Structure of 489446-42-6
*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. : | 489446-42-6 |
Formula : | C12H18BNO4 |
M.W : | 251.09 |
SMILES Code : | O=C(NCC1=CC=C(B(O)O)C=C1)OC(C)(C)C |
MDL No. : | MFCD04115637 |
InChI Key : | MUBGEKQUCSEECZ-UHFFFAOYSA-N |
Pubchem ID : | 3863163 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 18 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.42 |
Num. rotatable bonds | 6 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 3.0 |
Molar Refractivity | 69.78 |
TPSA ? Topological Polar Surface Area: Calculated from |
78.79 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.33 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.24 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.7 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.47 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.36 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.09 |
Solubility | 2.06 mg/ml ; 0.00822 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.59 |
Solubility | 0.651 mg/ml ; 0.00259 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.65 |
Solubility | 0.562 mg/ml ; 0.00224 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) |
No |
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 |
-6.89 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 |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.06 |
* 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 |
---|---|---|
With potassium carbonate;Pd-FibreCat 1007; In N,N-dimethyl-formamide; at 150℃; for 0.166667h;Microwave irradiation; | Preparation 19 N-(4'-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide 1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide (37 mg, 0.10 mmol), <strong>[489446-42-6]4-((tert-butoxycarbonylamino)methyl)phenylboronic acid</strong> (37 mg, 0.15 mmol), 1 M K2CO3 (0.2 mL, 0.2 mmol), Pd-FibreCat 1007 (8 mg, 0.1 mmol), and N,N-dimethylformamide (1 mL) were combined. The mixture was irradiated in the microwave at 150 C. for 10 minutes. The reaction was filtered and purified by reverse phase HPLC. The obtained material was dissolved in dichloromethane (2 mL) containing trifluoroacetic acid (2 mL) and stirred at 25 C. for 1 hour. The reaction was filtered and purified by reverse phase HPLC to yield N-(4'-(aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as the TFA salt (8.1 mg, 20%). ESI-MS m/z calc. 400.2, found 401.5 (M+1)+; retention time 2.55 minutes. | |
With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 0.166667h;Microwave irradiation; | 1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide (37 mg, 0.10 mmol), <strong>[489446-42-6]4-((tert-butoxycarbonylamino)methyl)phenylboronic acid</strong> (37 mg, 0.15 mmol), 1 M K2CO3 (0.2 mL, 0.2 mmol), Pd-FibreCat 1007 (8 mg, 0.1 mmol), and N,N-dimethylformamide (1 mL) were combined. The mixture was irradiated in the microwave at 150 C. for 10 minutes. The reaction was filtered and purified by reverse phase HPLC. The obtained material was dissolved in dichloromethane (2 mL) containing trifluoroacetic acid (2 mL) and stirred at 25 C. for 1 hour. The reaction was filtered and purified by reverse phase HPLC to yield N-(4'-(aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as the TFA salt (8.1 mg, 20%). ESI-MS m/z calc. 400.2. found 401.5 (M+1)+; retention time 2.55 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
For compounds (2-6) the commercially available 4-aminomethylphenylboronic acid and 3-aminomethylphenylboronic acid were BOC protected under standard conditions (Wei et al., 2000) and the appropriate boronic acid was used at the Suzuki coupling stage in the synthesis of compounds (2-6). The BOC group was removed with 4 M HCl in dioxane at RT after hydrazone coupling; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With potassium fluoride;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 150℃; for 0.666667h;microwave; | The first step of Scheme 7: To a microwave tube was added 4-benzyl-carbamic acid tert-butyl ester boronic acid (75 mg, 0.3 mmol), 4,5-Dibromo-3-ethoxycarbonylmethoxy-thiophene-2-carboxylic acid methyl ester (80 mg, 0.2 mmol), potassium fluoride (46 mg, 0.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol). The vessel was purged with argon and then diluted with THF (2 mL). The reaction was heated in the microwave at 150 C. for 40 minutes. The reaction was diluted with ethyl acetate (10 mL) and filtered through a layer of silica gel. Purification of the material by CombiFlash column chromatography eluting with a 10-35% ethyl acetate-hexane gradient to yield 61 mg of 4-Bromo-5-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-3-ethoxycarbonylmethoxy-thiophene-2-carboxylic acid methyl ester as a white solid (58%). 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.32 (t, J=7.07 Hz, 3H) 1.47 (s, 9H) 3.88 (s, 3H) 4.30 (q, J=7.16 Hz, 2H) 4.37 (d, J=5.81 Hz, 2H) 4.91 (s, 2H) 7.38 (d, J=8.34 Hz, 3H) 7.63 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; ethanol; water; at 100℃; for 0.833333h; | Example A82-[4-("aminomethyl')phenyll-N,8-dimethyl-8H-imida2or4,5-d1thiazolo[4,5-b1pyridin-5- amine A8A3.3 (20mg, 0.067 mmol), 4-(t-butyloxycarbonylaminomethyl)phenylboronic acid (18.6mg 0.074 mmol) and tetrakis(triphenylphosphine)palladium (0) (7.74 mg, 0.007 mmol) was added to a mixture of 2M aqueous sodium carbonate (0.14 mL) dioxane (0.35 mL) and ethanol (0.35 mL). The reaction mixture was heated under an argon74 EPO <DP n="76"/>atomosphere for 50 min. at 100 0C. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. Dichloromethane (1 mL) was added and the suspension cooled in an ice bath. Trifluoroacetic acid (1 mL) was added and the reaction mixture stirred at 0 0C for 45 min. The solvent was removed under reduced pressure and the crude product was dissolved in methanol and purified by automated reverse phase chromatography. The appropriate fractions were combined and the solvent removed under reduced pressure with the aid of heptane as an azeotroping agent to yield 19.8 mg of product as a pale yellow solid. M+H+ = 325.27. NMR 400 MHz J6DMSO delta 8.29 s, IH, 8.28-8.20 br s, 2H, 8.17 d, J = 8.2 hz, 2H, 7.65 d, J = 8.2 Hz, 2 H, 4.20-4.10 apparent quartet, 2H, 4.03, s, 3H, 3.06, s, 3H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃; for 1h;Microwave irradiation; | 4-[6-(Cvclopropylmethyl-amino)-pyrimidin-4-yll-iV*-(tert-butoxycarbonyl)-benzylamine; In a microwave reaction vessel, slurry 6-chloro-4-(cyclopropylmethyl-amino)-pyrimidine (560 mg, 3 mmol), [4-(N-tert-butoxycarbonyl-aminomethyl)phenyl]boronic acid (1.1 g, 4 mmol), and tetrakis(triphenylphosphine)palladium(0) (190 mg, 0.15 mmol) in toluene (4 mL). Add ethanol (1 mL) followed by potassium carbonate (0.9 g, 6 mmol) dissolved in water (300 DL). Irradiate in microwave (300 watts) at 120 0C for 60 min. Cool to room temperature, pour reaction mixture into IN NaOH (250 mL) and extract with DCM (3x100 mL). Wash the combined organic extracts with brine, dry over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with hexane/EtOAc (4: 1 to 2:3 over 45 min; 40 mL/min) to obtain the desired intermediate (450 mg, 38%) as a yellow solid. MS (ES+) m/z: 355 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃; for 1.5h;Microwave irradiation; | 4-r4-(Cvclopropylmethyl-amino)-pyrimidin-2-yll-N-(?grt-butoxycarbonyl)-benzylamine; Slurry 2-chloro-4-(cyclopropylmethyl-amino)-pyrimidine (370 mg, 2 mmol), [4-(N-tert- butoxycarbonyl-aminomethyl)phenyl]boronic acid (710 mg, 2.83 mmol), and tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.10 mmol) in toluene (3 mL). Add ethanol (0.5 mL) followed by potassium carbonate (550 mg, 4 mmol) dissolved in water (300 muL). Irradiate in microwave (300 watts) at 120 C for 90 min. Cool to room temperature, pour reaction mixture into water (100 mL) containing IN NaOH (25 mL) and extract with DCM (3x50 mL). Wash the combined organic extracts with brine, dry over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with hexane/EtOAc (4:1 to 1:4 over 45 min; 40 mL/min) to obtain the desired intermediate (105 mg, 20%) as a yellow solid. MS (ES+) m/z: 355 (M+H)+. Additionally recovered unreacted 2-chloro-4-(cyclopropylmethyl-amino)-pyrimidine (100 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃; for 1h;Microwave irradiation; | 4-r2-(Cvclopropylmethyl-amino)-pyrimidin-4-yll-N-(fert-butoxycarbonyl)-benzylamine; Slurry 4-chloro-2-(cyclopropylmethyl-amino)-pyrimidine (155 mg, 0.62 mmol), [4-(N- fert-butoxycarbonyl-ammomethyl)phenyl]boronic acid (160 mg, 0.86 mmol), and tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) in toluene (3 mL). Add ethanol (0.5 mL) followed by potassium carbonate (175 mg, 1.24 mmol) dissolved in water (300 muL). Irradiate in microwave (300 watts) at 120 C for 60 min. Cool to room temperature, pour reaction mixture into water (100 mL) containing IN NaOH (25 mL) and extract with DCM (3x50 mL). Wash the combined organic extracts with brine, dry over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (12 g) eluting with hexane/EtOAc (4:1 to 3:7 over 30 min; 30 mL/min) to obtain the desired intermediate (200 mg, 90%) as a light yellow solid. MS (ES+) m/z: 355 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; | N-(tgrt-Butoxycarbonyl')-4-r5-(3,3-dimethylbutyryl)tiophen-2-vn-benzylamine; To a solution of 2-bromo-5-(3,3-dimethylbutyryl)-thiophene (187 mg, 0.7 mmol) in dioxane (7 mL) add a solution of aqueous 2M Na2CO3 (0.9 mL), [4-(iV-t£rt-butoxycarbonyl- aminomethyl)phenyl]boronic acid (216 mg, 0.8 mmol) and tetrakis(triphenylphosphine)- palladium(O) (41 mg, 0.03 mmol). Heat the mixture at 90 0C overnight. Cool at room temperature, add water and extract with EtOAc. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate (174 mg, 63%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; for 1h;Heating / reflux; | 3,5-Dimethyl-isoxazole-4-sulfonic acid 4-(5-fluoro-2-methoxy-pyridin-3-yl) benzylamide Di-tert-butyl dicarbonate (3.5 g, 16 mmol) and triethylamine (13 ml, 9.4 mmol) were added to a stirred solution of 4-aminomethylphenylboronic acid (3 g, 16 mmol) in tetrahydrofuran (100 ml). The reaction was stirred under reflux for 1 hour, then the solvent evaporated and the residue partitioned between water and ethyl acetate. The organic phase was concentrated under reduced pressure to give tert-butoxycarbonylaminomethyl-4-phenyl-boronic acid (2.67 g, 10.6 mmol) as a white solid. Toluene (16 ml), ethanol (4 ml), 2M sodium carbonate solution and tetrakis(triphenylphosphine) palladium (0) were added to tert-butoxycarbonylaminomethyl-4-phenyl-boronic acid (1.349 g, 5.4 mmol) and 3-bromo-5-fluoro-2-methoxy-pyridine (0.505 g, 2.45 mmol) and the mixture stirred under reflux for 24 h. Water was added and the mixture extracted with ethyl acetate. The organic phase was separated and the solvent evaporated. The residue was purified on silica gel eluting with 3:1 heptane/ethyl acetate to give [4-(5-fluoro-2-methoxy-pyridin-3-yl-benzyl]-carbamic acid-tert-butyl ester as a yellow oil. Trifluoroacetic acid (2 ml, 0.026 mmol) was added to a solution of [4-(5-fluoro-2-methoxy-pyridin-3-yl-benzyl]-carbamic acid-tert-butyl ester (0.8 g, 2.41 mmol) in dichloromethane (4 ml) and the reaction mixture stirred for 2 h. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic phase was separated and the solvent evaporated to give 4-(5-fluoro-2-methoxy-pyridin-3-yl)-benzylamine. The title compound was prepared in a similar manner to N-[1-(2-allyl-5'-fluoro-2'-methoxy-biphenyl-4-yl)-ethyl]-3,4-difluoro-benzenesulfonamide (Example 34) using 4-(5-fluoro-2-methoxy-pyridin-3-yl)-benzylamine and 3,5-dimethyl-isoxazole-4-sulfonyl chloride. MS (ESI) m/z: 392 [M+H]+. | |
With triethylamine; In tetrahydrofuran; at 20℃; for 1h; | To a solution of 4-aminomethylphenylboronic acid (2.65 mmol) in THF (10 mL) were added di-tert-butyl dicarbonate (3.97 mmol) and triethylamine (1 mL). The mixture was stirred at room temperature for 1 h. After completion of the reaction, excess solvent was evaporated to dryness under reduced pressure. The residue was diluted with water (30 mL) and ethyl acetate (15 mL). The organic phase was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The NHBoc-protected boronic acid was then used for Suzuki coupling as described in compound 6 to afford compound 9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 24h;Heating / reflux; | 3,5-Dimethyl-isoxazole-4-sulfonic acid 4-(5-fluoro-2-methoxy-pyridin-3-yl) benzylamide Di-tert-butyl dicarbonate (3.5 g, 16 mmol) and triethylamine (13 ml, 9.4 mmol) were added to a stirred solution of 4-aminomethylphenylboronic acid (3 g, 16 mmol) in tetrahydrofuran (100 ml). The reaction was stirred under reflux for 1 hour, then the solvent evaporated and the residue partitioned between water and ethyl acetate. The organic phase was concentrated under reduced pressure to give tert-butoxycarbonylaminomethyl-4-phenyl-boronic acid (2.67 g, 10.6 mmol) as a white solid. Toluene (16 ml), ethanol (4 ml), 2M sodium carbonate solution and tetrakis(triphenylphosphine) palladium (0) were added to tert-butoxycarbonylaminomethyl-4-phenyl-boronic acid (1.349 g, 5.4 mmol) and 3-bromo-5-fluoro-2-methoxy-pyridine (0.505 g, 2.45 mmol) and the mixture stirred under reflux for 24 h. Water was added and the mixture extracted with ethyl acetate. The organic phase was separated and the solvent evaporated. The residue was purified on silica gel eluting with 3:1 heptane/ethyl acetate to give [4-(5-fluoro-2-methoxy-pyridin-3-yl-benzyl]-carbamic acid-tert-butyl ester as a yellow oil. Trifluoroacetic acid (2 ml, 0.026 mmol) was added to a solution of [4-(5-fluoro-2-methoxy-pyridin-3-yl-benzyl]-carbamic acid-tert-butyl ester (0.8 g, 2.41 mmol) in dichloromethane (4 ml) and the reaction mixture stirred for 2 h. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic phase was separated and the solvent evaporated to give 4-(5-fluoro-2-methoxy-pyridin-3-yl)-benzylamine. The title compound was prepared in a similar manner to N-[1-(2-allyl-5'-fluoro-2'-methoxy-biphenyl-4-yl)-ethyl]-3,4-difluoro-benzenesulfonamide (Example 34) using 4-(5-fluoro-2-methoxy-pyridin-3-yl)-benzylamine and 3,5-dimethyl-isoxazole-4-sulfonyl chloride. MS (ESI) m/z: 392 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[249] A mixture of 4-chloro-7-azaindole (1.516g, 10 mmole) in 1,4-dioxane (48mL) and water ?(12mL) in a 25OmL, two-necked round bottomed flask was charged with K2CO3 (0.82Og, 5.9mmole), [4- (N-BOC-aminornethyl)phenylboronic acid (2.88g, 11.5mmole), Pd(dppf)2Cl2-CH2Cl2 catalyst (371mg, 0.45mmole). Nitrogen was bubbled into the reaction mixture for 15min at rt and then heated at 1000C overnight under nitrogen atmosphere. The reaction mixture was cooled to rt and added triethylamine (3mL) and evaporated to dryness and purified by column chromatography. The crude was taken in methylene chloride and loaded onto the column. The column was eluted with 20-40% ethyl acetate in methylene chloride, the desired fractions from column were collected and the resulting solid was triturated with hot isopropyl ether, cooled to rt and filtered to give the title compound as a pale yellow solid. 1H NMR (CDCl3): delta 1.49 (s, 9H), 4.41 (d, 2H, J = 6.3 Hz), 4.98 (brs, IH), 6.79 (m, IH), 7.17 (d, IH, J = 4.8 Hz), 7.39 (t, IH, J = 3.0 Hz), 7.44 (d, 2H, J = 8.4 Hz), 7.73 (d, 2H, J = 8.4 Hz), 8.37 (d, IH5 J = 5.1 Hz), 10.01 (brs, IH); MS (ES+): m/z 324.09 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ISOPROPYLAMIDE; water; at 120℃; for 20h; | Stir 3'-chloro-4-(l,5-dimethyl-lH-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H- [l,2']bipyrazinyl (921 mg, 3.00 mmol), potassium carbonate (996 mg, 7.20 mmol), 4-benzyl (carbamic acid tert-butyl ester) boronic acid (940 mg, 3.60 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.015 mmol) in N,N-dimethylacetamide (6 mL). Add water (3 mL), degas for 5 min., and then heat at 120 0C for 20 hr. Cool to room temperature, add water (10 mL) and extract with DCM (3 x 10 mL). Pass the combined DCM extracts through an 1ST Phase Separator Frit.Concentrate the filtrate and purify by SCX-2 chromatography washing with methanol then eluting with 2 M ammonia in methanol. Further purify (silica gel chromatography, eluting with 5:95 to 15:85 methanol: DCM), to give N-{4-[4-(l,5-dimethyl-lH-pyrazol-4- ylmethyl)-3,4,5,6-tetrahydro-2H-[l,2']bipyrazinyl-3'-yl]-benzyl} -carbamic acid tert-butyl ester as an oil (1.3 g, 91%). MS (ES): m/z = 478 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With K2CO3; trifluoroacetic acid; In dichloromethane; N,N-dimethyl-formamide; | Preparation 19 N-(4'-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide 1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide (37 mg, 0.10 mmol), <strong>[489446-42-6]4-((tert-butoxycarbonylamino)methyl)phenylboronic acid</strong> (37 mg, 0.15 mmol), 1 M K2CO3 (0.2 mL, 0.2 mmol), Pd-FibreCat 1007 (8 mg, 0.1 mmol), and N,N-dimethylformamide (1 mL) were combined. The mixture was irradiated in the microwave at 150 C. for 10 minutes. The reaction was filtered and purified by reverse phase HPLC. The obtained material was dissolved in dichloromethane (2 mL) containing trifluoroacetic acid (2 mL) and stirred at 25 C. for 1 hour. The reaction was filtered and purified by reverse phase HPLC to yield N-(4'-(aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as the TFA salt (8.1 mg, 20%). ESI-MS m/z calc. 400.2, found 401.5 (M+1)+; retention time 2.55 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 100℃; for 1.33333h;Inert atmosphere; | Example 551 -methylethyl {(cis)-1 -acetyl-6-[4-(aminomethyl)phenyl]-2-methyl-1 ,2,3,4-tetrahydro- 4-quinolinyl}carbamate hydrochloride1 -Methylethyl [(cis)-1 -acetyl-6-bromo-2-methyl-1 ,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 61 )(212 mg, 0.574 mmol) , potassium carbonate (159 mg, 1 .148 mmol), tetrakis(triphenylphosphine)palladium(0) (33.2 mg, 0.029 mmol) and {4- [([(1 ,1 -dimethylethyl)oxy]carbonyl}amino)methyl]phenyl}boronic acid (173 mg, 0.689 mmol, available from Apollo) were dissolved in ethanol (1 .5 mL) and toluene (1.5 ml_). The reaction mixture was degassed for 20min then stirred and heated under nitrogen for 1 hr at 100 C. The reaction mixture was concentrated under vacum. The residue was partitioned between dichloromethane (10ml) and water (10ml). The organic layer was dried through a hydrophobic frit and concentrated in vacuo, then dissolved in DCM and purified by SP4 on a 25+M silica cartridge using a gradient of 0-50% EtOAc in cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the boc-protected product (250 mg). This was dissolved with 5ml of methanol and treated with 1 ml of acetyl chloride. After 1 h the reaction mixture was loaded on a 20g NH2 cartridge, which was previously conditioned with methanol. Column was washed with methanol (3CV). The appropriate fractions were combined and evaporated in vacuo to give the free base product (197mg). The product was dissolved with 3ml of methanol and treated with 1.1 eq of 2M HCI in to give a yellow solid (181 mg)LCMS (Method B): Rt = 0.63, MH+ = 396 | |
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 100℃; for 1h;Inert atmosphere; | 1-Methylethyl [(cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 61) (212 mg, 0.574 mmol), potassium carbonate (159 mg, 1.148 mmol), tetrakis(triphenylphosphine)palladium(0) (33.2 mg, 0.029 mmol) and {4-[([(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]phenyl}boronic acid (173 mg, 0.689 mmol, available from Apollo) were dissolved in ethanol (1.5 mL) and toluene (1.5 mL). The reaction mixture was degassed for 20 min then stirred and heated under nitrogen for 1 hr at 100 C. The reaction mixture was concentrated under vacuum. The residue was partitioned between dichloromethane (10 ml) and water (10 ml). The organic layer was dried through a hydrophobic frit and concentrated in vacuo, then dissolved in DCM and purified by SP4 on a 25+M silica cartridge using a gradient of 0-50% EtOAc in cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the boc-protected product (250 mg). This was dissolved with 5 ml of methanol and treated with 1 ml of acetyl chloride. After 1 h the reaction mixture was loaded on a 20 g NH2 cartridge, which was previously conditioned with methanol. Column was washed with methanol (3 CV). The appropriate fractions were combined and evaporated in vacuo to give the free base product (197 mg). The product was dissolved with 3 ml of methanol and treated with 1.1 eq of 2M HCl in to give a yellow solid (181 mg)LCMS (Method B): Rt=0.63, MH+=396 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With sodium carbonate;PdCl2[dppf]; In quinoclamine; water; | Tert-butyl 3-(1-(tert-butoxycarbonyl)-4-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-6-(4-((tert-butoxycarbonylamino)methyl)phenyl)-1H-indazole-1-carboxylate (6b) Tert-butyl 6-bromo-3-(1-(tert-butoxycarbonyl)-4-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazole-1-carboxylate (5, 800 mg, 1.308 mol) was dissolved in ACN:H2O (20 mL:2 mL), and <strong>[489446-42-6]4-((tert-butoxycarbonylamino)methyl)phenylboronic acid</strong> (985 mg, 3.92 mol), PdCl2(dppf) (0.3 eq) and Na2CO3 (415 mg, 3.924 mol) were added. The reaction mixture was stirred for 15 hours at room temperature. After evaporation, the reaction mixture was extracted with methylene chloride and water. The organic layer was washed with brine, dried with Mg2SO4, filtered, and then concentrated under reduced pressure. Purification by silica gel column chromatography (MC:MeOH=30:1) yielded a fluorescent solid substance (6b, 455 mg; yield=48%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium dihydrogenphosphate; 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex; In water; N,N-dimethyl-formamide; at 85 - 95℃;Inert atmosphere; | General procedure: Substrate (1 equiv) and boronic acid (1.2 equiv) were dissolved in DMF (15 mL). Nitrogen was bubbled through the solution for 2 min. An appropriate base in water (5 mL) and Pd catalyst (0.1 equiv) were added. The solution was then heated to 85-95 C under nitrogen. Upon consumption of the starting material, the solution was condensed under reduced pressure. The resulting material was diluted with ethyl acetate and filtered through celite or flushed through a Bakerbond SPE SiOH disposable extraction column. The filtrate was condensed under reduced pressure to afford the crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In ethanol; water; toluene; at 100℃;Inert atmosphere; | Step 4: Preparation of tert-butyl 4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)benzylcarbamate To a suspension of 3-bromo-2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.250 g, 1 eq.) in a mixture of toluene (5 mL), ethanol (5 mL), and saturated sodium bicarbonate (1 mL) was added <strong>[489446-42-6](4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid</strong> (0.1 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis (triphenylphosphine) palladium (0) added (0.025 g). The reaction was again degassed for 5 minutes and stirred at 100 C. overnight. The reaction mixture was cooled to room temperature and poured onto water (50 mL). The aqueous phase was extracted with dichloromethane (2*50 mL) and the organic extracts were combined and washed with water (1*50 mL), brine (1*50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (25-75% ethyl acetate in hexanes) gave the product which was triturated with ether to give tert-butyl 4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)benzylcarbamate (0.133 g, 40%). LCMS: 516 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With N-ethyl-N,N-diisopropylamine;copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 144h;Molecular sieve; | To a stirred mixture of 4.8 g (20 mmol) of 3-chloro-5-methoxy-lH-indole-2- carboxylic acid methyl ester, 7.53 g (30 mmol) of 4-(tert-butoxycarbonylamino- methyl)phenylboronic acid and 6.0 g (40 mmol) of copper(II) acetate in 150 mL of N f- dimethylformamide 14 mL (80 mmol) of N^V-diisopropylethylamine and 10 g of 3 A molecular sieves were added. The reaction mixture was vigorously stirred at room temperature with air bubbling for 6 days. The mixture was filtered through Celite. The filtrate was diluted with 500 mL of ethyl acetate and washed with 2 x 200 mL of 25% ammonium hydroxide solution. The organic layer was washed with 200 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with 2-propanol, the crystalline solid was filtered off and dried to yield 4.28 g (48%) of the title compound. MS (EI) 467.2 [M+Na]+. |
48% | With copper diacetate; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 20℃; for 144h;Molecular sieve; | c) 1-[4-(tert-Butoxycarbonylamino-methyl)-phenyl]-3-chloro-5-methoxy-1H-indole-2-carboxylic acid methyl ester To a stirred mixture of 4.8 g (20 mmol) of 3-chloro-5-methoxy-1H-indole-2-carboxylic acid methyl ester, 7.53 g (30 mmol) of 4-(tert-butoxycarbonylamino-methyl)phenylboronic acid and 6.0 g (40 mmol) of copper(II) acetate in 150 mL of N,N-dimethylformamide 14 mL (80 mmol) of N,N-diisopropylethylamine and 10 g of 3 A molecular sieves were added. The reaction mixture was vigorously stirred at room temperature with air bubbling for 6 days. The mixture was filtered through Celite. The filtrate was diluted with 500 mL of ethyl acetate and washed with 2*200 mL of 25% ammonium hydroxide solution. The organic layer was washed with 200 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with 2-propanol, the crystalline solid was filtered off and dried to yield 4.28 g (48%) of the title compound. MS (EI) 467.2 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.6% | With N-ethyl-N,N-diisopropylamine;copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 144h;Molecular sieve; | To a solution of 1 g (3.79 mmol) of 3-chloro-5-methoxy-2-(5-methyl- [ l,2,4]oxadiazol-3-yl)-lH-indole in 50 mL of N^V-dimethylformamide 1.14 g (4.55 mmol) of 4-(tert-butoxycarbonylaminomethyl)phenylboronic acid, 1.2 g (7.58 mmol) of copper(II) acetate, 2.6 mL (15.2 mmol) of N V-diisopropylethylamine and 2 g 3 A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 6 h. The mixture was filtered through Celite. The filter cake was washed with N,N-dimethylformamide and chloroform, the combined filtrates were concentrated in vacuo. The residue was taken up in chloroform and subsequently washed with concentrated aqueous ammonium hydroxide solution, water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent (Merck) and hexane:ethyl acetate = 2: 1 as eluent to yield 0.98 g (57.6%) of the title compound. MS (EI) 491.1 (M+Na)+. |
57.6% | With copper diacetate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 6h;Molecular sieve; | f) {4-[3-Chloro-5-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-indol-1-yl]-benzyl}-carbamic acid tert-butyl ester To a solution of 1 g (3.79 mmol) of 3-chloro-5-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-1H-indole in 50 mL of N,N-dimethylformamide 1.14 g (4.55 mmol) of 4-(tert-butoxycarbonylaminomethyl)phenylboronic acid, 1.2 g (7.58 mmol) of copper(II) acetate, 2.6 mL (15.2 mmol) of N,N-diisopropylethylamine and 2 g 3 A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 6 h. The mixture was filtered through Celite. The filter cake was washed with N,N-dimethylformamide and chloroform, the combined filtrates were concentrated in vacuo. The residue was taken up in chloroform and subsequently washed with concentrated aqueous ammonium hydroxide solution, water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent (Merck) and hexane:ethyl acetate=2:1 as eluent to yield 0.98 g (57.6%) of the title compound. MS (EI) 491.1 (M+Na)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine;copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 36h;Molecular sieve; | To a solution of 0.75 g (3.3 mmol) of 3-chloro-4-fluoro-lH-indole-2-carboxylic acid methyl ester in 30 mL of N,N-dimethylformamide 1.1 g (4.4 mmol) of 4-(tert- butoxycarbonylaminomethyl)phenylboronic acid, 1.0 g (6.4 mmol) of copper(II) acetate, 2.2 mL (12.7 mmol) of N,N-diisopropylethylamine and 1.4 g of 3A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 36 h. The mixture was filtered through Celite. The filter cake was washed with N^V-dimethylformamide and chloroform and the combined filtrates were concentarted in vacuo. The residue was taken up in chloroform and subsequently washed with concentrated aqueous ammonium hydroxide solution, water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent and hexane: ethyl acetate = 2:1 as eluent to yield 0.695 g (49%) of the title compound. MS (EI) 453.2 (M+Na)+. |
49% | With copper diacetate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 36h;Molecular sieve; | b) 1-[4-(tert-Butoxycarbonylamino-methyl)-phenyl]-3-chloro-4-fluoro-1H-indole-2-carboxylic acid methyl ester To a solution of 0.75 g (3.3 mmol) of 3-chloro-4-fluoro-1H-indole-2-carboxylic acid methyl ester in 30 mL of N,N-dimethylformamide 1.1 g (4.4 mmol) of 4-(tert-butoxycarbonylaminomethyl)phenylboronic acid, 1.0 g (6.4 mmol) of copper(II) acetate, 2.2 mL (12.7 mmol) of N,N-diisopropylethylamine and 1.4 g of 3 A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 36 h. The mixture was filtered through Celite. The filter cake was washed with N,N-dimethylformamide and chloroform and the combined filtrates were concentrated in vacuo. The residue was taken up in chloroform and subsequently washed with concentrated aqueous ammonium hydroxide solution, water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent and hexane:ethyl acetate=2:1 as eluent to yield 0.695 g (49%) of the title compound. MS (EI) 453.2 (M+Na)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With N-ethyl-N,N-diisopropylamine;copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 120h;Molecular sieve; | To a solution of 1.5 g (6.9 mmol) of 5-fluoro-2-(3-methyl-[l,2,4]oxadiazol-5- yl)-lH-indole in 80 mL of N^V-dimethylformamide, 2.6 g (10 mmol) of 4-(tert- butoxycarbonylaminomethyl)phenylboronic acid, 2.1 g (13.8 mmol) of copper(II) acetate, 4.8 mL (27.6 mmol) of N^V-diisopropylethylamine and 3 g of 3 A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 120 h. The mixture was filtered through Celite. The filter cake was washed with N^V-dimethylformamide and chloroform and the combined filtrates were concentrated in vacuo. The residue taken up in ethyl acetate and subsequently washed with concentrated aqueous ammonium hydroxide solution, water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent and hexane: ethyl acetate as eluent to yield 1.456g (50%) of the title compound. |
50% | With copper diacetate; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 20℃; for 120h;Molecular sieve; | b) {4-[5-Fluoro-2-(3-methyl-[1,2,4]oxadiazol-5-yl)-indol-1-yl]-benzyl}-carbamic acid tert-butyl ester To a solution of 1.5 g (6.9 mmol) of 5-fluoro-2-(3-methyl-[1,2,4]oxadiazol-5-yl)-1H-indole in 80 mL of N,N-dimethylformamide, 2.6 g (10 mmol) of 4-(tert-butoxycarbonylaminomethyl)phenylboronic acid, 2.1 g (13.8 mmol) of copper(II) acetate, 4.8 mL (27.6 mmol) of N,N-diisopropylethylamine and 3 g of 3 A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 120 h. The mixture was filtered through Celite. The filter cake was washed with N,N-dimethylformamide and chloroform and the combined filtrates were concentrated in vacuo. The residue taken up in ethyl acetate and subsequently washed with concentrated aqueous ammonium hydroxide solution, water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent and hexane:ethyl acetate as eluent to yield 1.456 g (50%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With N-ethyl-N,N-diisopropylamine;copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 96h;Molecular sieve; | To a solution of 1.9 g (7.55 mmol) of 3-chloro-5-fluoro-2-(5-methyl- [l ,3,4]oxadiazol-2-yl)-lH-indole in 40 mL of N,N-dimethylformamide 2.85 g (1 1.33 mmol) of 4-(tert-butoxycarbonylamino-methyl)-boronic acid, 2.75 g (15.1 mmol) of copper(II) acetate, 5.3 mL (30.2 mmol) of N,N-diisopropylethylamine and 4 g 3A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 96 h. The mixture was filtered through Celite. The filter cake was washed with N^ V-dimethylformamide and chloroform and the combined filtrates were concentrated in vacuo. The residue was treated with 300 mL of chloroform and extracted with 2x50 mL of 25% ammonium hydroxide solution and 2x50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and hexane:ethyl acetate = 3:1 as eluent and rechromatographed in chloroform: acetone = 5:1 to yield 1.99 g (57 %) of the title compound as a yellow foam. MS (EI) 457.1 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine;copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 144h;Molecular sieve; | To a solution of 0.1 g (0.42 mmol) of 3-chloro-2-(5-methyl-oxazol-2-yl)-indole in 4 mL of N^V-dimethylformamide 0.16 g (0.63 mmol) of 4-(tert- butoxycarbonylamino-methyl)-boronic acid, 0.16 g (0.84 mmol) of copper(II) acetate, 0.3 mL (1.68 mmol) of N^V-diisopropylethylamine and 0.4 g of 3A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 6 days. The mixture was filtered through Celite, the filter cake was washed with N^V-dimethylformamide and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and hexane:ethyl acetate = 4: 1 as eluent to yield 0.16 g (89 %) of the title compound as a yellow foam. MS (EI) 438.2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With N-ethyl-N,N-diisopropylamine;copper diacetate; In dimethyl sulfoxide; at 20℃; for 144h; | To a stirred mixture of 0.353 g (2.0 mmol) of 3-chloro-lH-indole-2-carbonitrile (Reference Example 4c), 0.753 g (3 mmol) of 4-(tert-butoxycarbonylamino- methyl)phenylboronic acid and 0.606 g (4 mmol) of copper(II) acetate in 24 mL of DMSO 1.4 mL (8 mmol) of N^V-diisopropylethylamine was added. The reaction mixture was vigorously stirred at room temperature with air bubbling for 6 days. The mixture was diluted with 60 mL of ethyl acetate and washed with 2 x 50 mL of 25% ammonium hydroxide solution. The organic layer was washed with 50 mL of 1M citric acid, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and hexane:ethyl acetate = 4:1 as eluent to yield 0428 g (56 %) of the title compound. MS (EI) 404.1 [M+Na]+. |
56% | With copper diacetate; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; for 144h; | a) [4-(3-Chloro-2-cyano-indol-1-yl)-benzyl]-carbamic acid tert-butyl ester To a stirred mixture of 0.353 g (2.0 mmol) of 3-chloro-1H-indole-2-carbonitrile (Reference Example 4c), 0.753 g (3 mmol) of 4-(tert-butoxycarbonylamino-methyl)phenylboronic acid and 0.606 g (4 mmol) of copper(II) acetate in 24 mL of DMSO 1.4 mL (8 mmol) of N,N-diisopropylethylamine was added. The reaction mixture was vigorously stirred at room temperature with air bubbling for 6 days. The mixture was diluted with 60 mL of ethyl acetate and washed with 2*50 mL of 25% ammonium hydroxide solution. The organic layer was washed with 50 mL of 1M citric acid, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and hexane:ethyl acetate=4:1 as eluent to yield 0428 g (56%) of the title compound. MS (EI) 404.1 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper diacetate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 72h;Molecular sieve; | A mixture of 5.85 g (25 mmol) of 3-chloro-2-(2-methyl-2H-tetrazol-5-yl)-lH- indole, 9.4 g (37.4 mmol) of 4-(tert-butoxycarbonylaminomethyl)phenylboronic acid, 7.6 g (50 mmol) of copper(II) acetate, 17.6 mL (100 mmol) of NJV- diisopropylethylamine, 12.2 g of 3 A molecular sieves in 200 mL of Nfl- dimethylformamide was vigorously stirred at room temperature with air bubbling for 24 h, and additional 2.0 g (7.9 mmol) of 4-(tert-butoxycarbonylaminomethyl)- phenylboronic acid was added. The mixture was stirred at room temperature with air bubbling for 48 h, then filtered through Celite. The filtrate was concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015- 0.040 mm) as adsorbent (Merck) and hexane:ethyl acetate = 4:1 as eluent to yield 11.8 g of the title compound as a yellow oil. | |
11.8 g | With copper diacetate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 72h;Molecular sieve; | e) {4-[3-Chloro-2-(2-methyl-2H-tetrazol-5-yl)-indol-1-yl]-benzyl}-carbamic acid tert-butyl ester A mixture of 5.85 g (25 mmol) of 3-chloro-2-(2-methyl-2H-tetrazol-5-yl)-1H-indole, 9.4 g (37.4 mmol) of 4-(tert-butoxycarbonylaminomethyl)phenylboronic acid, 7.6 g (50 mmol) of copper(II) acetate, 17.6 mL (100 mmol) of N,N-diisopropylethylamine, 12.2 g of 3 A molecular sieves in 200 mL of N,N-dimethylformamide was vigorously stirred at room temperature with air bubbling for 24 h, and additional 2.0 g (7.9 mmol) of 4-(tert-butoxycarbonylaminomethyl)-phenylboronic acid was added. The mixture was stirred at room temperature with air bubbling for 48 h, then filtered through Celite. The filtrate was concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and hexane:ethyl acetate=4:1 as eluent to yield 11.8 g of the title compound as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.7% | To a stirred mixture of 10.0 g (42.7 mmol) of 3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-lH-indole, 21.49 g (85.5 mmol) of 4-(tert-butoxycarbonylamino- methyl)phenylboronic acid and 12.98 g (85.5 mmol) of copper(II) acetate in 520 mL of DMSO 29.8 mL (310 mmol) of N^V-diisopropylethylamine and 20 g of 3 A molecular sieves were added. The reaction mixture was vigorously stirred at room temperature with air bubbling for 6 days. The mixture was filtered through Celite. The filtrate was diluted with 1000 mL of ethyl acetate and washed with 2 x 500 mL of 25% ammonium hydroxide solution. The organic layer was washed with 500 mL of 1M citric acid, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 350 mL of 10 % hydrogen chloride in ethyl acetate and stirred at room temperature for 2 h. The precipitated crude product was filtered off, washed with cold ethyl acetate and recrystallized from 2-propanol to yield 14.2 g (88.7%) of the title compound. | |
88.7% | With copper diacetate; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; ethyl acetate; at 20℃; for 144h;Molecular sieve; | c) 4-[3-Chloro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-indol-1-yl]-benzylamine hydro-chloride To a stirred mixture of 10.0 g (42.7 mmol) of 3-chloro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-1H-indole, 21.49 g (85.5 mmol) of 4-(tert-butoxycarbonylamino-methyl)phenylboronic acid and 12.98 g (85.5 mmol) of copper(II) acetate in 520 mL of DMSO 29.8 mL (310 mmol) of N,N-diisopropylethylamine and 20 g of 3 A molecular sieves were added. The reaction mixture was vigorously stirred at room temperature with air bubbling for 6 days. The mixture was filtered through Celite. The filtrate was diluted with 1000 mL of ethyl acetate and washed with 2*500 mL of 25% ammonium hydroxide solution. The organic layer was washed with 500 mL of 1M citric acid, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 350 mL of 10% hydrogen chloride in ethyl acetate and stirred at room temperature for 2 h. The precipitated crude product was filtered off, washed with cold ethyl acetate and recrystallized from 2-propanol to yield 14.2 g (88.7%) of the title compound. |
A614036 [1150114-76-3]
(4-(4-(tert-Butoxycarbonyl)piperazine-1-carbonyl)phenyl)boronic acid
Similarity: 0.83
A114471 [330794-35-9]
tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate
Similarity: 0.82
A298015 [380430-49-9]
(4-Boc-Aminophenyl)boronic acid
Similarity: 0.80
A118028 [380430-68-2]
(3-((tert-Butoxycarbonyl)amino)phenyl)boronic acid
Similarity: 0.79
A273709 [1224449-13-1]
(4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)methyl)phenyl)boronic acid
Similarity: 0.78
A614036 [1150114-76-3]
(4-(4-(tert-Butoxycarbonyl)piperazine-1-carbonyl)phenyl)boronic acid
Similarity: 0.83
A114471 [330794-35-9]
tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate
Similarity: 0.82
A298015 [380430-49-9]
(4-Boc-Aminophenyl)boronic acid
Similarity: 0.80
A118028 [380430-68-2]
(3-((tert-Butoxycarbonyl)amino)phenyl)boronic acid
Similarity: 0.79
A273709 [1224449-13-1]
(4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)methyl)phenyl)boronic acid
Similarity: 0.78
A614036 [1150114-76-3]
(4-(4-(tert-Butoxycarbonyl)piperazine-1-carbonyl)phenyl)boronic acid
Similarity: 0.83
A114471 [330794-35-9]
tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate
Similarity: 0.82
A298015 [380430-49-9]
(4-Boc-Aminophenyl)boronic acid
Similarity: 0.80
A118028 [380430-68-2]
(3-((tert-Butoxycarbonyl)amino)phenyl)boronic acid
Similarity: 0.79
A273709 [1224449-13-1]
(4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)methyl)phenyl)boronic acid
Similarity: 0.78
A114471 [330794-35-9]
tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate
Similarity: 0.82
A298015 [380430-49-9]
(4-Boc-Aminophenyl)boronic acid
Similarity: 0.80
A118028 [380430-68-2]
(3-((tert-Butoxycarbonyl)amino)phenyl)boronic acid
Similarity: 0.79
A254245 [1032528-06-5]
tert-Butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate
Similarity: 0.73
A215531 [108468-00-4]
1-(N-Boc-aminomethyl)-4-(aminomethyl)benzene
Similarity: 0.71