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CAS No. : | 68176-57-8 | MDL No. : | MFCD00052695 |
Formula : | C10H16N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WLOSFXSXVXTKBU-UHFFFAOYSA-N |
M.W : | 164.25 | Pubchem ID : | 432708 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 54.52 |
TPSA : | 52.04 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.92 cm/s |
Log Po/w (iLOGP) : | 1.78 |
Log Po/w (XLOGP3) : | 1.94 |
Log Po/w (WLOGP) : | 2.16 |
Log Po/w (MLOGP) : | 2.1 |
Log Po/w (SILICOS-IT) : | 1.54 |
Consensus Log Po/w : | 1.9 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.38 |
Solubility : | 0.678 mg/ml ; 0.00413 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.66 |
Solubility : | 0.362 mg/ml ; 0.0022 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.88 |
Solubility : | 0.217 mg/ml ; 0.00132 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.01 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
In 1,2-dichloro-ethane; at 20℃; for 18h; | 2d 1-(2-Amino-4-tert-butyl-phenyl)-3- [2-(2-tert-butyl-phenoxy)-6-methoxy-pyridin-3- yl] -thiourea and 1-(2-Amino-5-tert-butyl-phenyl)-3-[2-(2-tert-butyl-phenoxy)-6- methoxy-pyridin-3-yl]-thiourea [00297] To a solution of 4-(tert-butyl)-1, 2-diaminobenzene (20 mg, 0.12 mmol) in DCE (1 mL) was slowly added 2c (19 mg, 0.06 mmol). The reaction was stirred 18 h at rt and concentrated. The crude mixture containing 2d and 2d'was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 294 To a solution of Example 294c (0.060 mmol) in DCE (1 mL) was added 0.50 ml of a 0.24 M stock solution of 4-(tert-butyl)-1, 2-diaminobenzene in DCE. The reaction was stirred at room temperature for 6.5 h. 0.50 ml of a 0.24 M stock solution of EDC in DCM was added and the reaction was stirred overnight at rt. The cyclization was not complete, so an additional 0.50 ml of 0.24 M stock solution of EDC in DCM was added. The reaction was shaken at rt for 5 h and then concentrated down. Purification by preparative HPLC (continuous gradient from 20percent B to 100percent B; A = 90: 10: 0.1 H,, O : CH3CN: TFA; B = 90: 10: 0.1 CH3CN: H2O : TFA) afforded Example 294 (1.12 mg) as a yellow oil. [M+H] + = 420.13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dichloro-ethane; at 20℃; for 18h; | 3d 1- (2-Amino-4-tert-butyl-phenyl)-3- [2- (3-trifluoromethyl-phenoxy)-pyridin-3-yl]- thiourea and 1- (2-Amino-5-tert-butyl-phenyl)-3- [2- (3-trifluoromethyl-phenoxy)- pyridin-3-yl]-thiourea [00302] To a solution of 4-(tert-butyl)-1, 2-diaminobenzene (20 mg, 0.12 mmol) in DCE (1 mL) was slowly added 3c (19 mg, 0.06 mmol). The reaction was stirred 18 h at rt and concentrated. The crude mixture containing 3d and 3d'was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 106 [00331] The crude mixture from 106c (0.06 mmol) was dissolved in DCE (0.5 mL) and a solution of 4-(tert-butyl)-1, 2-diaminobenzene (20 mg, 0.12 mmol) in DCE (0.5 mL) was added. The mixture was shaken at rt for 6 h, then a solution of EDC (23 mg, 0.12 mmol) in DCM (0.5 mL) was added and the mixture was shaken 18 h at rt. Another solution of EDC (23 mg, 0.12 mmol) in DCM (0.5 mL) was added and the mixture was shaken at rt for another 5 h. The mixture was concentrated and purified by preparative HPLC (continuous gradient from 40percent B to 101percent, B ; A = 90: 10: 0.1 H20 : MeOH: TFA; B = 90: 10: 0.1 MeOH: H20 : TFA) to afford Example 106 (8.2 mg, 35percent yield over 4 steps) as a white powder. [M+H] + = 384.09. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | Example 123 [00338] A solution of the aniline 123c (18 mg, 0.06 mmol) in DCM (1 mL) was added dropwise to a solution of N, N-thiocarbonyl diimidazole (21.3 mg, 0.12 mmol) in DCM (0.5 mL) at 0°C. The reaction mixture was shaken at 0°C for 1 h, then at rt for 2 h. The mixture was concentrated. The residue was dissolved in DCM (0.5 mL) and passed through an SPE tube containing 2 g of silica. The product was eluted using 10-20percent ethyl acetate in hexane and was concentrated. The residue obtained was dissolved in DCE (0.5 mL) and a solution of 4- (tert-butyl)-1, 2- diaminobenzene (20 mg, 0.12 mmol) in DCE (0.5 mL) was added. The mixture was shaken at rt for 6 h, then a solution of EDC (23 mg, 0. 12 mmol) in DCM (0.5 mL) was added and the mixture was shaken 18 h at rt. Another solution of EDC (23 mg, 0.12 mmol) in DCM (0.5 mL) was added and the mixture was shaken at rt for another 5 h. The mixture was concentrated and purified by preparative HPLC (continuous gradient from 40percent B to 100percent, B; A = 90: 10: 0.1 H20 : MeOH: TFA; B = 90: 10: 0.1 MeOH: H20 : TFA) to afford Example 123 (1.7 mg, 3percent yield) as a colorless oil. [M+H] + = 473. 15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | Example 124; 5-(6-tert-butyl-lH-benzo [d] imidazol-2-ylamino)-6- (2-tert- butylphenoxy) picolinamide [00339] A solution of the aniline 123c' (17 mg, 0.06 mmol) in DCM (1 mL) was added dropwise to a solution of N, N-thiocarbonyl diimidazole (21.3 mg, 0.12 mmol) in DCM (0.5 mL) at 0°C. The reaction mixture was shaken at 0°C for 1 h, then at rt for 2 h. The mixture was concentrated. The residue was dissolved in DCM (0.5 mL) and passed through an SPE tube containing 2 g of silica. The product was eluted using 10-20percent ethyl acetate in hexane and was concentrated. The residue obtained was dissolved in DCE (0.5 mL) and a solution of 4- (tert-butyl)-1, 2- diaminobenzene (20 mg, 0.12 mmol) in DCE (0.5 mL) was added. The mixture was shaken at rt for 6 h, then a solution of EDC (23 mg, 0.12 mmol) in DCM (0.5 mL) was added and the mixture was shaken 18 h at rt. Another solution of EDC (23 mg, 0.12 mmol) in DCM (0.5 mL) was added and the mixture was shaken at rt for another 5 h. The mixture was concentrated and purified by preparative HPLC (continuous gradient from 40percent B to 100percent, B; A = 90: 10: 0.1 H20 : MeOH: TFA; B = 90: 10: 0.1 MeOH: H20 : TFA) to afford Example 124 (1. 3 mg, 3percent yield) as a colorless oil. [M+H] + = 458.15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | Example 125; [00341] A solution of 125a (20 mg, 0.07 mmol) in DCM (0. 5 mL) was added to a solution of N, N-thiocarbonyl diimidazole (26.0 mg, 0.13 mmol) in DCM (0.5 mL) at 0°C. The mixture was allowed to rt. After 5 h, more N, N-thiocarbonyl diimidazole (26.0 mg, 0.13 mmol) was added and the mixture was heated at 50°C for 18h. The reaction mixture was split into two equal portions. Half of the reaction mixture was treated with 4-(tert-butyl)-1, 2-diaminobenzene (26 mg, 0.16 mmol) for 5 days at rt. The mixture was concentrated and the residue was purified by prep-HPLC (continuous gradient from 40percent B to 100percent, B; A = 90: 10: 0.1 H20 : MeOH: TFA; B = 90: 10: 0.1 MeOH: H20 : TFA). The fractions containing the thiourea were concentrated and the residue was treated with a solution of EDC (23 mg, 0.12 mmol) in DCE (0.5 mL) for 18 h at rt. The mixture was concentrated and the residue was purified by prep-HPLC (continuous gradient from 40percent B to 100percent, B; A = 90: 10: 0.1 H20 : MeOH: TFA; B = 90: 10: 0.1 MeOH: H20 : TFA) to afford Example 125 (2.5 mg, 16percent yield) as a white powder. [M+H] + = 449.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Example 133 [00348] To a, solution of 133b (0.060 mmol) in DCE (1 mL) was added 4-(tert- butyl)-1, 2-diaminobenzene (29.57 mg, 0.180 mmol). The reaction was stirred overnight at rt. EDC (92.04 mg, 0.480 mmol) was added and the reaction was again stirred overnight at rt. The mixture was concentrated and purified by preparative HPLC (continuous gradient from 20percent B to 100percent B; A = 90: 10: 0.1 H20 : CH3CN : TFA ; B = 90: 10: 0.1 CH3CN : H20 : TFA) to afford Example 133 (17. 7 mg, 53percent yield) as an orange solid. [M+H] +-443. t2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Example 134 [003521 To a solution of 134c (0.060 mmol) in DCE (1 mL) was added 4-(tert- butyl)-1, 2-diaminobenzene (29.57 mg, 0. 180 mmol). The reaction was stirred overnight at rt. EDC (92.04 mg, 0. 480 mmol) was added and the reaction was again stirred overnight at rt. The mixture was concentrated and purified by preparative HPLC (continuous gradient from 20percent B to 100percent B; A = 90: 10: 0.1 H20 : CH3CN : TFA; B = 90: 10: 0.1 CH3CN: H20 : TFA) to afford Example 134 (16.8 mg, 52percent yield) as an orange solid. [M+H] + = 429.33. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Example 135 [00356] To a solution of 135b (0.060 mmol) in DCE (1 mL) was added 4- (tert- butyl)-1, 2-diaminobenzene (29. 57 mg, 0.180 mmol). The reaction was stirred overnight at rt. EDC (92.04 mg, 0. 480 mmol) was added and the reaction was again stirred overnight at rt. The mixture was concentrated and purified by preparative HPLC (continuous gradient from 20percent B to 100percent B; A = 90: 10: 0.1 H20 : CH3CN: TFA; B = 90: 10: 0.1 CH3CN : H20 : TFA) to afford Example 135 (14.9 mg, 47percent yield) as an orange solid. [M+H]+= 414.36. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | Example 136 [00362] To a solution of 136e (0.060 mmol) in DCE (1 mL) was added 4-(vert- butyl)-1, 2-diaminobenzene (19. 71 mg, 0.120 mmol). The reaction was stirred overnight at rt. EDC (23.01 mg, 0.120 mmol) was added and the reaction was again stirred overnight at rt. The mixture was concentrated and purified by preparative HPLC (continuous gradient from 20percent B to 100percent B; A = 90: 10: 0.1 H20 : CH3CN: TFA; B = 90: 10: 0.1 CH3CN : H2O : TFA) to afford Example 136 (5.4 mg, 16percent yield) as an orange solid. [M+H]+= 444.28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Example 137 [00366] To a solution of 137c (0.060 mmol) in DCE (1.0 mL) was added 4- (tert-butyl)-1, 2-diaminobenzene (29. 57 mg, 0. 180 mmol). The reaction was stirred overnight at rt. EDC (92.04 mg, 0. 480 mmol) was added and the reaction was again stirred overnight at rt. The mixture was concentrated and purified by preparative HPLC (continuous gradient from 20percent B to 100percent B; A = 90: l 0 : 0.1 H20 : CHgCN : TFA; B = 90 : 10: 0.1 CH3CN : H20 : TFA) to afford Example 137 (11.7 mg, 37percent yield) as a tan solid. [M+H] + = 415.28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Examples of o-phenylenediamines suitable for obtaining the benzimidazolones-(2) of the present invention are:...3-methyl-1,2-phenylendiamine4-methyl-1,2-phenylenediamine4-ethyl-1,2-phenylenediamine5-n-propyl-1,2-phenylenediamine4-tert.-butyl-1,2-phenylenediamine4-methoxy-1,2-phenylenediamine5-ethoxy-1,2-phenylenediamine5-methylsulphonyl-1,2-phenylenediamine... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 13 5-tert-butyl-N-(2-(3,3-dimethylindolin-1-yl)phenyl)-1H-benzo [d]imidazol-2-amine 4-tert-butyl-1,2-diamine benzene (94 mg, 0.517 mmol, 2 eq) was dissolved in DCE (4 mL). At 0° C., 1-(2-isothiocyanatophenyl)-3,3-dimethylindoline (80 mg, 0.285 mmol) in DCE (2 mL) was slowly added. The whole mixture was stirred overnight, EDC (78 mg, 0.41 mmol) was added and the mixture was stirred again overnight at rt. The mixture was concentrated and purified by preparative HPLC (A=90:10:0.1 H2O:MeOH:TFA; B=90:10:0.1 MeOH:H2O:TFA) to afford Example 13 as an off-white solid. LC-MS ESI m/z 411 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; copper(l) chloride; In toluene; acetonitrile; at 80℃; for 1h; | Example 19; 1,1'-Thiocarbonyldiimidazole (12 mg, 0.07 mmol) was added to 19f (20 mg, 0.06 mmol) in THF (0.5 mL) at rt and stirred overnight. The reaction was diluted with EtOAc and washed with water. The organics were dried (MgSO4), filtered and concentrated to give crude isothiocyanate. 4-tert-Butylbenzene-1,2-diamine (9 mg, 0.06 mmol) was added to the isothiocyanate in toluene (1.0 mL) and acetonitrile (0.5 mL) and stirred at rt overnight. Celite.(R). (10 mg), copper (I) chloride (11 mg, 0.12 mmol) and diisopropylethylamine (16 mg, 0.12 mmol) were added and the reaction was heated to 80° C. for 1 h. The reaction was cooled to rt and sat. NH4Cl solution (1 mL) was added and stirred for 1 h. The mixture was filtered through a Celite.(R). plug and then the organics were separated and evaporated to give the crude product. The crude product was taken up in DMF and purified by preperative HPLC to give Example 19 as a tan colored solid (4 mg, 14percent). (M+H)+=536. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Example 6; To a solution of benzene-1,2-diamine (44 mg, 0.26 mmol) in 2 mL of CH2Cl2 was added 6e (50 mg, 0.109 mmol) in DCM. The reaction mixture was stirred at rt for 3 h. Then EDC (57 mg, 0.26 mmol) was added to the reaction mixture and stirred at rt for 16 h. The crude residue was subjected to column chromatography using 0 to 5percent MeOH in CH2Cl2 as eluting solvent to afford Example 6 (63 mg, 98percent) as off-white powder. MS (ES) m/z 586 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 75; 2-[4-(5-tert-Butyl-lH-benzoimidazol-2-ylmethyl)-phenylcarbamoyl]-pyrrolidine-l- carboxylic acid benzyl ester (Compound 6075); Using General Procedure D from 35 mg of 4-tert-Butyl-benzene-l,2-diamine. MS: 483.1 (M+H*). General Procedure D; A mixture of (S)-Pyrrolidine-l,2-dicarboxylic acid 1-benzyl ester (F.W. = 249.27, 1.5 g, 4.0 mmol), HATU (1.6 g, 3.9 mmol), and DIEA (0.7 mL, 4.97 mmol) in DMF (30 mL) was stirred at room temperature for 1 h. (4-Amino-phenyl)-acetic acid (FW = 151.17, 0.5 g, 3.31 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was filtered and separated by reverse phase HPLC (0-100percent of buffer B; buffer A: water containing 0.1 percent TFA; buffer B: MeCN containing 0.1 percent TFA). The combined fraction was evaporated to furnish the desired product (S)-2-(4-Carboxymethyl- phenylcarbamoyl)-pyrrolidine-l-carboxylic acid benzyl ester.A mixture of (S)-2-(4-Carboxymethyl-phenylcarbamoyl)-pyrrolidine- 1 -carboxylic acid benzyl ester (0.5 g, 1.3 mmol), HATU (0.5 g, 1.3 mmol), and DIEA (0.25 mL, 1.9 <n="69"/>mmol) in DMF (16 rnL) was stirred at room temperature for 1 h. To each of the diamines described in the following Examples was added 2 mL of this solution and the mixture were stirred at room temperature for 20 h. The resulting mixtures (intermediates) were washed with water, dried in speed vacuum overnight. Each resulting intermediate was dissolved in glacial acetic acid (10 mL) and the mixture was heated to reflux for 3 h then concentrated to give the crude product. Purification of the crude products by reverse phase HPLC (20-100percent of buffer B; buffer A: water containing 0.1percent TFA; buffer B: MeCN containing 0.1percent TFA) furnished the corresponding desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 5; 6-toer/-Butyl-2- {(E)-2-[3-methoxy-4-(4-methyl-imidazol- 1 -yl)-phenyl]-vinyl} - lH-benzimidazole trifluoroacetate salt(E)-3-[3-Methoxy-4-(4-methyl-imidazol-l-yl)-phenyl]-acrylic acid (300 mg, 1.162 mmol) and A-tert- butyl-benzene-l,2-diamine (191 mg, 1.162 mmol) were placed in a 10-mL flask under nitrogen. Ethylene glycol (2 ml) was added and the reaction mixture heated to 185°C for 3h and then to 17O0C overnight. The reaction was quenched with water and the precipitated green solid collected. The solid was dried on high vacuum, then recrystallized from ethyl acatate (15 mL). The residue was purified by preparative etaPLC Reverse phase (C- 18), eluting with Acetonitrile/Water + 0.05percent TFA, to give the product (266 mg) as a yellow solid. 1H (600 MHz, dmso-d6): 1.33 (s, 9H), 2.14 (s, 3H), 3.90 (s, 3H), 7.06-7.78 (m, 1 IH). LCMS (ESI): calcd for C24H27N4O [M+H]+ 387.2, found 387.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.4% | In ethanol; toluene; at 20℃; for 4h; | Step 1: 6-tert-Butyl-quinoxalin-2-ol To a solution of 2 g (12.18 mmol) 4-tert-butyl-1,2-diaminobenzene in 20 mL ethanol under argon at room temperature, was added 3.139 mL (15.83 mmol) ethyl glyoxalate (50percent in toluene). The reaction mixture was stirred at room temperature for 4 h. The resulting suspension was filtered and washed with ethanol. The powder was dried to provide 257 mg (10.4percent) of the title compound as a white solid. MS(m/e): 201.0 (M-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In m-xylene; at 200℃; | Step 4 Compound P3 (50 mg, 0.22 mmol), 4-tert-butylbenzene-1 ,2-diamine (35 mg, 1 eq), and DMAP (26 mg, 1eq) were mixed together in m-xylenes and heated at 200 °C overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with NH4CI (saturated), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 89.91 :9.99:0.1 to 9.99:89.91 :0.1 H2O:MeCN:HCO2H) to give 14 mg of compound 1. LCMS: MH+=333.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | (Step 5)Preparation of 4-(5-tert-butyl-1H-benzo[d]imidazol-2-yl)benzene amineTo a solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid 3.6 g (20 mmol) of step 4 in dimethylformamide 50 mL were added 4-tert-butylbenzen-1,2-diamine 3.3 g (20 mmol), diisopropylethylamine 7 mL (40 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 11 g (30 mmol), followed by stirring at room temperature for 3 hrs.The reaction mixture was diluted with ethylacetate, washed with a saturated sodium bicarbonate solution and a saturated NaCl solution, and dried over magnesium sulfate before being concentrated in a vacuum.The residue thus obtained was dissolved in acetic acid/toluene (45 mL/5 mL), stirred at 70° C. for 4 hrs, cooled to room temperature, and concentrated in a vacuum.The concentrate was dissolved in ethylacetate, washed with a saturated sodium bicarbonate solution and a saturated NaCl solution, and dried over magnesium sulfate before vacuum concentration.Purification by column chromatography (developing solvent: ethylacetate/hexane=1/1) gave 5.2 g of the title compound (yield 85percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-benzoquinone; In acetonitrile; for 2h;Reflux;Product distribution / selectivity; | 84.4 g (0.39 mol) of 4-(3-chloropyridin-2-yl)benzaldehyde and 840 mL of acetonitrile were sequentially placed in a reactor. 63.7 g (0.39 mol) of 4-tert-butylbenzene-1,2-diamine and 42.1 g (0.39 mol) of 1,4-benzoquinone were added. The mixture was heated to reflux for 2 hours, cooled to room temperature and concentrated under reduced pressure. 340 mL of acetonitrile was added to the residue, and the mixture was heated to reflux so as to be completely dissolved, slowly cooled to 0 ~ 5°C, stirred at the same temperature for 2 hours, filtered and dried in a vacuum at 50°C, yielding the following compound in a 91percent yield. |
91% | With p-benzoquinone; In acetonitrile; for 2h;Reflux; | 84.4 g (0.39 mol) of 4-(3-chloropyridin-2-yl)benzaldehyde and 840 mL of acetonitrile were sequentially placed in a reactor. 63.7 g (0.39 mol) of 4-tert-butylbenzene-1,2-diamine and 42.1 g (0.39 mol) of 1,4-benzoquinone were added. The mixture was heated to reflux for 2 hours, cooled to room temperature and concentrated under reduced pressure. 340 mL of acetonitrile was added to the residue, and the mixture was heated to reflux so as to be completely dissolved, slowly cooled to 05° C., stirred at the same temperature for 2 hours, filtered and dried in a vacuum at 50° C., yielding the following compound in a 91percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | (Step 5) Preparation of 4-(5-tert-butyl-1H-benzo[d]imidazol-2-yl)benzene amine [114] To a solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid 3.6 g (20 mmol) of step 4 in dimethylformamide 50 mL were added 4-tert-butylbenzen-1,2-diamine 3.3 g (20 mmol), diisopropylethylamine 7 mL (40 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 11 g (30 mmol), followed by stirring at room temperature for 3 hrs. The reaction mixture was diluted with ethylacetate, washed with a saturated sodium bicarbonate solution and a saturated NaCl solution, and dried over magnesium sulfate before being concentrated in a vacuum. The residue thus obtained was dissolved in acetic acid/toluene (45 mL/5 mL), stirred at 70°C for 4 hrs, cooled to room temperature, and concentrated in a vacuum. The concentrate was dissolved in ethylacetate, washed with a saturated sodium bicarbonate solution and a saturated NaCl solution, and dried over magnesium sulfate before vacuum concentration. Purification by column chromatography (developing solvent: ethylacetate/hexane=1/1) gave 5.2 g of the title compound (yield 85percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 19h; | Step 4: N-(2-amino-4-(tert-butyl)phenyl)-5-((((3aR,4R,6R,6aR)-6-(4-((2,4- dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4-yl)methyl)(isopropyl)amino)pentanamideregioisomers XA solution of 5-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][l ,3]dioxol-4- yl)methyl)(isopropyl)amino)pentanoic acid (131 mg, 0.219 mmol) and 4-tert-butylbenzene- 1,2-diamine (40 mg, 0.24 mmol) in N,N-dimethylformamide (2.2 mL) was treated with N,N-diisopropylethylamine (84 uL, 0.48 mmol) dropwise followed by PyBop reagent (120 mg, 0.24 mmol). The solution was allowed to stir at room temperature for 19 h, whereupon HPLC indicated the reaction was complete. The reaction mixture was concentrated under high vacuum. The residue was taken up in 40 mL CH2C12 and washed with 20 mL portions of H20, 5percent citric acid, and brine. The organic phase was dried over Na2S04, filtered and concentrated to yield a tan viscous glass. The crude material was purified by flash chromatography (40g silica gel; 2percent 7N NH3 in CH3OH/CH2Cl2 to yield the title compound (140 mg, 86percent) was a slightly tan glass: MS (ESI+) for C4iH57N706 m/z 744.9 (M+H)+; HPLC purity (combined for the two regioisomers) 91 percent (ret. times, 3.25 and 3.28 min). |
Yield | Reaction Conditions | Operation in experiment |
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79% | [0553] Step 2: Synthesis of 4-(5-tert-Butyl-lH-benzoimidazol-2-yl)-butan-l-ol[0554] A mixture of 4-tert-butyl -benzene- 1,2-diamine (lg, 6.09mmol) and valerolactone (0.67g, 6.70mmol, l.leq.) in 4N HC1 aq (5ml) was sealed and heated for 2h at 100°C. LCMS analysis shows remaining diamine. Completion was achieved using excess of valerolactone (~1.3ml, 2eq.) heating at 100° for 4h. The reaction was cooled to RT and basified to pH 12 with a saturated solution of Na2C03. EtOAc (100ml) was added and organic separated, washed with saturated solution of Na2C03, water, brine, dried over Na2S04, filtered and concentrated. The residue was purified by flash columnchromatography over silica gel, eluted with DCM - MeOH from 2percent to 5percent gradually to yield 1.19g (79percent) of a beige solid; MS (ESI+) for C15H22N2O m/z 1 [M+H]+, 247.15; HPLC purity 100percent (ret. time, 1.42 min).1H NMR (500 MHz, CHLOROFORM-d) delta ppm 1.38 (9 H, s), 1.65 - 1.75 (2 H, m), 2.00 (2 H, quin, J=7.17 Hz), 2.98 (2 H, t, J=7.09 Hz), 3.72 (2 H, t, J=5.99 Hz), 7.31 (1 H, dd, J=8.51, 1.58 Hz), 7.48 (1 H, d, J=8.20 Hz), 7.56 (1 H, d, J=1.26 Hz). | |
67% | Compound 319(2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[[4-(5-tert-butyl-lH-benzimidazol-2-yl)butyl- isopropyl-amino]methyl]tetrahydrofuran-3,4-diolHStep 1. Preparation of 4-(5-tert-butyl-lH-benzimidazol-2-yl)butan-l-ol A mixture of 4-tert-butylbenzene-l,2-diamine (646 mg, 3.93 mmol) andtetrahydropyran-2-one (1.18 g, 11.80 mmol) in 50 mL of 4 M HC1 was refluxed for 8 h. Then the mixture was neutralized with K2C03 (aq) to pH = 8. The mixture was extracted with DCM (30 mL x4). The organic layers were concentrated and the residue was purified by SGC (DCM : MeOH = 20 : 1) to afford the product(650 mg, yield: 67 percent) as a pale solid. MS (ESI): m/z 247.7 [M+l]+. | |
49% | Compound 323(2R^R,4S,5S)-2-(6-amino-9H-purin-9-yl)-5 ((4-(5-(tert-butyl) H-benzo[d]imidazol-2- yl)butyl)thio)methyI)tetrahydrofuran-3,4-diolStep 1. Preparation of 4-(5-tert-butyl-lH-benzimidazol-2-yl)butan-l-olA solution of 4-tert-butylbenzene-l,2-diamine (6 g, 36.59 mmol) andtetrahydropyran-2-one (6.09 g, 60.98 mmol) in 4 M HC1 (100 mL) was heated to 100° C overnight. The reaction was evaporated, added water (50 mL), adjusted to pH = 8 with aq. NaHC03, extracted with EA (3x100 mL), washed with water (20 mL) and brine (20 mL), dried and concentrated. The residue was purified by SGC to obtain the product (4.4 g, Yield 49percent). 1H NMR (500 MHz, MeOD): 57.50-7.28 (m, 3H), 3.60 (t, J = 6.5 Hz, 2H), 2.91 (t, J = 7.5 Hz, 2H), 1.90 (t, J = 7.0 Hz, 2H), 1.60 (t, J = 7.0 Hz, 2H), 1.37 (s, 9H) ppm; ESI-MS (m/z): 247.2[M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
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With N-[([(1E)-1-cyano-2-ethoxy-2-oxoethylidene]amino}oxy)(morpholin-4-yl)methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 0.333333h; | Compound 22: (lR,25,3R,5R)-3-{4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-5-[({3-[(5- tert-butyl-lH-l,3-benzodiazol-2-yl)methyl]cyclobutyl}methyl)(propan-2- yl)amino] methyl }cyclopentane- 1 ,2-diolStage I: 3-[(2-amino-4-tert-butylphenyl)carbamoyl]methyl}-N-methoxy-N- methylcyclobutane-l-carboxamide[0700] N,N-Diisopropylethylamine (5.19 ml, 29.82 mmol) was added to a suspension of 2- {3-[methoxy(methyl)carbamoyl]cyclobutyl}acetic acid (3 g, 14.91 mmol), 4-tBu phenylene diamine (2.69 g, 16.4 mmol) and (l-cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (7.02 g,16.4 mmol) in dichloromethane (60 ml) at 0°C and stirred for 20 mins before being allowed to warm to RT. The reaction was left at RT for 4 h. The reaction mixture was concentrated, and the residue redis solved in EtOAc (60ml). The solution was washed with water (3 x 60ml), then brine (60ml), dried (MgS04) and concentrated under reduced pressure. The crude material was purified by dry flash chromatography, eluting with 100 percent EtOAc to afford the title compound (3.74 g, 46percent) as a brown oil: MS (ESf ) for C19H29N3O3 m/z 348.5 [M+H]+; LC purity 26percent and 44percent (UV), 18percent and 68percent (ELS), (ret. time, 1.65 and 1.71 min). |
Yield | Reaction Conditions | Operation in experiment |
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75% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; | Step 3. Preparation of N-(2-amino-4-(tert-butyl)phenyl)-5-((((3aS,4S,6R,6aR)-6- (6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4- yl)methyl)thio)pentanamideA solution of 5-((((3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][l ,3]dioxol-4-yl)methyl)thio)pentanoic acid (1100 mg, 2.88 mmol), HOBT (778 mg, 5.76 mmol) and EDCI (1 100 mg, 5.76 mmol) in DCM (25 mL) were added 4-tert- butylbenzene-l,2-diamine (614 mg, 3.74 mmol) in DCM (5 mL) and TEA (1160 mg, 11.52 mmol). The reaction was stirred at rt overnight. The reaction was diluted with DCM (30 mL), washed with water (20 mL) and brine (20 mL), dried and concentrated. The residue was purified by SGC to obtain the product (1200 mg, Yield 75percent). NMR (500 MHz, MeOD): delta 8.27 (s, 1H), 8.23 (s, 1H), 6.99-6.74 (m, 3H), 6.17 (s, 1H), 5.54 (d, J = 5.5 Hz, 1H), 5.05 (d, J = 5.5 Hz, 1H), 4.356-4.343 (m, 1H), 2.70-2.65 (m, 2H), 2.53-2.50 (m, 2H), 2.36-2.33 (m, 2H), 1.72-1.68 (m, 2H), 1.58 (s, 3H), 1.38 (s, 3H), 1.34-1.32 (m, 2H), 1.26 (s, 9H) ppm; ESI-MS (m/z): 570..3[M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
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52% | Step 7. Preparation of (2R,3S,4R,5R)-2-(((4-(5-(tert-butyl)-lH- benzo[d]imidazol-2-yl)butyl)(isopropyl)amino)methyl)-5-(9H-purin-9- yl)tetrahydrofuran-3,4-diolTrimethylaluminum ((1.22 mL, 2.43 mmol, 2.0 M toluene solution) was added to a 12 mL of toluene containing of 4-tert-butylbenzene-l,2-diamine (267 mg, 1.62 mmol) at rt. After stirring for 1.5 h ethyl 5-((((3aR,4R,6R,6aR)-2,2-dimethyl-6-(9H-purin-9- yl)tetrahydrofuro[3,4-d][l,3]dioxol-4-yl)methyl)(isopropyl)amino)pentanoate (300 mg, 0.65 mmol) was added and the mixture was heated to 85° C for 15 h. Then, the solution was poured into 100 mL of chloroform containing 50 g of silica gel and filtered off. The residue was washed with 30 mL of methanol and the filtrate was concentrated to obtain the crude (220 mg). The mixture of CH3COOH (4 mL) and the crude product was heated at 80 °C for 15 h and then the solution was concentrated. The residue was diluted with 15 mL of DCM and saturated NaHC03 was added to adjust to pH = 7. The solution was extracted with DCM (20 mL x 3). The combined organic phase was dried over Na2S04 and concentrated to obtain the product (190 mg, 52 percent) as a light yellow solid. ESI-MS (m/z): 562.3 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
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59% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; | Step 3. Preparation of Nl-(2-amino-4-(tert-butyl)phenyl)-N5- (((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d] [1 ,3]dioxol-4-yl)methyl)-N5-isopropylgIutaramideTo a solution of 5-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro [3,4-d][l ,3]dioxol-4-yl)methyl)(isopropyl)amino)-5-oxopentanoic acid (400 mg, 0.86 mmol), EDCI (332 mg, 1.73 mmol) and HOBt (234 mg, 1.73 mmol) in DCM (15 mL) was added 4-tert-butylbenzene-l ,2-diamine (2.0 eq., 1.73 mmol) and TEA (0.6 mL, 4.32 mmol). The mixture was stirred at rt overnight. The mixture was washed with water (15 mL x 2) and brine (15 mL). The organic phase was dried over Na2S04, filtered and concentrated. The residue was purified by Combi-flash (12 g silica gel, start 10 : 0 - EA : MeOH to 10 : 1 by gradient, 40 mL / min, 30 min, 1.2 total solvent volume) to afford the product (310 mg, 59percent) . LC-MS (m/z): 609.5 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
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General procedure: Example 75 2-(5- e/t-Butyl-1 H-benzimidazol-2-yl)piperidin-3-ol A 0.2M solution of 3-hydroxypiperidine-2-carboxylic acid (500 muIota_, 100 pmol) in DMA was added to a 0.2M solution of 4-terf-butyl-1 ,2-diaminobenzene (500 muIota_, 100 pmol) in DMA followed by BOP (44 mg, 100 pmol). The reaction was stirred at room temperature for 16 hours before concentrating in vacuo. A solvent mixture of THF/AcOH (5/1 , 1 mL) was added to the residue, and the reaction heated to 60°C for 16 hours. The reaction was cooled, concentrated in vacuo, dissolved in DMSO (1 mL) and purified using preparative HPLC (XTERRA-C18 (250 x 19 mm, 10 mu, mobile phase A: Acetonitrile, mobile phase B: 10mM ammonium acetate in water; eluting with a gradient of 10-70percent organic with a flow rate of 16 mL/min over 18 minutes) to afford the title compound. LCMS Rt =1 .33 minutes MS m/z 274 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
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With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In 1,4-dioxane; at 20 - 100℃; for 18h; | Example 78 Step 1 To a stirred solution of 4-ieri-butyl-1 ,2-diaminobenzene (375mg, 2.28mmol) in dioxane (4 mL) was added a solution of N-Boc-L-threonine (500 mg, 2.28 mmol) in dioxane (4 mL) followed by triethylamine (636 pL, 456 mmol) and T3P (1520 mg, 2.40 mmol). The reaction was stirred at room temperature for 10 minutes followed by heating to 100°C for 18 hours. The reaction was cooled and diluted with EtOAc (50 mL) and saturated aqueous sodium bicarbonate solution (40 mL). The organic layer was collected, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 15-100percent TBME in heptanes to afford terf-butyl [(1 R,2R)-1 -(5-terf-butyl-1 H-benzimidazol-2-yl)-2- hydroxypropyl]carbamate. Step 2 To ferf-butyl [(1 R,2R)-1 -(5-terf-butyl-1 H-benzimidazol-2-yl)-2-hydroxypropyl]- carbamate (105 mg, 0.302 mmol) was added DCM (5 mL) followed by TFA (700 pL) at 0°C. The reaction was allowed to warm to room temperature for 4 hours before cooling back to 0°C and quenching with saturated aqueous NaHCO3 solution (20 mL). The mixture was extracted with DCM, the organic layer collected, dried over MgSO and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with DCM:MeOH:NH3 (80:20:2) to afford the title compound (21 mg, 28percent). 1H NMR (400MHz, CDCI3): delta ppm 1 .20 (s, 3H), 1 .35 (s, 9H), 4.00 (m, 1 H), 4.37 (m, 1 H), 7.25 (m, 1 H), 7.42 (m, 1 H), 7.50 (m, 1 H). LCMS (2 minute run) Rt = 1 .02 minutes MS m/z 246 [M-H]~ |
Yield | Reaction Conditions | Operation in experiment |
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Example 102 (1 R)-1 -Amino- 1 -(5-fe/f-butyl-1 H-benzimidazol-2-yl)-2-methylpropan-2-ol A solution of 4-ferf-butyl-1 ,2-diaminobenzene (1 g, 6 mmol), N-boc-3-hydroxy-L-valine (1 .4 g, 6 mmol) and triethylamine (1 .5 mL, 15.1 mmol) in dioxane (50 mL) was stirred at 0°C for 15 minutes. T3P (50percent w/w in EtOAc, 4.6 mL, 7.3 mmol) was added dropwise and the reaction continued stirring at this temperature for 30 minutes. The reaction was then heated to reflux for 5 hours before cooling and diluting with EtOAc. The solution was washed with saturated aqueous sodium carbonate solution twice, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-50percent EtOAc in heptanes. The residue was dissolved in dioxane (10 mL) at 0°C and treated with 4M HCI in dioxane (10 mL). The reaction was stirred at room temperature for 2 hours before concentrating in vacuo. The residue was washed with EtOAc and pentane before basifying with saturated aqueous NaOH solution and extracting into EtOAc. The organic layer was collected, dried over Na2SO4, concentrated in vacuo and triturated with 10percent EtOH in pentane (5 mL) to afford the title compound (25 mg, 2percent). 1H NMR (400MHz, DMSO-d6): delta ppm 1 .08-1 .1 (m, 6H), 1 .21 -1 .39 (m, 9H), 2.17-2.27 (m, 2H), 3.81 (s, 1 H), 4.87 (s, 1 H), 7.18-7.21 (m, 1 H), 7.41 (m, 2H), 1 1 .9 (br s, 1 H). MS m/z 262 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
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With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In 1,4-dioxane; at 100℃; for 4h; | Preparation 26 tert-Butyl Gamma(1 S)-1 -(5-fe/f-butyl-1 H-benzimidazol-2-yl)-2-hvdroxy-1 - methylethyllcarbamate and fe/f-butyl [(1 R)-1 -(5-fe/f-butyl-1 H-benzimidazol-2-yl)-2- hydroxy-1 -methylethyllcarbamate and To a stirred solution of Rac-N-Boc-2-methylserine (Preparation 53, 700 mg, 3.19 mmol) in dioxane (30 ml_) was added 4-ieri-butyl-1 ,2-diaminobenzene (787 mg, 4.79 mmol), T3P (2130 mg, 3.35 mmol) and TEA (0.89 ml_, 6.39 mmol) and the reaction heated to 100°C for 4 hours. The reaction was cooled and partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer was collected and concentrated in vacuo. The residue was first purified using silica gel column chromatography eluting with 2/8 to 0/1 hepatane in TBDME followed by chiral separation using a Chiralpak-IC column, 220 nM eluting with heptanes:iPrOH 80:20 to afford two enantiomers: Peak 1 : 1 1 .24 minutes, 89percent ee Peak 2: 16.94 minutes, 99percent ee. Peak 1 was taken through to the next step and assumed (S). |
Yield | Reaction Conditions | Operation in experiment |
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Example 144 (R)-2-((S)-Amino-(6-( e/t-butyl)-1 H-benzord1imidazol-2-yl)methyl)butanamide (2S,3R)-1 -(fe/ -Butyldimethylsilyl)-3-ethyl-4-oxoazetidine-2-carboxylic acid (Tetrahedron, 46(7), 2255-62; 1990, 100 mg, 0.388 mmol) was dissolved in N,N- dimethylformamide (2 mL) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1 - yl)uronium hexafluorophosphate (418 mg, 1 .10 mmol) was added. The reaction mixture was stirred for 20 minutes then 4-(te/t-butyl)benzene-1 ,2-diamine (165 mg, 1 .00 mmol) was added and the reaction mixture stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted three times with ethyl ether. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed in-vacuo. The residue was purified by silica gel column chromatography eluting with 0-100percent ethyl acetate in hexanes to afford the amide as a mixture of isomers. The amide intermediate was stirred in acetic acid (2 mL) at 60°C for 18 hours. The acetic acid was removed in vacuo and the residue was dissolved in dichloromethane (2 mL) then 4-dimethylaminopyridine (0.12 g, 0.97 mmol) and di-te/t-butyldicarbonate (0.2 g, 1 mmol) were added. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was washed with aqueous saturated sodium bicarbonate solution and the organic phase dried over anhydrous magnesium sulfate then filtered and the solvent removed in vacuo. The residue was purified by silica gel column chromatography eluting with 0-50percent ethyl acetate in hexanes to afford the BOC protected benzimidazole. The benzimidazole was dissolved in tetrahydrofuran (3 mL) with 28percent aqueous ammonium hydroxide (1 mL) and stirred for 48 hours at ambient temperature. The solvent was removed in vacuo and the residue was dissolved in 4N HCI in 1 ,4- dioxane and stirred for 2 hours. The solvent was removed in vacuo and the residue was taken into methanol/dichloromethane and treated with macroporous triethylammonium methylpolystyrene carbonate resin to neutralize excess acid. The reaction mixture was filtered and the solvent removed in vacuo. The residue was purified by silica gel column chromatography eluting with 0-80percent CMA80 in dichloromethane to afford the title compound (38 mg). 1H NMR (300 MHz, DMSO-d6): delta ppm 0.81 (t, 3H), 1 .31 -1 .45 (m, 1 1 H), 2.94 (m, 1 H), 4.62 (m, 1 H), 7.29-7.37 (m, 2H), 7.47-7.59 (m, 2H), 7.74 (br s, 1 H), 8.54 (br s, 2H), 12.7 (br s, 1 H). LCMS Rt = 1 .01 minutes, MS m/z 289 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
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89 g | Preparation 24 tert-Butyl f(1 R,2S)-1 -(5-fe/t-butyl-1 H-benzimidazol-2-yl)-2-hvdroxypropyHcarbamate N-Boc-L-allo-threonine (Preparation 54, 67.12 g, 306 mmol), 4-terf-butyl- diaminobenzene (60.3 g, 367 mmol) and HOBt (56.3 g, 367 mmol) were dissolved in DMF (500 mL). NMM (67 mL, 612 mmol) was added and the mixture cooled to 0°C. EDCI (65.6 g, 336 mmol) was added portionwise over 1 .5 hours and the reaction was stirred at room temperature for 18 hours. EtOAc (2 L) was added followed by water (1 L) and the mixture stirred vigorously for 15 minutes. The aqueous layer was removed and washed further with EtOAc (2 x 30 mL). The organic layers were combined, dried over Na2SO and concentrated in vacuo. The residue was sonicated in pentane/DCM 10/1 twice and filtered to afford a pale pink solid that was dissolved in AcOH (500 mL) and stirred at 40°C for 24 hours followed by room temperature for 2 days. The solvent was removed in vacuo and the residue dissolved in EtOAc (1 .5 L). Saturated aqueous NaHCO3 (500 mL) was added and the mixture stirred vigorously. The organic layer was collected, washed with NaHCO3 solution (2 x 200 mL), dried over Na2SO and concentrated in vacuo. The residue was dissolved in DCM (500 mL) and purified using silica gel column chromatography eluting with 0-20percent acetone in cyclohexaneto afford the title compound as an off-white solid (89 g, quant). 1H NMR (400MHz, MeOD): delta ppm 1 .17 (d, 3H), 1 .40 (s, 9H), 1 .43 (s, 9H), 4.17 (m, 1 H), 4.80 (m, 1 H), 7.30 (m, 1 H), 7.45 (m, 1 H), 7.55 (m, 1 H). LCMS Rt = 1 .87 minutes MS m/z 348 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
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78% | Preparation 31 (2R,3S)-3-(( e/t-Butoxycarbonyl)amino)-3-(5-( e/t-butyl)-1 H-benzord1imidazol-2-yl)-2- methylpropanoic acid To a cooled solution (-78°C) of (2S,3R)-4-(benzyloxy)-2-((terf-butoxycarbonyl)amino)- 3-methyl-4-oxobutanoic acid (Preparation 66, 4.10 g, 12.2 mmol) in tetrahydrofuran (50 mL) was added N-methylmorpholine (2.0 mL, 18.23 mmol) followed by isobutyl chloroformate (1 .67 mL, 12.8 mmol) and the resulting white suspension stirred at - 78°C for 30 minutes. A solution of 4-(terf-butyl)benzene-1 ,2-diamine (2.40 g, 14.6 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude product was dissolved in ethyl acetate (200 mL) and washed with aqueous saturated sodium bicarbonate (3 x 50 mL), water (2x 50 mL). The organic layer was concentrated in vacuo and purified by silica gel column chromatography eluting with a gradient of dichloromethane: EtOAc. The residue was dissolved in methanol (50 mL) and palladium hydroxide was added (20percent wtpercent on carbon, 0.43 g). The reaction mixture was stirred under a hydrogen atmosphere (2 atm) at room temperature for 1 hour. The reaction mixture was filtered through a small pad of Arbocel and concentrated in vacuo. The residue was dissolved in acetic acid (100 mL) and stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase column chromatography eluting with a gradient of water/ MeCN to afford the title compound as off-white solid (3.54 g, 78percent). 1H NMR (400MHz, CDCI3): delta ppm 1 .13 (d, 3H), 1 .26 (s, 9H), 1 .37 (s, 9H), 3.41 (m, 1 H), 5.40 (br. s, 1 H), 5.54 (m, 1 H), 7.08 (m, 1 H), 7.40 (m, 1 H), 7.58 (m, 1 H), 7.62 (s, 1 H) LCMS (system 1 , acidic, 4.5min): Rt =2.09 minutes MS m/z 376 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
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58% | Preparation 33 Methyl (3S)-3-r(ferf-butoxycarbonyl)amino1-3-(5-ferf-butyl-1 H-benzimidazol-2-yl)-2- methylpropanoate A solution of (2S)-2-[(fe/t-butoxycarbonyl)amino]-4-methoxy-3-methyl-4-oxobutanoic acid (Preparation 62, 8.45 g, 32.3 mmol) in THF (300 mL) was cooled to -78°C and NMM (5.3 mL, 48.5 mmol) was added followed by a solution of isobutylchloroformate (4.44 mL, 34 mmol) in THF (20 mL) dropwise over 30 minutes. The resulting solution was added to a solution of 4-te/t-butyl-1 ,2-diaminobenzene (5.95 g, 36.22 mmol) in THF (100 mL) via cannula at -78°C. The reaction was stirred at -78°C for 1 hour, then allowed to warm to room temperature for 3 hours. The reaction was concentrated in vacuo and diluted with EtOAc (300 mL). The solution was washed with saturated aqueous NaHCO3 solution (2x100 mL), brine (3x100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in AcOH (150 mL) and stirred at room temperature for 4 days. The reaction was evaporated to dryness azeotroping with dioxane. The residue was purified using reverse phase column chromatography eluting with 5-40percent MeCN in 0.1 percent formic acid in water. The acetonitrile was evaporated and the remaining aqueous solution was baseified with saturated aqueous NaHCO3 solution. The product was extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified using silica gel column chromatography eluting with DCM/TBME 9/1 to afford the title compound as a yellow solid (7.25 g, 58percent). 1H NMR (400MHz, CDCI3): delta ppm 1 .10-1 .55 (m, 21 H), 3.25 and 3.52 (m, 1 H, diastereomers 1 :2 ratio), 3.65 and 3.72 (s, 3H, diastereomers 1 :2 ratio), 5.18 and 5.21 (m, 1 H, diastereomers 1 :2 ratio), 5.60 and 6.25 (m, 1 H, diastereomers 1 :2 ratio), 7.28- 7.80 (m, 3H). LCMS Rt = 2.59 minutes MS m/z 390 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73 mg | Preparation 12 (R)-ferf-Butyl (1 -(5-( e/t-butyl)-1 H-benzo[d1imidazol-2-yl)-2-hvdroxyethyl)carbamate (S)-2-((fe/t-Butoxycarbonyl)amino)-3-hydroxypropanoic acid (226 mg, 1 .10 mmol) was dissolved in N,N-dimethylformamide (5 ml_) and 1 -[bis(dimethylamino)methylene]-1 H- 1 ,2,3-triazolo[4,5-b]pyridinium-3-oxid-hexafluorophosphate (440 mg, 1 .10 mmol) was added. The reaction was stirred for 10 minutes then 4-(terf-butyl)benzene-1 ,2-diamine (164 mg, 1 .00 mmol) was added and the reaction mixture stirred for 18 hours. The reaction mixture was diluted with water and extracted twice with ethyl ether. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo. The residue was dissolved in 1 ,2-dichloroethane and anhydrous magnesium sulfate was added. The reaction was stirred at 65°C for 18 hours to complete the dehydration. The reaction mixture was filtered and loaded directly onto a 4g silica gel column for purification. The column was eluted with 0-10percent methanol in dichloromethane to afford 73 mg of product as a white solid. 1H NMR (400MHz, DMSO-d6): delta ppm 1 .33 (s, 9H), 1 .40 (s, 9H), 3.72 (m, 2H), 4.76 (m, 1 H), 4.95 (t, 1 H), 7.03, (m, 1 H), 7.21 (m, 1 H), 7.34-7.52 (m, 2H), 1 1 .95 (m, 1 H). LCMS Rt = 1 .03 minutes MS m/z 334 [M+H]+ (R)-ferf-Butyl (1 -(5-( e/t-butyl)-1 H-benzo[d1imidazol-2-yl)-2-hvdroxyethyl)carbamate (S)-2-((fe/t-Butoxycarbonyl)amino)-3-hydroxypropanoic acid (226 mg, 1 .10 mmol) was dissolved in N,N-dimethylformamide (5 ml_) and 1 -[bis(dimethylamino)methylene]-1 H- 1 ,2,3-triazolo[4,5-b]pyridinium-3-oxid-hexafluorophosphate (440 mg, 1 .10 mmol) was added. The reaction was stirred for 10 minutes then 4-(terf-butyl)benzene-1 ,2-diamine (164 mg, 1 .00 mmol) was added and the reaction mixture stirred for 18 hours. The reaction mixture was diluted with water and extracted twice with ethyl ether. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo. The residue was dissolved in 1 ,2-dichloroethane and anhydrous magnesium sulfate was added. The reaction was stirred at 65°C for 18 hours to complete the dehydration. The reaction mixture was filtered and loaded directly onto a 4g silica gel column for purification. The column was eluted with 0-10percent methanol in dichloromethane to afford 73 mg of product as a white solid. 1H NMR (400MHz, DMSO-d6): delta ppm 1 .33 (s, 9H), 1 .40 (s, 9H), 3.72 (m, 2H), 4.76 (m, 1 H), 4.95 (t, 1 H), 7.03, (m, 1 H), 7.21 (m, 1 H), 7.34-7.52 (m, 2H), 1 1 .95 (m, 1 H). LCMS Rt = 1 .03 minutes MS m/z 334 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In N,N-dimethyl-formamide; at 60℃; for 16h; | General procedure: Step 1 To 4-te/t-butyl-1 ,2-diaminobenzene (100 pmol, 1 eq) was added a solution of Monomer B in DMF (0.2M, 500 muIota_, 100 mupiiotaomicronIota, 1 eq) followed by TEA (28 muIota_, 200 mupiiotaomicronIota, 2 eq) and a solution of HATU in DMF (0.2 M, 500muIota_, 100 mupiiotaomicronIota, 1 eq). The reaction was shaken at 60°C for 16 hours before cooling and concentrating in vacuo to afford crude uncyclised Intermediate AB. Step 2 To crude uncyclised Intermediate AB was added acetic acid (1000 muIota_) and the reaction was shaken at 80°C for 1 hour. The reaction was cooled, concentrated in vacuo and dissolved in DMSO. The solution was filtered and purified using preparative HPLC to afford Intermediate AB. Step 3 To Intermediate AB was added DCM (1800 muiotatauiotaomicronIota) followed by 4M HCI in dioxane (200 muIota_) and the reaction was shaken at 30°C for 1 .5 hours. The reaction was concentrated in vacuo to afford the final compounds as their HCI salts. Prepared according to Library Protocol 2 using N-Boc-L-serine with purification by preparative HPLC: Preparative HPLC: Phenomenex Gemini C18; 250x21 .2mmx10um; Acetonitrile :NH4OH eluting with 41 -71 percent MeCN over 8.5 minute gradient time. Flow rate 30 mL/min. | |
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 60℃; for 16h; | General procedure: The title compounds were prepared in parallel format using thefollowing protocol: Step 1: To 4-alkyl-1, 2-diaminobenzene (100 mumol,1 eq) was added a solution of the required amino acid in DMF (0.2 M,500 muL, 100 mumol, 1 eq) followed by TEA (28 muL, 200 mumol, 2 eq) and asolution of HATU in DMF (0.2 M, 500 muL, 100 mumol, 1 eq). The reactionwas shaken at 60 °C for 16 h before cooling and concentrating in vacuoto afford crude uncyclised intermediate. Step 2: To crude uncyclizedintermediate was added acetic acid (1000 muL) and the reaction wasshaken at 80 °C for 1 h. The reaction was cooled, concentrated in vacuoand dissolved in DMSO. The solution was filtered and purified usingpreparative HPLC to afford the intermediate benzimidazole. Step 3: Tothe intermediate benzimidazole was added CH2Cl2 (1800 mumol) followedby 4M HCI in dioxane (200 muL) and the reaction was shaken at30 °C for 1.5 h. The reaction was concentrated in vacuo to afford productas the HCl salt. |
Tags: 68176-57-8 synthesis path| 68176-57-8 SDS| 68176-57-8 COA| 68176-57-8 purity| 68176-57-8 application| 68176-57-8 NMR| 68176-57-8 COA| 68176-57-8 structure
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