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[ CAS No. 189819-75-8 ] {[proInfo.proName]}

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Cat. No.: {[proInfo.prAm]}
Chemical Structure| 189819-75-8
Chemical Structure| 189819-75-8
Structure of 189819-75-8 * Storage: {[proInfo.prStorage]}
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Product Details of [ 189819-75-8 ]

CAS No. :189819-75-8 MDL No. :MFCD01321014
Formula : C10H21ClN2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :KLOQZAJAQQKCNC-UHFFFAOYSA-N
M.W : 236.74 Pubchem ID :2756033
Synonyms :

Calculated chemistry of [ 189819-75-8 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.9
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 66.27
TPSA : 55.56 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.66 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 1.53
Log Po/w (WLOGP) : 1.77
Log Po/w (MLOGP) : 1.15
Log Po/w (SILICOS-IT) : 0.32
Consensus Log Po/w : 0.95

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.07
Solubility : 2.0 mg/ml ; 0.00844 mol/l
Class : Soluble
Log S (Ali) : -2.31
Solubility : 1.17 mg/ml ; 0.00495 mol/l
Class : Soluble
Log S (SILICOS-IT) : -0.92
Solubility : 28.5 mg/ml ; 0.12 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.21

Safety of [ 189819-75-8 ]

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

Application In Synthesis of [ 189819-75-8 ]

* 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 [ 189819-75-8 ]

[ 189819-75-8 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 189819-75-8 ]
  • [ CAS Unavailable ]
  • [ 888944-25-0 ]
YieldReaction ConditionsOperation in experiment
98% Stage #1: 4-amino-1-(t-butoxycarbonyl)piperidine monohydrochloride; 4-nitrobenzaldehdye With triethylamine In methanol for 21h; Heating / reflux; Stage #2: With sodium tetrahydroborate In methanol at 20℃; for 6h; Stage #3: With sodium hydrogencarbonate In methanol; water 2 EXAMPLE 2 4-(4-Nitro-benzylamino)-piperidine-1-carboxylic acid tert-butyl ester (3): A solution of 4-amino-N-Boc-piperidine hydrochloride (1) (5.0 g, 21.12 mmol), 4-nitrobenzaldehyde (2) (3.19 g, 21.12 mmol) and triethylamine (2.9 ml, 21.12 mmol) was refluxed in methanol (100 ml) for 21 h followed by the addition of sodium borohydride (1.28 g, 33.79 mmol) at rt. Stirring was continued for 6 h. Saturated sodium bicarbonate solution was added to the reaction mixture and the product was extracted with ethyl acetate (3*100 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 7.2 g (98%) of 3 as an orange oil.
  • 2
  • [ 189819-75-8 ]
  • [ CAS Unavailable ]
  • [ 522665-10-7 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃;
  • 3
  • 4-amino-1-(t-butoxycarbonyl)piperidine monohydrochloride [ No CAS ]
  • [ 99185-87-2 ]
  • tert-Butyl 4-({3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoyl}amino)-1-piperidinecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; 1,1'-carbonyldiimidazole In dichloromethane for 2h; 256-279.i 3-[3-(2-Pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.60 g) was dissolved in dichloromethane (10 ml). 1,1-Carbonyldiimidazole (0.33 g) was added followed by tert-butyl 4-amino-1-piperidinecarboxylate hydrochloride (0.5 g) and triethylamine (0.31 ml). After 2 hours water, brine and dichloromethane were added and the phases separated. The organic phase was dried, filtered and evaporated and the residue was purified by chromatography eluding with ethyl acetate:methanol (33:1) to give the subtitle compound (0.40 g). 1H NMR (399.98 MHz, DMOS) δ 1.22-1.24 (2H, m), 1.39 (9H, s), 1.62-1.71 (2H, m), 2.66-2.71 (4H, m), 3.18-3.23 (2H, m), 3.65-3.83 (3H, m), 7.58-7.63 (1H), 8.01-8.04 (3H, m), 8.74-8.76(1H, m).
  • 4
  • [ 189819-75-8 ]
  • [ 1122-91-4 ]
  • [ 846605-66-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-amino-1-(t-butoxycarbonyl)piperidine monohydrochloride; 4-bromo-benzaldehyde With N-ethyl-N,N-diisopropylamine In methanol for 4h; Heating / reflux; Stage #2: With sodium tetrahydroborate In methanol at 20℃; for 0.25h; 1.a; 11 Example 1: a) 4- (4-Bromo-benzylamino)-piperidine-1-carboxylic acid ter-butyl ester:; According to typical procedure A), 5 g of 4-bromobenzaldehyde, 6.39 g of 4- amino-piperidine-1-carboxylic acid tert.-butyl ester hydrochloride and 4.6 ml DIPEA was refluxed in dry MeOH for 4 h, cooled to rt followed by the addition of 1.02 g sodium borohydride and stirring was continued for additional 15 min. Standard aqueous work up resulted in 9.62 g of the title compound which could be used for further transformations without purification. LC-MS: tR = 0.76 ; [M+H] + = 369.12.
Stage #1: 4-amino-1-(t-butoxycarbonyl)piperidine monohydrochloride; 4-bromo-benzaldehyde With triethylamine In methanol for 18h; Reflux; Stage #2: With sodium tetrahydroborate In methanol at 0 - 20℃; for 3h; 1 Synthesis of 4-[4-(Methyl^yridin-4-yl-amino)-benzyl]-[(E)-3-(4-trifluoromacryloyl]-amino}-piperidine-1-carboxylic acid tert-butyl esterStep 1 : To a solution of 4-amino-Boc-piperidine hydrochloride (1 1 .84 g, 50 mmol, 1 .0 eq.) in MeOH (100 mL), NEt3(6.96 mL, 50 mmol, 1 .0 eq.) and 4-bromobenzaldehyde (9.25 g, 50 mmol, 1 .0 eq.) were added in sequence. The resulting solution was refluxed for 18 hours. The solution was cooled to 0 °C and sodium borohydride (3.03 g, 80 mmol, 1.6 eq.) was added portionwise. The cooling bath was removed and the solution was stirred at r.t. for 3 hours. The resulting reaction mixture was quenched with sat. aq. NaHC03soln. (50 mL). The mixture was extracted with DCM (3x 50 mL). The comb. org. phases were washed with sat. aq. NaCI soln. (1x 50 mL), dried over MgS04, and concentrated in vacuo to give 4-(4- bromo-benzylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid. The product was used without further purification.LC-MS 4: tR= 0.69 min; [M+H]+= 369.0
  • 5
  • [ 189819-75-8 ]
  • [ 871231-21-9 ]
  • [ 871231-22-0 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20 - 35℃; for 66h; 5 4-{ [4-(4-Chloro-3-ffuoro-phenylamino)-thieno[2,3-d]pyrimidine-6-carbonyl]- amino}-piperidine-1-carboxylic acid tert-butyl ester N, N-Diisopropylamine (2.5 ml) was added to a solution of 4-(3-chloro-4-fluoro- phenylamino)-thieno[2,3-d]pyrimidine-6-carboxylic acid (2 g), hydroxybenzotriazole (830 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 g) and 1-Boc-4- amino piperidine hydrochloride (1.5 g) in dichloromethane (50 ml) at ambient temperature. The mixture was stirred at ambient temperature for 18 hours, after which time further quantities of 1-Boc-4-amino piperidine hydrochloride (500 mg), 1-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (500 mg) and N,N diisopropylamine (0.8 ml) were added. The mixture was stirred for 2 days at 35°C, then partitioned between water and dichloromethane, the organic phase was dried (Na2S04) and concentrated in vacuo to a gum. This was purified by silica gel chromatography to yield 4-[4-(4-chloro-3-fluoro-phenylamino)-thieno[2,3-d]pyrimidine-6-carbonyl]- amino }-piperidine- 1 -carboxylic acid tert-butyl ester as a white solid (2.76 g). (at)H-NMR (DMSO-d6) : 1.35-1.51 (11H, m), 1.75-1.85 (2H, m), 2.78-2.93 (2H, m), 3.88- 4.00 (3H, m), 7.43 (1H, t), 7.72-7.80 (lH, m), 8.16-8.21 (1H, m), 8.33 (lH, s), 8.57- 8.63 (2H, m), 10.00 (1H, s). LCMS M/z (+) (MH+).
  • 6
  • [ 189819-75-8 ]
  • [ 112539-08-9 ]
  • [ 871096-33-2 ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide); dichloromethane at 20℃; 6; F Examule 6; Preparation of Compound No. 27 in Table 2; Route F; ten- butyl 4-[(Z-amino-1,3-thiazol-4-yl)carbonyl]amino}piperidine-1-carbo(at)ylate; 2-Amino-4-thiazolecarboxylic acid hydrobromide (2.67g) and 1-BOC-4-aminopiperidine hydrochloride (2.81g) were suspended in dichloromethane (100ml) and stirred at room temperature. Dimethylaminopyridine (5. 8g) was added followed by 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.5g). To assist with solubility, N, N-dimethylformamide (5ml) was added and stirring was continued overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (100ml) and brine (50ml). The organic portion was concentrated in vacuo and adsorbed onto silica and purified by silica gel chromatography, eluting with 0- 5%methanol/dichloromethane to yield tert-butyl 4-[(2-amino-1,3-thiazol-4- yl)carbonyl]amino }piperidine-1-carboxylate as a brown brittle foam (1.7g). ¹H-NMR (D6-DMSO) : 1.4 (11H, m), 1.7 (2H, m), 2.8 (2H, m), 3.9 (3H, m), 7.0 (2H, s), 7.15 (1H, s), 7.5 (lH,d). LCMS M/z (+) (MH+)
  • 7
  • 4-amino-1-(t-butoxycarbonyl)piperidine monohydrochloride [ No CAS ]
  • [ 144-55-8 ]
  • [ 427-49-6 ]
  • [ 185030-18-6 ]
YieldReaction ConditionsOperation in experiment
With dmap; N-ethyl-N,N-diisopropylamine; In hydrochloric acid-methanol; N,N-dimethyl-formamide; Structural formula STR14 Step 1. Synthesis of N-(piperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide To a solution of 3.51 g of <strong>[427-49-6]2-cyclopentyl-2-hydroxy-2-phenylacetic acid</strong> in 40 ml of N,N-dimethylformamide, 2.63 g of 1,1'-carbonyidiimidazole was added and stirred at room temperature for 2 hours. To the reaction mixture 3.96 g of 4-amino-1-(t-butoxycarbonyl)piperidine monohydrochloride, 200 mg of 4-dimethylaminopyridine and 6.9 ml of diisopropylethylamine were added, followed by stirring overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture followed by an extraction with diethyl ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to provide 2.84 g of a white solid. The solid was dissolved in 30 ml of 10% hydrochloric acid-methanol, and stirred overnight at room temperature. Distilling the methanol off under reduced pressure, the residue was diluted with water and washed with diethyl ether. The aqueous layer was made basic with sodium hydroxide and extracted with chloroform. The organic layer was washed with water and then with brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 2.15 g of the title compound was obtained as a white solid.
  • 8
  • 4-amino-1-(t-butoxycarbonyl)piperidine monohydrochloride [ No CAS ]
  • [ 427-49-6 ]
  • [ 530-62-1 ]
  • N-(1-t-butoxycarbonylpiperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; (1) Synthesis of N-(1-t-butoxycarbonylpiperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide STR6 To a solution of 716 mg of <strong>[427-49-6]2-cyclopentyl-2-hydroxy-2-phenylacetic acid</strong> as obtained in Step (1A) of Example 1 in 5 ml of N,N-dimethylformamide, 540 mg of 1,1-carbonyldiimidazole was added at room temperature, and stirred for an hour at the same temperature. Further 846 mg of 4-amino-1-t-butoxycarbonylpiperidine hydrochloride and 1 ml of diisopropylethylamine were added, followed by 16 hours' stirring. The reaction mixture was poured into water and extracted with diethyl ether. The extract was sequentially washed with water and saturated saline solution, dried over anhydrous magnesium sulfate and removed of the solvent by reduced pressure distillation. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/1) to give 752 mg of the title compound as a white solid.
  • 9
  • [ 189819-75-8 ]
  • [ 37517-81-0 ]
  • [ 918641-92-6 ]
YieldReaction ConditionsOperation in experiment
78% With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; 19.1 Example 19; N1-(3-Fluoro-4-(2-(1-methy-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N3-(piperidin-4-yl)malonamide (43); Step 1: 3-(1-(tert-Butoxycarbonyl)piperidin-4-ylamino)-3-oxopropanoic acid (42) The mixture of tert-butyl 4-aminopiperidine-1-carboxylate hydrochloride (512 mg, 2.16 mmol), methyl 3-chloro-3-oxopropanoate (232 μL, 2.16 mmol), and DIPEA (828 μL, 4.75 mmol) in DCM (20 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (eluent EtOAc) to afford tert-butyl 4-(3-methoxy-3-oxopropanamido)piperidine-1-carboxylate as a white solid (500 mg, 78%). MS (m/z): 301.1 (M+H). This material (500 mg, 1.67 mmol) was dissolved in MeOH/THF/H2O (2 mL/2 mL/1 mL), and LiOH×H2O (280 mg, 6.75 mmol) was added to the solution. The reaction mixture was stirred for 2 hrs, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (eluent CH3Cl/MeOH/AcOH) to afford the title compound 42 (300 mg, 63% yield) as yellowish syrup. MS (m/z): 287.1 (M+H).
  • 10
  • 4-amino-1-(t-butoxycarbonyl)piperidine monohydrochloride [ No CAS ]
  • [ 582325-22-2 ]
  • [ 1033844-24-4 ]
YieldReaction ConditionsOperation in experiment
61% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h;Product distribution / selectivity; 1-Boc-4-aminopiperidine hydrochloride (55.9 g, 0.230 mol, 1.18 HCl), (benzotriaxol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 112 g, 0.253 mol), and N, N-diisopropylethylamine (DIPEA, 140 mL, 0.805 mol) were added to a solution of 6-(3-fluorophenvl)nicotinic acid (49.9 g, 0.230 mol) in dichloromethane (1 L). The reaction mixture was stirred at room temperature for 18 h, evaporated, and chromatographed (silica gel, ethyl acetate-hexane, 2:1). The appropriate fractions were collected and evaporated to give tert-butyl 4-(2-(3-fluorophenyl)nicotinamido)piperidine-1-carboxylate (56.4 g). MS(ES+) =400 (M+1).; Step B: tert-Butyl 4-(2-(3-fluorophenyl)nicotinamido)piperidine-1-carboxylate; 1-Boc-4-aminopiperidine hydrochloride (55.9 g, 0.230 mol, 1.18 HCl), BOP (112 g, 0.253 mol), and DIPEA (140 mL, 0.805 mol) were added to a solution of the compound from Step 1 (49.9 g, 0.230 mol) in dichloromethane (1 L). The reaction mixture was stirred at room temperature for 18 h, evaporated, and chromatographed (silica gel, ethyl acetate-hexane, 2:1). The product was evaporated to give tert-butyl 4-(2-(3-fluorophenyl)nicotinamido)piperidine-1-carboxylate (yield 61%, 56.4 g). MS(ES+)=400 (M+H) observed, 400.20 expected.
  • 11
  • [ 189819-75-8 ]
  • [ CAS Unavailable ]
  • [ 1036874-70-0 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate In toluene at 100℃; A; 18 1.0 eq of the arylbromide, 1.5 eq cesium carbonate and 1.2 eq of the amine were dissolved in Toluene. If the amine was taken as a salt another equivalent of cesium carbonate was used; if additionally the arylbromide was used as a salt (HCI- or TFA- salt of the isoquinolines) again, 1 additional equivalent of cesium carbonate was used. The solution was degassed and flushed with argon. Then, 0.03 eq Pd(OAc)2 and 0.045 eq BINAP were added and the solution was heated at 100 0C until the reaction was complete or no further improvement could be achieved. For product isolation, the solution was cooled to room temperature, filtered and the filtrate was evaporated. The residue was taken up in water and extracted ethyl acetate. The organic layer was separated, dried over magnesium sulfate and the solvent was removed i. vac. The crude product was purified by preparative HPLC.
  • 12
  • [ 189819-75-8 ]
  • [ 1169560-05-7 ]
  • [ 1169560-09-1 ]
YieldReaction ConditionsOperation in experiment
13.7% With caesium carbonate In ethanol at 100℃; for 48h; 6 t-butyl-4-(8-bromo-4-oxo-3,4-dihydrobenzofuro[3,2-d]pyrimidin-2- ylamino)piperidine-l-carboxylate was synthesized in a manner similar to Example 6, Compound 115, wherein N-methylpiperazine was substituted with tert-butyl 4- aminopiperidine-1-carboxylate (HCl salt) and Cs2CO3 was employed as a base. After heating at 100 0C for 48 hours, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford tert-butyl 4-(8-bromo-4-oxo-3,4-dihydrobenzofuro[3,2-d]pyrimidin-2- ylamino)piperidine-l-carboxylate.
YieldReaction ConditionsOperation in experiment
R.9.C tert-butyl 4-aminopiperidine-1-carboxylate hydrochloride Step C tert-butyl 4-aminopiperidine-1-carboxylate hydrochloride The compound (837 mg, 2.53 mmol) obtained in step B was added to ethanol (20 ml), hydrazine monohydrate (0.31 ml, 6.4 mmol) was added, and the mixture was heated under reflux for 1 hr. The reaction mixture was cooled, and diethyl ether was added to allow precipitation of a solid. The precipitated solid was filtered, and the obtained solution was concentrated under reduced pressure to give a colorless oil. The oil was dissolved in diethyl ether, 4N hydrochloric acid-dioxane solution (1 ml) was added at room temperature and the mixture was diluted with ethyl acetate to allow precipitation of a solid. This was filtered, washed with ethyl acetate, and dried under reduced pressure to give the title compound (598 mg, yield 100%) as a colorless solid. 1H-NMR (300 MHz, DMSO-d6); δ(ppm) 1.3-1.5 (m, 2H), 1.39 (s, 9H), 1.8-1.9 (m, 2H), 2.6-2.8 (m, 2H), 3.0-3.2 (m, 1H), 3.9-4.0 (m, 2H), 8.17 (brs, 3H).
  • 14
  • [ 189819-75-8 ]
  • [ 1268512-86-2 ]
  • [ 1268513-04-7 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5-[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid With benzotriazol-1-ol; triethylamine In dichloromethane for 0.5h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h; Stage #3: 4-amino-1-(t-butoxycarbonyl)piperidine monohydrochloride In dichloromethane at 20℃; D.d1 Example D.d1 : tert-Butyl 4-[(4-[5-(cyclopropylmethoxy)-1 ,3-benzodioxol-4-yl]-6-methyl-5- [2-(trimethylsilyl)ethoxy]methyl}-5/-/-pyrrolo[3,2-c(]pyrimidin-7-yl)carbonyl]amino}piperidine-1- carboxylate4-[5-(Cyclopropylmethoxy)-1 ,3-benzodioxol-4-yl]-6-methyl-5-[2-(trimethylsilyl)ethoxy]methyl}-5/-/- pyrrolo[3,2-cf]pyϖmidine-7-carboxylic acid from example D.c1 (3.98 g; 8.0 mmol), triethylamine (2.43 g; 24.0 mmol) and HOBt (1.08 g; 8.0 mmol) is stirred in dry dichloromethane (40 mL) for 30 min, before addition of EDC (1.84 g; 9.6 mmol). The reaction mixture is stirred for one hour at ambient temperature. After addition of tert-butyl 4-amino-piperidine-1 -carboxylate hydrochloride (2.27 g; 9.6 mmol) the reaction mixture is stirred at ambient temperature until the starting material is consumed according to LC-MS and chromatographed on silica gel (ethylacetate/cyclohexane - 1 :1 ) to yield the title compound as colorless foam.MS (ESI): m/z = 680 (MH+, 100%).1H-NMR (300 MHz, DMSO-d6): 9.02 (d, J = 7.2, 1 H, -NH); 9.01 (s, 1 H); 7.01 (d, J = 8.4, 1 H); 6.57 (d, J = 8.4, 1 H); 6.07 (s, 1 H); 5.92 (s, 1 H); 5.39 (d, J = 11.0, 1 H); 5.12 (d, J = 11.0, 1 H); 4.06 (m, 1 H); 3.85 (m, 2H); 3.76 (dd, J = 10.2, 6.5, 1 H); 3.68 (dd, J = 10.2, 6.9, 1 H); 3.13-2.94 (m, 4H); 2.91 (s, 3H); 1.93 (m, 2H); 1.46 (m, 2H); 1.42 (s, 9H); 0.86 (m, 1 H); 0.61 (m, 2H); 0.29 (m, 2H); 0.01 (m, 2H); -0.13 (s, 9H).
Stage #1: 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5-[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid With benzotriazol-1-ol; triethylamine In dichloromethane for 0.5h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h; Stage #3: 4-amino-1-(t-butoxycarbonyl)piperidine monohydrochloride In dichloromethane at 20℃; D.d1 Example D.d1 tert-Butyl 4-[(4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5-[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidin-7-yl)carbonyl]amino}piperidine-1-carboxylate 4-[5-(Cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5-[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid from example D.c1 (3.98 g; 8.0 mmol), triethylamine (2.43 g; 24.0 mmol) and HOBt (1.08 g; 8.0 mmol) is stirred in dry dichloromethane (40 mL) for 30 min, before addition of EDC (1.84 g; 9.6 mmol). The reaction mixture is stirred for one hour at ambient temperature. After addition of tert-butyl 4-amino-piperidine-1-carboxylate hydrochloride (2.27 g; 9.6 mmol) the reaction mixture is stirred at ambient temperature until the starting material is consumed according to LC-MS and chromatographed on silica gel (ethylacetate/cyclohexane-1:1) to yield the title compound as colorless foam. MS (ESI): m/z=680 (MH+, 100%). 1H-NMR (300 MHz, DMSO-d6): 9.02 (d, J=7.2, 1H, -NH); 9.01 (s, 1H); 7.01 (d, J=8.4, 1H); 6.57 (d, J=8.4, 1H); 6.07 (s, 1H); 5.92 (s, 1H); 5.39 (d, J=11.0, 1H); 5.12 (d, J=11.0, 1H); 4.06 (m, 1H); 3.85 (m, 2H); 3.76 (dd, J=10.2, 6.5, 1H); 3.68 (dd, J=10.2, 6.9, 1H); 3.13-2.94 (m, 4H); 2.91 (s, 3H); 1.93 (m, 2H); 1.46 (m, 2H); 1.42 (s, 9H); 0.86 (m, 1H); 0.61 (m, 2H); 0.29 (m, 2H); 0.01 (m, 2H); -0.13 (s, 9H).
  • 15
  • [ 189819-75-8 ]
  • [ 1269239-09-9 ]
  • [ 1269239-24-8 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid With benzotriazol-1-ol; triethylamine In dichloromethane for 0.5h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h; Stage #3: 4-amino-1-(t-butoxycarbonyl)piperidine monohydrochloride In dichloromethane at 20℃; D.d1 Example D.d1 : tert-Butyl 4-[(7-[5-(cyclopropylmethoxy)-1 ,3-benzodioxol-4-yl]-2-methyl-1- [2-(trimethylsilyl)ethoxy]methyl}-1/-/-pyrrolo[3,2-fc]pyridin-3-yl)carbonyl]amino}piperidine-1- carboxylate7-[5-(Cyclopropylmethoxy)-1 ,3-benzodioxol-4-yl]-2-methyl-1-[2-(trimethylsilyl)ethoxy]methyl}-1/-/- pyrrolo[3,2-fc]pyridine-3-carboxylic acid from example D.c1 (3.98 g; 8.0 mmol), triethylamine (2.43 g; 24.0 mmol) and HOBt (1.08 g; 8.0 mmol) is stirred in dry dichloromethane (40 ml_) for 30 min, before addition of EDC (1.84 g; 9.6 mmol). The reaction mixture is stirred for one hour at ambient temperature. After addition of tert-butyl 4-amino-piperidine-1 -carboxylate hydrochloride (2.27 g; 9.6 mmol) the reaction mixture is stirred at ambient temperature until the starting material is consumed according to LC-MS and chromatographed on silica gel (ethylacetate/cyclohexane - 1 :1 ) to yield the title compound as colorless foam.MS (ESI): m/z = 679 (MH+, 100%).1H-NMR (300 MHz, DMSO-d6): 9.56 (d, J = 7.7, 1 H, -NH); 8.45 (d, J = 4.9, 1 H); 7.10 (d, J = 4.9, 1 H); 6.96 (d, J = 8.6, 1 H); 6.56 (d, J = 8.6, 1 H); 5.99 (s, 1 H); 5.92 (s, 1 H); 5.29 (d, J = 10.9, 1 H); 5.11 (d, J = 10.9, 1 H); 4.08 (m, 1 H); 3.84 (m, 2H); 3.76 (dd, J = 10.2, 6.6, 1 H); 3.67 (dd, J = 10.2, 6.8, 1 H); 3.06(m, 2H); 3.03-2.87 (m, 2H); 2.87 (s, 3H); 1.93 (m, 2H); 1.45 (m, 2H); 1.42 (s, 9H); 0.89 (m, 1 H); 0.59 (m, 2H); 0.31 (m, 2H); 0.03 (m, 2H); -0.14 (s, 9H).
  • 16
  • [ 189819-75-8 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
69.9% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 18 - 25℃; for 0.5h; 3.1.25 Route 1 Intermediate 25: tert-butyl 4-^2S,5R)-6-(allyloxy)-4-methyl-7-oxo-l,6- diazabicyclo[3.2.11oct-3-ene rboxamido)piperidine-l-carboxylate General procedure: Route 1 Intermediate 25: tert-butyl 4-^2S,5R)-6-(allyloxy)-4-methyl-7-oxo-l,6- diazabicyclo[3.2.11oct-3-ene rboxamido)piperidine-l-carboxylate To a solution of (2S,5R)-6-(allyloxy)-4-methyl-7-oxo-l,6-diazabicyclo[3.2.1]oct-3-ene-2- carboxylic acid (Intermediatel5, 0.407 g, 1.71 mmol) in DMF (7 mL) at room temperature was added l-Boc-4-amino-piperidine hydrochloride (0.809 g, 3.42 mmol), 0-(7-azabenzotriazol-l- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.299 g, 3.42 mmol) and N,N- diisopropylethylamine (1.190 mL, 6.83 mmol). After 30 minutes, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate, brine and 1/1 brine/water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-60% ethyl acetate/hexanes) afforded the desired product (0.502 g, 69.9 %) as an off-white foam. MS: 421 ES+ (C21H32N4O5) 1H NMR (300 MHz. DMSO-dfi) δ: 1.32 (m, 2H); 1.39 (s, 9H); 1.66 (m, 2H); 1.79 (m, 3H); 2.81 (m, 2H); 3.14 (m, 1H); 3.32 (m, 1H); 3.73 (m, 1H); 3.84 (m, 3H); 4.14 (m, 1H); 4.36 (m, 2H); 5.24-5.42 (m, 3H); 5.88-6.02 (m, 1H); 8.00 (m, 1H).
  • 17
  • [ 189819-75-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 18 - 25 °C 2.1: acetic acid / dichloromethane / 0.5 h / 18 - 25 °C 2.2: 18 - 25 °C
  • 18
  • [ 189819-75-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 18 - 25 °C 2.1: acetic acid / dichloromethane / 0.5 h / 18 - 25 °C 2.2: 18 - 25 °C 3.1: trifluoroacetic acid / dichloromethane / 0 - 25 °C
  • 19
  • [ 189819-75-8 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 18 - 25℃; for 0.5h; 3.2.25 Intermediate 25: tert-butyl 4-(T2S,5R)-6-(aHyloxy)-4-methyl-7-oxo-l,6- diazabicyclo[3.2.11oct-3-enecarboxamido)piperidine-l-carboxylate Intermediate 25: tert-butyl 4-(T2S,5R)-6-(aHyloxy)-4-methyl-7-oxo-l,6- diazabicyclo[3.2.11oct-3-enecarboxamido)piperidine-l-carboxylate The title compound was prepared from (2R,5R)-6-(allyloxy)-4-methyl-7-oxo-l,6- diazabicyclo[3.2.1]oct-3-ene-2-carboxylic acid (Intermediate 32) following the procedure described in Route 1 for Intermediate 25. See Route 1 for final 2 steps.
  • 20
  • [ 189819-75-8 ]
  • [ 39221-42-6 ]
  • [ 1802528-29-5 ]
YieldReaction ConditionsOperation in experiment
67% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;
  • 21
  • 4-amino-1-(t-butoxycarbonyl)piperidine monohydrochloride [ No CAS ]
  • [ 1679-64-7 ]
  • tert-butyl 4-(4-(methoxycarbonyl)benzamido)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 18h; x.a tert-Butyl 4-(4-(methoxycarbonyl)benzamido)piperidine- 1 -carboxylate (122) 4-(Methoxycarbonyl)benzoic acid (1 .00 g, 5.55 mmol), DCM (25 mL), DMAP (34 mg, 5 mol%), ieri-butyl 4-aminopiperidine-1 -carboxylate hydrochloride salt (1.45 g, 6.1 1 mmol) and EDCI.HCI (1 .28 g, 6.66 mmol) were stirred at room temperature. After 18 hours the mixture was diluted with 10% w/v NaHSCu (50 mL) and DCM (50 mL). The aqueous phase was extracted with further DCM (2 50 mL), the pooled DCM extracts were washed with 1 :1 saturated aqueous NaHCC : water (50 mL), dried over sodium sulfate and concentrated in vacuo to give the desired compound (1.82 g, 91 % yield) as a white solid. 1H NMR (400 MHz, CDC ) δ 8.10 - 8.06 (m, 2H), 7.83 - 7.78 (m, 2H), 6.1 1 (d, J = 7.9 Hz, 1 H), 4.19 - 4.04 (m, 3H), 3.94 (s, 3H), 2.98 - 2.81 (m, 2H), 2.07 - 1.97 (m, 2H), 1.51 - 1.35 (m, 1 1 H). LCMS-B: RT 3.63 min; m/z 307.1 [M-'Bu+2H]+, 385.2 [M+Na] ', 263.1 [M-Boc+2H] m/z 361.2 [M-H]-
  • 22
  • [ 189819-75-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 18 h / 20 °C 2: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 - 20 °C 3: hydrogenchloride / 1,4-dioxane / 5 h / 20 °C 4: triethylamine; dmap / dichloromethane / 17 h / 20 °C 5: lithium hydroxide monohydrate / water; tetrahydrofuran; methanol / 3 h / 20 °C 6: triethylamine; HATU / N,N-dimethyl-formamide / 17 h / 20 °C
  • 23
  • [ 189819-75-8 ]
  • [ 1884246-48-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 18 h / 20 °C 2: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 - 20 °C
  • 24
  • [ 189819-75-8 ]
  • [ 1884246-50-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 18 h / 20 °C 2: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 - 20 °C 3: hydrogenchloride / 1,4-dioxane / 5 h / 20 °C
  • 25
  • [ 189819-75-8 ]
  • [ 1884246-51-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 18 h / 20 °C 2: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 - 20 °C 3: hydrogenchloride / 1,4-dioxane / 5 h / 20 °C 4: triethylamine; dmap / dichloromethane / 17 h / 20 °C
  • 26
  • [ 189819-75-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 18 h / 20 °C 2: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 - 20 °C 3: hydrogenchloride / 1,4-dioxane / 5 h / 20 °C 4: triethylamine; dmap / dichloromethane / 17 h / 20 °C 5: lithium hydroxide monohydrate / water; tetrahydrofuran; methanol / 3 h / 20 °C
  • 27
  • [ 189819-75-8 ]
  • [ 1884246-54-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 18 h / 20 °C 2: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 - 20 °C 3: hydrogenchloride / 1,4-dioxane / 5 h / 20 °C 4: triethylamine; dmap / dichloromethane / 17 h / 20 °C
  • 28
  • [ 189819-75-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 18 h / 20 °C 2: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 - 20 °C 3: hydrogenchloride / 1,4-dioxane / 5 h / 20 °C 4: triethylamine; dmap / dichloromethane / 17 h / 20 °C 5: lithium hydroxide monohydrate / water; tetrahydrofuran; methanol / 3 h / 20 °C
  • 29
  • [ 189819-75-8 ]
  • [ CAS Unavailable ]
  • [ 2758159-96-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate / dichloromethane 1.2: 1 h / 0 - 20 °C 1.3: 20 °C 2.1: hydrogen bromide; acetic acid / 0.5 h / 0 - 20 °C
  • 30
  • [ 189819-75-8 ]
  • [ 32315-10-9 ]
  • [ CAS Unavailable ]
  • [ 2758159-94-1 ]
YieldReaction ConditionsOperation in experiment
21% Stage #1: 4-amino-1-(t-butoxycarbonyl)piperidine monohydrochloride With sodium hydrogencarbonate In dichloromethane Stage #2: bis(trichloromethyl) carbonate With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h; Stage #3: Niclosamide With pyridine; dmap In dichloromethane at 20℃; 4.1.8 tertbutyl4-(((4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)phenoxy) carbonyl)amino)piperidine-1-carboxylate (9) A solution of tertbutyl 4-aminopiperidine-1-carboxylate hydrochloride (3.0g, 12.7 mmoL) in DCM (40.0mL) was fiercely mixed with saturated sodium bicarbonate solution (30.0mL). The organic phase was dried over anhydrous MgSO4, and then concentrated under reduced pressure to afford 2.3g of 4-aminopiperidine-1-carboxylate as a yellow oil in a 91.0% yield. Next, a cooled solution (0°C) of triphosgene (3.54g, 11.96 mmoL) in dry DCM (10.0mL) was introduced to a dry DCM solution (10.0mL) of the above yellow oil (2.3g, 11.5 mmoL) and N,N-diisopropylethylamine (3.8mL, 23.0 mmoL) in a dropwise fashion. The mixture was allowed to warm to r. t. and stirred for 1.0h, and then concentrated under diminished pressure to afford the residue without purification for next reaction. Finally, to a solution of niclosamide (3.76g, 11.5 mmoL) dissolved in a mixture of dry DCM (10.0mL) and dry pyridine (1.0mL) were added dropwise the above residue and 0.20g of 4-dimethylaminopyridine. The resulting solution was stirred at r.t. overnight. After the reaction was over, EtOAc (200.0mL) was added. The organic layer was washed with diluted hydrochloric acid (1M), water and brine in order, and dried by anhydrous Na2SO4, and then concentrated to afford a yellow solid, which was further purified by silica gel chromatography with a mixture of EtOAc and petroleum ether (V/V=1/10) as an eluent to yield 1.33g of 9 as an yellow solid. (0033) Yield, 21.0%. 1H NMR (400MHz, CDCl3) δ 8.40 (d, 1H, J=2.4Hz), 8.24 (dd, 1H, J=8.0, 2.4Hz), 8.03 (d, 1H, J=2.4Hz), 7.64 (dd, 1H, J=8.0, 2.4Hz), 7.50 (d, 1H, J=8.0Hz), 7.21 (d, 1H, J=8.0Hz), 3.96 (dt, 1H, J=8.0, 4.0Hz), 3.62-3.44 (m, 2H), 3.15-3.10 (m, 2H), 1.73-1.55 (m, 2H), 1.41 (s, 9H), 1.38-1.29 (m, 2H).
  • 31
  • [ 189819-75-8 ]
  • [ 888944-30-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sodium carbonate; sodium iodide / N,N-dimethyl-formamide / 0.17 h / 0 °C / Molecular sieve; Inert atmosphere; Schlenk technique 1.2: 6 h / 0 - 90 °C / Molecular sieve; Inert atmosphere; Schlenk technique 2.1: (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; 4,4'-di-tert-butyl-2,2'-bipyridine nickel(II) bromide; potassium carbonate / tetrahydrofuran / 20 h / 0 - 20 °C / Sealed tube; Inert atmosphere; Irradiation; Schlenk technique
  • 32
  • [ 189819-75-8 ]
  • [ 2344-80-1 ]
  • [ 2648801-83-4 ]
YieldReaction ConditionsOperation in experiment
46% Stage #1: 4-amino-1-(t-butoxycarbonyl)piperidine monohydrochloride With sodium carbonate; sodium iodide In N,N-dimethyl-formamide at 0℃; for 0.166667h; Molecular sieve; Inert atmosphere; Schlenk technique; Stage #2: Chloromethyltrimethylsilane In N,N-dimethyl-formamide at 0 - 90℃; for 6h; Molecular sieve; Inert atmosphere; Schlenk technique;
  • 33
  • [ 189819-75-8 ]
  • [ CAS Unavailable ]
  • [ 2766694-98-6 ]
  • [ 2766696-48-2 ]
YieldReaction ConditionsOperation in experiment
78.76% 3.6.16.e Step One Step One To a solution of compound 136, 5-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl) pyrimidine-2-carboxylic acid (200 mg, 400.39 umol) and tert-butyl 4-amino piperidine-1-carboxylate hydrochloride (113.74 mg, 480.46 umol) in DMF (8 mL) was added DIEA (155.24 mg, 1.20 mmol) and T3P (382.18 mg, 600.58 umol, 50% purity). The reaction mixture was stirred at 25° C. for 3 h. The resulting solution was quenched by saturated NH4Cl (50 mL) and extracted with EA (50 mL*2), the combined organic layer was washed by water (50 mL*2) and brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography to afford tert-butyl 4-(5-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)pyrimidine-2-carboxamido)piperidine-1-carboxylate (215 mg, 78.76% yield) as a yellow solid. MS: m/z=682.3 (M+1, ESI+).
  • 34
  • [ 189819-75-8 ]
  • [ 2766694-98-6 ]
  • [ 2766696-48-2 ]
YieldReaction ConditionsOperation in experiment
78.76% With propylphosphonic anhydride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 3h; 5.6.16.1 Step One To a solution of compound 136, 5-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl) pyrimidine-2-carboxylic acid (200 mg, 400.39 umol) and tert-butyl 4-amino piperidine-1-carboxylate hydrochloride (113.74 mg, 480.46 umol) in DMF (8 mL) was added DIEA (155.24 mg, 1.20 mmol) and T3P (382.18 mg, 600.58 umol, 50% purity). The reaction mixture was stirred at 25° C. for 3 h. The resulting solution was quenched by saturated NH4Cl (50 mL) and extracted with EA (50 mL*2), the combined organic layer was washed by water (50 mL*2) and brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography to afford tert-butyl 4-(5-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)pyrimidine-2-carboxamido)piperidine-1-carboxylate (215 mg, 78.76% yield) as a yellow solid. MS: m/z=682.3 (M+1, ESI+).
78.76% With propylphosphonic anhydride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 3h; 5.6.16.1 Step One To a solution of compound 136, 5-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl) pyrimidine-2-carboxylic acid (200 mg, 400.39 umol) and tert-butyl 4-amino piperidine-1-carboxylate hydrochloride (113.74 mg, 480.46 umol) in DMF (8 mL) was added DIEA (155.24 mg, 1.20 mmol) and T3P (382.18 mg, 600.58 umol, 50% purity). The reaction mixture was stirred at 25° C. for 3 h. The resulting solution was quenched by saturated NH4Cl (50 mL) and extracted with EA (50 mL*2), the combined organic layer was washed by water (50 mL*2) and brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography to afford tert-butyl 4-(5-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)pyrimidine-2-carboxamido)piperidine-1-carboxylate (215 mg, 78.76% yield) as a yellow solid. MS: m/z=682.3 (M+1, ESI+).
  • 35
  • [ 189819-75-8 ]
  • [ 6627-22-1 ]
  • [ 2763282-69-3 ]
YieldReaction ConditionsOperation in experiment
93.4% With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 15h; 110.1; 143.1 The first step: preparation of methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)pyrimidine-4-carboxylate: 6-Chloro-pyrimidine-4-carboxylic acid methyl ester (1 g, 5.80 mmol, 1.0 equiv.), 1-tert-butoxycarbonyl-4-aminopiperidine hydrochloride (1.65 g, 6.95 mmol, 1.2 equiv.) and DIPEA (N,N-diisopropylethylamine) (3.00 g, 23.18 mmol, 4.0 equiv.) was dissolved in MeCN (acetonitrile) (30 mL) and reacted at 90° C. for 15 hours. The reaction solution was concentrated, and the crude product was separated and purified by flash chromatography (silica gel, PE:EA=3:2) to obtain the target compound (1.82 g, 93.4%) as a yellow solid.
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