 (s, 2H), 3.55-3.48 (m, 4H), 2.68-2.60 (m, 2H), 2.49 (br s, 4H), 1.66-1.61 (m, 2H), 1.23 (s, 6H).
52.7%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 60h;
To a mixture of benzyl piperazine-1-carboxylate (150 mg, 0.681 mmol) and potassium carbonate (188 mg, 1.362 mmol) in DMF (2 mL) at 0 C was added 4-bromo- 2-methylbutan-2-ol (143 mg, 0.858 mmol) in DMF (0.2 mL) in one portion. The mixture was stirred at room temperature for 60 h, diluted with ethyl acetate (10 mL), and filtered through Celite. The filtrate was diluted with ethyl acetate (60 mL), washed with water (2 x 20 mL) and brine (20 mL), and dried over anhydrous MgSO4. The title intermediate (110 mg, 0.359 mmol, 52.7 % yield) was isolated as a white solid by ISCO chromatography (24 g silica gel, solid loading, 1-8% ethyl acetate/hexane). LCMS(M+H)+= 307.4.1H NMR (400 MHz, chloroform-d) δ 7.39-7.29 (m, 5H), 5.13 (s, 2H), 3.55-3.48 (m, 4H), 2.68-2.60 (m, 2H), 2.49 (br s, 4H), 1.66-1.61 (m, 2H), 1.23 (s, 6H).
52.7%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 60h;
To a mixture of benzyl piperazine-1-carboxylate (150 mg, 0.681 mmol) and potassium carbonate (188 mg, 1.362 mmol) in DMF (2 mL) at 0 C was added 4-bromo- 2-methylbutan-2-ol (143 mg, 0.858 mmol) in DMF (0.2 mL) in one portion. The mixture was stirred at room temperature for 60 h, diluted with ethyl acetate (10 mL), and filtered through Celite. The filtrate was diluted with ethyl acetate (60 mL), washed with water (2 x 20 mL) and brine (20 mL), and dried over anhydrous MgSO4. The title intermediate (110 mg, 0.359 mmol, 52.7 % yield) was isolated as a white solid by ISCO chromatography (24 g silica gel, solid loading, 1-8% ethyl acetate/hexane). LCMS(M+H)+= 307.4.1H NMR (400 MHz, chloroform-d) δ 7.39-7.29 (m, 5H), 5.13 (s, 2H), 3.55-3.48 (m, 4H), 2.68-2.60 (m, 2H), 2.49 (br s, 4H), 1.66-1.61 (m, 2H), 1.23 (s, 6H).
Stage #1: phenylmethyl 1-piperazinecarboxylate; tert-butyl N-(5-formyl-2,2-dimethyl-1,3-dioxan-5-yl)carbamate In methanol at 20℃; for 1h;
Stage #2: With methanol; sodium cyanotrihydridoborate for 12h;
59.a
A mixture of t-butyl(5-formyl-2,2-dimethyl-1,3-dioxan-5-yl) carbamate (0.5 g, 1.9 mmol) and Cbz- piperazine (0.51 g, 2.3 mmoL) in methanol (20 mL) was stirred at ambient temperature for 1 hour. Sodium cyanoborohydride (0.31 g, 4.8 mmol) was added and the reaction was stirred for 12 hours then concentrated to a volume of approx.5 mL. The mixture was purified by reversed phase HPLC (0-70% ACN in DI water, 0.1% TFA modifier, 30 minute gradient) The pure fractions were concentrated to afford the intermediate as a clear oil. Ion found by LCMS [M+H]+ = 464.2.
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