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Chemical Structure| 227940-72-9
Chemical Structure| 227940-72-9
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Product Details of [ 227940-72-9 ]

CAS No. :227940-72-9 MDL No. :MFCD17016673
Formula : C12H22N2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :ZFVNQMTWYYKBES-UHFFFAOYSA-N
M.W : 226.32 Pubchem ID :22490264
Synonyms :

Safety of [ 227940-72-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 227940-72-9 ]

* 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.

  • Downstream synthetic route of [ 227940-72-9 ]

[ 227940-72-9 ] Synthesis Path-Downstream   1~85

  • 1
  • [ 1538-75-6 ]
  • [ 227940-72-9 ]
  • [ 454695-25-1 ]
YieldReaction ConditionsOperation in experiment
With pyridine; dmap at 20℃; for 12h;
  • 2
  • [ 227940-71-8 ]
  • [ 227940-72-9 ]
YieldReaction ConditionsOperation in experiment
94% With hydrogen;palladium(II) hydroxide/carbon; In methanol; at 50℃; under 2844.39 Torr; for 2h; Example 8: Synthesis of 3,7-diazabicyclo[3.3.1]nonane-3-carboxyIic acid tert-butyl esterExample 8 relates to the synthesis of 3,7-diazabicyclo[3.3.1]nonane-3- carboxylic acid tert-butyl ester (or N-(tert-butoxycarbonyl)-3,7- diazabicyclo[3.3.1]nonane), which was prepared according to the following techniques:7-Benzyl-3,7-diazabicyclo [3.3.1 ] nonane-3-carboxylic acid tert-butyl ester (or N-benzyl-N'-(tert-butoxycarbonyI)-3,7- diazabicyclo[3.3.1]nonane); 7-Benzyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxylic acid tert-butyl ester was prepared according to procedures set forth by Stead et al. in Org. Lett. 7(20): 4459 (2005).3,7-Diazabicyclo[3.3.1]-3-carboxyIic acid tert-butyl ester 7-Benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester(0.49 g, 1.6 mmol) was dissolved in methanol (20 mL) and 20% Pd(OH)2/C (wet) (~ 2 g) was added under a nitrogen atmosphere. This mixture was warmed to about 5O0C and shaken for 2 h under 55 psi of hydrogen. The resulting mixture was EPO <DP n="35"/>filtered and concentrated to give 0.32 g (94% yield) of the title compound (MS m/z 227 (M+H)).
94% With hydrogen;20% palladium hydroxide-activated charcoal; In methanol; at 50℃; under 2844.39 Torr; for 2h; 7-Benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (0.49 g, 1.6 mmol) was dissolved in methanol (20 ml.) and 20% Pd(OH)2/C (wet) (~ 2 g) was added under a nitrogen atmosphere. This mixture was warmed to about 50 0C and shaken for 2 h under 55 psi of hydrogen. The resulting mixture was filtered and concentrated to give 0.32 g (94% yield) of the title compound (MS m/z 227 (M+H)).
93.33% With 10 wt% Pd(OH)2 on carbon; hydrogen; In methanol; at 55℃; Palladium hydroxide (0.5g),(Pearlman's catalyst), was added portion wise to a suspension of compound 12 (1.102g, 0.0367 mol) in methanol (25ml) in steel parr. The I reaction mixture was hydrogenated at 55C and 150 psi for about 17 hrs. Then it was 2 allowed to cool and filtered over sintered funnel with the aid of vacuum and concentrated to get pale yellow solid. Yield = 93.33%; MP:75C; IR ( Br): 2979.2, 2919.7, 2858.5, 1679.6, 1402.4, 1240.4, 1 172.3 1 131.9 cm"' ; IH NMR (300MHz, CDC13, ppm): 64.13-4.09 (brd, J= 12Hz, 2H, 2 x CONCH); 3.14-3.10 (m, 3H, 2 x CONCH, NCH); 3.01-2.96 (brd, J= 15Hz, I H, NCH); 2.25 (s, 2H, 2 x NH); 1.92- 1 .88 (d, J=12Hz, I H, CH); 1.80- 1 .76 (d, J= 12Hz, I H, CH); 1 .67 (s, bridge CH2); 1.48 (s,9H,CMe3); 13C NMR (50 MHz, CDCI3, ppm): 6155.49 (C=0), 79.78 (CMe3), 51 .50 (NCH2), 48.94 (C(0)NCH2), 31.39 (CH), 28.52 (CMe3), 28.15 (CMe3); MS (ESI):227.1481(M+H)+
93.33% With hydrogen; palladium(II) hydroxide; In methanol; at 55℃; under 7757.43 Torr; for 10h; 6.1.3 3,7-Diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (10) Palladium hydroxide (0.5 g) was added portion wise to a suspension of 8 (1.102 g, 36.7 mmol) in methanol (25 ml) in steel parr under nitrogen atmosphere. The reaction mixture was hydrogenated at 55 C and 150 psi for about 10 h. Then it was allowed to cool and filtered over sintered funnel with the aid of vacuum and concentrated to get pale yellow solid. Yield = 93.33%; MP: 75 C; IR (KBr): 2979.2, 2919.7, 2858.5, 1679.6, 1402.4, 1240.4, 1172.31131.9 cm-1; 1H NMR (300 MHz, CDCl3, ppm): delta 4.13-4.09 (d, J = 12 Hz, 2H, 2 * CONCH); 3.14-3.10 (m, 3H, 2 * CONCH, NCH); 3.01-2.96 (d, J = 15 Hz, 1H, NCH); 2.25 (s, 2H, 2 * NH); 1.92-1.88 (d, J = 12 Hz, 1H, CH); 1.80-1.76 (d, J = 12 Hz, 1H, CH); 1.67 (s, 2H, bridge CH2); 1.48 (s, 9H, CMe3); 13C NMR (50 MHz, CDCl3, ppm): delta155.49, 79.78, 51.50, 48.94, 31.39, 28.52, 28.15; MS (ESI): 227.1481(M+H)+.
92% With palladium 10% on activated carbon; hydrogen; In ethanol; for 4h; To a solution of 3 (350 mg, 1.11 mmol) in 30mL of dry ethanol was added 28 % of the Pd, 10 wt. % on activated carbon, and H2 was bubbled through the reaction mixture for 4 hrs. The reaction was monitored by TLC. The solution was filtered through a sintered funnel and evaporated to yield 230 mg of the product 4. Yield: 92 %. (HRMS): calcd for C12H23N2O2 m/z 227.1760, found m/z 227.1750
85% A mixture of 4 (20g, 0.063mol), ammonium formate (16g, 0.254mol) and 5% Pd/C (contains 50% H2O, 4g) in MeOH (350ml) was refluxed with stirring for 1h, cooled and filtered through celite. The solution was evaporated to the volume of 100ml and 10N NaOH (100ml) was added. The mixture was refluxed with stirring for 1h, extracted with CHCl3, washed with brine, dried over Na2SO4 and evaporated. The residue was purified by SiO2 column chromatography with CHCl3/MeOH (9/1) to afford 5 (12.2g, 85%) as a colorless oil. IR (thin film,nu, cm -1): 1691 (OC=O). EI-MS, m/z (RI, %): 227 [M+H]+ (68), 169 [M-t-Bu]+ (72), 126 [M-Boc+H]+ (48). 1H NMR (600MHz, CDCl3) delta 4.14-4.05 (m 2H, CH2NBoc), 3.19-3.02 (m, 4H, CH2NBoc, CH2NH), 2.97 (d, J=13.1Hz, 2H, CH2NH), 1.89 and 1.77 (d, AB system, J=12.6Hz, 2H, CH2), 1.72-1.55 (m, 3H, 2CH+NH), 1.47 (s, 9H, CMe3). 13C NMR (151MHz, CDCl3) delta 155.43 (C=O, Boc), 79.61 (CMe3), 51.82 (CH2NH), 49.46 and 48.42 (CH2NBoc), 31.57 (CH2), 28.51 (CMe3), 28.28 (CH).
(v) tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate The sub-title compound was prepared in quantitative yield according to the procedure described in step (iii) above, using <strong>[227940-71-8]tert-butyl 7-benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate</strong> (from step (iv) above) in place of 3,7-dibenzyl-3,7-diazabicyclo[3.3.1]nonane. 13C NMR in CDCl3: delta 28.05, 28.29, 31.33, 48.35, 49.11, 51.53, 79.34, 155.16
With palladium 10% on activated carbon; hydrogen; In ethanol; water; at 20℃; under 760.051 Torr; for 16h; Tert-butyl 7-benzyl-3,7-diazabicyclo[3.3.1 ]nonane-3-carboxylate (7 g; 21 .3 mmol), dissolved in 20 ml EtOH was carefully added to a suspension of Palladium 10% on charcoal 50% water in EtOH (180 ml): The reaction mixture was evacuated and put under hydrogen (1 atm) three times then stirring was continued under a hydrogen pressure (1 atm) at RT for 16 h. The reaction mixture was filtered over celite and the solvent was evaporated under reduced pressure to give tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate. LC-MS: tR = 0.42 min; [M+H]+ = 227.15. Method (B)

  • 3
  • [ 98-59-9 ]
  • [ 227940-72-9 ]
  • [ 454695-26-2 ]
YieldReaction ConditionsOperation in experiment
210 mg With pyridine; dmap at 20℃; for 12h;
  • 4
  • [ 227940-72-9 ]
  • 3-(toluene-4-sulfonyl)-3,7-diaza-bicyclo[3.3.1]nonane [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 210 mg / pyridine; DMAP / 12 h / 20 °C 2: TFA / CH2Cl2 / 0.5 h / 20 °C
Multi-step reaction with 3 steps 1: DMAP; pyridine / 12 h / 20 °C 2: DMAP; pyridine / 12 h / 20 °C 3: TFA / CH2Cl2 / 0.5 h / 20 °C
  • 5
  • [ 227940-72-9 ]
  • 3-(toluene-p-sulfonyl)-3,7-diazabicyclo[3.3.1]nonane-7-[(R)-binaphthyl-2,2'-diyl]phosphite [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 210 mg / pyridine; DMAP / 12 h / 20 °C 2: TFA / CH2Cl2 / 0.5 h / 20 °C 3: 50 mg / Et3N / toluene / 5 h / 80 °C
Multi-step reaction with 4 steps 1: DMAP; pyridine / 12 h / 20 °C 2: DMAP; pyridine / 12 h / 20 °C 3: TFA / CH2Cl2 / 0.5 h / 20 °C 4: 51 percent / Et3N / toluene / 12 h
  • 6
  • [ 227940-72-9 ]
  • 3-(toluene-p-sulfonyl)-3,7-diazabicyclo[3.3.1]nonane-7-[(R)-(3,3'-dimethyl)binaphthyl-2,2'-diyl]phosphite [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: 210 mg / pyridine; DMAP / 12 h / 20 °C 2.1: TFA / CH2Cl2 / 0.5 h / 20 °C 3.1: PCl3; Et3N / tetrahydrofuran / 45 h / 0 °C 3.2: 11.8 mg / Et3N / tetrahydrofuran / 1.5 h / 20 °C
  • 8
  • tert-butyl 7-benzyl-9-(2-tosylhydrazono)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [ No CAS ]
  • [ 227940-72-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 302 mg / NaBH3CN / dimethylformamide / 2 h / 100 °C 2: H2 / 10percent Pd/C / ethanol / 12 h / 20 °C
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; water / tetrahydrofuran / 0 - 20 °C / Reflux 2: hydrogen; palladium 10% on activated carbon / water; ethanol / 16 h / 20 °C / 760.05 Torr
  • 9
  • [ 227940-72-9 ]
  • N-(2,2-dimethylpropanoyl)-3,7-diazabicyclo[3.3.1]nonane [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: DMAP; pyridine / 12 h / 20 °C 2: TFA / CH2Cl2 / 0.5 h / 20 °C
  • 10
  • [ 227940-72-9 ]
  • C12H21Cl2N2OP [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: DMAP; pyridine / 12 h / 20 °C 2: TFA / CH2Cl2 / 0.5 h / 20 °C 3: PCl3; Et3N / tetrahydrofuran / 1 h / 0 °C
  • 11
  • [ 227940-72-9 ]
  • C14H19Cl2N2O2PS [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: DMAP; pyridine / 12 h / 20 °C 2: DMAP; pyridine / 12 h / 20 °C 3: TFA / CH2Cl2 / 0.5 h / 20 °C 4: PCl3; Et3N / tetrahydrofuran / 1 h / 0 °C
  • 12
  • [ 227940-72-9 ]
  • [ 454695-26-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: DMAP; pyridine / 12 h / 20 °C 2: DMAP; pyridine / 12 h / 20 °C
  • 13
  • [ 227940-72-9 ]
  • C34H37N2O3P [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: DMAP; pyridine / 12 h / 20 °C 2: TFA / CH2Cl2 / 0.5 h / 20 °C 3: PCl3; Et3N / tetrahydrofuran / 1 h / 0 °C 4: Et3N / tetrahydrofuran / 12 h / 20 °C
  • 14
  • [ 227940-72-9 ]
  • C36H35N2O4PS [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: DMAP; pyridine / 12 h / 20 °C 2: DMAP; pyridine / 12 h / 20 °C 3: TFA / CH2Cl2 / 0.5 h / 20 °C 4: PCl3; Et3N / tetrahydrofuran / 1 h / 0 °C 5: Et3N / tetrahydrofuran / 12 h / 20 °C
  • 15
  • [ 313238-71-0 ]
  • [ 227940-72-9 ]
  • [ 313238-75-4 ]
YieldReaction ConditionsOperation in experiment
76% In isopropyl alcohol at 20 - 60℃; 13.vi (vi) tert-Butyl 7-[2-[(benzyloxy)carbonyl]amino}-3-(4-cyanophenoxy)-propyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (vi) tert-Butyl 7-[2-[(benzyloxy)carbonyl]amino}-3-(4-cyanophenoxy)-propyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate benzyl 2-[(4-cyanophenoxy)methyl]-1-aziridinecarboxylate (1.0 g; 3.2 mmol; from step (iii) above) was mixed with tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (v) above; 0.73g; 3.2 mmol) and 30 ML of iso-propanol, and stirred at 60°C for 5 h, and then at rt overnight.. The solvent was evaporated and the crude material was purified on silica (DCM:5% MeOH) yielding 1.3 g (76%) of sub-title compound.
  • 16
  • [ 313476-97-0 ]
  • [ 227940-72-9 ]
  • [ 312955-28-5 ]
YieldReaction ConditionsOperation in experiment
88% With potassium carbonate In chloroform; acetonitrile at 70℃; for 23h; 29.d (d) tert-Butyl 7-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [0452] A mixture of 4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl methane-sulfonate (522 mg, 1.29 mmol, from step (c) above), tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (307 mg, 1.356 mmol, see Example F above) and K2CO3 (216 mg, 1.56 mmol) in chloroform:acetonitrile (10 mL of 1:1) was stirred at 70° C. for 23 h. The reaction mixture was filtered and the filtrate concentrated in vacuo to give 708 mg of crude product. This was purified by flash chromatography, eluting with a gradient of toluene:methanol (97:3 to 10:1), to yield 607 mg (88%) of the sub-title compound.
  • 17
  • [ 40465-45-0 ]
  • [ 227940-72-9 ]
  • [ 313477-03-1 ]
YieldReaction ConditionsOperation in experiment
71% In chloroform at 20℃; for 1.5h; 31.b (b) tert-Butyl 7-[(4-cyanoanilino)carbonyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [0470] A suspension of tert-butyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (2.0 g, 8.8 mmol, see Example F above) in chloroform (15 mL) was treated with 4-isocyanatobenzonitrile (1.53 g, 10.6 mmol). The mixture was stirred at rt for 1.5 h, at which time some solid particles were observed in the mixture. An additional 10 mL of chloroform was added in order to dissolve the particles. Mass spectroscopic analysis of the mixture indicated that the starting materials had been consumed, and so the solvent was removed in vacuo. The resulting residue was purified by flash chromatography, eluting with a gradient of DCM:MeCN (5:1 to 2:1) to yield 2.31 g (71%) of the sub-title compound.
  • 18
  • [ 70987-80-3 ]
  • [ 227940-72-9 ]
  • [ 227941-21-1 ]
YieldReaction ConditionsOperation in experiment
56% In water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran C C. C. 3.7-Diazabicyclo[3.3.1]nonane-3-carboxylic Acid, 7-[(2S)-3-(4-cyano-phenoxy)-2-hydroxypropyl]-1,1-dimethylethyl Ester [Compound A] 4-[(2S)-Oxiranylmethoxy]benzonitrile (5.19 g; 29.6 mmol; see A above) was added to a stirred solution of tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (6.7 g; 29.6 mmol; see B above) in IPA (30 mL) and H2O (3 mL) The reaction mixture was stirred at 60° C. for 12 h and then at rt for 48 h. The reaction mixture was concentrated, the residue dissolved in DCM, dried (MgSO4) and concentrated. The residue was purified using column chromatography (hexane:EtOAc:MeOH; 50:45:5) to give the title product as a white foam in a 56% yield (6.65 g). [α]20D=16 (c=1.0; MeOH). ESI-MS (M+1)+ 402 (m/z); 13C NMR (CDCl3): δ 28.44, 28.77, 29.33, 31.93,47.53, 49.34, 56.87, 60.14, 61.60, 65.03, 70.70, 79.37, 103.85, 115.32, 119.13, 133.79, 155.91, 162.16.
  • 19
  • [ 70987-79-0 ]
  • [ 87-69-4 ]
  • [ 227940-72-9 ]
  • tert-Butyl 7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-[3.3.1]nonane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% In methanol; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran 4 tert-Butyl 7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-[3.3.1]nonane-3-carboxylate Example 4 tert-Butyl 7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-[3.3.1]nonane-3-carboxylate The title compound was prepared analogously to the method described in Example 3 above from 4-[(2R)-oxiranylmethoxy]benzonitrile (0.98 g; 5.59 mmol; see Example D above) and tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.26 g; 5.59 mmol; see Example F above). After the reaction was complete, the residue was dissolved in DCM and washed with brine, separated, dried (Na2SO4) and concentrated. The residue was dissolved in MeOH (10 mL) and 1 eq. tartaric acid was added. Freeze-drying gave the product as the corresponding tartaric acid salt in 88% yield (2.7 g). 13C NMR (CDCl3): δ 28.44, 28.77, 29.33, 31.93, 47.53, 49.34, 56.87, 60.14, 61.60, 65.03, 70.70, 79.37, 103.85, 115.32, 119.13, 133.79, 155.91, 162.16.
  • 20
  • 3-Nitro-4-(2-oxiranylmethoxy)benzonitrile [ No CAS ]
  • [ 227940-72-9 ]
  • tert-butyl 7-[3-(4-cyano-2-nitrophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
54% In water 16.b (b) (b) tert-Butyl 7-[3-(4-cyano-2-nitrophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate 3-Nitro-4-(2-oxiranylmethoxy)benzonitrile (2.9 g; 13.2 mmol; from step (a) above) was added to a stirred solution of tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (3 g; 13.2 mmol; see Example F above) in IPA:H2O (12.5 mL; 9:1), and the reaction mixture was refluxed for 3 h. Concentration of the reaction mixture and purification by column chromatography (DCM:MeOH; 15:1) gave the title compound in a 54% yield. 13C NMR (CDCl3): δ 28.4, 31.8, 47.4, 49.8, 56.7, 59.8, 60.5, 65.0, 71.9, 79.2, 103.7, 116.1, 116.7, 129.3, 137.3, 139.3, 155.4, 155.8.
  • 21
  • [ 227940-93-4 ]
  • [ 227940-72-9 ]
  • tert-butyl 7-[4-(4-cyanophenyl)-4-[-1-(tert-butyl)-1,1-dimethylsilyl]-oxy}butyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% 30.d (d) (d) tert-Butyl 7-[4-(4-cyanophenyl)-4-[-1-(tert-butyl)-1,1-dimethylsilyl]-oxy}butyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate The sub-title compound was prepared in 96% yield according to the method described in Example 25(b) above from 4-[-1-(tert-butyl)-1,1-dimethylsilyl]oxy}-4-(4-cyanophenyl)butyl methanesulfonate (from step (c) above) and tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (see Example F above).
  • 22
  • 4-(3-chloropropoxy)-3-hydroxybenzonitrile [ No CAS ]
  • [ 227940-72-9 ]
  • tert-Butyl 7-[3-(4-cyano-2-hydroxyphenoxy)propyl]-3,7-diazabicyclo-[3.3.1]nonane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% In methanol; acetonitrile 62.b (b) (b) tert-Butyl 7-[3-(4-cyano-2-hydroxyphenoxy)propyl]-3,7-diazabicyclo-[3.3.1]nonane-3-carboxylate A solution of 4-(3-chloropropoxy)-3-hydroxybenzonitrile (0.50 g; 2.36 mmol; from step (a) above) and tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (0.80 g; 3.54 mmol; see Example F above) in acetonitrile (20 mL) was stirred for 20 h at 47° C. The reaction was concentrated in vacuo and the residue chromatographed on a column of silica (4 cm *24 cm) eluding with a mixture of CH2Cl2 and CH3OH (98:2). After eluding 1 litre of the above eluant, the ratio of CH2Cl2 to CH3OH was changed to 95:5. Fractions containing the desired product were combined and concentrated in vacuo to afford 0.49 g of a semi-solid. This material was slurried with hexane to afford the title compound as an off white solid (0.40 g; 42%). mp 127-130° C.; CI-MS (M+1)+402 (m/z); 1H NMR (CDCl3): δ 1.42 (s, 9H), 1.65 (br s, 2H), 1.92 (m, 4H), 2.25 (m, 4H), 3.01 (m, 4H), 4.12 (m, 4H), 6.91 (d, 1H), 7.18 (m, 2H); 13C NMR (CDCl3): δ 26.2, 28.5, 31.2, 47.9, 49.2, 55.1, 58.2, 59.1, 67.5, 79.6, 104.2, 102.5, 118.2, 119.5, 125.3, 146.8, 150.5, 155.8.
  • 23
  • 4-[(E)-4-chloro-2-butenyl]oxy}benzonitrile [ No CAS ]
  • [ 227940-72-9 ]
  • [ 227940-62-7 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide In acetonitrile 66.b (b) (b) tert-Butyl 7-[4-(4-cyanophenoxy)-2-butenyl]-3,7-diazabicyclo[3.3.1]-nonane-3-carboxylate tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.13 g; 5 mmol; see Example F above) was added to a stirred solution of 4-(4-cyanophenoxy)-1-chloro-2-butene (1.04 g; 5 mmol; from step (a) above) in MeCN (25 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and partitioned between diethyl ether and KHS04 (0.3 M). The aqueous layer was treated with NaOH (2M) and subsequently extracted with CH2Cl2. The organic layer was washed with water, dried, concentrated and purified using column chromatography (CH2Cl2:MeOH; 95:5) to give the title compound (0.84 g; 2.1 mmol). 13C NMR (CDCl3): δ 28.75, 32.18, 47.90, 49.04, 58.19, 59.05, 60.76, 68.77, 78.49, 103.93, 115.65, 119.37, 125.66, 133.95, 155.39, 161.96.
  • 24
  • methanesulfonic acid 4-(4-cyanophenoxy)-butyl ester [ No CAS ]
  • [ 227940-72-9 ]
  • tert-Butyl 7-[4-(4-cyanophenyl)butyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% 68.e (e) (e) tert-Butyl 7-[4-(4-cyanophenyl)butyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate The title compound was prepared in 73% yield from methanesulfonic acid 4-(4-cyanophenoxy)-butyl ester and tert-butyl 3,7-diazabicyclo[3.3.1]-nonane-3-carboxylate (from step (d) above) according to the method described in Example 25(b) above. 13C NMR (CDCl3): δ 26.23, 28.72, 29.09, 31.56, 36.01, 47.67, 48.72, 58.31, 58.81, 59.19, 78.39, 109.38, 119.19, 129.17, 129.42, 131.91, 132.16, 148.41, 155.05.
  • 25
  • 4-(3-chloro-2-hydroxy-2-hydroxymethylpropoxy)benzonitrile [ No CAS ]
  • NaHCO3 (satd.) [ No CAS ]
  • [ 227940-72-9 ]
  • [ 227940-69-4 ]
YieldReaction ConditionsOperation in experiment
31% With potassium carbonate In diethyl ether; acetonitrile 74.c (c) (c) 7-[3-(4-Cyanophenoxy)-2-hydroxy-2-hydroxymethylpropyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester A mixture of 4-(3-chloro-2-hydroxy-2-hydroxymethylpropoxy)benzonitrile (180 mg; 0.74 mmol; from step (b) above), tert-butyl 3,7-diazabicyclo-[3.3.1]nonane-3-carboxylate (230 mg; 1.0 mmol; see Example F above) and K2CO3 (140 mg; 1.0 mmol) in MeCN (5 mL) was refluxed for 48 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was dissolved in diethyl ether and the solution was acidified with KHSO4 (aq.). The aqueous layer was collected and NaHCO3 (satd.) was added followed by ether extraction. The organic layer was collected, dried, concentrated and subjected to column chromatography (DCM:MeOH; 20:1) to give the title compound in a 31% yield. 13C NMR in D2O (MeOH as internal standard): δ 28.49, 29.05, 30.46, 47.81, 48.55, 60.25, 60.94, 61.19, 65.15, 69.41, 70.08, 72.93, 79.78, 104.13, 115.31, 119.03, 133.91, 154.98, 161.72; FAB-MS (M+1)+431.7 (m/z).
  • 26
  • [ 3101-60-8 ]
  • [ 227940-72-9 ]
  • tert-Butyl 7-[3-(4-tert-butylphenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-[3.3.1nonane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
7% In water; isopropyl alcohol; (b) tert-Butyl 7-[3-(4-tert-butylphenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate A mixture of tert-butyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (2.2 g; 9.70 mmol; see Example F above) and <strong>[3101-60-8]4-tert-butyl-1-(2-oxiranylmethoxy)benzene</strong> (2.0 g; 9.70 mmol; from step (a) above) in 2-propanol (10 mL) and water (1 mL) was stirred at 60° C. for 18 h. The reaction mixture was concentrated to give an oil which was dissolved in hexanes and allowed to stand until solids formed. The solids were collected and dried to give the desired product (0.28 g; 7percent) as a white solid. mp 75-77° C.; 1H NMR (CDCl3): delta 1.32 (s, 9H), 1.47 (s, 9H), 1.62-1.78 (m, 2H), 1.79-1.96 (m, 2H), 2.13-2.38 (m, 2H), 2.42-2.57 (m, 2H), 2.87-3.25 (m, 4H), 3.82-4.30 (m, 5H), 6.86 (d, 2H), 7.31 (d, 2H); 13C NMR (CDCl3): delta 28.9, 29.1, 29.4, 29.7, 31.3, 31.7, 32.1, 34.3, 47.9, 48.1, 48.9, 49.6, 57.4, 58.1, 60.6, 61.9, 62.5, 65.5, 65.9, 70.7, 77.4, 79.7, 114.3, 126.4, 143.6, 155.8, 156.2, 156.8; CI-MS (M+1)+433 (m/z).
  • 27
  • [ 37142-39-5 ]
  • [ 227940-72-9 ]
  • 7-[2-(4-Cyanophenoxy)ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With triethanolamine In acetonitrile 69 7-[2-(4-Cyanophenoxy)ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester Example 69 7-[2-(4-Cyanophenoxy)ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester tert-Butyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (3.62 g; 16 mmol; see Example F above) was added to added to a stirred solution of 4-(2-bromoethoxy)benzonitrile (3.62g; 16 mmol; see Example 67(a) above) and TEA (3.34 mL; 24 mmol) in MeCN (70 mL) and the reaction mixture was stirred at 60° C. overnight and then stored at room temperature for 48 h. The solids were filtered off, washed with IPA (2*100 mL) and the filtrate concentrated. The residue was partitioned between DCM and NaHCO3 (sat.), the organic layer was separated, dried (MgSO4) and concentrated. The oily residue was subjected to column chromatography (DCM:MeOH; 25:1) to give the title compound in a 72% yield. 13C NMR (CDCl3): δ 29.73, 30.25, 30.44, 32.73, 48.83, 50.00, 58.24, 59.71, 60.48, 68.04, 79.67, 104.48, 116.37, 120.65, 135.04, 156.35, 163.23.
  • 28
  • 4-(3-methyl-2,3-oxiranylbutoxy)benzonitrile [ No CAS ]
  • [ 227940-72-9 ]
  • [ 227940-57-0 ]
YieldReaction ConditionsOperation in experiment
0.540 g (27%) In dichloromethane; water; isopropyl alcohol 61.d (d) (d) tert-Butyl-7-[[3-(4-cyanophenoxy)-1,1-dimethyl-2-hydroxy]propyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate A mixture of 4-(3-methyl-2,3-oxiranylbutoxy)benzonitrile (0.956 g; 4.70 mol; from step (c) above) and tert-butyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.06 g; 4.70 mmol; see Example F) was refluxed in iso-propanol:H2O (10:1; 10 mL) for 5 days. The reaction mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 (150 mL), washed with water (50 mL), brine (50 mL), dried over Na2SO4 and concentrated in vacuo to afford a light yellow oil. Purification via column chromatography on silica gel eluding with CH2Cl2:CH3OH (80:1) gave 0.540 g (27%) of the title compound. Rf 0.43 (CH2Cl2:CH30OH (25:1)); 1H NMR (CDCl3) δ 7.61 (d, 2H), 6.98 (d, 2H), 3.88-4.62 (m,5H), 3.65 (brs, 1H), 2.89-3.33 (m, 6H), 2.78 (m, 2H), 1.66 (brs, 1H), 1.48 (s, 9H), 1.26 (s, 3H), 1.17 (s, 3H); CI-MS (M+1)+430 (m/z).
  • 29
  • [ 88-14-2 ]
  • [ 227940-72-9 ]
  • [ 1025008-22-3 ]
YieldReaction ConditionsOperation in experiment
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In dichloromethane at 20℃; 9 Example 9: Synthesis of N-(furan-2-ylcarbonyl)-3,7- diazabicyclo[3.3.1jnonane trifluoroacetateExample 9 relates to the synthesis of (3,7-diazabicyclo[3.3.1]non-3-yl)- furan-2-ylmethanone trifluoroacetate (or N-(furan-2-ylcarbonyl)-3,7- diazabicyclo[3.3.1]nonane trifluoroacetate), which was prepared according to the following techniques, illustrative of the coupling reaction used to make heteroaromatic amides of 3 ,7-diazabicyclo[3.3.1 ]nonane:3,7-Diazabicyclo[3.3.1]non-3-yl)-furan-2-yl methanone trifluoroacetate (or N-(f uran-2-ylcarbonyl)-3,7-diazabicycIo [3.3.1] nonane trifluoroacetate); Furan-2-carboxylic acid (0.032 g, 0.29 mmol) was combined with triethylamine (0.870 mmol, 0.121 mL) in dry dichloromethane (1 mL) and HBTU(0.11 g, 0.29 mmol) was added. A solution of 3,7-diazabicyclo[3.3.1]-3-carboxylic acid tert-butyl ester (0.059 g, 0.26 mmol) in dichloromethane (0.5 mL) was added, and the mixture was stirred at ambient temperature overnight. The mixture was treated with 10% aqueous sodium hydroxide and extracted with chloroform (2 x 2 mL). The combined organic extracts were washed with water (2 x 1 mL), and concentrated. The resulting residue was dissolved in DMF (0.3 mL) and purified by HPLC (acetonitrile/water gradient). Fractions containing the desired material were pooled and concentrated, leaving the tert-butoxycarbonyl-protected product.This material was dissolved in a mixture of trifluoroacetic acid (0.5 mL) and dichloromethane (0.5 mL), and the mixture was stirred at ambient temperature forIh. The volatiles were removed by rotary evaporation, followed by high vacuum treatment, to give 36 mg of an oil (41% yield) (1H NMR (d4-methanol, 300 MHz)2.10 (bs, 2H), 2.35 (bs, 2H), 3.30-3.45 (m, 4H), 3.55 (m, 2H), 6.65 (m, IH), 7.15(d, IH), and 7.75 (d, IH). MS m/z 221 (M+H)).
  • 30
  • [ 21508-19-0 ]
  • [ 227940-72-9 ]
  • [ 1025008-23-4 ]
YieldReaction ConditionsOperation in experiment
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; Example 10: Synthesis of N-(5-chlorofuran-2-ylcarbonyl)-3,7- diazabicyclo [3.3.1] nonane trifluoroacetateExample 10 relates to the synthesis of (3,7-diazabicyclo[3.3.1]non-3-yl)-5- chlorofuran-2-ylmethanone trifluoroacetate (or N-(5-chlorofuran-2-ylcarbonyl)-3,7- diazabicyclo[3.3.1]nonane trifluoroacetate), which was prepared by a process similar to that described in Example 9, according to the following techniques:; 5-Chlorofuran-2-carboxylic acid (0.96 g, 6.5 mmol) was combined with triethylamine (21 mmol, 2.9 mL) in dry dichloromethane (10 niL), and HBTU (2.47 g, 65.1 mmol) was added. A solution of 3,7-diazabicyclo[3.3.1]-3-carboxylic acid tert-butyl ester (1.5 g, 66 mmol) in dichloromethane (5 mL) was added, and the mixture was stirred at ambient temperature overnight. The mixture was treated with 10% aqueous sodium hydroxide and extracted with chloroform (2 x 20 mL). The combined organic extracts were washed with water (2 x 10 mL), and concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with an ethyl acetate in hexane gradient, to give the tert- butoxycarbonyl-protected product, as a viscous oil. This material was dissolved in a mixture of trifluoroacetic acid (20 mL) and dichloromethane (20 mL), and the mixture was stirred at ambient temperature for Ih. The volatiles were removed by rotary evaporation, followed by high vacuum treatment, to give 1.38 g (57.5% yield) of viscous yellow oil (1H NMR (dVmethanol, 300 MHz) 2.00 (bs, 2H), 2.15 (bs, 2H), 3.15-3.35 (m, 6H), 4.25 (m, 2H), 6.53 (d, IH) and 7.10 (d, IH). MS m/z 255 (M+H)).
  • 31
  • [ 15761-39-4 ]
  • [ 227940-72-9 ]
  • [ 1018901-83-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 1-(tert-butoxycarbonyl)-L-proline With TEA; chloroformic acid ethyl ester In tetrahydrofuran Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In tetrahydrofuran Further stages.;
  • 32
  • [ 13734-41-3 ]
  • [ 227940-72-9 ]
  • [ 1018901-85-3 ]
YieldReaction ConditionsOperation in experiment
Stage #1: t-Boc-L-valine With TEA; chloroformic acid ethyl ester In tetrahydrofuran Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In tetrahydrofuran Further stages.;
  • 33
  • [ 13139-15-6 ]
  • [ 227940-72-9 ]
  • [ 1018901-81-9 ]
YieldReaction ConditionsOperation in experiment
Stage #1: <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-leucine With TEA; chloroformic acid ethyl ester In tetrahydrofuran Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In tetrahydrofuran Further stages.;
  • 34
  • [ 13734-34-4 ]
  • [ 227940-72-9 ]
  • [ 1018901-77-3 ]
YieldReaction ConditionsOperation in experiment
64% Stage #1: <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-phenylalanine With TEA; chloroformic acid ethyl ester In tetrahydrofuran at 0℃; for 0.5h; Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In tetrahydrofuran at 0 - 20℃; for 17h; Further stages.;
  • 35
  • [ 33305-77-0 ]
  • [ 227940-72-9 ]
  • [ 1018901-87-5 ]
YieldReaction ConditionsOperation in experiment
Stage #1: Boc-Phe(p-NO2)-OH With TEA; chloroformic acid ethyl ester In tetrahydrofuran Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In tetrahydrofuran Further stages.;
  • 36
  • [ 2900-27-8 ]
  • [ 227940-72-9 ]
  • [ 1018901-79-5 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With TEA; chloroformic acid ethyl ester In tetrahydrofuran Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In tetrahydrofuran Further stages.;
  • 37
  • [ 227940-72-9 ]
  • [ 118517-06-9 ]
  • [ 1018901-77-3 ]
YieldReaction ConditionsOperation in experiment
394 mg In tetrahydrofuran at 0 - 20℃;
  • 38
  • [ 1177013-51-2 ]
  • [ 227940-72-9 ]
  • [ 1177014-25-3 ]
YieldReaction ConditionsOperation in experiment
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; diisopropylamine In dichloromethane at 20℃; for 16h; 20.a A mixture of the product of example Ii (150 mg) and 3,7-diaza-bicyclo[3.3.1]nonane- 3-carboxylic acid tert-butyl ester (177 mg) [Prepared according to O. Huttenloch, E. Laxman, H. Waldmann, Chem. Eur. J, 8(20), 4767 (2002)] in dichloromethane (2 ml) was treated with TBTU (188 mg) and diisopropylamine (350 μl). The reaction mixture was stirred at room temperature for 16 h. The reaction was worked up by addition of an aqueous NH4Cl solution (5%) and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in toluene/acetone as eluent.Yield: 153 mg. 1H NMR (CDCl3) δ 1.18 (d, 6H, isopropoxy), 1.4 (bs, 9H, tert.-Bu), 6.45 (s, IH, H-2, pyrrole), 6.69 (s, IH, H7-Ar), 6.93 (s, IH, H-9 Ar), 7.04, 7.27 (m, 3H, thienyl). TLC Rf = 0.62 (toluene/acetone 3/2). LC/MS-ESI: [M+H]+ = 592
  • 39
  • [ 124-38-9 ]
  • [ 1256777-52-2 ]
  • [ 227940-72-9 ]
  • [ 1256777-77-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 9-isopropoxy-8-methoxy-1-thiophen-2-yl-5,6-dihydro-imidazo[5,1-a]isoquinoline With n-butyllithium In tetrahydrofuran; n-heptane at -40℃; for 0.166667h; Stage #2: carbon dioxide In tetrahydrofuran; n-heptane at -40℃; for 0.25h; Stage #3: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate With N-ethylmorpholine;; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 2h; 29.a To a suspension of the product of example 21e (150 mg) in dry THF (5 ml) was added at -40 0C a n-BuLi solution (290 μl, 1.6 M in heptane). After stirring for 10 min at -40 0C, the reaction mixture was poured on CO2 pellets. The mixture was stirred for 15 min and concentrated in vacuo at 35 0C. To a solution of the residue in DMF (2 ml) and N- ethylmorpholine (152 μl), were added 3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (200 mg) [Prepared according to O. Huttenloch, E. Laxman, H. Waldmann, Chem. Eur. J, 8Λ(20), 4767 (2002)] and TBTU (213 mg). After stirring at room temperature for 2 h, the reaction mixture was poured in a n aqueous NH4Cl solution (5 %) and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in toluene/ethyl acetate [0 → 100 % (v/v)] as eluent. Yield: 158 mg. LC/MS-ESI: [M+H]+ = 593.1 ; TLC Rf = 0.27 (toluene/ethyl acetate 1 : 1)
  • 40
  • C20H20N2O4S [ No CAS ]
  • [ 227940-72-9 ]
  • [ 1256777-77-1 ]
YieldReaction ConditionsOperation in experiment
With N-ethylmorpholine;; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 2h; 29.a (a). 7-(9-Isopropoxy-8-methoxy-1-thiophen-2-yl-5,6-dihydro-imidazo[5,1-a]iso-quinoline-3-carbonyl)-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester To a suspension of the product of example 21e (150 mg) in dry THF (5 ml) was added at -40° C. a n-BuLi solution (290 μl, 1.6 M in heptane). After stirring for 10 min at -40° C., the reaction mixture was poured on CO2 pellets. The mixture was stirred for 15 min and concentrated in vacuo at 35° C. To a solution of the residue in DMF (2 ml) and N-ethylmorpholine (152 μl), were added 3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (200 mg) [Prepared according to O. Huttenloch, E. Laxman, H. Waldmann, Chem. Eur. J., 8, (20), 4767 (2002)] and TBTU (213 mg). After stirring at room temperature for 2 h, the reaction mixture was poured in an aqueous NH4Cl solution (5%) and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in toluene/ethyl acetate [0→100% (v/v)] as eluent. Yield: 158 mg. LC/MS-ESI: [M+H]+=593.1; TLC Rf=0.27 (toluene/ethyl acetate 1:1)
  • 42
  • [ 227940-72-9 ]
  • C26H31ClN4O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane 2: trifluoroacetic acid / dichloromethane 3: triethylamine / dichloromethane
  • 43
  • [ 227940-72-9 ]
  • C25H30ClN5O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane 2: trifluoroacetic acid / dichloromethane 3: dichloromethane
  • 44
  • [ 227940-72-9 ]
  • C25H31ClN4O6S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane 2: trifluoroacetic acid / dichloromethane 3: triethylamine / dichloromethane
  • 45
  • [ 227940-72-9 ]
  • C30H38ClN5O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane 2: trifluoroacetic acid / dichloromethane 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane 4: trifluoroacetic acid / dichloromethane
  • 46
  • [ 227940-72-9 ]
  • C28H32ClN7O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane 2: trifluoroacetic acid / dichloromethane 3: triethylamine / dichloromethane
  • 47
  • [ 227940-72-9 ]
  • C28H33ClN4O7S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane 2: trifluoroacetic acid / dichloromethane 3: triethylamine / dichloromethane
  • 48
  • [ 227940-72-9 ]
  • [ 280-74-0 ]
YieldReaction ConditionsOperation in experiment
98% With trifluoroacetic acid In dichloromethane at 20℃; for 2h; (b) Removal of Boc from 4 To an ice-cooled solution of 4 (230 mg, 1.02 mmol) in dry dichloromethane (1 mL) was added TFA (1 mL, 2.70 mmol) and stirred at room temperature for 2 hrs. The reaction mixture was subjected to vacuum to remove CH2Cl2 and TFA to afford 126 mg of the product 5. Yield: 98 %. IR (KBr): 3443 (br), 2927, 2854, 1676 (br), 1461, 1425, 1201, 1128 cm-1. (HRMS): calcd for C7H15N2 m/z 127.1235, found m/z 127.1235
With trifluoroacetic acid In dichloromethane
  • 49
  • [ 618-30-4 ]
  • [ 227940-72-9 ]
  • [ 1025008-23-4 ]
  • 50
  • [ 618-30-4 ]
  • [ 227940-72-9 ]
  • [ 1025007-67-3 ]
  • 51
  • [ 3439-02-9 ]
  • [ 227940-72-9 ]
  • C17H23BrN2O4 [ No CAS ]
  • 52
  • [ 3439-02-9 ]
  • [ 227940-72-9 ]
  • [ 1392331-02-0 ]
  • 53
  • [ 14903-90-3 ]
  • [ 227940-72-9 ]
  • C17H23BrN2O4 [ No CAS ]
  • 54
  • [ 14903-90-3 ]
  • [ 227940-72-9 ]
  • [ 1392331-03-1 ]
  • 55
  • [ 212197-74-5 ]
  • [ 227940-72-9 ]
  • C18H23N3O4 [ No CAS ]
  • 56
  • [ 212197-74-5 ]
  • [ 227940-72-9 ]
  • [ 1392331-04-2 ]
  • 57
  • [ 1369496-50-3 ]
  • [ 227940-72-9 ]
  • C18H23N3O4 [ No CAS ]
  • 58
  • [ 1369496-50-3 ]
  • [ 227940-72-9 ]
  • [ 1392331-05-3 ]
  • 59
  • [ 1917-15-3 ]
  • [ 227940-72-9 ]
  • C18H26N2O4 [ No CAS ]
  • 60
  • [ 1917-15-3 ]
  • [ 227940-72-9 ]
  • [ 1392331-07-5 ]
  • 61
  • [ 4412-96-8 ]
  • [ 227940-72-9 ]
  • C18H26N2O4 [ No CAS ]
  • 62
  • [ 4412-96-8 ]
  • [ 227940-72-9 ]
  • [ 1392331-08-6 ]
  • 63
  • [ 956317-36-5 ]
  • [ 227940-72-9 ]
  • [ 1429776-76-0 ]
YieldReaction ConditionsOperation in experiment
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 1h; 1.1 5-Methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (320 mg; 1.73 mmol) is dissolved in MeCN (10 mL) followed by the addition of TBTU (555 mg; 1.73 mmol) and DIPEA (508 mg; 3.93 mmol). Stirring is continued for 15 minutes followed by the addition of tert-butyl 3,7-diazabicyclo[3.3.1 ]nonane-3-carboxylate (356 mg; 1.57 mmol). Stirring is continued at rt. for an additional 1 h. Brine (50) is added to the reaction mixture and the product is extracted with DCM (2 * 50 ml). The combined organic layers are dried over MgS04, filtered and concentrated under reduced pressure. The product is purified by FC (EtOAc / heptanes = 1 / 1 ) to give tert-butyl 7-(5-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoyl)-3,7-diazabicyclo [3.3.1]nonane-3-carboxylate as a colorless solid.
  • 64
  • [ 143007-15-2 ]
  • [ 227940-72-9 ]
  • [ 1429776-79-3 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In 5,5-dimethyl-1,3-cyclohexadiene for 1h; Reflux; 237.1 tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.5 g; 6.63 mmol) and 2-chloro-6,7-difluoroquinoxaline (1.564 g; 6.63 mmol) are dissolved in xylene (30 ml) followed by the addition of K2C03 (4.58 g; 33.1 mmol). The suspension is heated to reflux for 1 h and cooled again to rt followed by the addition of water (250 ml). The product is extracted with EtOAc (2 x 125 ml). The combined organic layers are dried over MgS04, filtered and the solvent is evaporated under reduced pressure. The residue is dried at HV to give tert-butyl 7-(6,7-difluoroquinoxalin-2-yl)-3,7-diazabicyclo[3.3.1 ] nonane-3-carboxylate.
  • 65
  • [ 227940-72-9 ]
  • [ 1485122-49-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine; 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide / dichloromethane / 24 h / Cooling with ice 2: trifluoroacetic acid / dichloromethane / 4 h / Cooling with ice
Multi-step reaction with 2 steps 1: 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide; triethylamine / dichloromethane / Cooling with ice 2: trifluoroacetic acid / dichloromethane
  • 66
  • [ 2018-66-8 ]
  • [ 227940-72-9 ]
  • [ 1485122-44-8 ]
YieldReaction ConditionsOperation in experiment
75% With 1-hydroxy-pyrrolidine-2,5-dione; triethylamine; dicyclohexyl-carbodiimide In dichloromethane for 24h; Cooling with ice;
With 1-hydroxy-pyrrolidine-2,5-dione; triethylamine; dicyclohexyl-carbodiimide In dichloromethane Cooling with ice; Compound synthesis and purification General procedure: All BPMs were synthesized following our previously described protocol with some modifications [57]. To an ice-cold solution of t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Z)-protected amino acid (1.65 mmol) in 65 ml of dry dichloromethane, N-hydroxysuccinimide (1.65 mmol) and N,N'-dicyclohexylcarbodiimide (1.65 mmol) were added and stirred for 10 min. Following this, bispidine (0.75 mmol) and triethylamine (0.192 ml, 1.65 mmol) were added. The reaction mixture was stirred overnight, filtered and washed with 0.2 N H2SO4, saturated aqueous NaHCO3 and finally with water. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to yield the crude product. It was then purified by silica gel chromatography. For the selective removal of N-Boc Group, B9 (1 mmol) was dissolved in 500 mol% of a 1 M solution of HCl in ethyl acetate (prepared by bubbling dry HCl into dry ethyl acetate and then diluting to 1 M with additional ethyl acetate). The reaction mixture was stirred at room temperature until the disappearance of starting material as determined by TLC (typically 3-5 h). The precipitated product (B10) was isolated by filtration. The information on chemical characterization of BPMs is given as supplementary data (Supplementary Figures S1-S27).
  • 67
  • N-benzyl-L-pyroglutamic acid [ No CAS ]
  • [ 227940-72-9 ]
  • 7-(1-benzyl-5-oxo-pyrrolidine-2-carbonyl)-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% Stage #1: N-benzyl-L-pyroglutamic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In dichloromethane at 0 - 20℃; Inert atmosphere; 4 7-(1-Benzyl-5-oxo-pyrrolidine-2-carbonyl)-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (4a) General procedure: 6.1.4 7-(1-Benzyl-5-oxo-pyrrolidine-2-carbonyl)-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (4a) DCC (0.308 g, 1.2 eq, 1.495 mmol) dissolved in dry DCM (5 ml) was added to the stirring reaction mixture containing N-benzyl pyroglutamic acid (0.273 g, 1 eq, 1.25 mmol) and HOBt (0.252 g, 1.5 eq, 1.86 mmol) dissolved in dry DCM (10 ml) at 0 °C and continued to stir for 15 min at same temperature. Then N-Boc bispidine (0.281 g, 1 eq, 1.25 mmol) dissolved in dry DCM (5 ml) was added drop wise to the stirring reaction mixture and continued to stir for a period of 2-3 h. The reaction mixture was then brought to room temperature and concentrated. The concentrated mass was then dissolved in diethyl ether and washed successively with dilute citric acid (1 * 20 ml), dilute NaHCO3 (1 * 20 ml), brine and then extracted with ethyl acetate (3 * 20 ml). The combined organics were dried with anhydrous Na2SO4 and concentrated to obtain sticky oily product (0.534 g). Yield = 79%; = -15.1890 (Methanol, c = 0.3160); IR (Neat): 3017.0, 2366.7, 2337.8, 1678.9, 1432.0, 1217.9 cm-1; 1H NMR (300 MHz, CDCl3, ppm): δ 7.36-7.14 (m, 5H, Ph-H); 5.15-5.10 (d, J = 15 Hz, 1H, PhCHA); 4.59-4.54 (d, J = 12 Hz, 1H, NC2'HA); 4.09-4.06 (d, J = 15 Hz, 1H, PhCHB; m, 2H, NC2H); 3.81-3.76 (d, J = 15 Hz, 1H, NC8'HA); 3.51-3.47 (d, J = 12 Hz, 1H, NC2'HB); 3.08-2.86 (m, 4H, PhCHB', NC8'HB, NC4'HA, C6'H2); 2.51-2.40 (m, 2H, C4HA, C4'HB); 2.26-2.16 (m, 1H, C4HB); 2.16-1.89 (m, 4H, C3H2, C3'H, Ca7'H); 1.70 (s, 2H, C9'H); 1.41 (s, 9H, CMe3); 13C NMR (50 MHz, CDCl3, ppm): δ 176.16, 174.85, 135.40, 128.84, 128.53, 127.95, 49.48, 49.00, 45.36, 29.99, 34.49, 28.35, 27.70, 27.32, 22.88; MS (ESI): m/z = 427.9 (M+).
59.17% Stage #1: N-benzyl-L-pyroglutamic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In dichloromethane at 20℃; 7 Example 7: 7-(l-Benzyl-5-oxo-pyrrolidine-2-carbonyl)-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-buryl ester, (la): DCC (308 mg, 1.2 eq, 1.495mmol) dissolved in DCM (5ml) was added to the stirring reaction mixture containing N-benzyl pyroglutamic acid, 3 (273 mg, 1 eq, 1.25 mmol) and HOBt (252.58 mg, 1.5 eq, 1.86 mmol) dissolved in dry DCM (10 ml) at 0°C and continued to stir for 15 minutes at same temperature. Then N-Boc bispidine, 5 (281 .82 mg, 1 eq, 1.25 mmol) dissolved in dry DCM (5 ml) was added drop wise to the stirring reaction mixture and continued to stir for about 2- 3 hrs. The reaction mixture was then brought to 25°C and concentrated. The concentrated mass was then dissolved in diethyl ether and washed successively with dilute citric acid ( 1 x 20 ml), dilute NaHC03 (1 x 20 ml), brine and then extracted with ethyl acetate (3 χ 20ml). The combined organ ics were dried with anhydrous Na2S04 and concentrated to obtain sticky oily product (534mg). Yield = 59.17%; ?°c= - 15.1 890 (Methanol, c = 0.3160); IR (Neat): 3017.0, 2366.7, 2337.8, 1678.9, 1432.0, 1217.9 cm"' ; NMR (300 MHz, CDC13, ppm):8 7.36-7.14 (m, 5H, Ph-H); 5.15- 5.10 (brd, J=15Hz, I H, PhCHA); 4.59-4.54 (brd, J=12Hz, I H, NC2 HA); 4.09-4.06 (m, 2H, NC2H, PhCHB); 3.81-3.76 (br d, J=15Hz, IH, NC8-HA); 3.51-3.47(d, J=12Hz, IH, NC2-HB); 3.08-2.86 (m, 4H, PhCHB% NCg-Ηβ, NC4 HA, C6 H2); 2.51 -2.40 (m, 2H, C4HA, C4-HB); 2.26-2.16 (m, IH, C4HB); 2. 16-1.89 (m, 4H, C3H2, C3-H, CrH); 1.70 (s, 2H, C9'H2); 1.41 (s, 9H, CMe3); ,3C NMR (50 MHz, CDC , ppm): δ 176. 16 (COOH), 174.85 (C=0), 135.40 (Ph), 128.84 (Ph), 128.53 (Ph), 127.95 (Ph), 49.48 (NCH), 49.00 (NCH2), 45.36 (NCr, NC8-), 29.99 (C9-), 34.49 (bridge CH2 ), 28.35 (C3-), 27.70 (Cr), 27.32(CMe3), 22.88 (CH2); MS (ESI):m/z = 427.9 (M+)
  • 68
  • [ 87341-45-5 ]
  • [ 227940-72-9 ]
  • 7-[1-(4-methylbenzyl)-5-oxo-pyrrolidine-2-carbonyl]-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% Stage #1: (2S)-N-(4-methylbenzyl) pyroglutamic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In dichloromethane at 0 - 20℃; Inert atmosphere; 4 7-[1-(4-Methylbenzyl)-5-oxo-pyrrolidine-2-carbonyl]-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert butyl ester (4c) General procedure: DCC (0.308 g, 1.2 eq, 1.495 mmol) dissolved in dry DCM (5 ml) was added to the stirring reaction mixture containing N-benzyl pyroglutamic acid (0.273 g, 1 eq, 1.25 mmol) and HOBt (0.252 g, 1.5 eq, 1.86 mmol) dissolved in dry DCM (10 ml) at 0 °C and continued to stir for 15 min at same temperature. Then N-Boc bispidine (0.281 g, 1 eq, 1.25 mmol) dissolved in dry DCM (5 ml) was added drop wise to the stirring reaction mixture and continued to stir for a period of 2-3 h. The reaction mixture was then brought to room temperature and concentrated. The concentrated mass was then dissolved in diethyl ether and washed successively with dilute citric acid (1 * 20 ml), dilute NaHCO3 (1 * 20 ml), brine and then extracted with ethyl acetate (3 * 20 ml). The combined organics were dried with anhydrous Na2SO4 and concentrated to obtain sticky oily product. Yield: 80%; [α]27°CD[α]D27°C:-16.7970 (Methanol, c=0.0980); IR (Neat): 3412.3, 2925.2, 1667.9, 1423.3, 1364.3, 1245.4, 1172.5, 1135.0cm-1; 1H NMR (300MHz, CDCl3, ppm): δ 7.14-7.11 (d, J=7.8Hz, 2H, Ph-H), 7.07-7.04 (d, J=7.8Hz, 2H, Ph-H); 5.13-5.08 (d, J=15Hz, PhCHA); 4.61-4.56 (m, 1H, NC2′HA); 4.15-4.07 (m, 1H, NC2H); 3.76-3.71 (d, J=15Hz, 1H, PhCHB); 3.54-3.50 (d, J=12Hz, 1H, NC8′HA); 3.04-2.94 (m, 4H, NC2′HB, NC8′HB, NC4′HA, NC6′HA); 2.34 (s, 1H, CH3); 2.22-2.00 (m, 6H, C4HA, C6′HB, C4′HB, C4HB, C3H2); 1.91-1.90 (m, 2H, C3′H, C7′H); 1.80 (s, 2H, C9′H); 1.42 (s, 9H, CMe3); 13C NMR (50MHz, CDCl3, ppm): δ 175.68, 168.33, 137.29, 129.28, 128.58, 49.52, 45.03, 34.64, 30.04, 28.35, 27.74, 27.35, 22.81, 21.08; MS (ESI): m/z=441.9 (M+)
50.91% With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 3h; Inert atmosphere; 11 Example 11: 7-[l-(4-Methyl-benzyl)-5-oxo-pyrrolidine-2-carbonyl]-3,7-diaza-bicyclo[3.3.1]nonane-3-carbo xylic acid tert-butyl ester, (le) Compound 5 (305.53mg, l eq, 1.350mmol) dissolved in dry DCM (10ml) was added to N-(4-methylbenzyl)pyroglutamic acid (314 mg, 1 eq, 1.350 mmol) dissolved in dry DCM (5ml). Then DIPEA (0.470ml, 2 eq, 2.76 mmol) was added drop wise to the stirring reaction mixture at 0°C under nitrogen atmosphere. Then PyBOP (702.52 mg, 1 eq, 1.350 mmol) dissolved in dry DCM was added drop wise to the stirring reaction mixture at same temperature and continued to stir for about 3hrs. The reaction mixture was washed successively with 20% citric acid (1 x 20 ml), 20% NaHC03 ( 1 x 20 ml) and brine. The combined organics were dried with anhydrous Na2S04 and concentrated to get the sticky oily product. Then it was purified by column chromatography on silica gel to obtain pure product. Yield: 50.91 %; Wf : - 16.7970 (Methanol, c = 0.0980); IR (Neat): 3412.3, 2925.2, 1667.9, 1423.3, 1364.3, 1245.4, 1 172,5, 1 135.0 cm" l ;1H NMR (300 MHz, CDC13, ppm): δ 7.28-7.04 (m, 4H, Ph); 5.13-5.08 (d, J= 15Hz, PhCHA); 4.61-4.56 (m, 1 H, NC2-HA); 4.15-4.07 (m, 1H, NC2H); 3.76-3.71 (d, J=15Hz, 1H, PhCHB); 3.54-3.50 (d, J=12Hz, 1H, NC8 HA); 3.04-2.94 (m, 4H, NCRHB, NC8'HB; NC4>HA, NC6-HA); 2.34 (s, 1H, CH3); 2.22-2.00 (m, 6H, C4HA, C6 HB, C4-HB, C4HB, C3H2); 1.91 -1.90 (m, 2H, C3>H, CRH); 1.80 (s, 2H, C9'H2); 1.42 (s, 9H, CMe3); 13C NMR (50 MHz, CDCI3, ppm): δ 175.68 (C=0), 168.33 (CO), 137.29 (Ph), 129.28 (Ph), 1 28.58 (Ph), 49.52 (NCH2), 45.03 (NCH2), 34.64 (bridge CH2), 30.04 (CH2), 28.35 (CMe3), 27.74 (CH3), 27.35 (CH3), 22.81 (CH3), 21.08 (PhCMe3); MS (ESI): m/z = 441.9 (M+)
  • 69
  • [ 87341-45-5 ]
  • [ 227940-72-9 ]
  • (5S)-5-(7-benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)-1-(4-methylbenzyl)pyrrolidin-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
59.13% Stage #1: (2S)-N-(4-methylbenzyl) pyroglutamic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In dichloromethane at 20℃; 12 Example 12: 5-(7-Benzyl-3,7-diaza-bicyclo[3.3.1]nonane-3-carbonyl)-l-(4-methyl-benzyl)-pyrrolidin-2- one (If): DCC (335.69mg, l eq, 1.36 mmol) dissolved in dry DCM (5ml) was added to the stirring reaction mixture containing N-(4-methyl benzyl) pyroglutamic acid (316.30 mg, 1 eq, 1.356 mmol) and HOBt (274.85 mg, 1 .2eq 1.627mmol) dissolved in dry DCM (10ml) at 0°C and continued to stir for 15 minutes at same temperature. Then N-benzyl bispidine (293 mg, 1 eq, 1.356 mmol) dissolved in dry DCM (5ml) was added drop wise to the stirring reaction mixture and continued to stir for about 2-3 hrs. The reaction mixture was then brought to 25°C and concentrated. The concentrated mass was then dissolved in diethyl ether and washed successively with 20% citric acid (1 x 20 ml), 20% NaHC03 (1 x 20 ml), brine and then extracted with ethyl acetate (3 χ 20ml). The combined organics were dried with anhydrous Na2S04 and concentrated to obtain sticky oily product which get solidified later Then it was purified by column chromatography on silica gel (DCM : Methanol = 7:3) to obtain pure product. Yield = 59.13%; MP: 133°C; [ °c; + 0.9200 (Methanol, c = 0.1260); IR (KBr): 3445.7, 2362.3, 1637.4, 1466.5, 1219.1 cm"'; *H NMR (300 MHz,CDCl3, ppm):67.30-7.07 (m, 9H, 2 χ Ph); 5.18- 5.14 (br d, J=12Hz, IH, PhCHA); 4.59-4.45(m, IH, NC2-HA); 4.17-4.15 (m, IH, NC2H); 3.79-3.74 (m, IH, PhCHB); 3.51-3.47 (m, 2H, PhCHA-, NC8-HA); 3.27-3.10 (m, IH, PhCHB;); 3.02-2.86 (m, 4H, NC2'HB, NC8'HB, NC4-HA, NC -Ha), 2.55 (m, 2H, C4HA), 2.33(s, 3H, CH3); 2.33(m, 2H, NC4-HB,'NC6-Hb); 2.09-2.06 (m, 2H, C4HB, C3HA); 1.97 (m, IH, C3HB); 1.89 (m, 2H, C3-H, C7 H); 1.70 (s, 2H, C9 H2); MS (ESI):m/z - 432.2(M+ 1 )+
  • 70
  • [ 1615250-18-4 ]
  • [ 227940-72-9 ]
  • 7-[1-(2-bromo-benzyl)-5-oxo-pyrrolidine-2-carbonyl]-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% Stage #1: (2S)-N-(2-bromophenylmethyl)-pyroglutamic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In dichloromethane at 0 - 20℃; Inert atmosphere; 4 7-[1-(2-Bromo-benzyl)-5-oxo-pyrrolidine-2-carbonyl]-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (4b) General procedure: DCC (0.308 g, 1.2 eq, 1.495 mmol) dissolved in dry DCM (5 ml) was added to the stirring reaction mixture containing N-benzyl pyroglutamic acid (0.273 g, 1 eq, 1.25 mmol) and HOBt (0.252 g, 1.5 eq, 1.86 mmol) dissolved in dry DCM (10 ml) at 0 °C and continued to stir for 15 min at same temperature. Then N-Boc bispidine (0.281 g, 1 eq, 1.25 mmol) dissolved in dry DCM (5 ml) was added drop wise to the stirring reaction mixture and continued to stir for a period of 2-3 h. The reaction mixture was then brought to room temperature and concentrated. The concentrated mass was then dissolved in diethyl ether and washed successively with dilute citric acid (1 * 20 ml), dilute NaHCO3 (1 * 20 ml), brine and then extracted with ethyl acetate (3 * 20 ml). The combined organics were dried with anhydrous Na2SO4 and concentrated to obtain sticky oily product. Yield: 89%; MP: 138°C; [α]27°CD[α]D27°C: 3.7608 (Methanol, c=0.2180); IR (KBr): 3458.8, 2927.9, 1679.6, 1434.4, 1241.5,1172.5, 1134.3cm-1; 1H NMR (300MHz, CDCl3, ppm): δ 7.5-7.1 (m, 4H, Ph-H); 5.1-5.0 (d, J=15Hz, 1H, PhCHA); 4.5 (d, 1H, NC2′HA); 4.1-4.0 (d, J=15Hz, 1H, PhCHB; m, 1H, NC2H); 3.5 (d, J=15Hz, 1H, NC8′HB); 3.1-2.8 (m, 4H, NC2′HB, NC8′HB, NC4′H, NC6′HA); 2.4-2.3 (m, 3H, C4HA, NC4′H, NC6′HB); 2.2-2.0 (m, 2H, C4HB, C3HA); 1.9 (m, 1H, C3HB); 1.8 (m, 2H, C3′H, C7′H); 1.7 (s, 2H, C9′H); 1.4 (s, 9H, CMe3); 13C NMR (50MHz, CDCl3, ppm): δ 135.84, 132.75, 131.39, 129.38, 127.76, 124.13, 79.73, 56.85, 49.59, 46.51, 45.30, 34.64, 28.32, 28.13, 27.70, 27.29, 22.82; MS(ESI): m/z: 528.0 (M+Na)+
49.64% With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane 8 7-j1-(2-Bromo-benzyl)-5-oxo-pyrrolidine-2-carbonylJ-3,7-diaza-bicyclo[3.3.ljnonane-3-carbOxylic acid tert-butyl ester, (Ib) The compound was prepared from N-(2-bromobenzylpyroglutamic acid using DCC (249.08mg, 1.2 eq, 1.207mmol) containing and HOBt (203.91 mg, 1 .5eq, 1.509 mmol) dissolved in dry DCM (10ml) followed by the addition ofN-Boc bispidine, 5 (227.5 l mg, l eq, 1.006 mmol) dissolved in dry DCM. Yield: 49.64%; MP: 138°C; : 3.7608 (Methanol, c = 0.2180); IR (KBr): 3458.8, 2927.9, 1679.6, 1434.4, 1241.5,1 172.5, 1 134.3 cm" 1; NMR (300 MHz, CDC13) ppm): δ 7.5-7.1 (m, 4H, Ph-H); 5.1 -5,0 (d, 1 H, PhCHA); 4.5 (d, 1 H, NC2.HA); 4.1 -4.0 (m, 2H, NC2H, PhCHB); 3.5 (d, l H, NC8-HB); 3.1 -2.8 (m, 4H, NCrHB, NQ HB, NC4 H, NC6'HA); 2.4-2.3 (m, 3H, C4HA, NC4>H, NC6-HB); 2.2-2.0 (m, 2H, C4HB, C3HA); 1 .9 (m, 1 H, C3HB); 1.8 (m, 2H, C3 H, CrH); 1.7 (s, 2H, C9 H2); 1.4 (s, 9H, CMe3); 13C NMR (50 MHz, CDC13, ppm): 6135.84 (Ph), 132.75 (Ph), 131.39 (Ph), 129.38 (Ph), 127.76 (Ph), 124.13 (Ph), 79.73 (CMe3), 56.85 (CCH3), 49.59 (COONCH), 46.51 (NCH), 45.30 (OCONCH), 34.64 (bridge CH2), 28.32 (CH), 28.13 (CH), 27.70 (CMe3), 27.29 (CMe3), 22.82 (CMe3); MS(ESI):m/z: 528.0 (M+Na)+
  • 71
  • [ 227940-72-9 ]
  • [ 497948-85-3 ]
  • C21H34N4O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene; <i>tert</i>-butyl alcohol at 140℃; for 1.33333h; Microwave irradiation; Sealed tube; 15 5.11. General procedure E: Buchwald-Hartwig cross couplingreaction/microwave procedure General procedure: In a microwave vessel, palladium acetate (5-10 mol%), (R,S)-BINAP or XPhos (10-30 mol %), sodium tert-butoxide (1.5-3 equiv),the appropriate amine (1-1.3 equiv), 2-[(5-bromopyridin-3-yl)oxy]-N,N-dimethylethanamine 16a (1 equiv) were added anddissolved in a mixture of toluene with tert-butanol (5:1) (1 mL).The reaction vessel was sealed with a septum and placed intothe microwave cavity. Microwave irradiation of 150W was usedand the temperature ramped from rt to 140 C. Once 140 C wasreached the reaction mixture was held for 80 min. After coolingdown, the reaction vessel was opened and the reaction mixturewas filtered on a C-18 SPE column and eluted with methanol.The solvent was removed under reduced pressure. The crude compoundwas purified by preparative HPLC system using RP C-18 silicageland appropriate MeOH/H2O gradients. The chromatogramswere scanned at 254 and 220 nm. The appropriate fractions werecollected. The fractions containing the desired product were concentratedunder reduced pressure.
  • 72
  • 2-(3-bromo-5-fluorophenoxy)-N,N-dimethylethane-1-amine [ No CAS ]
  • [ 227940-72-9 ]
  • C22H34FN3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene; <i>tert</i>-butyl alcohol at 160℃; for 2h; Inert atmosphere; 16 5.12. General procedure F: Buchwald-Hartwig cross coupling/Qtubeprocedure General procedure: A Q-tube was loaded with palladium acetate (5-10 mol %),(R,S)-BINAP or XPhos (10-30 mol %), sodium tert-butoxide (1.5-3 equiv), the appropriate amine (1.2-1.3 equiv), the appropriatebromo-containing compounds 16a, 16b, or 16c (1 equiv) and thendissolved in a mixture of toluene with tert-butanol (5:1) (2 mL).The Q-tube was flushed with nitrogen and the reaction mixturewas heated at 160 C for 2 h. The pressure was released and thereaction vessel was opened. The reaction mixture was filtered ona C-18 SPE column and eluted with cyclohexane. The solvent was removed under reduced pressure. The crude compound was purifiedby preparative HPLC system using RP C-18 silicagel and appropriateMeOH/H2O gradients. The chromatograms were scanned at254 and 220 nm. The appropriate fractions were collected. Thefractions containing the desired product were concentrated underreduced pressure.
  • 73
  • 2-(5-bromo-2,3-difluorophenoxy)-N,N-dimethylethanamine [ No CAS ]
  • [ 227940-72-9 ]
  • C22H33F2N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene; <i>tert</i>-butyl alcohol at 160℃; for 2h; Inert atmosphere; 17 5.12. General procedure F: Buchwald-Hartwig cross coupling/Qtubeprocedure General procedure: A Q-tube was loaded with palladium acetate (5-10 mol %),(R,S)-BINAP or XPhos (10-30 mol %), sodium tert-butoxide (1.5-3 equiv), the appropriate amine (1.2-1.3 equiv), the appropriatebromo-containing compounds 16a, 16b, or 16c (1 equiv) and thendissolved in a mixture of toluene with tert-butanol (5:1) (2 mL).The Q-tube was flushed with nitrogen and the reaction mixturewas heated at 160 C for 2 h. The pressure was released and thereaction vessel was opened. The reaction mixture was filtered ona C-18 SPE column and eluted with cyclohexane. The solvent was removed under reduced pressure. The crude compound was purifiedby preparative HPLC system using RP C-18 silicagel and appropriateMeOH/H2O gradients. The chromatograms were scanned at254 and 220 nm. The appropriate fractions were collected. Thefractions containing the desired product were concentrated underreduced pressure.
  • 74
  • [ 132311-92-3 ]
  • [ 227940-72-9 ]
  • tert-butyl 7-((S)-1-(4-cyanobenzyl)-5-oxopyrrolidine-2-carbonyl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
53% Stage #1: (S)-1-(4-cyanobenzyl)-5-oxopyrrolidine-2-carboxylic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In dichloromethane at 0 - 20℃; Inert atmosphere; 4 tert-Butyl-7-((S)-1-(4-cyanobenzyl)-5-oxopyrrolidine-2-carbonyl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (4d) General procedure: DCC (0.308 g, 1.2 eq, 1.495 mmol) dissolved in dry DCM (5 ml) was added to the stirring reaction mixture containing N-benzyl pyroglutamic acid (0.273 g, 1 eq, 1.25 mmol) and HOBt (0.252 g, 1.5 eq, 1.86 mmol) dissolved in dry DCM (10 ml) at 0 °C and continued to stir for 15 min at same temperature. Then N-Boc bispidine (0.281 g, 1 eq, 1.25 mmol) dissolved in dry DCM (5 ml) was added drop wise to the stirring reaction mixture and continued to stir for a period of 2-3 h. The reaction mixture was then brought to room temperature and concentrated. The concentrated mass was then dissolved in diethyl ether and washed successively with dilute citric acid (1 * 20 ml), dilute NaHCO3 (1 * 20 ml), brine and then extracted with ethyl acetate (3 * 20 ml). The combined organics were dried with anhydrous Na2SO4 and concentrated to obtain sticky oily product. Yield=53%; MP: 160-165°C; 1H NMR (300MHz, CDCl3, ppm) δ7.64-7.61 (d, J=7.8Hz, 2H, Ph-H), 7.28 (d, J=7.8Hz, 2H, Ph-H) 5.17-5.12 (d, J=15Hz, 1H, PhCHA), 4.59-4.55 (d, 1H, C(O)NC2′HA), 4.12-3.92 (d, 1H, PhCHB), 3.87 (d, J=15Hz, 1H, NC2H), 3.12 (m, 1H, PhCHA), 3.10-3.01 (m, 2H, PhCHB′, C(O)NC4′HA), 2.60-2.51 (m, 1H, C(O)NC2′HB), 2.40-2.50 (m, 2H, C(O)NC8′HB, NC6′HA), 2.12 (m, 1H, C4HA), 2.10-1.90 (m, 2H, C4′HB, NC6′HB, NC8′HA), 1.90-1.82 (m, 2H, C4HB, C3HA), 1.99-1.97 (bs, 4H, C3HB, C3′H, C7′H, C9′H), 1.43 (s, 9H, (CH3)3); 13C NMR (50MHz,CDCl3, ppm): δ 175.87, 169.33, 154.89, 142.20, 132.46, 128.87, 127.58, 111.52, 79.93, 56.99, 49.56, 46.54, 45.20, 30.27, 29.69, 29.52, 28.56, 28.38, 27.74, 27.32, 23.09; IR (KBr): 3896, 3744, 3700, 3576, 3456, 2924, 2859, 2361, 2228, 1679, 1418cm-1; MS (ESI): m/z=452.5 (M+)
  • 75
  • (S)-1-(4-chlorobenzyl)-5-oxopyrrolidine-2-carboxylic acid [ No CAS ]
  • [ 227940-72-9 ]
  • tert-butyl 7-((S)-1-(4-chlorobenzyl)-5-oxopyrrolidine-2-carbonyl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% Stage #1: (S)-1-(4-chlorobenzyl)-5-oxopyrrolidine-2-carboxylic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In dichloromethane at 0 - 20℃; Inert atmosphere; 4 tert-butyl 7-((S)-1-(4-chlorobenzyl)-5-oxopyrrolidine-2-carbonyl)-3,7-diazabicyclo [3.3.1] nonane-3-carboxylate (4e) General procedure: DCC (0.308 g, 1.2 eq, 1.495 mmol) dissolved in dry DCM (5 ml) was added to the stirring reaction mixture containing N-benzyl pyroglutamic acid (0.273 g, 1 eq, 1.25 mmol) and HOBt (0.252 g, 1.5 eq, 1.86 mmol) dissolved in dry DCM (10 ml) at 0 °C and continued to stir for 15 min at same temperature. Then N-Boc bispidine (0.281 g, 1 eq, 1.25 mmol) dissolved in dry DCM (5 ml) was added drop wise to the stirring reaction mixture and continued to stir for a period of 2-3 h. The reaction mixture was then brought to room temperature and concentrated. The concentrated mass was then dissolved in diethyl ether and washed successively with dilute citric acid (1 * 20 ml), dilute NaHCO3 (1 * 20 ml), brine and then extracted with ethyl acetate (3 * 20 ml). The combined organics were dried with anhydrous Na2SO4 and concentrated to obtain sticky oily product. Yield=77%; 1H NMR (300MHz, CDCl3, ppm): δ 7.30-7.28 (d, J=7.8Hz, 2H, Ph-H), 7.27-7.12 (d, J=7.8Hz, 2H, Ph-H) 5.11-5.04 (d, J=15Hz, 1H, PhCHA), 4.59-4.54 (d, 1H, C(O)NC2′HA), 4.20-4.00 (d, J=15Hz, 1H, PhCHB, NC8′HA), 3.79 (d, 12Hz, 1H, NC2H), 3.56 (d, J=15Hz, 1H, PhCHA′), 3.09-3.04 (m, 2H, PhCHB′, C(O)NC4′HA), 2.99-2.96 (m, 1H, C(O)NC2′HB), 2.91-2.86 (m, 2H, C(O)NC8′HB, NC6′HA), 2.50-2.48 (m, 1H, C4HA), 2.44-2.43 (m, 2H, C4′HB, NC6′HB), 2.41-2.40 (m, 2H, C4HB, C3HA), 1.94 (bs, 2H, C3HB, C3′H) 1.81(bs, 2H, C7′H, C9′H), 1.41 (s, 9H, (CH3)3); 13C NMR (50MHz,CDCl3, ppm); δ 175.57, 169.53, 154.93, 134.94, 133.46, 129.87, 128.78, 79.58, 56.5, 56.49, 56.47, 49.54, 44.70, 29.81, 28.35, 27.74, 22.92; IR(KBr): 3869, 3759, 3496, 3010, 2926, 2860, 1679, 1423cm-1; MS(ESI): m/z=461.9 (M+)
  • 76
  • [ 59749-37-0 ]
  • [ 227940-72-9 ]
  • tert-butyl 7-((S)-1-(2,6-dichlorobenzyl)-5-oxopyrrolidine-2-carbonyl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% Stage #1: C12H11Cl2NO3 With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In dichloromethane at 0 - 20℃; Inert atmosphere; 4 tert-butyl 7-((S)-1-(2,6-dichlorobenzyl)-5-oxopyrrolidine-2-carbonyl)-3,7-diazabicyclo [3.3.1] nonane-3-carboxylate (4f) General procedure: DCC (0.308 g, 1.2 eq, 1.495 mmol) dissolved in dry DCM (5 ml) was added to the stirring reaction mixture containing N-benzyl pyroglutamic acid (0.273 g, 1 eq, 1.25 mmol) and HOBt (0.252 g, 1.5 eq, 1.86 mmol) dissolved in dry DCM (10 ml) at 0 °C and continued to stir for 15 min at same temperature. Then N-Boc bispidine (0.281 g, 1 eq, 1.25 mmol) dissolved in dry DCM (5 ml) was added drop wise to the stirring reaction mixture and continued to stir for a period of 2-3 h. The reaction mixture was then brought to room temperature and concentrated. The concentrated mass was then dissolved in diethyl ether and washed successively with dilute citric acid (1 * 20 ml), dilute NaHCO3 (1 * 20 ml), brine and then extracted with ethyl acetate (3 * 20 ml). The combined organics were dried with anhydrous Na2SO4 and concentrated to obtain sticky oily product. Yield=63%; 1H NMR (300MHz, CDCl3, ppm): δ 7.64-7.61 (m, 2H, Ph), 7.28 (m, 2H, Ph) 5.17-5.12 (d, J=15Hz, 1H, PhCHA), 4.59-4.55 (d, 12Hz, 1H, C(O)NC2′HA), 4.12-3.92 (d, J=15Hz, 1H, PhCHB), 3.87 (d, 12Hz, 1H, NC2H), 3.12 (m, 1H, PhCHA′), 3.10-3.01 (m, 2H, PhCHB′, C(O)NC4′HA), 2.60-2.51 (m, 1H, C(O)NC2′HB), 2.40-2.50 (m, 2H, C(O)NC8′HB, NC6′HA), 2.12 (m, 1H, C4HA), 2.10-1.90 (m, 2H, C4′HB, NC6′HB, NC8′HA), 1.90-1.82 (m, 2H, C4HB, C3HA), 1.99-1.97 (bs, 4H, C3HB, C3′H, C7′H, C9′H), 1.43 (s, 9H, (CH3)3); IR (KBr): 3896, 3744, 3700, 3576, 3456, 2924, 2859, 2361, 2228, 1679, 1418cm-1; MS (ESI): m/z=498.2 (M+H)+
  • 77
  • [ 87341-48-8 ]
  • [ 227940-72-9 ]
  • tert-butyl 7-((S)-1-(4-methoxybenzyl)-5-oxopyrrolidine-2-carbonyl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
54% Stage #1: (S)-(+)-N-p-methoxybenzyl-5-oxoproline With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In dichloromethane at 0 - 20℃; Inert atmosphere; 4 tert-butyl 7-((S)-1-(4-methoxybenzyl)-5-oxopyrrolidine-2-carbonyl)-3,7-diazabicyclo[3.3.1] nonane-3-carboxylate (4g) General procedure: DCC (0.308 g, 1.2 eq, 1.495 mmol) dissolved in dry DCM (5 ml) was added to the stirring reaction mixture containing N-benzyl pyroglutamic acid (0.273 g, 1 eq, 1.25 mmol) and HOBt (0.252 g, 1.5 eq, 1.86 mmol) dissolved in dry DCM (10 ml) at 0 °C and continued to stir for 15 min at same temperature. Then N-Boc bispidine (0.281 g, 1 eq, 1.25 mmol) dissolved in dry DCM (5 ml) was added drop wise to the stirring reaction mixture and continued to stir for a period of 2-3 h. The reaction mixture was then brought to room temperature and concentrated. The concentrated mass was then dissolved in diethyl ether and washed successively with dilute citric acid (1 * 20 ml), dilute NaHCO3 (1 * 20 ml), brine and then extracted with ethyl acetate (3 * 20 ml). The combined organics were dried with anhydrous Na2SO4 and concentrated to obtain sticky oily product. Yield=54%; 1H NMR (300MHz, CDCl3, ppm): δ 7.28-7.23 (m, 2H, Ph), 6.83-6.72 (m, 2H, Ph), 5.14-5.10 (d, J=15Hz, 1H, PhCHA), 4.61-4.56 (d, 12Hz, 1H, C(O)NC2′HA), 4.20-4.04 (m, 2H, PhCHB, NC2H), 3.85-3.75 (s, 3H, OCH3), 3.74-3.71 (m, 1H, PhCHA′), 3.60-3.48 (m, 1H, PhCHB′), 3.04-3.00 (m, 2H, C(O)NC2′HB, C(O)NC4′HA), 2.94-2.88 (m, 2H, C(O)NC8′HB, NC8′HA), 2.49-2.55 (m, 2H, C4HA, NC6′HA), 2.31-2.25 (m, 2H, C4′HB, NC6′HB), 2.20 (m, 2H, C4HB, C3HA), 1.80 (m, 4H, C3HB, C3′H, C7′H, C9′H), 1.42 (s, 9H, (CH3)3); 13C NMR (50MHz,CDCl3, ppm): 172.17, 169.73, 159.90, 139.16, 137.77, 129.58, 120.78, 114.11, 114.03, 113.96, 113.22, 113.05, 79.74, 55.21, 55.18, 49.49, 45.31, 33.76, 29.63, 28.32, 22.81; IR (KBr): 3900, 3565, 3366, 3013, 2926, 2856, 2196, 1679, 1434, 1363, 1219cm-1; MS (ESI): m/z=457.5 (M+)
  • 78
  • [ 227940-72-9 ]
  • [ 87341-51-3 ]
  • tert-butyl 7-((S)-1-(naphthalen-1-ylmethyl)-5-oxopyrrolidine-2-carbonyl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
47% Stage #1: N-(naphthalen-1-ylmethyl)-(S)-pyroglutamic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In dichloromethane at 0 - 20℃; Inert atmosphere; 4 tert-butyl 7-((S)-1-(naphthalen-1-ylmethyl)-5-oxopyrrolidine-2-carbonyl)-3,7-diazabicyclo [3.3.1] nonane-3-carboxylate (4h) General procedure: DCC (0.308 g, 1.2 eq, 1.495 mmol) dissolved in dry DCM (5 ml) was added to the stirring reaction mixture containing N-benzyl pyroglutamic acid (0.273 g, 1 eq, 1.25 mmol) and HOBt (0.252 g, 1.5 eq, 1.86 mmol) dissolved in dry DCM (10 ml) at 0 °C and continued to stir for 15 min at same temperature. Then N-Boc bispidine (0.281 g, 1 eq, 1.25 mmol) dissolved in dry DCM (5 ml) was added drop wise to the stirring reaction mixture and continued to stir for a period of 2-3 h. The reaction mixture was then brought to room temperature and concentrated. The concentrated mass was then dissolved in diethyl ether and washed successively with dilute citric acid (1 * 20 ml), dilute NaHCO3 (1 * 20 ml), brine and then extracted with ethyl acetate (3 * 20 ml). The combined organics were dried with anhydrous Na2SO4 and concentrated to obtain sticky oily product. Yield=47%; 1H NMR (300MHz, CDCl3, ppm): δ 8.05-7.37 (m, 7H, Naphthyl), 5.62-5.67 (d, J=15Hz, 1H, PhCHA),5.04-4.97 (d, J=15Hz, 1H, PhCHB), 4.62-4.52 (d, 12Hz, 1H, C(O)NC2′HA), 4.11-4.07 (m, 1H, NC2H, NC8′HA), 3.77-3.76 (m, 1H, PhCHA′), 3.24-3.20 (m, 1H, PhCHB′), 3.01-2.91 (m, 3H, C(O)NC4′HA, C(O)NC8′HB, C(O)NC2′HB), 2.66-2.42 (m, 3H, NC6′HA1H, C4HA, C4′HB), 2.39 (m, 1H, NC6′HB), 2.07-2.03 (m, 5H, C4HB, C3HA, C3HB, C3′H, C7′H), 1.70 (bs, 2H, C9′H), 1.42 (s, 9H, (CH3)3); IR (KBr): 3947, 3675, 3484, 3421, 3287, 2923, 2853, 2361, 1674, 1452, 1365cm-1; MS (ESI): m/z=447.5 (M+)
  • 79
  • [ 227940-72-9 ]
  • C42H45N5O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: triethylamine / acetonitrile / 12 h / 20 °C / Cooling with ice 2.1: trifluoroacetic acid / dichloromethane / 4 h / 20 °C / Cooling with ice 3.1: 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide / dichloromethane / 0.17 h / Cooling with ice 3.2: 24 h
  • 80
  • [ 227940-72-9 ]
  • C37H46N4O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: triethylamine / acetonitrile / 12 h / 20 °C / Cooling with ice 2.1: trifluoroacetic acid / dichloromethane / 4 h / 20 °C / Cooling with ice 3.1: 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide / dichloromethane / 0.17 h / Cooling with ice 3.2: 24 h
  • 81
  • [ 227940-72-9 ]
  • C26H27N3O [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine / acetonitrile / 12 h / 20 °C / Cooling with ice 2: trifluoroacetic acid / dichloromethane / 4 h / 20 °C / Cooling with ice
  • 82
  • [ 227940-72-9 ]
  • [ 873303-99-2 ]
  • C31H35N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.250 g With triethylamine In acetonitrile at 20℃; for 12h; Cooling with ice;
  • 83
  • [ 1161-13-3 ]
  • [ 227940-72-9 ]
  • C29H37N3O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1-hydroxy-pyrrolidine-2,5-dione; triethylamine; dicyclohexyl-carbodiimide In dichloromethane Cooling with ice; Compound synthesis and purification General procedure: All BPMs were synthesized following our previously described protocol with some modifications [57]. To an ice-cold solution of t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Z)-protected amino acid (1.65 mmol) in 65 ml of dry dichloromethane, N-hydroxysuccinimide (1.65 mmol) and N,N'-dicyclohexylcarbodiimide (1.65 mmol) were added and stirred for 10 min. Following this, bispidine (0.75 mmol) and triethylamine (0.192 ml, 1.65 mmol) were added. The reaction mixture was stirred overnight, filtered and washed with 0.2 N H2SO4, saturated aqueous NaHCO3 and finally with water. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to yield the crude product. It was then purified by silica gel chromatography. For the selective removal of N-Boc Group, B9 (1 mmol) was dissolved in 500 mol% of a 1 M solution of HCl in ethyl acetate (prepared by bubbling dry HCl into dry ethyl acetate and then diluting to 1 M with additional ethyl acetate). The reaction mixture was stirred at room temperature until the disappearance of starting material as determined by TLC (typically 3-5 h). The precipitated product (B10) was isolated by filtration. The information on chemical characterization of BPMs is given as supplementary data (Supplementary Figures S1-S27).
  • 84
  • [ 227940-72-9 ]
  • [ 7432-21-5 ]
  • C31H38N4O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1-hydroxy-pyrrolidine-2,5-dione; triethylamine; dicyclohexyl-carbodiimide In dichloromethane Cooling with ice; Compound synthesis and purification General procedure: All BPMs were synthesized following our previously described protocol with some modifications [57]. To an ice-cold solution of t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Z)-protected amino acid (1.65 mmol) in 65 ml of dry dichloromethane, N-hydroxysuccinimide (1.65 mmol) and N,N'-dicyclohexylcarbodiimide (1.65 mmol) were added and stirred for 10 min. Following this, bispidine (0.75 mmol) and triethylamine (0.192 ml, 1.65 mmol) were added. The reaction mixture was stirred overnight, filtered and washed with 0.2 N H2SO4, saturated aqueous NaHCO3 and finally with water. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to yield the crude product. It was then purified by silica gel chromatography. For the selective removal of N-Boc Group, B9 (1 mmol) was dissolved in 500 mol% of a 1 M solution of HCl in ethyl acetate (prepared by bubbling dry HCl into dry ethyl acetate and then diluting to 1 M with additional ethyl acetate). The reaction mixture was stirred at room temperature until the disappearance of starting material as determined by TLC (typically 3-5 h). The precipitated product (B10) was isolated by filtration. The information on chemical characterization of BPMs is given as supplementary data (Supplementary Figures S1-S27).
  • 85
  • [ 12093-10-6 ]
  • [ 227940-72-9 ]
  • 3-(tert-butyloxycarbonyl)-7-ferrocenylmethyl-3,7-diazabicyclo[3.3.1]nonane [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 2h; 4.5 3-(tert-Butyloxycarbonyl)-7-ferrocenylmethyl-3,7-diazabicyclo[3.3.1]nonane 6 To a solution of 5 (1g, 4.4mmol) in THF (50ml) was added ferrocenecarboxaldehyde (1.13g, 5.3mmol) and by portions sodium triacetoxyborohydride (3.50g, 16.5mmol). The mixture was stirred for 2hat room temperature, diluted with water, basified with sodium hydroxide solution to pH 10, extracted with ether, washed with brine, dried over Na2SO4 and evaporated. The residue was purified by Al2O3 column chromatography with AcOEt/petroleum ether (1/9) to afford 6 (1.57g, 83%) as an orange powder. M. p. 112° . Anal. C, 64.95; H, 7.69; N, 6.57%. Calc. for C23H32FeN2O2: C, 65.10; H, 7.60; N, 6.60%. IR (KBr, ν, cm -1): 1690 (OC=O), 1105, 998, 819, 487 (FcH). EI-MS, m/z (RI, %): 424 [M]+ (53), 368 [M-t-Bu+H]+ (14), 324 [M-Boc+H]+ (28). 1H NMR (500MHz, CDCl3) δ 4.18-4.11 (m, 1H, CH2NBoc+2H, C5H4), 4.11-4.06 (s, 5H, C5H5+m, 2H, C5H4), 3.98 (d, J=13.0Hz, 1H, CH2NBoc), 3.34 (d, J=13.3Hz, 1H, CH2Fc), 3.26 (d, J=13.3Hz, 1H, CH2Fc), 3.06 (dd, J=13.1, 3.7Hz, 1H, CH2NBoc), 2.99 (dd, J=13.1, 3.8Hz, 1H, CH2NBoc), 2.89 (d, J=10.7Hz, 1H, CH2NCH2Fc), 2.81 (d, J=10.7Hz, 1H, CH2NCH2Fc), 2.22 (d, J=11.0Hz, 2H, CH2NCH2Fc), 2.18 (d, J=11.0Hz, 2H, CH2NCH2Fc), 1.79 (br s, 1H, CH), 1.73 (br s, 1H, CH), 1.61 (d, J=12.2Hz, 1H, CH2), 1.55-1.47 (m, 1H, CH2+s, 9H, CMe3). 13C NMR (126MHz, CDCl3) δ 155.21 (C=O), 83.03 (ipso-C5H4), 78.48 (CMe3), 70.06 (C5H4), 68.42 (C5H5), 67.49 (C5H4), 58.40 (CH2Fc), 57.77 and 57.55 (CH2NCH2Fc), 48.76 and 47.69 (CH2NBoc), 31.27 (CH2), 29.12 (CH), 29.02 (CH), 28.76 (CMe3.
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