Structure of 192130-34-0
*Storage: {[sel_prStorage]}
*Shipping: {[sel_prShipping]}
The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
4.5
*For Research Use Only !
Change View
Size | Price | VIP Price | US Stock |
Global Stock |
In Stock | ||
{[ item.pr_size ]} |
Inquiry
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,1,item.pr_is_large_size_no_price, item.discount_usd) ]} {[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]} |
Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]} | Inquiry {[ item.pr_usastock ]} In Stock Inquiry - | {[ item.pr_chinastock ]} {[ item.pr_remark ]} In Stock 1-2 weeks - Inquiry - | Login | - + | Inquiry |
Please Login or Create an Account to: See VIP prices and availability
US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days
1-2weeks
Inquiry
{[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
{[ getRatePrice(item.pr_usd,1,item.mem_rate,item.pr_is_large_size_no_price, item.pr_usd) ]}
Inquiry
{[ getRatePrice(item.pr_usd,item.pr_rate,1,item.pr_is_large_size_no_price, item.vip_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
In Stock
- +
Please Login or Create an Account to: See VIP prices and availability
US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
CAS No. : | 192130-34-0 |
Formula : | C11H23N3O2 |
M.W : | 229.32 |
SMILES Code : | NCCN1CCN(C(OC(C)(C)C)=O)CC1 |
MDL No. : | MFCD02683049 |
InChI Key : | QSYTWBKZNNEKPN-UHFFFAOYSA-N |
Pubchem ID : | 1514400 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 16 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.91 |
Num. rotatable bonds | 5 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 70.92 |
TPSA ? Topological Polar Surface Area: Calculated from |
58.8 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.64 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.02 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.26 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.32 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.01 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.53 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.92 |
Solubility | 27.6 mg/ml ; 0.12 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.77 |
Solubility | 39.4 mg/ml ; 0.172 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.02 |
Solubility | 21.9 mg/ml ; 0.0955 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
Yes |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.71 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.48 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 4-methyl-morpholine; benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | A solution of Compound 4-7 (0.24 g, 0.58 mmol) in dimethylformamide (3 mL) was combined with N-methylmorpholine (0.19 mL, 1.74 mmol), 1-hydroxybenzotriazole (0.04 g, 0.29 mmol), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 0.26 g, 0.70 mmol) and Compound 4-8 (0.16 g, 0.70 mmol). The reaction mixture was stirred overnight at rt, quenched with saturated ammonium chloride, and extracted with ethylacetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by RP HPLC (gradient elution with 10-60percent acetonitrile in water, each with 0.1percent TFA) and lyophilized to yield Compound 66 as white solid (trifluoroacetate salt, 0.26 g, 72percent). 1H NMR (300 MHz, DMSO) delta 7.58-7.53 (m, 2H), 7.37 (d, J=8.5 Hz, 1H), 7.30 (m, 1H), 7.12-7.05 (m, 3H), 4.70 (s, 2H), 4.3-3.1 (m, 21H), 2.0-1.8 (m, 4H), 1.42 (s, 9H); MS (ES+) m/z 626.1 (M+1); Anal Calcd. for C33H44ClN5O5-3.6CF3CO2H: C, 46.58; H, 4.63; N, 6.76. Found: C, 46.25, H, 4.48; N, 6.73. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Example 130; tert-Butyl 4-(2-{2-[6-chloro-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3- dihydrobenzimidazol-1 -yl]-2-phenylacetylamino}ethyl)piperazine-1 -carboxylate; 474 mg (1.00 mmol) of 6-chloro-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3- dihydrobenzimidazol-1-yl]phenylacetic acid (XIIIa), 204 mg (1.50 mmol) of HOBt and <n="136"/>850 mg (1.10 mmol) of solid phase-bound PS-carbodiimide (Argonaut, 1.3 mmol/g) were dissolved in 10 ml of dry dichloromethane in a screw-cap tube and checked mechanically at room temperature for 10 min. 241 mg (1.05 mmol) of 1-Boc-(2- aminoethyl)piperazine were added, and the mixture was then checked mechanically overnight. Three equivalents of solid phase-bound MP-carbonate were then added to the reaction mixture, and checking was continued for 2 h. The solid phase-bound reagents were filtered off and washed with dichloromethane. The filtrate was concentrated in vacuo, and the residue was dried in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 0.5-5percent methanol in dichloromethane). Yield: 574 mg (84percent) of colorless oil.1H-NMR (methanol-d4): 1.46 (s, 9H), 2.28-2.52 (m, 6H), 3.32-3.50 (m, 6H), 3.89 (s, 3H), 6.20 (s, 1 H), 6.80 (s, 1 H), 7.07-7.14 (m, 3H), 7.24-7.38 (m, 5H), 7.86 (d, J = 8.6 Hz, 1 H), 8.01 (d, J = 8.8 Hz, 2H). MS (API-ES, pos) m/z = 684, 686 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 20 - 130℃; for 15.25h; | A vial was charged with palladium (II) acetate (0.012 g, 0.054 mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.034 g, 0.054 mmol). Toluene (1.0 mL) was added and the system was flushed with argon. The vial was capped and the mixture stirred at room temperature for 15 min. A resealable tube was charged with 4-(4-chloro-3-phenyl-furo[2,3-b]pyridin-2-yl)-phenol (6) (0.174 g, 0.541 mmol), 4-N-(tert-butoxycarbonyl)-1-aminoethylpiperazine (0.248 g, 1.08 mmol), and potassium carbonate (1.495 g, 10.82 mmol). The Pd/BINAP solution was added along with 1.0 mL of toluene, and the system was flushed with argon. The tube was sealed and the mixture stirred at 130 C. for 15 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford a brown solid. This material was purified via column chromatography on silica gel (eluting with 0-50% (90:10:1, dichloromethane/methanol/ammonium hydroxide)-dichloromethane) to afford 4-{2-[2-(4-hydroxy-phenyl)-3-phenyl-furo[2,3-b]pyridin-4-ylamino]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester 7a as a tan solid. MS (MH+) 515.2; Calculated 514 for C30H34N4O4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With hydrazine hydrate; In ethanol; for 24h;Reflux; | General procedure: Example 4 Production of 2-(4-Cyclohexylpiperazin-1-yl)ethylamine. Hydrazine monohydrate (0.8 g, 16 mmol) was added to an ethanol (30 mL) solution of the compound obtained in Example 3 (2.8 g, 8.2 mmol) at room temperature, and the mixture was heated under refluxing for 24 hours. The precipitated crystals were filtered away, and the solvent of the filtrate was distilled off under a reduced pressure. The residue was purified with silica gel column chromatography (chloroform : methanol = 95:5), to give the captioned compound (1.3 g, 75percent) as an oily product. 1H-NMR (DMSO-d6) delta: 1.05-1.17 (m, 5H), 1.53-1.55 (m, 1H), 1.68-1.71 (m, 4H), 2.11-2.13 (m, 1H), 2.30-2.45 (m 7H), 2.48-2.51 (m, 3H), 3.67 (t, J=6.6 Hz, 2H). |
Following the procedure of Example 6, and substituting the following for N,N-dimethylethylenediamine:...1-(2-aminoethyl)-4-phenylpiperidine,1-(2-aminoethyl)-2,6-dimethylpiperidine,1-(2-aminoethyl)-4-hydroxy-4-phenylpiperidine,1-(2-aminoethyl)-4-phenyl-1,2,3,6-tetrahydropyridine,1-(2-aminoethyl)-4-tertiarybutoxycarbonylpiperazine,1-(2-aminoethyl)-4-methylpiperazine,1-(2-aminoethyl)-4-phenylpiperazine,1-(2-aminoethyl)-4-(phenylmethyl)-piperazine, and... | ||
When in the procedure of Example 20 the following are reacted with 3-phenoxypyrrolidinecarbonyl chloride:N-(2-aminoethyl)morpholine,N-(2-aminoethyl)pyrrolidine,N-(2-aminoethyl)piperidine,1-(2-aminoethyl)-4-methylpiperazine, and1-(2-aminoethyl)-4-(t-butoxycarbonyl)piperazine, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 20℃; for 2h;molecular sieve 3 A; | 687 g of 4-amino-2-(trifluoromethyl)benzonitrile with 311 mul of thiophosgene in 4 ml of N,N-dimethylformamide was stirred for one hour at room temperature under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with water and then concentrated by evaporation in a vacuum. The thus obtained crude isothiocyanate was combined with the cyanoamine that was produced and filtered by two hours of stirring from 743 mul of acetone cyanohydrin with 930 mg of 1,1-dimethylethyl 4-(2-aminoethyl)piperazine-1-carboxylate and 406 mg of a molecular sieve 3 A in 20 ml of tetrahydrofuran at room temperature, and it was heated to boiling for one hour with 0.57 ml of triethylamine in 40 ml of tetrahydrofuran. After concentration by evaporation in a vacuum, the title compound was obtained as a crude product, which was immediately further reacted. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In diethyl ether; acetonitrile; at 70℃; for 4h; | N-(5-tert-Butylisoxazol-3-yl)-N- {3- [ (2-chloropyrimidin-5-yl) ethynyl] phenyl} urea (Intermediate 9) (0.22 g) and tert-butyl 4-(2-aminoethyl)-piperazine-1-carboxylate (0.38 g) were stirred in MeCN (10 mL) and hydrogen chloride (I. OM solution in ether) (0.11 mL) was added dropwise. The reaction mixture was stirred and heated at 70°C for 4 hours. The solvent was evaporated and the residue was dissolved in DCM (20 mL) and TFA (10 mL). The reaction mixture was stirred at ambient temperature for 2 hours, the solvent was evaporated and the product was purified by flash chromatography on silica using 1-20percent (7N NH3 in MeOH) in DCM as eluent. The product was triturated with ether to give the title compound as an off-white solid (274 mg, 99percent); 'H NMR (DMSO-d6) 1.29 (s, 9H), 2.45-2. 57 (m, 2H), 2.57-2. 65 (m, 4H), 3.03-3. 10 (m, 4H), 3.39-3. 49 (m, 2H), 6.49 (s, 1H), 7.10-7. 16 (m, 1H), 7.29-7. 35 (m, 2H), 7.51 (t, 1H), 7.75 (s, 1H), 8.40-8. 52 (m, 3H), 8.99 (s, 1H), 9.62 (s, 1H) ; MS m/e MH+ 489. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With pyridine; for 12h; | EXAMPLE 24; N-(2-methanosulfonylethyl)-piperazine hydrochloride; Methanesulfonyl chloride (0.7 mL, 9.0 mmol) was added to a cooled solution of <strong>[192130-34-0]4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester</strong> (1.33 g, 5.8 mmol) in pyridine (25.0 mL). The reaction was stirred for 12 h and partitioned between partitioned between aqueous sodium bicarbonate and methylene chloride. The organic phase was washed with 1 M hydrochloric acid, aqueous sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the crude residue by chromatography over silica gel using 0-5percent methanol in methylene chloride gave 4-(2-methanesulfonylamino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.70 g, 70percent). |
70% | With pyridine; for 12h; | EXAMPLE43 N-(2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethyl)-methanesulfonamide; Methanesulfonyl chloride (0.7 mL, 9.0 mmol) was added to a cooled solution of <strong>[192130-34-0]4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester</strong> (1.33 g, 5.8 mmol) in pyridine (25.0 mL). The reaction was stirred for 12 h and partitioned between partitioned between aqueous sodium bicarbonate and methylene chloride. The organic phase was washed with 1M hydrochloric acid, aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the crude residue by flash chromatography over silica gel using 0-5percent methanol in methylene chloride gave 4-(2-methanesulfonylamino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.70 g, 70percent). |
70% | With pyridine; for 12h; | Methanesulfonyl chloride (0.7 mL, 9.0 mmol) was added to a cooled solution of 4-(2-amino- ethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.33 g, 5.8 mmol) in pyridine (25.0 mL). The reaction was stirred for 12 h and partitioned between partitioned between aqueous sodium bicarbonate and methylene chloride. The organic phase was washed with 1M hydrochloric acid, aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the crude residue by chromatography over silica gel using 0-5percent methanol in methylene chloride gave 4-(2-methanesulfonylamino-ethyl)-piperazine-l- carboxylic acid tert-butyl ester (0.70 g, 70percent). To a cooled solution of 4-(2-methanesulfonylamino-ethyl)-piperazine- I -carboxylic acid tert- butyl ester (0.64 g, 0.2 mmol) in dioxane (20 mL) was added hydrochloric acid (4M in dioxane, 10 mL) and the reaction was stirred at room temperature for 12 h and concentrated to give N- (2-methanosulfonylethyl) -piperazine dihydrochloride as a white solid (0.55 g, 95percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 20 - 130℃; for 2.25h; | A resealable tube was charged with 4-chloro-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-phenyl-furo[2,3-b]pyridine 6c (0.048 g, 0.110 mmol), 4-N-(tert-butoxycarbonyl)-1-aminoethylpiperazine 9a (0.051 g, 0.221 mmol), and potassium carbonate (0.304 g, 2.20 mmol). The Pd/BINAP solution was added along with 1.5 mL of toluene, and the system was flushed with argon. The tube was sealed and the mixture stirred at 130° C. for 2 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford an orange brown oil. This oil was purified via preparative thin layer chromatography (eluting twice with 95:5:0.5, dichloromethane/methanol/ammonium hydroxide) to afford 4-(2-{2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-phenyl-furo[2,3-b]pyridin-4-ylamino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester 10d as an off white solid. MS (MH+) 628.1; Calculated 627 for C36H45NO5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 20 - 130℃; for 20.25h; | A resealable tube was charged with 4-chloro-2-(3-fluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-3-phenylfuro[2,3-b]pyridine 6e (0.096 g, 0.213 mmol), 4-N-(tert-butoxycarbonyl)-1-aminoethylpiperazine (0.098 g, 0.426 mmol), potassium carbonate (0.589 g, 4.26 mmol), and toluene (3 mL). The Pd/BINAP solution was added along with 1.5 mL of toluene, and the system was flushed with argon. The tube was sealed and the mixture stirred at 130° C. for 20 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford an orange brown oil. This oil was purified via preparative thin layer chromatography (eluting with 95:5:0.5, dichloromethane/methanol/ammonium hydroxide) to afford tert-butyl 4-(2-(2-(3-fluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-3-phenylfuro[2,3-b]pyridin-4-ylamino)ethyl)piperazine-1-carboxylate (not shown) as a yellow oil. MS (MH+) 644.4; Calculated 643 for C37H46FN5O4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In butan-1-ol; at 100℃; for 24h; | To a mixture of 6j (0.812 g, 1.86 mmol, 1.0 equiv) in n-BuOH (30 mL) was added tert-butyl-4-(2-aminoethyl)piperazine-1-carboxylate (2.80 g, 13.0 mmol, 7.0 equiv). After heating at 100° C. for 24 hrs, the solvent was removed in vacuo. The resulting residue was purified by silica gel chromatography (5percent MeOH:CH2C12) to afford carbamate 8c. MS (MH+) 630.1; Calculated 629.3 for C38H39N5O4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 1.5h; | A mixture of 69 (0.2 g, 0.57 mmol), 4-(2-amino-ethyl)-piperazine-l-carboxylic acidtert-butyl ester (0.26 g, 1.13 mmol) and DIEA (0.20 mL, 1.14 mmol) in 1-butanol (5 mL) washeated to 120°C for 1.5 h. After concentration, the residue was purified by silica gelchromatography using 2-5percent MeOH/DCM, to give 4-[2-(5,6-diphenyl-furo[2,3-d]pyrimidin-4-ylamino)-ethyl]-piperazine-l-carboxylic acid tert-butyl ester 71 (0.20 g). Compound 71 wassubjected to 20 mL of 20percent TFA/DCM at rt for 2 h, then the reaction was concentrated almostto dryness under reduced pressure, and purified by silica gel column chromatography using0.1percent MeOH/DCM containing ImL ammonium hydroxide, to give 72 (0.15 g). MS: 400.2(M+l). 'HNMRtDMSO-dg) ppm 8.36 (s, 1H), 7.61-7.33 (m, 10H), 5.49 (t, 1H, J=4.48Hz),3.45 (dd, 2H, Jr=5.10Hz, J2=5.84Hz), 2.33 (t, 2H, J=5.80Hz), 2.13 (br, 4H), 1.95 (br, 1H)(note: some peaks overlapped with water peak in DMSO-de). 'HNMR (CCla-d) ppm 8.43 (s,1H), 7.60-7.50 (m, 6H), 7.50-7.26 (m, 4H), 5.39 (t, 1H), 3.54 (dd, 2H, J^S.OSHz, J2=6.20Hz),2.73 (t, 4H, J=4.71Hz), 2.44 (t 2H, J=5.91Hz), 2.28 (br, 4H), 1,87 (br, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.6 g (26%) | With triethylamine; In N-methyl-acetamide; methanol; | a 4-(2-Amino-ethyl)-piperazine-1-carboxylic Acid Tert-butyl Ester A solution of N-tert-butoxycarbonyl-piperazin (5 g, 26.8 mmol), triethylamine (7.44 ml, 53.6 mmol), and chloroethylamine (3.11 g, 26.8 mmol) in dimethylformamide (50 ml) was stirred at room temperature for 72 hours. The reaction mixture was filtered, partitioned between H2O and ethyl acetate. The aqueous phase was lyophilized, the residue stirred with methanol and the precipitate collected by suction. The precipitate was purified by flash chromatography on silica gel (dichloromethane/methanol/aqueous ammonia=9/1/0.1) to give 1.6 g (26percent) of the desired product. MS m/z: 230 ((M+H)+, 91percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In dichloromethane; N,N-dimethyl-formamide; | (c) tert-Butyl 4-[2-({4-chloro-2-[2-(dimethylamino)-2-oxoethoxy]benzoyl}amino)ethyl]-1-piperazinecarboxylate The product from step (b) (0.7 g) and 1,1'-carbonyldiimidazole (0.62 g) were dissolved in N,N-dimethylformamide (10 ml) and stirred at room temperature for 1 hour. tert-Butyl 4-(2-aminoethyl)-1-piperazinecarboxylate (2.73 g) was added, the solution stirred for 16 hours and then evaporated to leave a gum. Dichloromethane and sodium bicarbonate solution were added, the organic phase was separated, dried and concentrated to a gum which was purified by chromatography (ethyl acetate:triethylamine, 10:1) to give the product as a solid (0.62 g), m.p. 139-140° C. MS: ESI: 469.22 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; trifluoroacetic acid; In dichloromethane; | (a) 4-Chloro-2-methoxy-N-[2-(1-piperazinyl)ethyl]benzamide trifluoroacetate A solution of 4-chloro-2-methoxybenzoyl chloride (2.1 g), tert-butyl 4-(2-aminoethyl)-1-piperazinecarboxylate (3.0 g) and triethylamine (2.6 ml) in dichloromethane (100 ml) was stirred at room temperature for 72 hours. The solution was washed with brine, dried and treated with trifluoroacetic acid. After 16 hours the solution was concentrated and the residue triturated under ether to give the product as an oil (4.1 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | In tetrahydrofuran; at 180℃; for 0.583333h;Microwave irradiation in sealed vial; | A microwave vial was charged with 4-(4-benzylphenylamino)-6-fluoro-1 ,7- naphthyridine-3-carbonitrile (0.100 g, 0.282 mmol), 1-N-BOC-4-(2- aminoethyl)piperazine and 2 mL THF, crimp-sealed, and heated in a microwave reactor at 180 0C for 35 minutes, until TLC analysis (5percent MeOH in CH2CI2) showed disappearance of the 6-fluoronaphthyridine. This process was repeated with 3 additional aliquots of the fluoronaphthyridine (0.12O g, 0.100 g, 0.10O g), and the contents of all 4 vials were then combined, partitioned between 50 mL each EtOAc and brine, and worked up as described above for the synthesis of WAY-191220. The crude product was purified by flash chromatography over silica gel (5percent MeOH in CH2CI2) and lyophilized to give pure 4-(4-benzylphenylamino)-6-(2-(1 -N-BOC- piperazin-4-yl)ethylamino)-1 ,7-naphthyridine-3-carbonitrile (0.151 g, 23percent yield): 1H NMR (400 MHz, DMSO-D6) t 1.39 (s, 9 H) 2.34 - 2.44 (m, 4 H) 2.57 (t, J=6.6 Hz, 2 H) 3.21 - 3.42 (m, 6 H) 3.99 (s, 2 H) 6.59 (t, J=5.3 Hz, 1 H) 7.03 (s, 1 H) 7.14 - 7.34 (m, 9 H) 8.22 (s, 1 H) 8.81 (s, 1 H) 9.56 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
After cooled to room temperature, a part (10 ml) of the reaction mixture was removed and concentrated to give N-[2-(benzylidene)aminoethyl]piperazine (1.4 g). Di(t-butyl) dicarbonate (45 g) was added to the remainder (about 240 ml) of the reaction mixture, and the mixture was stirred overnight at room temperature. 1 N aqueous potassium hydrogen sulfate (220 ml) was added thereto, and the mixture was vigorously stirred for 5 hours at room temperature, and the aqueous layer was partitioned by adding diethyl ether. The aqueous layer was basified by adding sodium hydroxide (solid), and the organic layer was partitioned by adding chloroform, washed with water, dried, and evaporated to give the title compound (14.9 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium hydrogencarbonate; triethylamine; In tetrahydrofuran; | 64-1) 1-[2-(4-Fluorobenzoylamino)ethyl]-4-(t-butoxycarbonyl)piperazine The 1-(2-aminoethyl)-4-(t-butoxycarbonyl)piperazine (1.33 g) obtained in Example 58 and 4-fluorobenzoyl chloride (1.1 g) were dissolved in tetrahydrofuran (20 ml), then triethylamine (1.6 ml) was added thereto, and the mixture was stirred overnight at room temperature. The organic layer was partitioned by adding aqueous saturated sodium bicarbonate and ethyl acetate, and the organic layer was washed with water, dried, and evaporated. The residue was purified by Cromatorex NH silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound (1.42 g, 70 percent) was obtained as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine; In tetrahydrofuran; water; | 66-1) 1-[2-(4-Fluorobenzenesulfonylamino)ethyl]-4-(t-butoxycarbonyl)piperazine The 1-(2-aminoethyl)-4-(t-butoxycarbonyl)piperazine (2.01 g) obtained in Example 58 and 4-fluorobenzene sulfonylchloride (2.05 g) were dissolved in tetrahydrofuran (20 ml), and triethylamine (2.4 ml) was added thereto, and the mixture was stirred overnight at room temperature. Water (50 ml) was added to the reaction mixture which was then extracted with ethyl acetate, and the organic layer was washed with water, dried, and evaporated. The residue was purified by Cromatorex NH silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound (2.61g, 77percent) was obtained as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 20℃; for 0.5h; | EXAMPLE 24 2-[4-((4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-{4-[2-(11,1-dioxo-isothiazolidine-2-yl)-ethyl]-piperazine-1-carbonyl}-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl)-3-ethoxy-phenyl]-2-methyl-propionitrile To a stirred solution of 1-Boc-4-(2-aminoethyl)-piperazine (1.26 g, 6.8 mmol, Aldrich) and triethylamine (1 mL) in tetrahydrofuran (10 mL), 3-chloro-propylsulfonyl chloride (0.68 mL, 6.94 mmol, Aldrich) was added slowly at room temperature. The mixture was stirred for 30 min at room temperature and the reaction was quenched with water. It was extracted with ethyl acetate and the extracts were combined and dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo to give 4-[2-(3-chloro-propane-1-sulfonylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; In dichloromethane; at 20℃; for 96h; | To a solution of 4-N-(2-aminoethyl)1-N-Boc-piperazine (2.06 g, 8.99 mmol) in CH2CI2 was added triethylamine (2.5 ml_, 17.9 mmol) and 2,4- dichlorobenzenesulfonyl chloride (2.65 g, 10.8 mmol). The reaction mixture was stirred at room temperature for 4 days. The reaction was then concentrated in vacuo and purified by column chromatography (10-70percent ethyl acetate:hexane) to produce 3.46 g (88percent) of the title compound as a white solid: LCMS (m/z): 438.0/440.0 I(M/M+2)+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20 - 70℃; for 1h; | Cat. TsOH monohydrate was added to a suspension of methyl 14'-cyclohexyl-2,2- dimethylspiro[l,3-dioxane-5,7'-indolo[l,2-e][l,5]benzoxazocine]-H'-carboxylate in MeOH/THF 1:2 (0.03 M), and the solution was stirred at RT for 3 h. Filtration on a pad of neutral alumina using EtOAc as eluent afforded after evaporation of the solvent in vacuo methyl 14-cyclohexyl- 7, 7-bis(hydroxymethyl)-7,8-dihydro-6H-indolo[l,2-e][l,5]benzoxazocine- 11 -carboxylate (quant). This material was dissolved in dry MeCN (0.2M) and DIPEA (4.0 eq) and trifluoromethane sulfonic anhydride (3.5 eq) was added at 0 0C. The mixture was stirred at 0 0C for 15 min, then more DIPEA (4 eq) was added at RT. 7ert-butyl 4-(2-aminoethyl)piperazine-l- carboxylate (2 eq) was added, and the mixture was stirred at 70 0C for 1 h. After removal of the solvent in vacuo EtOAc was added, the solution was washed with H2O and brine, dried over Na2SO4 and the solvent was removed in vacuo. The crude methyl \\-{2-[4-(tert- butoxycarbonyl)piperazin- 1 -yljethyl} - 14'-cyclohexylspiro[azetidine-3 ,7'-indolo[ 1 ,2- e][l,5]benzoxazocine]-l l'-carboxylate was taken in DCM/TFA 3:1 (0.13M) and stirred at RT for 2 h. The mixture was evaporated to dryness and the residual material was dissolved in EtOAc. The solution was washed with sat. aq. NaHCO3 and brine. The organic phase was dried overNa2SO4 and the solvent evaporated in vacuo. The residue was dissolved in dry dioxane (0.06M) and sulfamide (5 eq) was added. The mixture was stirred at reflux for 3 h, then overnight at RT. The residue obtained after evaporation was purified by FC (EtOAc/MeOH, 9:1) to afford the title compound in 40percent yield. (ES+) m/z 622 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In chloroform; at 20℃; for 4h; | A solution of tert-butyl 4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazine-1-carboxylate (250 mg, 0.62 mmol) in CH2Cl2 (2.5 mL) at 0° C. was treated with TFA (2.5 mL) and stirred at 0° C. for 1.5 h. After this time, the solvents were evaporated in vacuo and the excess TFA removed by azeotroping with toluene (3.x.10 mL). The residue was suspended in CHCl3 (3 mL) and pyridine (3 mL) and treated with benzenesulfonyl chloride (1.1 eq, 0.68 mmol, 0.09 mL), warmed to room temperature and stirred for 12 h. The solvents were removed in vacuo and the residue partition between water (5 mL) and EtOAc (5 mL). The aqueous layer was extracted with EtOAc (2.x.5 mL) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. Column chromatography (hexane-EtOAc, 1:1) gave the product (107 mg, 39percent for two steps) as a yellow solid; 1H-NMR (500 MHz, DMSO-d6) 3.09 (br s, 8H, 2.x. piperazine N(CH2)2), 7.08 (br s, 2H, NH2), 7.67-7.70 (m, 2H, phenyl H-3 H-5), 7.74-7.78 (m, 3H, phenyl H-2, H-4 H-6), 8.16 (s, 1H, pyridine H-6);LC (Method A)-MS (ESI, m/z): Rt=7.04 min-442, 444 [(M+H)+, Br isotopic pattern). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Cyclohexanecarboxaldehyde (145muL, 1.2mmol) and Boc-aminoethylpiperazine (229mg, 1mmol) were stirred in DCM (10ml) at room temperature for 30mins before the addition of STAB (424mg, 2mmol) and acetic acid (114mul_, 2mmol). The reaction was stirred at room temperature for 24hr before being quenched with 2M NaOH (20ml) and the product extracted with DCM (3 x 10ml). The combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield a brown oil. The brown oil was dissolved in DCM (10ml) before the addition of triethylamine (278mul, 2mmol) and indole-3-glyoxylyl chloride (414mg, 2mmol). The reaction was stirred at room temperature for 24hr. The solvent was removed in vacuo and the reaction quenched with water (20ml). The product was extracted with EtOAc (3 x 20ml), and the combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield the product, 4-(2- {cyclohexylmethyl-[2-(1H-indol-3-yl)-2-oxo-acetyl]-amino}-ethyl)-piperazine-1- carboxylic acid tert-butyl ester 84, as a brown oil which was carried through to the next step without further purification | ||
Cyclohexanecarboxaldehyde (145muL, 1.2mmol) and Boc-aminoethylpiperazine (229mg, 1 mmol) were stirred in DCM (10ml) at room temperature for 30mins before the addition of STAB (424mg, 2mmol) and acetic acid (114muL, 2mmol). The reaction was stirred at room temperature for 24hr before being quenched with 2M NaOH (20ml) and the product extracted with DCM (3 x 10ml). The combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield a brown oil. The brown oil was dissolved in DCM (10ml) before the addition of triethylamine (278mul, 2mmol) and indole-3-glyoxylyl chloride (414mg, 2mmol). The reaction was stirred at room temperature for 24hr. The solvent was removed in vacuo and the reaction quenched with water (20ml). The product was extracted with EtOAc (3 x 20ml), and the combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield the product, 4-(2- {cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}-ethyl)-piperazine-1- carboxylic acid tert-butyl ester 84, as a brown oil which was carried through to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 2-HEXYLMERCAPTO-6- (3, 4, 5-trimethoxyphenyl)-pyrimidin-4-carboxylic acid (Example 1A, 150 mg, 0.37 MMOL), HATU (210 mg, 1.5 equiv. ) and HOAT (85 mg, 1.5 equiv. ) in DMF (1.5 ML), DIISOPROPYLETHYLAMINE (200, UL) is added at 4°C, and the reaction mixture stirred for 30 minutes at 4°C, followed by addition of 1- (2-AMINOETHYL)-4-TERT-BUTOXYCARBONYL- piperazine (127 mg, 1.5 equiv. ) in DMF (0.5 ml) at 4°C. The reaction mixture is stirred for 4 hours at room temperature, extracted with ethyl acetate and 0.5 N aqueous HCI solution, the organic layer washed with saturated aqueous NaHCO3 solution and brine, dried (MgSO4), the solvents evaporated and the residue chromatographed on SiO2 with ethanol/ethyl acetate (1: 6), to yield the title compound as an oil. MS: 618.2 [M+H] + ; H-NMR (300 MHz, DMSO-d6) : 8.72 (br. t, J=9, NH); 8.19 (s, 1 arom. H); 7.54 (s, 2 arom. H); 3.91 (s, 2 MEO) ; 3.76 (s, MeO) ; 3.5-3. 4 (m, 2H); 3.35-3. 25 (m, 4H); 2.6-2. 45 (m, 2H); 2.4-2. 35 (m, 4H); 1.8-1. 7 (m, 2H); 1.55-1. 4 (m, 2H); 1.40 (s, tBu); 1.35-1. 25 (m, 4H); 0.9-0. 8 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 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; for 18h; | Example 49 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(2-piperazin-1-yl-ethyl)-benzamide (I-49) A mixture of 0.100 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.077 g (0.33 mmole) of (2-amino-ethyl)-carbamic acid tert-butyl ester, 0.102 g (0.27 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.036 g (0.27 mmole) of 1-hydroxybenzotriazole, 0.195 mL (1.12 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluding with hexanes-ethyl acetate (gradient, 100:0-60:40) to give 0.14 g of 4-{2-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester as a colorless oil. |
A137408 [219509-79-2]
1-tert-Butyl 4-methyl piperazine-1,4-dicarboxylate
Similarity: 1.00
A188186 [76535-75-6]
Di-tert-butyl piperazine-1,4-dicarboxylate
Similarity: 1.00
A231223 [53788-49-1]
tert-Butyl 4-methylpiperazine-1-carboxylate
Similarity: 1.00
A256884 [57260-71-6]
tert-Butyl piperazine-1-carboxylate
Similarity: 1.00
A621523 [539822-98-5]
tert-Butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate
Similarity: 1.00
A621523 [539822-98-5]
tert-Butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate
Similarity: 1.00
A129258 [112257-19-9]
tert-Butyl methyl(2-(methylamino)ethyl)carbamate
Similarity: 0.95
A327041 [140447-78-5]
1-(2-N-Boc-Aminoethyl)piperazine
Similarity: 0.95
A386673 [121492-06-6]
N-Boc-(2-Aminoethyl)-N-methylamine
Similarity: 0.95
A191369 [1017606-58-4]
(S)-tert-Butyl 4-(2-aminopropyl)piperazine-1-carboxylate
Similarity: 0.93
A137408 [219509-79-2]
1-tert-Butyl 4-methyl piperazine-1,4-dicarboxylate
Similarity: 1.00
A188186 [76535-75-6]
Di-tert-butyl piperazine-1,4-dicarboxylate
Similarity: 1.00
A231223 [53788-49-1]
tert-Butyl 4-methylpiperazine-1-carboxylate
Similarity: 1.00
A256884 [57260-71-6]
tert-Butyl piperazine-1-carboxylate
Similarity: 1.00
A621523 [539822-98-5]
tert-Butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate
Similarity: 1.00