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Chemical Structure| 178311-48-3 Chemical Structure| 178311-48-3

Structure of 178311-48-3

Chemical Structure| 178311-48-3

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Product Details of [ 178311-48-3 ]

CAS No. :178311-48-3
Formula : C12H23N3O2
M.W : 241.33
SMILES Code : O=C(N1CC(N2CCNCC2)C1)OC(C)(C)C
English Name :tert-Butyl 3-(piperazin-1-yl)azetidine-1-carboxylate
MDL No. :MFCD09264407
InChI Key :KEQBTRKQDYXHTO-UHFFFAOYSA-N
Pubchem ID :19360775

Safety of [ 178311-48-3 ]

Application In Synthesis of [ 178311-48-3 ]

* 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 [ 178311-48-3 ]

[ 178311-48-3 ] Synthesis Path-Downstream   1~14

  • 1
  • [ 178311-48-3 ]
  • [ 1629269-74-4 ]
  • [ 1629269-75-5 ]
YieldReaction ConditionsOperation in experiment
673 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 16h; 37 Tert-Butyl 3-(4-(2-((4-Chloro-5-iodo-2-methoxyphenyl)amino)propanoyl)piperazin-1-yl)azetidine-1-carboxylate Tert-Butyl 3-(4-(2-((4-Chloro-5-iodo-2-methoxyphenyl)amino)propanoyl)piperazin-1-yl)azetidine-1-carboxylate To a solution of 2-(4-chloro-5-iodo-2-methoxyphenylamino)propanoic acid (760 mg, 2.13 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (669 mg, 2.78 mmol), EDCI.HCl (818 mg, 4.26 mmol), HOBt (575 mg, 4.26 mmol) in DMF (8 mL) at 0° C., Et3N (861 mg, 8.52 mmol) was added. The resulting mixture was stirred at RT for 16 h and then partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=1:1) to afford the desired product (673 mg, 55% yield) as a white solid. ESI-MS m/z: 579.4[M+H]+.
673 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 16h; 49 Tert-Butyl 3 -(4-(2-((4-Chloro-5 -iodo-2-methoxyphenyl)amino)propanoyl)piperazin- 1-yl)azetidine- 1 -carboxylate To a solution of 2-(4-chloro-5 -iodo-2-methoxyphenylamino)propanoic acid (760 mg, 2.13 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (669 mg, 2.78 mmol), EDCI.HC1 (818 mg, 4.26 mmol), HOBt (575 mg, 4.26 mmol) in DMF (8 mL) at 0°C, Et3N (861 mg, 8.52 mmol) was added. The resulting mixture was stirredat RT for 16 h and then partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether = 1: 1) to afford the desired product (673 mg, 55% yield) as a white solid. ESI-MS m/z: 579.4 [M + H].
  • 2
  • [ 178311-48-3 ]
  • [ 1629269-83-5 ]
  • [ 1629269-84-6 ]
YieldReaction ConditionsOperation in experiment
46% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h; 40 tert-Butyl-3-(4-(3-(5-bromo-4-chloro-2-methoxyphenyl)propanoyl)piperazin-1-yl)azetidine-1-carboxylate tert-Butyl-3-(4-(3-(5-bromo-4-chloro-2-methoxyphenyl)propanoyl)piperazin-1-yl)azetidine-1-carboxylate To a stirred solution of 3-(5-bromo-4-chloro-2-methoxyphenyl)propanoic acid (350 mg, 1.2 mmol) in DMF (30 mL) at RT, tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (317 mg, 1.3 mmol), BOP (731 mg, 1.4 mmol) and DIEA (461 mg, 3.6 mmol) were added and the mixture was stirred at RT for 1 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (285 mg, 46% yield).
46% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h; 52 tert-Butyl-3 -(4-(3 -(5 -bromo-4-chloro-2-methoxyphenyl)propanoyl)piperazin- 1- yl)azetidine- 1 -carboxylate To a stirred solution of 3-(5-bromo-4-chloro-2-methoxyphenyl)propanoic acid (350 mg, 1.2 mmol) in DMF (30 mL) at RT, tert-butyl3-(piperazin-1-yl)azetidine-1-carboxylate (317 mg, 1.3 mmol), BOP (731 mg, 1.4 mmol) and DIEA (461 mg, 3.6 mmol) were added and the mixture was stirred at RT forh. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 50:1) to afford the desired product (285 mg, 46% yield).
  • 3
  • [ 178311-48-3 ]
  • [ 1629269-93-7 ]
  • [ 1629269-94-8 ]
YieldReaction ConditionsOperation in experiment
95% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h; 41 tert-Butyl 3-(4-(2-((4-chloro-2-methoxy-5-(1-methylcyclopropyl)phenyl)amino)acetyl)piperazin-1-yl)azetidine-1-carboxylate tert-Butyl 3-(4-(2-((4-chloro-2-methoxy-5-(1-methylcyclopropyl)phenyl)amino)acetyl)piperazin-1-yl)azetidine-1-carboxylate To a solution of 2-((4-chloro-2-methoxy-5-(1-methylcyclopropyl)phenyl)amino)acetic acid (110 mg, 0.41 mmol) and tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (118 mg, 0.49 mmol) in DMF (15 mL) at RT, BOP (217 mg, 0.49 mmol) and DIEA (159 mg, 1.23 mmol) were added and the resulting mixture was stirred at RT for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the desired product (192 mg, 95% yield).
95% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h; 53 tert-Butyl 3 -(4-(2-((4-chloro-2-methoxy-5 -(1-methylcyclopropyl)phenyl)amino)acetyl)piperazin- 1 -yl)azetidine- 1 -carboxylate To a solution of 2-((4-chloro-2-methoxy-5 -(1-methylcyclopropyl)phenyl)amino)acetic acid (110 mg, 0.41 mmol) and tert-butyl 3- (piperazin-1-yl)azetidine-1-carboxylate (118 mg, 0.49 mmol) in DMF (15 mL) at RT, BOP (217 mg, 0.49 mmol) and DIEA (159 mg, 1.23 mmol) were added and the resulting mixture was stirred at RT for 1 h. The mixture was partitioned between ethylacetate and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the desired product (192 mg, 95% yield).
  • 4
  • [ 178311-48-3 ]
  • [ 1508278-47-4 ]
  • [ 1629268-97-8 ]
YieldReaction ConditionsOperation in experiment
31% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 15h; 8 tert-Butyl 3-(4-(2-(4,5-dichloro-2-hydroxyphenylamino)acetyl)piperazin-1-yl)azetidine-1-carboxylate Example 8 tert-Butyl 3-(4-(2-(4,5-dichloro-2-hydroxyphenylamino)acetyl)piperazin-1-yl)azetidine-1-carboxylate A mixture of 2-(4,5-dichloro-2-hydroxyphenylamino)acetic acid (500 mg, 2.12 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (565 mg, 2.34 mmol), EDCI.HCl (488 mg, 2.54 mmol), HOBt (343 mg, 2.54 mmol), Et3N (428 mg, 4.24 mmol) in DMF (20 mL) was stirred at room temperature for 15 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed withed saturated aqueous NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=30:1) to afford the desired product (300 mg, 31% yield). ESI-MS m/z: 457.4 [M-H]-.
31% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 15h; 38 tert-Butyl 3-(4-(2-(4,5-dichloro-2-hydroxyphenylamino)acetyl)piperazin- 1 -yl)azetidine1 -carboxylate A mixture of 2-(4,5-dichloro-2-hydroxyphenylamino)acetic acid (500mg, 2.12 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (565 mg,2.34mmol), EDCI.HC1 (488 mg, 2.54 mmol), HOBt (343 mg, 2.54 mmol), Et3N (428 mg, 4.24 mmol) in DMF (20 mL) was stirred at room temperature for 15 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed withed saturated aqueous NaHCO3 solution and brine, dried over Na2504 andconcentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 30:1) to afford the desired product (300 mg, 31% yield). ESMS m/z: 457.4 [M-Hf.
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide Analogously, further derivatives can be synthesized via a similar synthetic approach. For example, compound 10 (1 -(4-(azetidin-3 -yl)piperazin- 1 -yl)-2-((4,5 -dichloro-2- hydroxyphenyl)amino)ethan- 1-one) is synthesized according to the scheme. Additionally, the amino acid intermediate can be formed via demethylation of ethyl 2- (4,5 -dichloro-2-methoxyphenylamino)acetate with BBr3 in dichloromethane followed by hydrolysis of the ester with lithium hydroxide. The corresponding acid is alkylated with an amine, for example, tert-butyl 3 -(piperazin- 1 -yl)azetidine- 1 -carboxylate to from the amide. The amine is deprotected via HC1/MeOH, and compound 10 is isolated via known techniques.
  • 5
  • [ 178311-48-3 ]
  • [ 1508278-51-0 ]
  • [ 1629269-70-0 ]
YieldReaction ConditionsOperation in experiment
67% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 16h; 36 tert-Butyl 3-(4-(2-(4-Chloro-5-iodo-2-methoxyphenylamino)acetyl)piperazin-1-yl)azetidine-1-carboxylate Example 36 tert-Butyl 3-(4-(2-(4-Chloro-5-iodo-2-methoxyphenylamino)acetyl)piperazin-1-yl)azetidine-1-carboxylate To a solution of 2-(4-chloro-5-iodo-2-methoxyphenylamino)acetic acid (2.0 g, 5.88 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (1.84 g, 7.64 mmol), EDCI.HCl (2.26 g, 11.76 mmol), and HOBt (1.59 g, 11.76 mmol) in DMF (3 mL) at 0° C., Et3N (3.28 mL, 23.52 mmol) was added. The resulting mixture was stirred at RT for 16 h and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was washed by a mixture of ethyl acetate/petroleum ether=1:5 to afford the desired product (2.24 g, 67% yield) as a white solid. ESI-MS m/z: 565.4[M+H]+.
67% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 16h; 48 tert-Butyl 3 -(4-(2-(4-Chloro-5 -iodo-2-methoxyphenylamino)acetyl)piperazin- 1- yl)azetidine- 1 -carboxylate To a solution of 2-(4-chloro-5 -iodo-2-methoxyphenylamino)acetic acid (2.0 g, 5.88 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (1.84 g, 7.64 mmol), EDCI.HC1 (2.26 g, 11.76 mmol), and HOBt (1.59 g, 11.76 mmol) in DMF (3 mL) at 0°C, Et3N (3.28 mL, 23.52 mmol) was added. The resulting mixture was stirred at RT for 16 h and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was washed by a mixture of ethyl acetate / petroleum ether = 1:5 to afford the desiredproduct (2.24 g, 67% yield) as a white solid. ESI-MS m/z: 565.4 [M + H].
  • 6
  • [ 178311-48-3 ]
  • [ 1629270-40-1 ]
  • [ 1629270-41-2 ]
YieldReaction ConditionsOperation in experiment
76% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 16h; 53 (S)-tert-Butyl 3-(4-(2-((5-bromo-4-chloro-2-methoxyphenyl)amino)propanoyl)piperazin-1-yl)azetidine-1-carboxylate (S)-tert-Butyl 3-(4-(2-((5-bromo-4-chloro-2-methoxyphenyl)amino)propanoyl)piperazin-1-yl)azetidine-1-carboxylate To a solution of (S)-2-(5-bromo-4-chloro-2-methoxyphenylamino)propanoic acid (1.6 g, 5.21 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (1.88 g, 7.82 mmol), EDCI.HCl (2.0 g, 10.42 mmol), HOBt (1.41 g, 10.42 mmol) in DMF (20 mL) at 0° C., Et3N (1.58 g, 15.63 mmol) was added. The resulting mixture was stirred at RT for 16 h and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (methanol/dichloroethane=1:50) to afford the desired product (2.1 g, 76% yield). ESI-MS m/z: 531.3[M+H]+.
76% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 16h; 64 (S)-tert-Butyl 3 -(4-(2-((5 -bromo-4-chloro-2-methoxyphenyl)amino)propanoyl)piperazin- 1 -yl)azetidine- 1 -carboxylate To a solution of (S)-2-(5 -bromo-4-chloro-2-methoxyphenylamino)propanoic acid (1.6 g, 5.21 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (1.88 g, 7.82 mmol), EDCI.HC1 (2.0 g, 10.42 mmol), HOBt(1.41 g, 10.42 mmol) in DMF (20 mL) at 0°C, Et3N (1.58 g, 15.63 mmol) was added. The resulting mixture was stirred at RT for 16 h and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography onsilica gel (methanol dichloroethane = 1:50) to afford the desired product (2.1 g, 76% yield). ESI-MS m/z: 531.3 [M+H].
  • 7
  • [ 178311-48-3 ]
  • [ 1508278-55-4 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Stage #1: 1-(Tert-butoxycarbonyl)-3-(1-piperazinyl)azetidine; 2-(4,5-dichloro-2-methoxyphenylamino)acetic acid With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide Stage #2: With hydrogenchloride In methanol Using a modified approach, compound 12 (3-(4-((4,5-dichloro-2- hydroxyphenyl)glycyl)piperazin- 1 -yl)azetidine- 1 -carbaldehyde) is synthesized according to the following scheme.Hydrolysis of ethyl 2-(4,5 -dichloro-2-methoxyphenylamino)acetate with aqueous lithium hydroxide and subsequent acidification furnishes the corresponding acid. Coupling to tert-butyl 3 -(piperazin- 1 -yl)azetidine- 1 -carboxylate to form the amide was achieved via BOP and diisopropyl ethyl amine in DMF. The Boc group was removed via HC1/methanol, and the resulting amine was coupled to formic acid via addition of BOP and DIPEA in DMF to furnish the corresponding formamide. The methyl group was removed to via BBr3 in dichloromethane to give the corresponding phenol product, compound 12.
  • 8
  • [ 178311-48-3 ]
  • [ 2048186-65-6 ]
  • [ 2048187-35-3 ]
YieldReaction ConditionsOperation in experiment
In dimethyl sulfoxide at 120℃; for 96h; Sealed tube; 10 7- [4- (azetidin-3-yl)piperazin- 1 -yl] - 2-(2-methyl-[l,2,4]triazolo[l,5-a]pyrimidin-6-yl)pyrido[l,2-a]pyrimidin-4-one (0367) In a sealed tube, 7-fluoro-2-(2-methyl-[l,2,4]triazolo[l,5-a]pyrimidin-6-yl)-4H-pyrido[l,2- a]pyrimidin-4-one (Intermediate (VI- 1), 50 mg, 0.169 mmol, and tert-butyl 3-(piperazin-l- yl)azetidine-l-carboxylate (122 mg, 0.506 mmol, 3 eq.) were stirred in DMSO (2 ml) at 120°C for 96 hours. The crude was purified by preparative HPLC. (0368) The isolated solid was then treated following the General Procedure 1 for Boc deprotection to afford the product 7-(4-(azetidin-3-yl)piperazin-l-yl)-2-(2-methyl-[l,2,4]triazolo[l,5- a]pyrimidin-6-yl)-4H-pyrido[l,2-a]pyrimidin-4-one 2,2,2-trifluoroacetate (18.8 mg, 0.035 mmol, 98.4 % yield) as a yellow solid. MS m/z 418.3 [M+H]+.
  • 9
  • [ 178311-48-3 ]
  • [ 2378259-33-5 ]
  • [ 2378259-34-6 ]
YieldReaction ConditionsOperation in experiment
85% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In 2-methyltetrahydrofuran; ethyl acetate at -20 - -10℃; for 1h; 1.g-1; 9 Step g-1: Compound H-1 (60.6 g, 0.237 mol) and compound I-1 (1-tert-butoxycarbonyl-3- (1-piperazinyl) azetidine, 57.2 g, 0.237 mol)And N, N-diisopropylethylamine (126mL, 0.711mol) were dissolved in anhydrous methyltetrahydrofuran (1.5L),Reduce the temperature to -20 -10 , then slowly add 50% T3P / ethyl acetate solution (180mL, 284.4mmol), and react at -20 -10 for 1h.TLC monitors the disappearance of raw materials. Control the reaction temperature <-10 , slowly add water (1.5L), warm to room temperature after the addition, separate the organic phase,The aqueous phase was extracted with DCM / MeOH (10: 1, 1.5 L × 2). The combined organic phases were dried, filtered, and concentrated to give a crude yellow solid.Purification by column chromatography (DCM / MeOH = 40: 1) to obtain yellow pure solid compound J-1 (96.5 g, yield: 85%,
43% With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine at 20℃; for 1h; 8 Step 8: Preparation of tert-butyl 3-(4-((4-chloro-2-hydroxy-5-(l- methylcyclopropyl)phenyl)glycyl)piperazin- 1 -yl)azetidine- 1 -carboxylate To a solution of tert-butyl 3-(piperazin-l-yl)azetidine-l-carboxylate (250 mg, 1.03 mmol) were added DIEA (530 mg, 4.1 mmol), (4-chloro-2-hydroxy-5-(l- methylcyclopropyl)phenyl)glycine (290 mg, 1.13 mmol) and PyBOP (1.07 g, 2.06 mmol). The mixture was stirred at 20°C for 1 hour. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated. The residue was purified by column chromatography on silica gel with DCM: MeOH (50:1-20:1) to give tert-butyl 3-(4-((4-chloro-2-hydroxy-5-(l-methylcyclopropyl)phenyl)glycyl)piperazin-l- yl)azetidine-l-carboxylate (210 mg, yield: 43%) as a brown oil. LC/MS (ESI) m/z 479.2 [M+l] +; 1H-NMR (400MHz, CDCb) d 6.84-6.79 (m, 1H), 6.43 (s, 1H), 3.96-3.88 (m, 4H), 3.82-3.79 (m, 2H), 3.71 (s, 2H), 3.48 (d, J = 4.0 Hz, 2H), 3.11-3.08 (m, 1H), 2.36 (d, J = 4.0 Hz, 4H), 1.93 (s, 2H), 1.82-1.73 (m, 3H), 1.41 (s, 9H), 1.26-1.23 (m. 2H).
  • 10
  • [ 2222117-24-8 ]
  • [ 178311-48-3 ]
YieldReaction ConditionsOperation in experiment
87% With 10% Pd/C; hydrogen In methanol at 25℃; for 20h; 7 Step 7: Preparation of tert-butyl 3-(piperazin-l-yl)azetidine-l-carboxylate To a solution of benzyl 4-(l-(tert-butoxycarbonyl)azetidin-3-yl)piperazine-l- carboxylate (1.7 g, 4.53 mmol) in methanol (50 mL) was added Pd/C (0.5 g, 10%). The resulting mixture was stirred under H2 at 25°C for 20h. The mixture was filtered, evaporated under reduced pressure to afford tert-butyl 3-(piperazin-l-yl)azetidine-l-carboxylate (950 mg, yield: 87%) as a colorless oil.
77.8% With Pd/C; hydrogen In methanol at 20℃; for 5h; 12.2 tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate Dissolve 4-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperazine-1-carboxylic acid benzyl ester (12a) (1.0g, 2.67mmol) with 10mL methanol in 100mL single-mouth round bottom 0.2g Pd/C (10wt%) was added to the flask, and after hydrogen replacement, the reaction was stirred and reacted for 5 hours at room temperature under a hydrogen atmosphere. The reaction solution was filtered with a sand core funnel, the filter cake was washed with 40 mL methanol, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (12b), colorless Oil (0.50 g, yield: 77.8%).
With 10% Pd/C; hydrogen In methanol at 40℃; Step b A mixture of benzyl 4-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperazine-1-carboxylate (60 g, 160 mmol) and 10% Pd/C (9 g) in MeOH (600 mL) was stirred at 40 °C for 16 h under a H2 atmosphere (50 psi). Upon completion, the mixture was filtered and evaporated to give the title compound (37 g, crude) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.93 - 3.87 (m, 2H), 3.79 (m, 2H), 3.09 - 3.01 (m, 1H), 2.92 - 2.89 (m, 4H), 2.32 (s, 4H), 1.41 (s, 9H).
With 10% Pd/C; hydrogen In methanol at 40℃; Step b A mixture of benzyl 4-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperazine-1-carboxylate (60 g, 160 mmol) and 10% Pd/C (9 g) in MeOH (600 mL) was stirred at 40 °C for 16 h under a H2 atmosphere (50 psi). Upon completion, the mixture was filtered and evaporated to give the title compound (37 g, crude) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.93 - 3.87 (m, 2H), 3.79 (m, 2H), 3.09 - 3.01 (m, 1H), 2.92 - 2.89 (m, 4H), 2.32 (s, 4H), 1.41 (s, 9H).
95.57 % With Pd/C; hydrogen In methanol at 20℃; 1.2 tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate Benzyl 4-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperazine-1-carboxylate (1B, 7g, 18.64mmol), palladium on carbon (0.7g) and methanol ( 70mL) into the reaction flask, the hydrogen was ventilated three times, and the hydrogenation reaction was carried out at room temperature for 2 hours.TLC monitored the complete reaction of the raw material, spread an appropriate amount of diatomaceous earth, filter with suction, wash with methanol (10 mL), and concentrate the filtrate to dryness under reduced pressure at 45°C to obtain 1C (4.3 g, yield: 95.57%)
100 % With Pd/C; hydrogen In methanol at 20℃; 2.2 Step 2: Preparation of 2B Add 2A (4.5 g, 11.99 mol) and palladium carbon (1.28 g) to methanol (30 mL) and react under a hydrogen balloon at room temperature for about 20 h. Spread an appropriate amount of diatomaceous earth, filter, wash with a small amount of ethyl acetate, and concentrate the filtrate under reduced pressure to dryness to obtain 2B (2.89 g, yield: 100%).

  • 11
  • [ 178311-48-3 ]
  • [ 2394769-53-8 ]
  • [ 2734713-44-9 ]
YieldReaction ConditionsOperation in experiment
74.5% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 10h; 12.3 tert-butyl3-(4-(4-((4-(methylsulfonamido)phenethyl)amino)quinazolin-2-yl)piperazin-1- yl)azetidine-1-carboxylate Weigh tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (12b) (0.12g, 0.48mmol), dissolve it in a 100mL single-necked round bottom flask with 10mL dimethyl sulfoxide, Weigh N-(4-(2-(((2-chloroquinazolin-4-yl)amino)ethyl)phenyl)methanesulfonamide intermediate 2 (0.15g, 0.398mmol) and N, N- Diisopropylethylamine (0.27g, 2.07mmol) was added to the reaction, heated to 100°C and reacted for 10 hours. The reaction was quenched by adding 30mL water, extracted with ethyl acetate (3x 25mL), the organic phases were combined, and 45mL saturated common salt was used. Wash with water once, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography to obtain 3-(4-(4-(((4-(methylsulfonamido)phenethyl)amino) Quinazolin-2-yl)piperazin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (12c), brown solid (0.172 g, yield: 74.5%).
  • 12
  • [ 178311-48-3 ]
  • [ 2757424-75-0 ]
  • [ 2757424-76-1 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane for 0.5h; 12 Compound 7 was dissolved in DCM and treated with DIPEA (3 eq) and HATU (1.3 eq). Compound 8 was dissolved in DCM and treated with DIPEA (3 eq). The compound 8 solution was poured into the compound 7 solution. The reaction was complete in 0.5 h. The reaction mixture was directly purified using a Combiflash chromatography system with liquid loading, and eluted with DCM/MeOH to afford compound 9
  • 13
  • [ 178311-48-3 ]
  • [ 1242137-15-0 ]
  • [ 2757424-78-3 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane for 0.5h; 13 Synthesis of 4-(3-(4-(4-(l-(2-(2,6-dioxopiperidin-3-yl)-l ,3-dioxoisoindolin-5-yl)azetidin- 3-yl)piperazine-l-carbonyl)-3-fluorophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-l- yl)-2-(trifhioromethyl)benzonitrile (Cpd. No. 18) Compound 1 was dissolved in DCM, and treated with DIPEA (3 eq) and HATXJ (1.3 eq). Compound 2 was dissolved in DCM and treated with DIPEA (3 eq). The compound 2 solution was poured into compound 1 solution. The reaction was complete in 0.5 h. The reaction mixture was directly purified using a Combiflash chromatography system with liquid loading, and eluted with DCM/MeOH to afford compound 3.
  • 14
  • [ 178311-48-3 ]
  • [ 2757571-66-5 ]
  • [ 2757571-69-8 ]
YieldReaction ConditionsOperation in experiment
89% Stage #1: 1-(Tert-butoxycarbonyl)-3-(1-piperazinyl)azetidine; 2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; 2.1 Step 1: Synthesis of 4-((1r,3r)-3-(5-(4-(azetidin-3-yl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile. 2-((1r,3r)-3-(3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-carboxylic acid and tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate were dissolved in DMF. To the solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was extracted by EA, washed by water and the organic phase was dried with Na2SO4. tert-Butyl 3-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-carbonyl)piperazin-1-yl)azetidine-1-carboxylate was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. The desired intermediate 4-((1r,3r)-3-(5-(4-(azetidin-3-yl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile was obtained by deprotection with TFA in DCM in 89% yield. ESI-MS: 561.25.
 

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Technical Information

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