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CAS No. : | 99724-19-3 | MDL No. : | MFCD00059040 |
Formula : | C9H18N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DQQJBEAXSOOCPG-UHFFFAOYSA-N |
M.W : | 186.25 | Pubchem ID : | 2757234 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.89 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 54.49 |
TPSA : | 50.36 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.94 cm/s |
Log Po/w (iLOGP) : | 2.24 |
Log Po/w (XLOGP3) : | 0.7 |
Log Po/w (WLOGP) : | 0.49 |
Log Po/w (MLOGP) : | 0.56 |
Log Po/w (SILICOS-IT) : | 0.55 |
Consensus Log Po/w : | 0.91 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.17 |
Solubility : | 12.5 mg/ml ; 0.0673 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.34 |
Solubility : | 8.61 mg/ml ; 0.0462 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.76 |
Solubility : | 3.21 mg/ml ; 0.0173 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.64 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | 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 |
---|---|---|
99% | With hydrogen In tetrahydrofuran; methanol for 12 h; | ^-Butyl-l-benzylpyrrolidin-3-ylcarbamate (15.75 g, 57.0 mmol) obtained in Preparation Example 2-11 was dissolved in methanol and tetrabutylfuran (4:1) (114 ml) in a 500 ml vessel, and a catalytic quantity of 10percent active palladium/carbon was added thereto. The resulting mixture was reacted under a hydrogen atmosphere for 12 hrs. After the completion of reaction, the reaction mixture was filtered through a cellite pad to remove the active palladium/carbon and the solvent was removed under reduced pressure therefrom. Then, the residue thus obtained was subjected to a silica gel column chromatography to obtain 9.51 g of the title compound (yield 99percent).1H-NMR (200 MHz, CDCl3) δ 1.41 (s, 9H), 2.26 (m, 2H), 2.55 (m, 3H), 2.74 (m, IH), 4.84 (br, IH).LCZMS (M+H): 187; ^-Butyl-l-benzylpyrrolidin-3-ylcarbamate (15.75 g, 57.0 mmol) obtained in Preparation Example 4-v was dissolved in 114 ml of a mixture of methanol and tetrabutylfuran (4:1) in a 100 ml vessel. To the resulting mixture, a catalytic quantity of 10percent active palladium/carbon was added, and the resulting mixture was reacted under a hydrogen atmosphere for 12 hrs. After the completion of reaction, the reaction mixture was filtered through a cellite pad to remove the active palladium/carbon catalyst and the solvent was removed under reduced pressure therefrom. Then, the residue thus obtained was subjected to a silica gel column chromatography to obtain 9.51 g of the title compound (yield 99percent).1H-NMR (200 MHz, CDCl3) δ 1.41 (s, 9H), 2.26(m, 2H), 2.55(m, 3H), 2.74(m, IH), 4.84(br, IH), LCMS(M4H): 187 |
99% | With hydrogen In methanol; tetrabutylfuran for 12 h; | The starting material (15.75 g, 57.0 mmol) was dissolved in methanol and tetrabutylfuran (4:1) (114 ml) in the 100 ml reaction vessel, catalytic quantities of 10percent active palladium/carbon was added thereto, and reacted under the hydrogen for 12 hrs. After the completion of the reaction, the 5 reduction mixture was filtered through a cellite pad to remove palladium/carbon and the solvent was removed therefrom under a reduced pressure. Then, the mixture was subjected to silica gel column chromatography to obtain 9.5 Ig of the title compound (yield: 99percent).0 1H-NMR (200 MHz, CDCl3) δ 1.41 (s, 9H), 2.26 (m, 2H), 2.55 (m, 3H), 2.74 (m, IH), 4.84 (br, IH). LC/MS (M+H): 187 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.7% | With potassium hydroxide In methanol at 15 - 20℃; for 1 h; | 60 g of methanol and 8.6 g (0.1 mols) of (S)-3-aminopyrrolidine (Chemical purity 99.8 percent, optical purity 99.5 percent ee - hereinafter referred to as S-AP) were fed into a 200-ml 4-neck flask equipped with a stirrer, a pH sensor and two strapped dropping funnels, and stirred at 15 to 20°C. 21.8 g (0.1 mols) of di-tertiary butyl dicarbonate (by Tokyo Chemical) was fed into it via one dropping funnel, and 25 g (0.11 mols) of methanolic solution of 25 percent potassium hydroxide was thereinto via the other dropping funnel. With stirring at 15 to 20°C, di-tertiary butyl dicarbonate was dropwise added to the reaction system over a period of about 1 hour. During this, the methanolic solution of 25 percent potassium hydroxide was dropwise added thereto so as to make the reaction system have a pH of from 11.8 to 12.2. The reaction mixtures were analyzed for its composition, and it comprised 4 percent of the starting 3-aminopyrrolidine, 86.7 percent of the product, 3-amino-1-tertiary butoxycarbonylpyrrolidine (hereinafter referred to as 1-BocAP), and 8.4 percent of 1-tertiary butoxycarbonyl-3-tertiary butoxycarbonylaminopyrrolidine (hereinafter referred to as DiBocAP). After the reaction, the reaction mixtures were concentrated under reduced pressure to make 32 g. 100 g of toluene was added to the concentrated solution, and inorganic salts were precipitated with stirring. The precipitated crystals were filtered away, and the filtrate was distilled under reduced pressure to obtain a fraction at 120 to 125°C/0.7 kPa, (S)-3-amino-1-tertiary butoxycarbonylpyrrolidine. Its weight was 15.2 g, and its yield was 81.7 percent. (Chemical purity 99.1 percent; optical purity 99.5 percent ee. ) The positional isomer, 3-tertiary butoxycarbonylaminopyrrolidine was 0.4 percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.7% | With potassium hydroxide In methanol at 15 - 20℃; for 1 h; | 60 g of methanol and 8.6 g (0.1 mols) of (S)-3-aminopyrrolidine (Chemical purity 99.8 percent, optical purity 99.5 percent ee - hereinafter referred to as S-AP) were fed into a 200-ml 4-neck flask equipped with a stirrer, a pH sensor and two strapped dropping funnels, and stirred at 15 to 20°C. 21.8 g (0.1 mols) of di-tertiary butyl dicarbonate (by Tokyo Chemical) was fed into it via one dropping funnel, and 25 g (0.11 mols) of methanolic solution of 25 percent potassium hydroxide was thereinto via the other dropping funnel. With stirring at 15 to 20°C, di-tertiary butyl dicarbonate was dropwise added to the reaction system over a period of about 1 hour. During this, the methanolic solution of 25 percent potassium hydroxide was dropwise added thereto so as to make the reaction system have a pH of from 11.8 to 12.2. The reaction mixtures were analyzed for its composition, and it comprised 4 percent of the starting 3-aminopyrrolidine, 86.7 percent of the product, 3-amino-1-tertiary butoxycarbonylpyrrolidine (hereinafter referred to as 1-BocAP), and 8.4 percent of 1-tertiary butoxycarbonyl-3-tertiary butoxycarbonylaminopyrrolidine (hereinafter referred to as DiBocAP). After the reaction, the reaction mixtures were concentrated under reduced pressure to make 32 g. 100 g of toluene was added to the concentrated solution, and inorganic salts were precipitated with stirring. The precipitated crystals were filtered away, and the filtrate was distilled under reduced pressure to obtain a fraction at 120 to 125°C/0.7 kPa, (S)-3-amino-1-tertiary butoxycarbonylpyrrolidine. Its weight was 15.2 g, and its yield was 81.7 percent. (Chemical purity 99.1 percent; optical purity 99.5 percent ee. ) The positional isomer, 3-tertiary butoxycarbonylaminopyrrolidine was 0.4 percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetonitrile; | 7-[3-t-Butoxycarbonylamino-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic Acid A suspension of 49.5 g (0.175 mole) of 1-cyclopropyl-1,4-dihydro-4-oxo-6,7,8-trifluoroquinoline-3-carboxylic acid, 37.3 g (0.2 mole) of 1,1dimethylethyl (3-pyrrolidinyl)carbamate, 40.4 g (0.4 mole) of triethylamine in 1.5 1 of acetonitrile was refluxed for three hours. The precipitate was removed by filtration, washed with acetonitrile, then ethyl ether, and dried in vacuo to give 75.0 g of the title compound, mp 239-240 C. | |
With triethylamine; In acetonitrile; | 7-[3-t-Butoxycarbonylamino-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic Acid A suspension of 49.5 g (0.175 mole) of 1-cyclopropyl-1,4-dihydro-4-oxo-6,7,8-trifluoroquinoline-3-carboxylic acid, 37.3 g (0.2 mole) of 1,1-dimethylethyl (3-pyrrolidinyl)carbamate, 40.4 g (0.4 mole) of triethylamine in 1.5 liters of acetonitrile was refluxed for three hours. The precipitate was removed by filtration, washed with acetonitrile, then ethyl ether, and dried in vacuo to give 75.0 g of the title compound; mp 239-240 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h; | Method B: /-Butylpyrrolidin-3-ylcarbamate (1.5 g, 8.05 mmol) obtained in Preparation Example 2-vi was dissolved in N,N'- dimethylformamide (20 ml) at 0C in a 100 ml vessel, and K2CO3 (2.23 g, 16.1 mmol, 2 eq.) and iodoethane (0.64 ml, 8.05 mmol, 1 eq.) were added thereto while stirring. The resulting mixture was heated from 0 C to room temperature, and reacted for 12 hrs. After the completion of reaction, the solvent was distilled off under reduced pressure and the residue was extracted with ethyl ester. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate and brine in order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 1.13 g of the title compound as pale yellow oil (yield 66%).1H-NMR (200 MHz, CDCl3) delta 1.10 (t, J = 7.4 Hz, 3H), 1.44 (s, 9H), 1.69 (m, IH), 2.27 (m, 2H), 2.48 (q, J = 7.0 Hz, 2H), 2.57 (m, IH), 2.81 (m, IH), 4.16 (br, IH), 4.86 (br, IH).LC/MS (M+H): 215; Method B: ^-butyl pyrrolidin-4-ylcarbamate (1.5 g, 8.05 mmol) obtained in Preparation Example 4-vi was dissolved in N5N1- dimethylformamide (20 ml) in a 100 ml vessel at 0C , and K2CO3 (2.23 g,16.1 mmol, 2 eq.) and iodoethane (0.64 ml, 8.05 mmol, 1 eq.) were added thereto while stirring. The resulting mixture was heated from 0 C to room temperature and reacted for 12 hrs. After the completion of reaction, the solvent was distilled off under reduced pressure and the residue thus obtained was extracted with ethyl ester. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 1.13 g of the title compound as pale yellow oil (yield 66%).1H-NMR (200 MHz, CDCl3) delta 1.10(t, J=7.4 Hz, 3H), 1.44(s, 9H), 1.69(m, IH), 2.27(m, 2H), 2.48(q, J=7.0 Hz, 2H), 2.57(m, IH), 2.8 l(m, IH), 4.16(br, lH), 4.86(br, IH)LCZMS(M+H): 215 |
66% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h; | Method B: The starting material (1.5 g, 8.05 mmol) was dissolved in N,N-dimethylformamide (20 ml) at 0 C in the 100 ml reaction vessel, K2CO3 5 (2.23 g, 16.1 mmol, 2 eq.) and iodoethane (0.64 ml, 8.05 mmol, 1 eq.) were added thereto while stirring, heated from 0C to room temperature, and kept for 12 hrs. After the completion of the reaction, the solvent was distilled under a reduced pressure and the remaining was extracted with ethyl ester. The extract was washed with saturated sodium bicarbonate and salt water in o order. The resulting organic layer was washed with saturated sodium bicarbonate and salt water, dried over anhydrous magnesium sulfate, concentrated under a reduced pressure and then subjected to silica gel column chromatography to obtain 1.13 g of the title compound as pale yellow oil (yield: 66%). 51H-NMR (200 MHz, CDCl3) delta 1.10 (t, J = 7.4 Hz, 3H), 1.44 (s, 9H), 1.69 (m, IH), 2.27 (m, 2H), 2.48 (q, J = 7.0 Hz, 2H), 2.57 (m, IH), 2.81 (m, IH), 4.16 (br, IH), 4.86 (br, IH). LC/MS (M+H): 215. 0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h; | Step 1. (3-(methoxycarbonyl)phenyl)(3-(/ert-butoxycarbonylamino)pyrrolidin-1- yl)methanone. A mixture of wowo-methyl isophthalate (0.5180 g, 2.87 mmol, 1.0 equiv), lambda/-Boc-3- aminopyrrolidine (0.6680 g, 3.58 mmol, 1.24 equiv), EDCI-ICl ( 1.005 g, 5.24 mmol, 1.8 equiv), HOBt (0.610 g, 4.5 mmol, 1.57 equiv), and DIEA (5 mL, 28.7 miriol, 10 equiv) in CH2Cl2 (30 mL) was stirred at rt for 24 h. The reaction mixture was diluted with CH2Cl2, washed with 1 N HCI and 10% Na2CO3, and dried over Na2SO4. After the solvent was removed, the crude product (0.7387 g, 74%) was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | To a solution of 1 ,1-dimethylethyl 3-pyrrolidinylcarbamate (5 g, 26.8 mmol) in 250 ml. dichloromethane (DCM), was added diisopropylethylamine (6.9 g, 53.6 mmol), followed by 3,4-dimethoxysulfonyl chloride (6.3 g, 26.8 mmol). The reaction appeared complete by LCMS after 3 hours at room temperature. After stirring overnight, the reaction progress was unchanged by LCMS. The mixture was concentrated by half in vacuo. Water was added and the solution was acidified by addition of 1 N HCI. The organic layer was washed with 1 N HCI, saturated sodium bicarbonate solution, and brine. The organic layer was dried over magnesium sulfate (MgSO4), filtered, concentrated, and dried in vacuo. The final product was afforded as a tan solid and 96% purity by LCMS (M+H = 387.2) and NMR (7.99 g, 77% yield). 1H NMR (CDCI3, 400 MHz) delta: 7.45 (1 H, dd), 7.28 (1 H, d), 6.97 (1 H, d), 4.5 (1 H, m), 4.17 (1 H, m), 3.96 (3H, s), 3.94 (3H, s), 3.35 (2H, m), 3.20 (2H, m), 1.75 (1 H, m), 1.42 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | EXAMPLE 18A tert-butyl 1-{4-[4-(aminocarbonyl)-1H-benzimidazol-2-yl]benzyl}pyrrolidin-3-ylcarbamate A solution of EXAMPLE 7B (300 mg, 1.13 mmol) and <strong>[99724-19-3]3-(tert-butoxycarbonylamino)pyrrolidine</strong> (631 mg, 3.39 mmol) in 1:1 methanol/N,N'-dimethylformamide (20 mL) was stirred at ambient temperature for 2 hours. Sodium cyanoborohydride (213 mg, 3.39 mmol) and zinc chloride (154 mg, 1.13 mmol) were added and the mixture stirred at 50 C. for 18 hours. The mixture was concentrated and the residue purified by HPLC (Zorbax C-8, 0.1% trifluoroacetic acid/acetonitrile/water) to provide the title compound (415 mg, 84%). MS (DCI/NH3) m/z 436 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | 5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), 3-(teroom temperature-Butoxycarbonylamino)pyrrolidine (40 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H25N3O4: 371.1845, found 371.1851. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium hydrogencarbonate; In ethanol; for 4h;Heating / reflux; | tert-Butyl 3-(4-benzylpiperazin-1 -yl)pyrrolidine-1 -carboxylate (XXId); 6.23 g (26.8 mmol) of benzylbis(2-chloroethyl)amine hydrochloride were dissolved in ethanol (100 ml) and, while stirring, 5.00 g (26.8 mmol) of Lambda/-Boc-3-aminopyrrolidine and 9.02 g (107 mmol) of sodium bicarbonate were added. The resulting reaction solution was heated under reflux for 4 h. The cooled reaction mixture was concentrated in vacuo, 100 ml of water were added, and the aqueous phase was extracted with ethyl acetate (4x60 ml). The combined organic phases were washed with saturated aqueous NaHCO3 solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 0-5% methanol in dichloromethane). Yield: 6.15 g (66%) of yellow solid1H-NMR (DMSO-de): 1.38 (m, 9H), 1.52-1.68 (m, 1 H), 1.93-2.03 (m, 1 H), 2.19-2.52- (m, 7H), 2.64-2.78 (m, 1 H), 2.48-2.96 (m, 1 H), 3.06-3.21 (m, 1 H), 3.30-3.49 (m, 5H), 7.19-7.36 (m, 5H). MS (API-ES,pos) m/z = 346 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 0.5h;Microwave irradiation; | Example 10; Synthesis of terf-butyl [1 -(6-adamantan-2-yl-2-aminopyrimidin-4- yl)pyrrolidin-3-vncarbamate formate salt (Intermediate 13); Intermediate 12 (42.6mg), tert-butyl pyrrolidin-3-ylcarbamate (CAS RN 99724-19-3) (30mg) and triethylamine (0.023ml) are dissolved in dry NMP (1ml) and heated under microwave irradiation at 150 0C for 30 mins. The solution is diluted with DMSO and purified by preparative HPLC (Method A) to afford the title compound as a colorless solid as its formate salt (46mg, 57%). LCMS 414 [M+H]+ RT 2.48 mins (pH 2.5). 1H NMR 300 MHz (CDCI3) (delta ppm): 8.48 (HCOOH), 6.40 (0.5H, br s), 5.80 (1H1 m), 5.52 (0.5H, br m),4.16 - 4.43 (1 H, m), 3.35 - 3.90 (4H, m), 2.95 (1 H, m), 1.60 - 2.55 (18H, m), 1.47 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; for 0.5h;Microwave irradiation; | Example 30; Synthesis of terf-butyl (1-(2-amino-6-f(E)-2-phenylvinv?pyrimidin-4- yl)pyrrolidin-3-yl)carbamate (Intermediate 62); Intermediate 61 (339mg), 3-(ferf-butoxycarbonylamino)pyrrolidine (300mg) and triethylamine (0.225ml) are dissolved in dry NMP (3ml) and heated at 120 0C for 30 mins under microwave irradiation. The solution is then diluted with MTBE (15ml) and washed with saturated brine (3 x 8 ml), dried (MgStheta4) and concentrated to dryness in vacuo.Purification of the crude product by flash chromatography, eluting with DCM-MeOH 95:5 affords the title compound as a yellow foam (596mg, quant.) Rf (DCM-MeOH 95:5) 0.23.LCMS 382 [M+H]+, RT 2.33 mins (pH 2.5). 1H NMR 300 MHz (CDCI3) (delta ppm): 7.66 (1 H, d), 7.54 (2H, dd), 7.21 - 7.40 (3H, m), 6.83 (1 H, d), 5.80 (1 H, s), 4.69 (2H, br s), 4.32 (1 H, m), 3.73 (1H, m), 3.55 (2H, m), 1.89 - 2.41 (4H, m), 1.43 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine; In ethanol; at 120℃; for 0.833333h;Microwave irradiation; | Example 33; Synthesis of terf-butyl (1-r2-amino-6-(4-methylcvclohex-1-en-1- yl)pyrimidin-4-yllpyrrolidin-3-yllcarbamate (Intermediate 64); Intermediate 63 (66.5mg), 3-(terf-butoxycarbonylamino)pyrrolidine (68mg) and triethylamine (0.049ml) are dissolved in absolute EtOH (3ml) and heated at 120 0C for 50 mins under microwave irradiation. The solution is then concentrated to dryness in vacuo.Purification of the crude product by flash chromatography, eluting with DCM-MeOH 97:3 then 95:5 affords the title compound as a pale orange solid (81 mg, 72%) Rf (DCM-MeOH95:5) 0.42. LCMS 374 [M+H]+, RT 2.40 mins (pH 2.5). 1 H NMR 300 MHz (CDCI3) (delta ppm): 6.90 (1 H, m), 5.70 (1 H, s), 5.31 (2H, br s), 4.91 (1 H, br m), 4.30 (1 H, br m), 3.70 (1 H, m), 3.55 (2H, m), 3.38 (1 H, m), 2.15 - 2.48 (4H, m), 1.62 - 2.01 (4H, m), 1.45 (9H, s), 1.32 (1 H, m), 1.00 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.0% | Part A.1- (4-Chlorocarbonyl-phenyl)-cyclopropanecarboxylic acid methyl ester (0.78 g, 3.28 mmol), pyrrolidin-3-yl- carbamic acid tert-butyl ester (0.60 g, 3.22 mmol) and DIEA (1.18mL, 6.44 mmol) were stirred inCH2Cl2 (10 mL) at rt underN2 overnight.H20 was added. The mixture was extracted with EtOAc, washed with brine, dried overMgSO4, filtered, dried in vacuo. The residue was dissolved in MeOH (20 mL) and 1N NaOH (10 mL) was added. The reaction was heated at50 C for 2.5h. The solvents were evaporated. The residue was extracted with Et2O, theH20 layer was acidified with citric acid, and extracted with Et20 (2x), washed with brine, dried overMgSO4, filtered, and concentrated to dryness to yield 1- [4- (3-tert-butoxycarbonylamino-pyrrolidine-l-carbonyl)-phenyl]- cyclopropanecarboxylic acid methyl ester (1.08 g, yield: 83.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.4%; 81.7% | With potassium hydroxide; In methanol; at 15 - 20℃; for 1h;pH 11.8 - 12.2; | 60 g of methanol and 8.6 g (0.1 mols) of (S)-3-aminopyrrolidine (Chemical purity 99.8 %, optical purity 99.5 % ee - hereinafter referred to as S-AP) were fed into a 200-ml 4-neck flask equipped with a stirrer, a pH sensor and two strapped dropping funnels, and stirred at 15 to 20C. 21.8 g (0.1 mols) of di-tertiary butyl dicarbonate (by Tokyo Chemical) was fed into it via one dropping funnel, and 25 g (0.11 mols) of methanolic solution of 25 % potassium hydroxide was thereinto via the other dropping funnel. With stirring at 15 to 20C, di-tertiary butyl dicarbonate was dropwise added to the reaction system over a period of about 1 hour. During this, the methanolic solution of 25 % potassium hydroxide was dropwise added thereto so as to make the reaction system have a pH of from 11.8 to 12.2. The reaction mixtures were analyzed for its composition, and it comprised 4 % of the starting 3-aminopyrrolidine, 86.7 % of the product, 3-amino-1-tertiary butoxycarbonylpyrrolidine (hereinafter referred to as 1-BocAP), and 8.4 % of 1-tertiary butoxycarbonyl-3-tertiary butoxycarbonylaminopyrrolidine (hereinafter referred to as DiBocAP). After the reaction, the reaction mixtures were concentrated under reduced pressure to make 32 g. 100 g of toluene was added to the concentrated solution, and inorganic salts were precipitated with stirring. The precipitated crystals were filtered away, and the filtrate was distilled under reduced pressure to obtain a fraction at 120 to 125C/0.7 kPa, (S)-3-amino-1-tertiary butoxycarbonylpyrrolidine. Its weight was 15.2 g, and its yield was 81.7 %. (Chemical purity 99.1 %; optical purity 99.5 % ee. ) The positional isomer, 3-tertiary butoxycarbonylaminopyrrolidine was 0.4 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 45℃; for 2.5h; | To a solution of the compound of the Example 67 (h) (64 mg, 0.176 MMOL), PYRROLIDIN-3-YL-CARBAMIC acid tert-butyl ester (66 mg, 0.352 MMOL), 4- methylmorpholine (0.1 mL, 0.909 MMOL), 1-hydroxy-7-azabenzotriazole (48 mg, 0.352 MMOL) in DIMETHYLFORMAMIDE (3 mL) was added 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (68 mg, 0.352 MMOL). The resultant mixture was stirred under argon at 45 C for 2.5 h, at which time it was diluted with ethyl acetate (30 mL) and washed with water (3 X 10 mL). The organic phase was washed with brine (1 X 10 mL), dried over magnesium sulfate, and concentrated. Purification on silica gel (20: 1 X 10 : 1 dichloromethane/methanol) provided the product (85 mg, 91 % yield) as a pale yellow oil that solidified upon standing. MS (ES+) m/z 533.6 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
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81% | With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 20h; | A mixture consisting of 4-chloro-2-[4-9[(1, 1- dimethylethyl) oxy] carbonyl} amino) -1,2, 5-oxadiazol-3-yl]-1-ethyl-1H-imidazo[4, 5- c] pyridine-7-carboxylic acid (410 mg, 1 MMOL), PYRROLIDIN-3-YL-CARBAMIC ACID TERT- butyl ester (327 mg, 2 MMOL), HOAT (272 mg, 2 MMOL), EDCI (383 mg, 2 MMOL) and N-methyl morpholine (2 mL) in DMF (4 mL) was stirred at room temperature for 20 h. The mixture was partitioned between EtOAc and 1 N HCI. The organic extract was washed with water then brine, dried (Na2SO4) and all VOLITILES REMOVED IN vacuo. Chromatography on silica (eluted with75% EtOAc, 25% hexanes) afforded the title compound (375 mg, 81 %). MS: (M+H) + = m/z 577. |
Yield | Reaction Conditions | Operation in experiment |
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83% | With triethylamine; In tetrahydrofuran; at 20℃; for 24h; | [0204] A. 1-Cbz-3-(t-butyloxycarbonyl)aminopyrrolidine [CHEMMOL-00014] [0205] To a solution of 3-(t-butyloxycarbonyl)aminopyrrolidine (5.0 g, 26.8 mmol) in THF (40 mL) was added triethylamine (3.7 mL, 26.8 mmol), followed by the addition of benzyl chloroformate (3.8 mL, 26.8 mmol) slowly. After the reaction mixture was stirred for 24 h at room temperature, the reaction mixture was filtered and solvent removed in vacuo. The residue was dissolved in EtOAc and washed sequentially with 1 N NaHCO3 (100 mL), 1.5 N citric acid (100 mL), and water. The organic layer was dried (MgSO4) and concentrated to dryness in vacuo to give the title compound (7.13 g, 83%). [0206] TLC Rf (C) 0.41; [0207] MS 321 (M+H)+; [0208] Analysis for C17H24N2)4: [0209] Calcd: C, 63.73; H, 7.55; N, 8.74; [0210] Found: C, 64.01, H, 7.39, N, 8.71.; [0304] B. 1-Cbz-3-(t-butyloxycarbonyl)aminopyrrolidine [0305] The title compound was prepared according to the procedure described in Example 1A.; 1-Cbz-(t-butyloxycarbonyl)aminopyrrolidine [0287] The title compound may be prepared according to the procedure described in Example 1A. |
83% | With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | [Referential Example 27] 3-Aminopyrrolidine-1-carboxylic acid benzyl ester trifluoroacetate; [Show Image] [Show Image] 1) 3-(N-tert-butoxycarbonyl)aminopyrrolidine-1-carboxylic acid benzyl ester; Benzyl chloroformate (1.43 ml) was added to a solution of pyrrolidine-3-carbamic acid tert-butyl ester (1.862 g) and triethylamine (1.39 ml) in dichloromethane (20 ml) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the residue, and the phases were separated. The organic layer was washed with 5% aqueous citric acid, water, and brine in this order, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 3-(N-tert-butoxycarbonyl)aminopyrrolidine-1-carboxylic acid benzyl ester (2.676 g, 83%) as a solid. 1H-NMR (400 MHz, CDCl3) delta: 1.44 (9H, s), 1.74-1.89 (1H, br m), 2.07-2.19 (1H, br m), 3.19-3.31 (1H, br m), 3.42-3.53 (2H, br m), 3.62-3.70 (1H, m), 4.13-4.27 (1H, br), 4.52-4.66 (1H, br), 5.12 (2H, s), 7.25-7.41 (5H, m). |
With dmap; In dichloromethane; | A. 3-tert-Butoxycarbonylamino-pyrrolidine-1-carboxylic acid benzyl ester To a mixture of 19.0 g (102 mmol) of 3-(t-butoxycarbonylamino) pyrrolidine and 14.28 g (117 mmol) of 4-dimethylaminopyridine in 115 mL of methylene chloride at 0 C. was added 20.0 g (117 mmol) of benzyl chloroformate dropwise. The mixture was allowed to warm to 24 C. and was stirred overnight. The mixture was diluted with chloroform and washed twice with 10% HCl, twice with saturated aqueous sodium bicarbonate and once with brine. The mixture was dried over MgSO4 and concentrated to give 30A in quantitative yield. The crude material was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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80% | With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 12h; | Example 38 {1-[8-(3-Sulfamoyl-phenylamino)-thiazolo[4,5-h]quinazoline-2-carbonyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester Diisopropylethylamine (68 mul, 0.39 mmol) was added to a mixture of 8-(3-Sulfamoyl-phenylamino)-thiazolo[4,5-h]quinazoline-2-carboxylic acid (78 mg, 0.19 mmol), <strong>[99724-19-3]3-(tert-butoxycarbonylamino)pyrrolidine</strong> (36.2 mg, 0.19 mmol) and PyBrop (91 mg, 0.19 mmol) in dimethylformamide (1 ml). The reaction mixture was stirred at room temperature for 12 h. The reaction was concentrated under reduced pressure, redissolved in isopropanol (10 mL) and water was added (5 mL). The precipitate formed was isolated by filtration and washed with water (1*5 mL), dilute NaHSO4 (1*5 mL), water (1*5mL), saturated Na2CO3 (1*5mL), water (1*5mL), isopropanol (1*5 mL), diethyl ether (4*5 mL) giving a yellow powder (87 mg, 80% yield). MS (ES+) 570, (ES-) 568. |
Yield | Reaction Conditions | Operation in experiment |
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38% | Example 122: (E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-3-aminopyrrolidine dihydrochloride (Compound 122) The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (800 mg, 2.66 mmol) obtained in Step 6 of Example 1, (pyrrolidin-3-yl)carbamic acid tert-butyl ester (1.00 g, 5.32 mmol), 1-hydroxybenzotriazole monohydrate (470 mg, 3.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (720 mg, 3.72 mmol) and N-methylmorpholine (0.58 mL, 5.32 mmol) in a similar manner to Example 5, was dissolved in methanol (5.00 mL), and the solution was added with 4 moL/L hydrogen chloride-methanol solution (2.00 mL), followed by heating under reflux at 60C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 122 (398 mg, 38%). 1H-NMR (270 MHz, DMSO-d6) delta 2.23 (br, 1H), 3.54-3.87 (m, 6H), 7.22 (dd, J = 7.7, 7.7 Hz, 1H), 7.41 (dd, J = 7.7, 7.7 Hz, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 16.8 Hz, 1H), 7.66 (d, J = 16.8 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 8.21 (d, J = 8.3 Hz, 1H), 8.30 (br, 1H), 8.42 (br, 1H). APCI-MS (m/z); 333 [M+H] | |
38% | Example 71: (E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-3-aminopyrrolidine dihydrochloride (Compound 71) The product obtained using Compound 15 (800 mg, 2.66 mmol), (pyrrolidin-3-yl)carbamic acid tert-butyl ester (1.00 g, 5.32 mmol), 1-hydroxybenzotriazole monohydrate (470 mg, 3.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (720 mg, 3.72 mmol) and N-methylmorpholine (0.58 mL, 5.32 mmol) in a similar manner to Example 61, was dissolved in methanol (5.00 mL), and the solution was added with 4 moL/L hydrogen chloride-methanol solution (2.00 mL), followed by heating under reflux at 60C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 71 (398 mg, 38%). 1H-NMR (270 MHz, DMSO-d6) d 2.23 (br, 1H), 3.54-3.87 (m, 6H), 7.22 (dd, J = 7.7, 7.7 Hz, 1H), 7.41 (dd, J = 7.7, 7.7 Hz, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 16.8 Hz, 1H), 7.66 (d, J = 16.8 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 8.21 (d, J = 8.3 Hz, 1H), 8.30 (br, 1H), 8.42 (br, 1H). APCI-MS (m/z); 333 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With water; In acetonitrile; at 20℃; | EXAMPLE 18 2-(2S-2-Benzyloxycarbonylamino-2-isopropylmethyl-acetamido)-3-(3-tert-butoxycarbonylamino-pyrrolidino)-acrylamide To a solution of (3S,4S)-3-(2S-2-benzyloxycarbonylamino-2-isopropylmethyl-acetamido)-4-acetoxy-azetidin-2-one (100 mg, 0.257 mmole) in acetonitrile (3 ml) and water (1 ml), 3-tert-butoxycarbonylamino-pyrrolidine (239 mg, 1.28 mmole) was added and stirred at room temperature overnight. After removal of acetonitrile under vacuum, the residue was dissolved in ethyl acetate and washed with water, brine and dried with Na2SO4. After removal of solvent, 120 mg of the title compound was obtained as white solid. Yield: 90%; m.p.: 140-142 C. 1H-NMR: (DMSO-d6), (ppm): 0.8-1.0 (6H, m), 1.3-2.0 (5H, m), 1.37 (9H, s), 3.0-3.2 (1H, m), 3.3-3.7 (3H, m), 3.9-4.1 (2H, m), 5.01 (2H, s), 6.25 (2H, s), 7.12 (1H, d, J=6.5 Hz), 7.22 (1H, s), 7.3-7.4 (5H, m), 7.66 (1H, d, J=6.5 Hz), 8.75 (1H, s). MS (ES+): 518 (M+H), calcd for C26H39N5O6 517. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide | 18 Preparation 18 Preparation 18 A suspension of 2-fluoro-4-methylpyridine (1.11 g), 3-(tert-butoxycarbonylamino)pyrrolidine (1.68 g) and potassium carbonate (1.49 g) in N,N-dimethylformamide (20 ml) was stirred at 100° C. for 16 hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water five times and brine, dried over sodium sulfate and evaporated under reduced pressure to give 1-(4-methylpyridin-2-yl)-3-(tert-butoxycarbonylamino)pyrrolidine (1.36 g). 1H-NMR (CDCl3): δ1.45(9H,s), 1.9-2.1(1H,m), 2.2-2.4(1H,m), 2.25(3H,s), 3.3-3.8(4H,m), 4.2-4.4(1H,m), 4.6-4.8(1H,m), 6.18(1H,s), 6.41(1H,d,J=5.0 Hz), 8.01(1H,d,J=5.0 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In toluene; | a) (+/-)-2-Chloro-5-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-pyrrolidinyl]-benzoic acid, ethyl ester Prepared as described in Example 5a) using <strong>[76008-73-6]5-bromo-2-chloro-benzoic acid, ethyl ester</strong> (0.50 g), 3-pyrrolidinyl-carbamic acid 1,1-dimethylethyl ester (0.42 g), cesium carbonate (0.86 g), palladium (II) acetate (21 mg) and (R)-BINAP (88 mg) and toluene (3 ml) to afford the subtitle compound as an oil (0.25 g). MS (APCI+ve) 311/313 (M-BOC)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; methanol; for 12h; | ^-Butyl-l-benzylpyrrolidin-3-ylcarbamate (15.75 g, 57.0 mmol) obtained in Preparation Example 2-11 was dissolved in methanol and tetrabutylfuran (4:1) (114 ml) in a 500 ml vessel, and a catalytic quantity of 10% active palladium/carbon was added thereto. The resulting mixture was reacted under a hydrogen atmosphere for 12 hrs. After the completion of reaction, the reaction mixture was filtered through a cellite pad to remove the active palladium/carbon and the solvent was removed under reduced pressure therefrom. Then, the residue thus obtained was subjected to a silica gel column chromatography to obtain 9.51 g of the title compound (yield 99%).1H-NMR (200 MHz, CDCl3) delta 1.41 (s, 9H), 2.26 (m, 2H), 2.55 (m, 3H), 2.74 (m, IH), 4.84 (br, IH).LCZMS (M+H): 187; ^-Butyl-l-benzylpyrrolidin-3-ylcarbamate (15.75 g, 57.0 mmol) obtained in Preparation Example 4-v was dissolved in 114 ml of a mixture of methanol and tetrabutylfuran (4:1) in a 100 ml vessel. To the resulting mixture, a catalytic quantity of 10% active palladium/carbon was added, and the resulting mixture was reacted under a hydrogen atmosphere for 12 hrs. After the completion of reaction, the reaction mixture was filtered through a cellite pad to remove the active palladium/carbon catalyst and the solvent was removed under reduced pressure therefrom. Then, the residue thus obtained was subjected to a silica gel column chromatography to obtain 9.51 g of the title compound (yield 99%).1H-NMR (200 MHz, CDCl3) delta 1.41 (s, 9H), 2.26(m, 2H), 2.55(m, 3H), 2.74(m, IH), 4.84(br, IH), LCMS(M4H): 187 |
99% | With hydrogen;palladium 10% on activated carbon; In methanol; tetrabutylfuran; for 12h; | The starting material (15.75 g, 57.0 mmol) was dissolved in methanol and tetrabutylfuran (4:1) (114 ml) in the 100 ml reaction vessel, catalytic quantities of 10% active palladium/carbon was added thereto, and reacted under the hydrogen for 12 hrs. After the completion of the reaction, the 5 reduction mixture was filtered through a cellite pad to remove palladium/carbon and the solvent was removed therefrom under a reduced pressure. Then, the mixture was subjected to silica gel column chromatography to obtain 9.5 Ig of the title compound (yield: 99%).0 1H-NMR (200 MHz, CDCl3) delta 1.41 (s, 9H), 2.26 (m, 2H), 2.55 (m, 3H), 2.74 (m, IH), 4.84 (br, IH). LC/MS (M+H): 187 |
palladium; In methanol; | 1,1-Dimethylethyl (3-Pyrrolidinyl)carbamate A mixture of 27.6 g (0.1 mole) of 1,1-dimethylethyl[1-(phenylmethyl)-3-pyrrolidinyl]carbamate, 1.0 g of 20% palladium on carbon and 140 mL of methanol was shaken in an atmosphere of hydrogen at about 50 psi and room temperature for 24 hours. The catalyst was removed by filtering through Celite, and the filtrate was concentrated in vacuo to give 18.4 g of 1,1-dimethylethyl (3-pyrrolidinyl)carbamate which solidified upon standing. |
palladium; In tetrahydrofuran; | 1,1-Dimethylethyl (3-Pyrrolidinyl)carbamate A mixture of 101.5 g (0.37 mole) of 1,1-dimethylethyl[1-(phenylmethyl)-3-pyrrolidinyl]carbamate, 5.0 g of 20% Palladium on carbon and 1 liter of tetrahydrofuran was shaken in an atmosphere of hydrogen at about 50 psi and room temperature for 24 hours. The catalyst was removed by filtering through Celite, and the filtrate was concentrated in vacuo to give 6.8 g of 1,1-dimethylethyl (3-pyrrolidinyl)carbamate which solidified upon standing and was of sufficient purity to be used as is for the ensuing steps. | |
palladium; In methanol; | 1,1-Dimethylethyl (3-Pyrrolidinyl)carbamate A mixture of 27.6 g (0.1 mole) of 1,1-dimethylethyl[1-(phenylmethyl)-3-pyrrolidinyl]carbamate, 1.0 g of 20% Palladium on carbon and 140 ml of methanol was shaken in an atmosphere of hydrogen at about 50 psi and room temperature for 24 hours. The catalyst was removed by filtering through Celite, and the filtrate was concentrated in vacuo to give 18.4 g of 1,1-dimethylethyl (3-pyrrolidinyl)carbamate which solidified upon standing. | |
palladium; In methanol; | 1,1-Dimethylethyl (3-Pyrrolidinyl)carbamate A mixture of 27.6 g (0.1 mole) of 1,1-dimethylethyl[1-(phenylmethyl)-3-pyrrolidinyl]carbamate, 1.0 g of 20% Palladium on carbon and 140 ml of methanol was shaken in an atmosphere of hydrogen at about 50 psi and room temperature for 24 hours. The catalyst was removed by filtering through Celite, and the filtrate was concentrated in vacuo to give 18.4 g of 1,1-dimethylethyl (3-pyrrolidinyl)carbamate which solidified upon standing. | |
palladium; In methanol; | Step B Preparation of 1,1-Dimethylethyl (3-pyrrolidinyl)carbamate A mixture of 27.6 g (0.1 mol) of 1,1-dimethylethyl[1-(phenylmethyl)-3-pyrrolidinyl]carbamate, 1.0 g of 20% Palladium on carbon and 140 ml of methanol is shaken in an atmosphere of hydrogen at about 50 psi and room temperature for 24 hours. The catalyst is removed by filtering through Celite, and the filtrate is concentrated in vacuo to give 18.4 g of 1,1-dimethylethyl (3-pyrrolidinyl)carbamate which solidifies upon standing. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h; | A solution of tert-butyl N-(pyrrolidin-3-yl)carbamate (1 g, 5.37 mmol, 1.00 equiv), potassium carbonate (1.5 g, 10.85 mmol, 2.00 equiv), 6-chloropyridine-3-carbonitrile (742 mg, 5.36 mmol, 1.00 equiv) in DMF (10 mL) was stirred for 1 h at 80 C. The resulting solution was quenched with 40 ml water. The solution was extracted with EtOAc (3*40 mL) and the organic layers combined. The solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc/hexane (4:1) to afford 1.37 g (88%) of the title compound as a white solid. LCMS (ESI, m/z): 289.17 [M+H]+ |
78% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 72h; | Stir a solution of diisopropylethylamine (9.5 mL, 54.3 mmol), 6- chloronicotinonitrile (5 g, 36.2 mmol) and 3-tert-butyloxycarbonylpyrrolidine (10 g, 54.3 mmol) in DMF (10 mL). After 3 days, dilute with dichloromethane and an aqueous saturated solution of sodium bicarbonate and separate the layers. Extract the aqueous layer once with dichloromethane, dry (sodium sulfate), filter and concentrate. Filter through a plug of silica gel, wash with dichloromethane and concentrate to give [l-(5- cyanopyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester as a white solid (8.13 g, 78%). 1R NMR (400 MHz, CDCl3) delta 8.38 (dd, IH, J = 2.4 Hz, 1.0 Hz), 7.58-7.55 (m, EPO <DP n="21"/>IH), 6.33 (dd, IH5 J = 9.8 Hz, 1.0 Hz), 4.85-4.7 (m, IH), 4.40-4.25 (m, IH)5 3.85-3.30 (m, 4H)5 2.35-2.25 (m, IH)5 2.08-1.90 (m, IH)5 1.43 (s, 9H); MS (ES): m/z = 289 [M+H]+. |
75% | With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; | To a suspension of tert-butyl pyrrolidin-3-ylcarbamate (1.14 g, 6.14 mmol) in DMF (10 mL) was added 6-chloronicotinonitrile (0.85 g, 6.14 mmol) and sodium carbonate (1.31 g, 1.23 mmol). The reaction mixture was stirred at room temperature overnight, diluted with water (40 mL) and then extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a white solid (1.32 g, 75%).MS (ESI, pos. ion) m/z: 289.1 [M+H]+;'H NMR (600 MHz, CDCls): delta (ppm) 8.38 (d, J= 1.9 Hz, 1H), 7.57 (dd, J= 8.9, 2.1 Hz, 1H), 6.33 (d, J = 8.9 Hz, 1H), 4.79-4.73 (m, 1H), 4.35 (s, 1H), 3.87-3.26 (m, 4H), 2.32-2.24 (m, 1H), 2.03- 1.96 (m, 1H), 1.43 (s, 9H). |
75% | With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; | The compound tert-butyl pyrrolidine-3-carbamate (1.14 g, 6.14 mmol)Suspended in DMF (10 mL)Then, 6-chloro-3-cyanopyridine (0.85 g, 6.14 mmol)And sodium carbonate (1.31 g, 1.23 mmol),The resulting reaction mixture was stirred at room temperature overnight,Then diluted with water (40 mL)The resulting mixture was extracted with ethyl acetate (30 mL x 3)The combined organic phases were washed with saturated brine (50 mL)The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 4/1) to give the title compound as a white solid (1.32 g, 75 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 1h; | Add 2,6-dibromopyridine (500 mg, 2.11 mmol), pyrrolidin-3-ylcarbamic acid tert- butyl ester (372 mg, 2.00 mmol), tris(dibenzylideneacetone)dipalladium (0) (193 mg, 0.21 mmol), 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (526 mg, 0.84 mmol), and cesium carbonate (1.37 g, 4.21 mmol) to a dry flask under nitrogen. Add degassed anhydrous toluene (10 mL) to the flask. Heat at 100 0C for one hour. Cool to room temperature and dilute with dichloromethane, filter through a pad of Celite, concentrate to give a residue. Chromatograph the residue on silica gel eluting with 10:90 to 20:80 ethyl acetate:hexanes to give (3S)-[l-(6-bromopyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (260 mg, 38%). 1H NMR (400 MHz, MeOH-d4) delta 7.31 (t, IH, J = 8.0 Hz), 6.66 (d, IH, J = 8.0 Hz), 6.36 (d, IH, J = 8.0 Hz), 4.22-4.16 (m, IH), 3.68-3.64 (m, IH), 3.56-3.49 (m, IH), 3.47-3.41 (m, IH), 3.26-3.22 (m, IH), 2.26-2.18 (m, IH), 1.98-1.90 (m, IH), 1.44 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.5 g (98%) | In water; acetonitrile; trifluoroacetic acid; | EXAMPLE 54 7-[3-Amino-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic Acid A suspension of 5.65 g (20 mmole) of <strong>[100361-18-0]7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid</strong>, 4.65 g (25 mmole) of 3-t-butoxycarbonylaminopyrrolidine, 7.9 g (50 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 150 ml of acetonitrile was stirred at 60 C. for one hour. The solvent was removed in vacuo and the residue was dissolved in 100 ml of trifluoroacetic acid. After stirring at room temperature for one hour, the solvent was removed in vacuo and the residue was suspended in water and the pH adjusted to 11.5 with 50% sodium hydroxide. After filtering through a fiber glass pad to clarify, the filtrate was acidified to 6.6 with 6 M hydrochloric acid. The resulting precipitate was removed by filtration, washed with water, 2-propanol, ether and dried in vacuo to give 6.5 g (98%) of the title compound, mp 284-286 C. |
6.5 g (98%) | In water; acetonitrile; trifluoroacetic acid; | EXAMPLE 54 7-[3-Amino-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic Acid A suspension of 5.65 g (20 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyri dine-3-carboxylic acid, 4.65 g (25 mmole) of 3-t-butoxycarbonylaminopyrrolidine, 7.9 g (50 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 150 ml of acetonitrile was stirred at 60 C. for one hour. The solvent was removed in vacuo and the residue was dissolved in 100 ml of trifluoroacetic acid. After stirring at room temperature for one hour, the solvent was removed in vacuo and the residue was suspended in water and the pH adjusted to 11.5 with 50% sodium hydroxide. After filtering through a fiber glass pad to clarify, the filtrate was acidified to 6.6 with 6M hydrochloric acid. The resulting precipitate was removed by filtration, washed with water, 2-propanol, ether and dried in vacuo to give 6.5 g (98%) of the title compound, mp 284-286 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In isopropyl alcohol; at 100℃; | To a mixture of racemic pyrrolidin-3-yl-carbamic acid tert-butyl ester (102 mg, 0.55 mmol), 4-chloroquinoline (Sigma-Aldrich, Inc) (82 mg, 0.5 mmol), was added isopropanol (2.5 mL), and the mixture was stirred overnight at 100 C. After cooling to rt, it was concentrated in vacuo. The residue was partitioned between aqueous K2CO3 and DCM. The organic layer was drawn off, washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain 155 mg (100%) of crude (1-quinolin-4-yl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (27a) which was used as such for the next step. LC/MS (ESI): 314 (MH)+. The crude 27a (78 mg, 0.25 mmol) was suspended in 5 mL of 50% TFA/DCM and stirred at RT for 1 h. The mixture was then concentrated in vacuo and the residue was washed with anhydrous ether and the washings were discarded. This was repeated twice more and the residual solid was dried in vacuo to obtain 97 mg (90%) of the crude 1-quinolin-4-yl-pyrrolidin-3-ylamine (27b) as a yellow semi-solid which was used as such for the next step. LC/MS (ESI): 214 (MH)+. The crude 27b (22 mg, 0.05 mmol) was dissolved in anhydrous THF and triethylamine (20 mg, 0.2 mmol) was added followed by (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester (30 mg, 0.1 mmol), prepared as described in Example 2a, and the mixture was stirred at 70 C. for 1 h. The mixture was then concentrated in vacuo and the residue was partitioned between aqueous K2CO3 and EtOAc. The organic layer was drawn off, washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain the crude product which was purified by flash column chromatography (silica gel; 1-2% MeOH/DCM followed by 90:9:1 DCM:MeOH:NH3) to yield 10 mg (54%) of pure (4-isopropyl-phenyl)-3-(1-quinolin-4-yl)-pyrrolidin-3-yl-urea. 1H NMR (300 MHz, CDCl3): delta 8.07-7.97 (m, 2H), 7.94-7.84 (m, 2H), 7.62-7.5 (m, 2H), 7.31-7.23 (m, 3H), 7.11-7.05 (m, 2H), 5.81 (d, 1H), 4.74-4.64 (m, 1H), 4.09-4.00 (dd, 1H), 3.66-3.38 (m, 3H), 2.88-2.74 (heptet, 1H), 2.34-1.90 (m, 2H), 1.18 (d, 6H). LC/MS (ESI): calcd mass 374.2, found 375.2 (MH)+. |
100% | EXAMPLE 27; (4-Isopropyl-phenyl)-3-(1-quinolin-4-yl)-pyrrolidin-3-yl-urea (Compound No. 27); To a mixture of racemic pyrrolidin-3-yl-carbamic acid tert-butyl ester (102 mg, 0.55 mmol), 4-chloroquinoline (Sigma-Aldrich, Inc) (82 mg, 0.5 mmol), was added isopropanol (2.5 mL), and the mixture was stirred overnight at 100 C. After cooling to rt, it was concentrated in vacuo. The residue was partitioned between aqueous K2CO3 and DCM. The organic layer was drawn off, washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain 155 mg (100 %) of crude (1-quinolin-4-yl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (27a) which was used as such for the next step. LC/MS (ESI) : 314 (MH)+. The crude 27a (78 mg, 0.25 mmol) was suspended in 5 mL of 50 % TFA/DCM and stirred at RT for 1 h. The mixture was then concentrated in vacuo and the residue was washed with anhydrous ether and the washings were discarded. This was repeated twice more and the residual solid was dried in vacuo to obtain 97 mg (90%) of the crude 1-quinolin-4-yl-pyrrolidin-3-ylamine (27b) as a yellow semi-solid which was used as such for the next step. LC/MS (ESI): 214 (MH)-. The crude 27b (22 mg, 0.05 mmol) was dissolved in anhydrous THF and triethylamine (20 mg, 0.2 mmol) was added followed by (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester (30 mg, 0.1 mmol), prepared as described in Example 2a, and the mixture was stirred at 70 C. for 1 h. The mixture was then concentrated in vacuo and the residue was partitioned between aqueous K2CO3 and EtOAc. The organic layer was drawn off, washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain the crude product which was purified by flash column chromatography (silica gel; 1-2% MeOH/DCM followed by 90:9:1 DCM:MeOH:NH3) to yield 10 mg (54%) of pure (4-isopropyl-phenyl)-3-(1-quinolin-4-yl)-pyrrolidin-3-yl-urea. 1H NMR (300 MHz, CDCl3): delta 8.07-7.97 (m, 2H), 7.94-7.84 (m, 2H), 7.62-7.5 (m, 2H), 7.31-7.23 (m, 3H), 7.11-7.05 (m, 2H), 5.81 (d, 1H), 4.74-4.64 (m, 1H), 4.09-4.00 (dd, 1H), 3.66-3.38 (m, 3H), 2.88-2.74 (heptet, 1H), 2.34-1.90 (m, 2H), 1.18 (d, 6H). LC/MS (ESI): calcd mass 374.2, found 375.2 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; at 100℃; | A solution of <strong>[214470-55-0]4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile</strong> (125 mg, 0.502 mmol), as prepared in the previous step, in isopropanol (1 mL) was treated with pyrrolidin-3-yl-carbamic acid tert-butyl ester (93.5 mg, 0.502 mmol). After stirring at 100 C. overnight, the reaction was cooled to RT and solvent was removed by rotovap to obtain a crude solid. Then, TFA (1 mL) was added and stirred for 1 h, TFA was concentrated under reduced pressure and CHCl3 (1 mL) was added with ice. Aqueous K2CO3 was added dropwise until pH 10. The organic phase was dried over Na2SO4 and concentrated in vacuo to afford the title compound as a solid (110 mg, 74%). | |
In isopropyl alcohol; at 100℃; | d. 4-(3-Amino-pyrrolidin-1-yl)-6,7-dimethoxy-quinoline-3-carbonitrile A solution of <strong>[214470-55-0]4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile</strong> (125 mg, 0.502 mmol), as prepared in the previous step, in isopropanol (1 mL) was treated with pyrrolidin-3-yl-carbamic acid tert-butyl ester (93.5 mg, 0.502 mmol). After stirring at 100 C. overnight, the reaction was cooled to RT and solvent was removed by rotovap to obtain a crude solid. Then, TFA (1 mL) was added and stirred for 1 h, TFA was concentrated under reduced pressure and CHCl3 (1 mL) was added with ice. Aqueous K2CO3 was added dropwise until pH 10. The organic phase was dried over Na2SO4 and concentrated in vacuo to afford the title compound as a solid (110 mg, 74%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20 - 100℃; for 0.375h; | A vial was charged with 4-chloro-7-fluoro-quinazoline (2.00 g, 11.0 mmol) (WO 9609294 A1), pyrrolidin-3-yl-carbamic acid tert-butyl ester (2.05 g, 11.0 mmol), DMSO (2.64 mL), and DIPEA (2.10 mL, 12.0 mmol) in quick succession. The mixture was stirred at "rt" for 20 min, during which time the reaction spontaneously warmed and became a homogeneous reddish-brown solution. The reaction was then stirred at 100 C. for 2.5 min to ensure complete reaction. The solution was shaken with water (20 mL) to dissolve the DMSO into the aqueous phase, and was extracted with EtOAc (1*20 mL). The organic layer was washed with 4 M NaCl (1*20 mL) and dried (Na2SO4). Upon addition of Na2SO4 to the organic phase, the title compound began to precipitate out. This was collected by filtration (easily decanted from the wet drying agent), dried, and powdered to afford the title compound as an off-white powder (1.42 g, 39%). |
39% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20 - 100℃; for 0.375h; | EXAMPLE NO. 70; 1-(4-Isopropyl-phenyl)-3-(1-{7-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-quinazolin-4-yl}-pyrrolidin-3-yl)-urea (Compound No. 70); a. [1-(7-Fluoro-quinazolin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester; A vial was charged with 4-chloro-7-fluoro-quinazoline (2.00 g, 11.0 mmol) (WO 9609294 A1), pyrrolidin-3-yl-carbamic acid tert-butyl ester (2.05 g, 11.0 mmol), DMSO (2.64 mL), and DIPEA (2.10 mL, 12.0 mmol) in quick succession. The mixture was stirred at ?rt? for 20 min, during which time the reaction spontaneously warmed and became a homogeneous reddish-brown solution. The reaction was then stirred at 100 C. for 2.5 min to ensure complete reaction. The solution was shaken with water (20 mL) to dissolve the DMSO into the aqueous phase, and was extracted with EtOAc (1×20 mL). The organic layer was washed with 4 M NaCl (1×20 mL) and dried (Na2SO4). Upon addition of Na2SO4 to the organic phase, the title compound began to precipitate out. This was collected by filtration (easily decanted from the wet drying agent), dried, and powdered to afford the title compound as an off-white powder (1.42 g, 39%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In isopropyl alcohol; at 100℃; for 1h; | a. (1-Thieno[3,2-d]pyrimidin-4-yl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester A solution of 4-chlorothieno[3,2-d]pyimidine (400 mg, 2.35 mmol), Pyrrolidine-3-yl-carbamic acid tert-butyl ester (436 mg, 2.35 mmol), diisopropylethylamine (285 mg, 2.82 mmol) in isopropanol (10 mL) was heated to 100 C. for 1 hr. The resulting mixture was cooled to RT, poured into ethyl acetate (50 mL), and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (5% MeOH/EtOAc) to provide the title compound (645 mg, 86% yield). 1H NMR (400 MHz, CD3OD) delta 8.34 (s, 1H), 8.02 (d, 1H), 7.32 (d, 1H), 4.23 (m, 1H), 4.18-3.92 (m, 3H), 3.78 (m, 1H), 2.26 (m, 1H), 2.04 (m, 1H), 1.42 (s, 9H). LC/MS (ESI): calcd mass 320.1, found 321.2 (MH)+. |
86% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 1h; | A solution of 4-chlorothieno[3,2-d]pyimidine (400 mg, 2.35 mmol), Pyrrolidine-3-yl-carbamic acid tert-butyl ester (436 mg, 2.35 mmol), diisopropylethylamine (285 mg, 2.82 mmol) in isopropanol (10 mL) was heated to 100 C. for 1 hr. The resulting mixture was cooled to RT, poured into ethyl acetate (50 mL), and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (5% MeOH/EtOAc) to provide the title compound (645 mg, 86% yield). 1H NMR (400 MHz, CD3OD) delta 8.34 (s, 1H), 8.02 (d, 1H), 7.32 (d, 1H), 4.23 (m, 1H), 4.18-3.92 (m, 3H), 3.78 (m, 1H), 2.26 (m, 1H), 2.04 (m, 1H), 1.42 (s, 9H). LC/MS (ESI): calcd mass 320.1, found 321.2 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.2% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 1h; | To a suspension of <strong>[14160-93-1]4-amino-6-chloro-pyrimidine-5-carbaldehyde</strong> (239 mg, 1.52 mmol) in CH3CN (2 mL) was added 3-(tert-butoxycarbonylamino)pyrrolidine (312 mg, 1.67 mmol), followed by DIEA (392.9 mg, 3.04 mmol). The mixture was stirred at 90 C. for 1 h. It was cooled to room temperature and the precipitate was filtered off, washed with CH3CN and dried in vacuo to afford the product as a white solid (290.6 mg, 62.2%). 1H NMR (DMSO-d6) delta 9.92 (s, 1H), 8.58 (br, 1H), 7.95 (s, 1H), 7.68 (br, 1H), 7.22 (d, J=6.16 Hz, 1H), 4.02 (m, 1H), 3.80 (m, 2H), 3.66 (m, 1H), 3.45 (m, 1H), 2.03 (m, 1H), 1.82 (m, 1H), 1.38 (s, 9H); LC/MS (ESI) calcd for C14H22N5O3 (MH)+ 308.2, found 308.3. |
62.2% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 1h; | a. [1-(6-Amino-5-formyl-pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester To a suspension of <strong>[14160-93-1]4-amino-6-chloro-pyrimidine-5-carbaldehyde</strong> (239 mg, 1.52 mmol) in CH3CN (2 mL) was added 3-(tert-butoxycarbonylamino)pyrrolidine (312 mg, 1.67 mmol), followed by DIEA (392.9 mg, 3.04 mmol). The mixture was stirred at 90 C. for 1 h. It was cooled to room temperature and the precipitate was filtered off, washed with CH3CN and dried in vacuo to afford the product as a white solid (290.6 mg, 62.2%). 1H NMR (DMSO-d6) delta 9.92 (s, 1H), 8.58 (br, 1H), 7.95 (s, 1H), 7.68 (br, 1H), 7.22 (d, J=6.16 Hz, 1H), 4.02 (m, 1H), 3.80 (m, 2H), 3.66 (m, 1H), 3.45 (m, 1H), 2.03 (m, 1H), 1.82 (m, 1H), 1.38 (s, 9H); LC/MS (ESI) calcd for C14H22N5O3 (MH)+ 308.2, found 308.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine; In dichloromethane; at 0 - 20℃; for 4h; | Method C: ^-Butylpyrrolidin-3-ylcarbamate (1 g, 5.4 mmol) obtained in Preparation Example 2-vi was dissolved in dichloromethane (14 ml) at 0C in a 50 ml vessel, and triethylamine(0.83 ml, 5.94 mmol, 1.1 eq.) and cyclohexylcarbonyl chloride (0.79 ml, 5.94 mmol, 1.1 were added thereto while stirring. The resulting mixture was heated from 0C to room temperature, and reacted for 4 hrs. After the completion of reaction, the solvent was distilled off under reduced pressure and the residue was extracted with dichloromethane. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 1.57 g of the title compound as pale yellow oil (yield 98%). EPO <DP n="85"/>1H-NMR (200 MHz, CDCl3) delta 1.26 (m, 4H), 1.46 (s, 9H), 1.79 (m, 6H), 1.98 (m, IH), 2.08-2.49 (m, 2H), 3.39 (m, IH), 3.59 (m, 2H), 3.73 (m, IH), 4.22 (m, IH), 4.63 (m, IH). LC/MS (Mt+H): 297; Method C: ^-Butyl-pyrrolidin-4-ylcarbamate (1 g, 5.4 mmol) obtained in Preparation Example 4-vi was dissolved in dichloromethane (14 ml) in a 50 ml vessel at 0C , and triethylamine (0.83 ml, 5.94 mmol, 1.1 eq.) and cyclohexylcarbonyl chloride (0.79 ml, 5.94 mmol, 1.1 eq.) were added thereto while stirring. The resulting mixture was heated from 0C to room temperature and kept for 4 hrs. After the completion of reaction, the solvent EPO <DP n="172"/>was distilled off under reduced pressure and the residue thus obtained was extracted with dichloromethane. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 1.57 g of the title compound as pale yellow oil (yield 98%).1H-NMR (200 MHz, CDCl3) delta 1.26(m, 4H), 1.46(s, 9H), 1.79(m, 6H), 1.98(m, IH), 2.08-2.49(m, 2H), 3.39(m, IH), 3.59(m, 2H), 3.73(m, IH), 4.22(m, IH), 4.63(m, IH) LC/MS(MfH): 297 |
98% | With triethylamine; In dichloromethane; at 0 - 20℃; for 4h; | Method C: The starting material (1 g, 5.4 mmol) was dissolved in dichloromethane (14 ml) at 0C in the 50 ml reaction vessel, triethyl 5 amine(0.83 ml, 5.94 mmol, 1.1 eq.) and cyclohexylcarbonyl chloride (0.79 ml, 5.94 mmol, 1.1 were added thereto while stirring, heated from 0C to room temperature, and kept for 4 hrs. After the completion of the reaction, the solvent was distilled under a reduced pressure and the remaining was extracted with dichloromethane. The extract was washed with sodium o bicarbonate and salt water in order. The resulting organic layer was washed with saturated sodium bicarbonate and salt water, dried over anhydrous magnesium sulfate, concentrated under a reduced pressure and then subjected to silica gel column chromatography to obtain 1.57 g of the title compound as <n="27"/>pale yellow oil (yield: 98%).1H-NMR (200 MHz, CDCl3) delta 1.26 (m, 4H), 1.46 (s, 9H), 1.79 (m, 6H)5 1.98 (m, IH), 2.08-2.49 (m, 2H), 3.39 (m, IH), 3.59 (m, 2H), 3.73 (m, IH), 4.22 (m, IH), 4.63 (m, IH). LC/MS (M+H): 297 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Method A: /-Butylpyrrolidin-3-ylcarbamate (1.24 g, 6.7 mmol) obtained in Preparation Example 2-vi was dissolved in methanol (14 ml) in a 250 ml vessel, and acetone (3.44 ml, 46.9 mmol) and acetic acid (0.19 ml, 3.35 mmol) were added thereto while stirring. To the resulting mixture, NaCNBH3 (842 mg, 13.4 mmol) was added in 4-divided portions and reacted for 18 hrs. After the completion of reaction, ice water was poured to the reaction product. Then the resulting mixture was stirred and extracted with ethyl acetate. The organic layer was separated, washed with an aqueous sodium bicarbonate solution and brine in order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 897 mg of the title compound as a white solid (yield 58%).1H-NMR (200 MHz, CDCl3) delta 1.40 (d, J = 6.6 Hz, 6 Hz), 1.44 (s, 9H), 2.12 (m, IH), 2.48 (m, IH), 3.27 (m, IH), 3.39 (m, 3H), 3.57 (m, IH), 4.38 (m, IH), 5.41 (m, IH).LC/MS (M+H): 229; Method A: £-Butyl pyrrolidin-4-ylcarbamate (1.24 g, 6.7 mmol) obtained in Preparation Example 4-vi was dissolved in methanol (14 ml) in a 250 ml vessel, and acetone (3.44 ml, 46.9 mmol) and acetic acid (0.19 ml, 3.35 mmol) were added thereto while stirring. To the resulting mixture, NaCNBH3 (842 ml, 13.4 mmol) was added in 4-divided portions and reacted for 18 hrs. After the completion of reaction, ice water was poured to the reaction product and then the resulting mixture was stirred and extracted with ethyl acetate. The organic layer was separated, washed with aqueous sodium bicarbonate and brine in order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 897 mg of the title compound as a white solid (yield 58%).1H-NMR (200 MHz, CDCl3) delta 1.40(d, J=6.6 Hz, 6 Hz), 1.44(s, 9H), 2.12(m, IH), 2.48(m, IH), 3.27(m, IH), 3.39(m, 3H), 3.57(m, IH), 4.38(m, IH), 5.41(m, IH)LCMS(M4H): 229 | |
58% | With sodium cyanoborohydride; acetic acid; In methanol; for 18h; | Method A: ?-butyl pyrrolidin-3-ylcarbamate(1.24 g, 6.7 mmol) was o dissolved in methanol (14 ml) in the 250 ml reaction vessel, acetone (3.44 ml,46.9 mmol) and acetic acid (0.19 ml, 3.35 mmol) were added thereto while stirring, and 4 portions OfNaCNBH3 (842 mg, 13.4 mmol) were added thereto dropwise and kept for 18 hrs. After the completion of the reaction, ice water <n="25"/>was poured thereinto and then the mixture was stirred and extracted with ethyl acetate. The extract was washed with sodium bicarbonate and salt water in order. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under a reduced pressure and then subjected to silica gel column chromatography to obtain 897 g of title compound as a white solid (yield: 58%).1H-NMR (200 MHz, CDCl3) delta 1.40 (d, J = 6.6 Hz, 6Hz), 1.44 (s, 9H), 2.12 (m, IH), 2.48 (m, IH), 3.27 (m, IH), 3.39 (m, 3H), 3.57 (m, IH), 4.38 (m, IH), 5.41 (m, IH). LC/MS (M+H): 229 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.2% | at 120℃; for 5h; | A mixture of 2-fluoropyridine (1.0 g, 10.3 mmol) and tert-butyl pyrrolidin-3-ylcarbamate (1.80 g, 9.66 mmol) was heated at 120 0C for 5 h. After cooling to RT, the solid formed was treated with ether, filtered, and washed with ether. The solid was collected and dried to give the desired product (2.50 g, 98.2%). LCMS: (M+H) = 264.1. |
51% | With N-ethyl-N,N-diisopropylamine; at 120℃; for 6h; | A mixture of 2-fluoropyridine (1.75 mL, 20.1 mmol), tert-butyl pyrrolidin-3- ylcarbamate (250 mg, 1.34 mmol), and DIPEA (0.23 mL, 1.3 mmol) was heated to 120 C for 6 h. The reaction mixture was then concentrated to remove excess 2- fluoropyridine, and was then purified by flash-column chromatography on silica gel (gradient elution, 5 to 60% ethyl acetate-hexanes) to give tert-butyl (1-(pyridin-2- yl)pyrrolidin-3-yl)carbamate (180 mg, 51%) as a white solid. MS (ES+) C14H21N3O2 requires: 263, found: 264 [M + H]+. |
19% | With triethylamine; In ethanol; at 120℃; for 0.5h; | [00221] A mixture of 2-fluoropyridine (58.3 mg, 0.600 mmol), tert-butyl pyrrolidin-3- ylcarbamate (55.9 mg, 0.300 mmol), and TEA (84.0 L, 0.600 mmol) in EtOH (1 mL) was heated at 120 C for 30 min. The reaction was concentrated and the crude was purified by flash chromatography (12 g silica gel) using hexanes/EtOAc (0-50% over 10 min, flow rate 30 mL/min) to give Intermediate 48A (15 mg, 0.057 mmol, 19% yield) as a white solid. LCMS = 264.3 [M+l], RT=1.1 1 min (Method H). NMR (400 MHz, chloroform-d) delta ppm 8.15 (1 H, dd, J=5.05, 1.01 Hz), 7.44 (1 H, ddd, J=8.59, 6.95, 1.89 Hz), 6.55 (1 H, dd, J=6.44, 5.18 Hz), 6.35 (1 H, d, J=8.34 Hz), 4.74 (1H, br. s.), 4.35 (1 H, br. s.), 3.71 (1 H, dd, J=10.61, 6.06 Hz), 3.46 - 3.64 (2 H, m), 3.34 (1 H, dd, J=10.61, 4.04 Hz), 2.27 (1 H, td, J=13.20, 7.45 Hz), 1.96 (1 H, td, J=12.51, 5.56 Hz), 1.45 (9 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of EXAMPLE 7A (168.3 mg), <strong>[162167-97-7]tert-butyl 3-(aminomethyl)piperidine-1-carboxylate</strong> (107 mg), and N,N-diisopropylethylamine (450 muL) in acetonitrile (4.0 mL) was heated in a microwave reactor for 10 minutes at 50° C., and 20 minutes at 190° C., cooled, treated with tert-butyl pyrrolidin-3-ylcarbamate (112 mg), heated in a microwave reactor for 30 minutes at 100° C., cooled and concentrated. A solution of the concentrate in a mixture of tetrahydrofuran (2 mL) and methanol (1 mL) was treated with sodium hydroxide (2M, 800 muL), stirred for 4 hours at 50° C., cooled, concentrated, treated with water, acidified to pH 6 with 1M HCl, and filtered. The solid was treated with trifluoroacetic acid (2 mL), stirred for 2 hours at 25° C., and concentrated. The concentrate was purified by reverse phase high performance liquid chromatography (HPLC) on a C8 column with 10-100percent acetonitrile in water containing 0.1percent trifluoroacetic acid. NMR (300 MHz, DMSO-d6) delta ppm 8.94 (s, 1H), 8.80-8.67 (m, 1H), 8.44-8.16 (m, 4H), 8.10 (d, 1H), 4.46-4.34 (m, 2H), 4.08-3.82 (m, 4H), 3.28-3.10 (m, 2H), 2.86-2.67 (m, 2H), 2.44-2.26 (m, 2H), 2.19-2.06 (m, 1H), 1.87-1.20 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of EXAMPLE 1C (357.4 mg) in acetonitrile (10.2 mL) at 25 C. was treated with <strong>[52721-69-4]2-(2-fluorophenyl)ethanamine</strong> (0.14 mL), stirred for 2 hours at 25 C., and 16 hours at 50 C., cooled, treated with potassium carbonate (374.5 mg), stirred for 2 days at 85 C., cooled to 25 C., treated with tert-butyl pyrrolidin-3-ylcarbamate (284.6 mg), stirred for 2 days at 25 C., and concentrated. A suspension of the concentrate in tetrahydrofuran (8 mL) and 4N HCl/dioxane (14 mL) was stirred for 2 hours at 25 C., treated with diethyl ether, and centrifuged; and the solid triturated with diethyl ether. The resulting solid was suspended in methanol and dichloromethane. The supernate was concentrated and the concentrate purified by reverse phase high performance liquid chromatography (HPLC) on a C8 column with 0% to 100% acetonitrile in water containing 0.1% trifluoroacetic acid. NMR (300 MHz, DMSO-d6) delta ppm 8.26 (bs, 1H), 8.16 (m, 3H), 7.30 (m, 2H), 7.13 (m, 2H), 4.47 (m, 2H), 4.14 (q, 2H), 3.99 (m, 2H), 3.86 (m, 3H), 3.10 (dd, 2H), 2.64 (d, 3H), 2.32 (m, 1H), 2.11 (m, 1H), 1.21 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-ethyl-N,N-diisopropylamine; In ethanol; at 150℃; for 0.5h;Microwave irradiation; | Example 1 Synthesis of fert-butyl [1 -(2-amino-6,7-dihvdro-5/-/- cvclopenta[dlpyrimidin-4-yl)pyrrolidin-3-yllcarbamate (Intermediate 1 ) <n="42"/>4-Chloro-6,7-dihydro-5/-/-cyclopenta[d]pyrimidin-2-amine (CAS No 5461 -89-2) (54mg), tert-butyl pyrrolidin-3-ylcarbamate (63mg) and DIPEA (0.059ml) are treated with absolute EtOH (2ml) and heated under microwave irradiation at 15O0C for 30 mins. The solution is concentrated in vacuo and the residue purified by flash chromatography, eluting with DCM-MeOH 95:5, then 94:6 to afford the title compound as a colourless crystalline solid (93mg, 90%). Rf (DCM-MeOH 94:6) 0.29. LCMS 320 [M+H]+, RT 1.98 mins (pH 2.5). 1 H NMR 300 MHz (CDCI3) (delta ppm): 6.07 (2H, bm), 4.65 (1 H, m), 4.28 (1 H, m), 3.95 (1 H, dd), 3.80 (2H, m), 3.62 (1 H, m), 3.02 (2H, t), 2.88 (2H, t), 1 .87 - 2.30 (4H, m), 1.45 (9H, s). Intermediates 2 and 3 are prepared in a similar manner to the method described for Intermediate 1 in Example 1 . The reagents used and the results obtained are tabulated below (Table 1 ). The free base of the compounds is obtained unless otherwise stated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Trimethylsilylethyl ether 44 (0.03g, 0.0508 mmol) was dissolved in 2 mL dry tetrahydrofuran. To this was added triethylamine (0.028mL, 0.2032 mmol) and 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (0.1016mL, 0.1016nunol. ) Stirred at room temperature 10 minutes until starting material consumed. Diluted with dichloromethane, washed with washed with 1M HCI solution, saturated brine, concentrated to give crude. Dissolved in 1.5 mL dichloromethane, added catalytic dimethylaminopyridine, triethylamine (0.16mL, 0.6 mmol) and cooled to 0 C. To this was added triphosgene (0.03g, 0.1016 mmol) and stirred 40 minutes. BOC- aminopyrrolidine (0.038g, 0.2032 mmol) was then added and stirred at room temperature for 10 minutes. The mixture was diluted with dichloromethane, washed with 1M HCI, brine, concentrated volatiles to give crude product. Chromatographed (10% to 30% acetone/toluene) to give 225 (0.0108g, 0.0153mmol, 30%. ) (at)H NMR (CDC13) No. 9.03 (dd, 1H), 8.11 (d, 1H), 8.03 (s, 1H), 7.74 (d, 4H), 7.50 (dd, 1H), 7.27 (m, 8H), 7.07 (dd, 2H), 4.80 (s, 2H), 4.65 (br s, 1H), 4.30 (br s, 1H), 4.24 (s, 2H), 3.95 (br s, 1H), 3.74 (m, 2H), 3.58 (m, 2H), 1.48 (s, 9H) MS: 703 M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.8% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 15h;Inert atmosphere; | 3-N-Boc-amino pyrrolidine (120 mg, 0.644 mmol), cesium carbonate (252 mg, 0.773 mmol), and 3-bromochlorobenzene (75.7 mul, 0.644 mmol) were suspended in dry toluene. Argon was bubbled through the suspension for 2 minutes and then tris(dibenyzlideneacetone)dipalladium (35.4 mg, 0.0387 mmol) and rac-2,2- bis(diphenylphosphino)-l,l '-binaphthyl (60.4 mg, 0.0966 mmol) were added. The reaction vial was capped and heated to 110 0C with rapid stirring. After 15 hours, reaction was cooled to ambient temperature and applied directly to a silica gel column. Elution was a gradient of 5-70% ethyl acetate-hexanes provided the title compound (120 mg, 0.404 mmol, 62.8 % yield) as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | To a solution of teri-butylpyrrolidine-3-ylcarbamate (0.93 g, 4.99 mmol) and cyclobutanone (0.52 g, 7.5 mmol) in DCM (10 ml) at rt was added sodium triacetoxyborohydride (1.58 g, 7.5 mmol). The reaction mixture was stirred for 1 h then quenched with 2 M NaOH (10 ml). The organic layer was separated and the aqueous extracted with DCM (20 ml) the combined organic layers were dried over MgS04 and concentrated to give ½rt-butyl-l-cyclobutylpyrrolidin-3-ylcarbamate (1.04 g, 87%) as a yellow oil. NMR (CDC13, 300 MHz) 4.83 (1H, br-s), 4.13 (1H, br-s), 2.85 (1H, m), 2.75 - 2.49 (3H, m), 2.25 (2H, m), 1.91 (4H, m), 1.71 (2H, m) and 1.42 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.7% | With caesium carbonate; XPhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 20 - 95℃;Inert atmosphere; | Step 2 tert-Butyl 1-(7-(5,6-dimethoxypyridin-2-ylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamate Procedure: To a stirred solution of 5-chloro-N-(5,6-dimethoxypyridin-2-yl)thiazolo[5,4-d]pyrimidin-7-amine (344 mg, 1.06 mmol), tert-butyl pyrrolidin-3-ylcarbamate (289 mg, 1.55 mmol), X-Phos (256 mg, 0.53 mmol) and Cs2CO3 (1.3 g, 3.9 mmol) in 120 mL of dioxane at room temperature under nitrogen was added Pd2(dba)3 (138 mg, 0.24 mmol) in one portion. Then the reaction was stirred at 95 C. under nitrogen for 24 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (2:1)) to give tert-butyl 1-(7-(5,6-dimethoxypyridin-2-ylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamate (260 mg, 51.7%) as an oil. LC-MS: 474.2 [M+H]+, tR=1.67 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.8% | With caesium carbonate; XPhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 20 - 95℃;Inert atmosphere; | Step 1 tert-butyl 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamate Procedure: To a stirred solution of (5-chloro-thiazolo[5,4-d]pyrimidin-7-yl)-(3,4-dimethoxy-phenyl)-amine (150 mg, 0.46 mmol), tert-butyl pyrrolidin-3-yl carbamate (130 mg, 0.69 mmol), X-Phos (115 mg, 0.24 mmol) and Cs2CO3 (580 mg, 1.78 mmol) in 60 mL of dry dioxane was added Pd2(dba)3 (60 mg, 0.065 mmol) in one portion at room temperature under nitrogen. Then the reaction mixture was degassed with nitrogen for 15 minutes. The final mixture was stirred at 95 C. under nitrogen for 24 hours. The solvent was evaporated and crude purified by silica gel chromatography (silica gel 200-300 mesh, petroleum ether:ethyl acetate=1:2) to give tert-butyl 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamate (191 mg, 87.8%) as a solid. LC-MS: 473.2 [M+H]+, tR=1.56 min. |
87.8% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 95℃; for 24h;Inert atmosphere; | To a stirred solution of (5-chloro-thiazolo[5,4- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In methanol; at 140℃; for 6h;microwave irradiation; | (i) Preparation of 58b: (4aS,6aS,6bR,13aR)-benzyl 12-amino-15-(6-(3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)pyridin-3-yl)-2,2,6a,6b,9,9,13a-heptamethyl-2,3,4,4a,5,6,6a,6b,7,8,8a,9,11,13,13a,13b,14,15b-octadecahydro-1H-chryseno[1,2-f]indazole-4-a-carboxylate To a solution of 41b (246 mg, 0.36 mmol) in MeOH (4 mL) was added tert-butyl pyrrolidin-3-ylcarbamate (1.0 g, 5.36 mmol). The reaction mixture was heated at 140 C. for 6 hours using microwave irradiation. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (20 mL). The solution was washed with brine then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (306 mg, 100%). APCI MS m/z 845 [C52H72N6O4+H]+. |
100% | In methanol; at 140℃; for 6h;Microwave irradiation; | (i) Preparation of 58b: (4aS,6aS,6bR,13aR)-Benzyl 12-amino-15-(6-(3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)pyridin-3-yl)-2,2,6a,6b,9,9,13a-heptamethyl-2,3,4,4a,5,6,6a,6b,7,8,8a,9,11,13,13a,13b,14,15b-octadecahydro-1H-chryseno[1,2-f]indazole-4a-carboxylate To a solution of 41b (246 mg, 0.36 mmol) in MeOH (4 mL) was added tert-butyl pyrrolidin-3-ylcarbamate (1.0 g, 5.36 mmol). The reaction mixture was heated at 140C for 6 hours using microwave irradiation. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (20 mL). The solution was washed with brine then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (306 mg, 100%). APCI MS m/z 845 [C52H72N6O4 + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 160℃; for 0.5h;Microwave irradiation; | A mixture of <strong>[630422-06-9]1-chloroisoquinoline-3-carbonitrile</strong> (438 mg, 2.322 mmol), tert-butyl pyrrolidin-3-ylcarbamate (519 mg, 2.79 mmol) and Et3N (0.653 mL, 4.64 mmol) in NMP (3 mL) was heated at 160 C. for 30 minutes in a microwave reactor. The crude reaction mixture, which contained the title compound, was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;Inert atmosphere; | To a suspension of 4-bromobenzoic acid (1.13 g, 5.64 mmol) in DCM (150 mL) was added tert-butyl pyrrolidin-3-ylcarbamate (1.00 g, 5.37 mmol), followed by the addition of EtaOmicronAlphaTau (0.49 g, 0.56 mmol) and EDCI (0.32 g,1.68 mmol) at 0 C under N2 atmosphere. The mixture was stirred at 0 C for 30 minutes, then warm to rt and stirred overnight. The mixture was washed with brine (200 mL), and the separated organic phase was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a white needle solid (1.63 g, 82%>). lU NMR (400 MHz, CDCI3): delta 7.55-7.53 (m, 2H), 7.41-7.38 (m, 2H), 4.71-4.64 (m, 1H), 4.30- 4.11 (m, 1H), 3.90-3.70 (m, 2H), 3.54-3.27 (m, 2H), 2.31-2.14 (m, 1H), 1.90-1.85 (m, 1H), 1.40 (s, 9H). |
82% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;Inert atmosphere; | The compound 4-bromobenzoic acid (1.13 g, 5.64 mmol)Suspended in DCM (150 mL), cooled to 0 C and thenUnder nitrogen protection,To the reaction mixture was added tert-butyl pyrrolidine-3-carbamate(1.00 g, 5.37 mmol),H0AT (0.49 g, 0.56 mmol) and EDCI (0.32 g, 1.68 mmol),The reaction was stirred at 0 C for 30 minutes, warmed to room temperature, stirred overnight,The organic phase was then concentrated under reduced pressure and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 1/1) to give the title compound as a white needle-like solid ( 1.63 g, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With triethylamine; In dimethyl sulfoxide; at 70℃; for 5h; | 5-Bromo-2-nitropyridine (10.0 g, 49.3 mmol) and tert-butyl pyrrolidin-3- ylcarbamate (11.9 g, 64.0 mmol) were dissolved in DMSO (30 mL), and triethylamine (8.93 mL, 64.0 mmol) was added. The mixture was stirred at 70 C for 5 h, then cooled to rt and poured into water. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulphate, and the solvent was evaporated. The residue was triturated with ethyl acetate, and the precipitate was collected by suction filtration. The mother liquor was purified by preparative HPLC to yield a second batch. 10.5 g (69%) of the title compound were obtained. 1H-NMR (400MHz, DMSO-d6): delta [ppm]= 1.39 (s, 9H), 1.82 - 1.91 (m, 1 H), 2.07 - 2.16 (m, 1 H), 3.17 (dd, 1 H), 3.29 - 3.37 (m, 1 H), 3.42 - 3.50 (m, 1 H), 3.55 (dd, 1 H), 4.05 - 4.14 (m, 1 H), 6.42 (d, 1 H), 7.20 (d, 1 H), 7.62 (dd, 1 H), 8.11 (d, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With potassium carbonate; for 4h;Reflux; | To a solution of 2, 6-dichloronicotinonitrile 1 (346 mg, 2.0 mmol) in ethanol (10 mL) was added tert-butyl piperidin-4-ylcarbamate 2 (372 mg, 2.0 mmol) and K2CO3 (552 mg, 4.0 mmol). The mixture was heated to reflux and stirred for 4 h. After cooling to room temperature, the solvent was evaporated and the crude product was purified by silica gel column chromatography eluting with 20: 1 to 5: 1 PE/EA to afford the title compound as a white solid (365 mg, 57%). MS (ESI, method A): m/z = 345.1 [M + Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.5% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 14h; | To a solution of tert-butyl pyrrolidin-3-ylcarbamate (1.86 g, 10.0 mmol) in DMF (59 mL) were added HATU (7.61 g, 12 mmol), z-Pr2NEt (5.2 mL, 30 mmol) and cyanoacetic acid (1.02 g, 12.0 mmol). The reaction mixture was stirred at room temperature for 14 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v) = 2/3) to give the title compound as yellow oil (1.10 g, 43.5%).MS (ESI, pos. ion) m/z: 198.1 [(M -C4H8)+H]+. |
43.5% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | The compound, tert-butyl pyrrolidine-3-carbamate (1.86 g, 10.0 mmol)Was dissolved in DMF (59 mL)Then, HATU (7.61 g, 12 mmol) was added to the reaction solution,i-Pr2NEt (5.2 mL, 30 mmol)And cyanoacetic acid (1.02 g, 12.0 mmol),The resulting reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc / PE (v / v) = 2/3) to give the title compound as a yellow oil (1.10 g , 43.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | j00832j A solution of (S)-2-(6-(4-chlorophenyl)-8-methoxy- 1 -methyl-4H-benzo[/][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (0.15 g, 0.37 mmol) in DCM (15 mL) were charged with EDCI (0.108 g, 0.56 mmol), DMAP (0.055 g, 0.45 mmol), and stirred at room temperature for 10 mm. To this solution, tert-butyl pyrrolidin-3-ylcarbamate (0.077 g, 0.41 mmol) was added and the resulting solution was stirred at room temperature for 4 h. The reaction mixture was partitioned between DCM (15 mL) and H20 (10 mL) and separated. Theaqueous layer was extracted with DCM (3 X 15 mL) and the combined organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo resulting in a crude compound which was purified by column chromatography on silica gel (100-200 mesh), eluting with 5% methanol in chloroform to give 0.20 g (98 % yield) of the title compound as an off white solid. MS (ES): m/z = 565.40, 567.40 [M+H] LCMS: tR = 2.49 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 85℃; for 24h; | Step A. tert-Butyl (1 -(3 -cyano-2-fluorophenyl)pyrrolidin-3 -yl)carbamateTo a solution of <strong>[840481-82-5]3-bromo-2-fluorobenzonitrile</strong> (3.0 g, 15 mmol) in 1,4-dioxane (120 mL),tert-butyl pyrrolidin-3-ylcarbamate (2.8 g, 15 mmol), Pd2(dba)3 (1.4 g, 1.5 mmol), Xantphos (1.7 g, 3.0 mmol), and Cs2CO3 (9.8 g, 30 mmol) were added at RT. The mixture was stirred at 85 C for 24 h. The mixture was filtered through a pad of Celite, treated with water (200 mL), extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by column chromatography(10-30% EtOAc in heptane) to give the title compound. MS (ESI) mlz = 328 (M+Na) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 16.5h;Inert atmosphere; | [00578] Step 1 : To a solution of 2-bromo anisole (1.2 g, 6.45 mmol) in degassed toluene (20 mL) was added a suspension of Pd2(dba)2 (494 mg, 0.54 mmol), BINAP (1 g, 1.61 mmol) and tert-butyl pyrrolidin- 3-ylcarbamate (1 g, 5.37 mmol), and the mixture was stirred at 100 C for 16.5 h under argon. The reactant was portioned between water (30 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (20 mL x2). The combined organic layers were washed with brine (10 mL x 2) and concentrated to dryness. The crude product was purified by Combi flash (1406) (PE/EtOAc = 50/1 -20/1) to give tert-butyl (l-(2-methoxyphenyl)pyrrolidin-3-yl)carbamate (1.43 g, yield: 91%) as yellow oil. (1407) [00579] lH NMR (400 MHz, CDC13): delta = 6.91-6.84 (m, 4H), 6.73 (d, J= 6.4 Hz, 1H), 4.85 (brs, 1H), 4.30 (brs, 1H), 3.83 (s, 3H), 3.55-3.44 (m, 2H), 3.25-3.15 (m, 2H), 2.31-2.23 (m, 1H), 1.85-1.79 (m, 1H), 1.45 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 2-( 1H-7-azabenzotniazol-1-yl)-1,1,3,3-tetrarmethyluroniumhexafluorophosphate methanaminium; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 15h; | Step 1 tert-Butyl (1-(3-isopropyl- 1H-pyrazole-5-carbonyl)pyrrolidin-3-yl)carbamateTo a solution of tert-butyl N-pyrrolidin-3-ylcarbamate (1 g, 5.4 mmol) in DMF (15 ml) was added3-isopropyl-IH-pyrazole-5-carboxylic acid (0.9 g, 5.9 mmol), DIEA (1.9 ml, 10.7 mmol) and1-IATU (2.6 g, 7.0 mmol). The mixture was stirred at room temperature for 15 hrs, then dilutedwith H20 (20 ml), and extracted with EtOAc (60 ml x 2). The combined organic layers were driedover anhydrous Na2SO4, filtered, concentrated and the residue was purified by silica gel flashchromatography eluted with 0-10% MeOH in DCM to give the desired product (1.3 g, 75% yield) as a white solid. LCMS (ESI) mlz: 323.0 [M+Hjt RT = 1.11 mm (LCMS Method A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.5% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1h;Sealed tube; Microwave irradiation; Inert atmosphere; | General procedure: 6-chloronicotinate (2 mmol) and amine 5a-5g (3 mmol) were added to amicrowave vial (10 ml) equipped with a stir bar. NMP (3 mL) was then addedfollowed by triethylamine (6 mmol). The vial was sealed and irradiated in themicrowave at 180 C (high absorption) for 60 min. The mixture was then dilutedwith H2O (10 mL) and extracted with EtOAc (3 × 15 mL). The combinedorganic layers were dried over MgSO4 and concentrated. The residuewas purified by flash chromatography on silica gel using ethylacetate-petroleum ether gradient elution (1:4 - 1:2, v/v) to afford the titlecompound 7a-7g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 50℃; for 2h; | Into a 50-mL round-bottom flask was added a solution of tert-butyl 5-[[(tert- butoxy)carbonyl](5-[3-[(4-nitrophenoxycarbonyl)amino]phenyl]-1,3,4-thiadiazol-2-yl)amino]- 1H-indazole-1-carboxylate (100 mg, 0.15 mmol, 1.00 equiv), tert-butyl N-(pyrrolidin-3- yl)carbamate (98.99 mg, 0.53 mmol, 3.58 equiv) and N,N-diisopropylethylamine (DIPEA) (0.14 mL, 0.846 mmol, 5.64 equiv) in tetrahydrofuran (5.4 mL). The resulting solution was stirred for 2 h at 50 C in an oil bath, and then it was concentrated under vacuum to provide a residue that was then purified by silica gel column with DCM/methanol (10:1) as eluent to furnish 98 mg (92%) of tert-butyl 5-[[(tert-butoxy)carbonyl][5-(3-[[(3-[[(tert- butoxy)carbonyl]amino]pyrrolidin-1-yl)carbonyl]amino]phenyl)-1,3,4-thiadiazol-2-yl]amino]- 1H-indazole-1-carboxylate as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.4% | With triethylamine; In acetonitrile;Inert atmosphere; | General procedure: A mixture of 6e-i, 7a-d (0.4mmol), tert-butyl pyrrolidin-3-yl carbamate (112 mg, 0.6 mmol) and triethylamine (0.25 mL, 1.8 mmol) in dry acetonitrile (10 mL) was stirred for 2 h at room temperature under an atmosphere of nitrogen, and concentrated under reduced pressure. The residue was dissolved in water (30 mL) and extract with chloroform (30 mL×3). The combined extracts were dried over anhydrous Na2SO4 and concentrated to dryness under reduced pressure. The solid was washed with ethanol and ether successively to get the title compounds 7e-i, 8a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.1% | With triethylamine; In acetonitrile;Inert atmosphere; | General procedure: A mixture of 6e-i, 7a-d (0.4mmol), tert-butyl pyrrolidin-3-yl carbamate (112 mg, 0.6 mmol) and triethylamine (0.25 mL, 1.8 mmol) in dry acetonitrile (10 mL) was stirred for 2 h at room temperature under an atmosphere of nitrogen, and concentrated under reduced pressure. The residue was dissolved in water (30 mL) and extract with chloroform (30 mL×3). The combined extracts were dried over anhydrous Na2SO4 and concentrated to dryness under reduced pressure. The solid was washed with ethanol and ether successively to get the title compounds 7e-i, 8a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.1% | With triethylamine; In acetonitrile;Inert atmosphere; | General procedure: A mixture of 6e-i, 7a-d (0.4mmol), tert-butyl pyrrolidin-3-yl carbamate (112 mg, 0.6 mmol) and triethylamine (0.25 mL, 1.8 mmol) in dry acetonitrile (10 mL) was stirred for 2 h at room temperature under an atmosphere of nitrogen, and concentrated under reduced pressure. The residue was dissolved in water (30 mL) and extract with chloroform (30 mL×3). The combined extracts were dried over anhydrous Na2SO4 and concentrated to dryness under reduced pressure. The solid was washed with ethanol and ether successively to get the title compounds 7e-i, 8a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine; In acetonitrile;Inert atmosphere; | General procedure: A mixture of 6e-i, 7a-d (0.4mmol), tert-butyl pyrrolidin-3-yl carbamate (112 mg, 0.6 mmol) and triethylamine (0.25 mL, 1.8 mmol) in dry acetonitrile (10 mL) was stirred for 2 h at room temperature under an atmosphere of nitrogen, and concentrated under reduced pressure. The residue was dissolved in water (30 mL) and extract with chloroform (30 mL×3). The combined extracts were dried over anhydrous Na2SO4 and concentrated to dryness under reduced pressure. The solid was washed with ethanol and ether successively to get the title compounds 7e-i, 8a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.1% | With triethylamine; In acetonitrile;Inert atmosphere; | General procedure: A mixture of 6e-i, 7a-d (0.4mmol), tert-butyl pyrrolidin-3-yl carbamate (112 mg, 0.6 mmol) and triethylamine (0.25 mL, 1.8 mmol) in dry acetonitrile (10 mL) was stirred for 2 h at room temperature under an atmosphere of nitrogen, and concentrated under reduced pressure. The residue was dissolved in water (30 mL) and extract with chloroform (30 mL×3). The combined extracts were dried over anhydrous Na2SO4 and concentrated to dryness under reduced pressure. The solid was washed with ethanol and ether successively to get the title compounds 7e-i, 8a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.4% | With triethylamine; In acetonitrile;Inert atmosphere; | General procedure: A mixture of 6e-i, 7a-d (0.4mmol), tert-butyl pyrrolidin-3-yl carbamate (112 mg, 0.6 mmol) and triethylamine (0.25 mL, 1.8 mmol) in dry acetonitrile (10 mL) was stirred for 2 h at room temperature under an atmosphere of nitrogen, and concentrated under reduced pressure. The residue was dissolved in water (30 mL) and extract with chloroform (30 mL×3). The combined extracts were dried over anhydrous Na2SO4 and concentrated to dryness under reduced pressure. The solid was washed with ethanol and ether successively to get the title compounds 7e-i, 8a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.5% | With triethylamine; In acetonitrile;Inert atmosphere; | General procedure: A mixture of 6e-i, 7a-d (0.4mmol), tert-butyl pyrrolidin-3-yl carbamate (112 mg, 0.6 mmol) and triethylamine (0.25 mL, 1.8 mmol) in dry acetonitrile (10 mL) was stirred for 2 h at room temperature under an atmosphere of nitrogen, and concentrated under reduced pressure. The residue was dissolved in water (30 mL) and extract with chloroform (30 mL×3). The combined extracts were dried over anhydrous Na2SO4 and concentrated to dryness under reduced pressure. The solid was washed with ethanol and ether successively to get the title compounds 7e-i, 8a-d. Ethyl-7-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-1-(5-(4-chlorophenyl)oxazol-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate 7e. The title compound 7e was obtained from 6e as a yellow solid (86.5%), mp: 226 - 227 C. 1H NMR (400 MHz, DMSO-d6): delta 8.72 (1H, s), 8.18 (1H, d, J = 8 Hz), 7.99 (1H, s), 7.81 (2H, d, J = 8 Hz), 7.57 (1H, d, J = 8 Hz), 6.70 (1H, d, J = 8.0 Hz), 4.23 (2H, q, J = 7.2 Hz), 4.12 - 4.00 (1H, m), 3.63 - 3.16 (4H, m), 2.11 - 1.72 (2H, m), 1.31 (9H, s), 1.27 (3H, t, J = 7.2 Hz). MS-ESI (m/z): 580(M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.9% | With triethylamine; In acetonitrile;Inert atmosphere; | General procedure: A mixture of 6e-i, 7a-d (0.4mmol), tert-butyl pyrrolidin-3-yl carbamate (112 mg, 0.6 mmol) and triethylamine (0.25 mL, 1.8 mmol) in dry acetonitrile (10 mL) was stirred for 2 h at room temperature under an atmosphere of nitrogen, and concentrated under reduced pressure. The residue was dissolved in water (30 mL) and extract with chloroform (30 mL×3). The combined extracts were dried over anhydrous Na2SO4 and concentrated to dryness under reduced pressure. The solid was washed with ethanol and ether successively to get the title compounds 7e-i, 8a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 120℃; for 10h;Sealed tube; Inert atmosphere; | A sealed tube was charged with compound 18, (0.4 mmol), K2CO3 (4 mmol) and KI (1.6 mmol) under a N2 atmosphere in dry DMF. 1-Boc-3-aminopyrrolidine (1.6 mmol) was added and the reaction mixture heated to 120C for 10h. The reaction mixture was diluted with excess amount of water and extracted with 5% Methanol/CHCl3 system. The residue was purified by column chromatography using CHCl3/Methanol system to get 22 as yellow gummy (72%) semisolid. 1H NMR (CDCl3, 300MHz) delta 8.08 (d, J=6.0Hz, 2H), 7.57 (d, J=9.0Hz, 1H), 7.06 (s, 1H), 6.99 (d, J=9.0Hz, 2H), 6.90 (d, J=6.0Hz, 1H), 4.47 (s, 2H), 4.14 (d, J=3.0Hz, 4H), 3.55-3.38 (m, 12H), 2.53-2.14 (m, 9H), 1.42 (s, 18H); 13C NMR (CDCl3, 75MHz) delta 162.3, 161.3, 157.1, 155.4, 151.4, 135.9, 128.8, 119.8, 119.4, 114.7, 112.9, 96.1, 79.2, 66.9, 66.2, 61.1, 52.8, 52.6, 52.5, 49.7, 32.4, 28.4, 28.2. MS (ESI) m/z [M+Na]+ 702.26. HRMS (ESI) m/z calculated for C37H53N5O7 [M+Na]+ 702.3843; found 702.3845. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With triethylamine; In tetrahydrofuran; at 20℃; for 16h; | A solution of 2,4-dichioropyrimidine (1.0 g, 6.71 mmol) and tert-butyl pyrrolidin-3-ylcarbamate ( 1 .35 g, 6.74 mmol) in THF (25 mL) was charged with triethylamine (1 .4 mL, 10.0 mmol) at 0 C, The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was evaporated to dryness, and the residue was taken up in CH2C12; the organic layer was washed with water followed by brine; dried over sodium sulphate, filtered and concentrated. The crude material obtained was purified by combi -flash companion (silica gel, CH3OH/CH2CI2) to provide tert-butyl ( l-(2-chloropyrimidin-4- yl)pyrrolidin-3-yl)carbamate 417o (550 mg, 69%). 1H NMR (300 MHz, CDCI3): delta 8.01 (d, ./ 6.0 Hz, 1H), 6.20 (d, J = 6.0 Hz, 1H), 4.86 (br s, 1H), 3.85 (br s, 1H), 3.66-3.12 (m, 3H), 2.18 (br s, 2H), 1.58-1.35 (m, 10H); ESI+APCI MS m/z 313 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; | To a solution of 5-brorno-2-chloropyrimidine (600 mg, 3.1 nunol) and N,N-diisopropylethylamine (1.35 mL., 7.7 mmoi) in DMF (5 mL) was added tert-butyl pyrrolidin-3-ylcarbamate (634 mg, 3.4 mmol), the reaction mixture was stirred at room temperature fur 16 h under N2 atmosphere. The reaction mixture was diluted with water and extracted with EtOAc (2 x 20 rnL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was triturated with n-Hexane and dried to give tert-butyl (1-(5-bromopyrimidin-2-yl)pyrrolidin-3-yl)carbamate 308f (700 rng, 66%) as an off-white solid. E SI+APCI MS ith 344 [M -4- H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; for 3h; | EXAMPLE 4 Synthesis of 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid To a suspension of <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid</strong> (2 g) in anhydrous acetonitrile were added 3-t-butoxycarbonylaminopyrrolidine (1.86 g) and 1,8-diazabicyclo[5,4,0]undec-7-en (DBU, 1.02 g) and then the mixture was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform (50 ml). The resulting solution was washed with 10% aqueous citric acid solution (20 ml), and with saturated saline solution successively. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was dissolved in hot methanol (20 ml) and then cooled. The resulting crystals were collected by filtration to give 7-(3-t-butoxycarbonylamino-1-pyrrolidinyl)-1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (2.25 g) as yellowish white prisms, mp 224-226 C. (decompd.). Analysis (%) for C23 H28 FN3 O6.1/4 H2 O; Calcd. (Found): C, 59.28 (59.18); H, 6.22 (6.08); N, 9.02 (8.82). To a suspension of these crystals (2.23 g) in methanol (16 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 80℃; for 4h; | To a suspension of 7-chloro-2-methylsulfanyl-6-(l -naphthyl)pyrido[2,3-d]pyrimidine (60 mg, 0.18 mmol) (22-3) in 1,4-dioxane (1 mL) was added N,iV"-diisopropylethylamine (0.09 mL, 0.53 mmol) and 3-N-boc-amino pyrrolidine (0.03 mL, 0.21 mmol) (22-4). The resulting mixture was stirred at 80 C for 4 h during which time additional portions of N,N"- diisopropylethylamine and 3-N-boc-amino pyrrolidine (22-4) were added. The solvent was removed under reduced pressure and the resulting residue was dissolved in DCM and the organic layer was washed with 1M citric acid, water, saturated aqueous sodium bicarbonate and brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure to give 81 mg (94%) of tm-bu1yl iV-[l-[2-methylsulfanyl-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin-3- yl]carbamate (22-5). LCMS (ESI): [M+H]?= 488.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 20℃; for 2h; | The compound 3-Boc-aminopyrrolidine (651 mg, 3.5 mmol) was taken in EtOAc (20 mL).Add DIEA (0.92 mL, 5.25 mmol),Add ethyl bromide (0.3 mL, 3.85 mmol),The reaction was stirred at room temperature. Stop the reaction after 2h,Concentration, column chromatography (MeOH: DCM = 1: 40, MeOH: DCM = 1: 30)Obtained a yellowish solid 600mg,The yield was 80%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 40℃; for 3h; | The compound 3-Boc-aminotetrahydropyrrole (651 mg, 3.5 mmol) was added to acetonitrile (20 mL).Add DIEA (0.92 mL, 5.25 mmol) and add bromo-n-propane (0.38 mL, 4.2 mmol).Heat to 40 C reaction, stop reaction after 3h,Concentration, column chromatography (MeOH: DCM = 1: 40, MeOH: DCM = 1: 30)Obtained a yellowish solid650mg,The yield was 81%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.7% | With N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 40℃; for 4h; | The compound 3-Boc-aminopyrrolidine (558 mg, 3 mmol) was taken in EtOAc (20 mL).Add DIEA (0.78 mL, 4.5 mmol) and add bromo n-butane (0.38 mL, 3.6 mmol).The reaction was heated to 40 C, and the reaction was quenched after 4 h, concentrated, ethyl acetate (50 mL)Wash with saturated NaCl solution (20 mL×2) and dry over anhydrous magnesium sulfate.Column chromatography (MeOH: DCM = 1:40, MeOH: DCM = 1: 30)Obtained a yellowish solid390mg,The yield was 53.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.4% | With N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 40℃; for 3h; | The compound 3-Boc-aminopyrrolidine (651 mg, 3.5 mmol) was taken in EtOAc (20 mL).Add DIEA (0.92 mL, 5.25 mmol),Add bromoisobutane (0.46 mL, 4.2 mmol),Heat to 40 C reaction, stop reaction after 3h,Concentration, column chromatography (MeOH: DCM = 1: 40, MeOH: DCM = 1: 30)Obtained a yellowish solid300mg,The yield was 35.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 40℃; for 4h; | The compound 3-Boc-aminopyrrolidine (372 mg, 2 mmol),Add acetonitrile (15 mL),Add DIEA (0.52 mL, 3 mmol),Add 3-methyl-bromobutane (0.29 mL, 2.4 mmol),Heat to 40 C reaction, stop reaction after 4h,Concentrated, added ethyl acetate (50 mL).Wash with saturated NaCl solution (20 mL × 2).Dry over anhydrous magnesium sulfate, column chromatography (MeOH: DCM = 1:40, MeOH: DCM = 1:30)Obtained 420 mg of a yellowish solid.The yield was 82%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 40℃; for 4h; | The compound 3-Boc-aminopyrrolidine (372 mg, 2 mmol),Add acetonitrile (15 mL),Add DIEA (0.52 mL, 3 mmol),Add 3-bromopentane (0.3 mL, 2.4 mmol),The reaction was heated to reflux. concentrate,Ethyl acetate (50 mL) was added and washed with a saturated NaCI solution (20 mL×2).Dry over anhydrous magnesium sulfate, column chromatography (MeOH: DCM = 1:40, MeOH: DCM = 1:30)Obtained a yellowish solid330mg,The yield was 64%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.48 g | With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; | To a stirred solution of <strong>[10386-27-3]2-bromo-4-cyanopyridine</strong> (CAS Number 10386-27-3; 0.500 g, 2.73 mmol) and tert-butyl pyrrolidin-3-ylcarbamate (CAS Number 99724-19- 3; 0.509 g, 2.73 mmol) in DMF (10 ml) was added Na2CO3 (0.578 g, 5.46 mmol). The reaction mixture was stirred at rt for 16 h. The resulting mixture was diluted with water (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with brine solution (50 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (18percent EtOAc in hexane) yielding tert-butyl (1 -(4-cyanopyridin-2- yl)pyrrolidin-3-yl)carbamate (0.480 g, 1 .67 mmol). LCMS: Method C, 1 .871 min, MS: ES+ 289.48. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 90℃; for 12h; | Preparation of tert-butyl (l-(5-(3-cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate. To a mixture of 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile (Intermediate P42; 850 mg, 2.60 mmol) and 3-(tert- butoxycarbonylamino)pyrrolidine (679 mg, 3.65 mmol) in DMSO (5.2 mL) was added DIEA (1.36 mL, 7.81 mmol). The reaction mixture was stirred 12 h at 90C. After cooling to ambient temperature, the reaction mixture was diluted into cold water and stirred for 2 h at ambient temperature. The suspension was filtered and the solids were rinsed with water. The isolated solids were dried under vacuum for 48 h to afford the title compound (1.26 g, 98% yield) in sufficient purity for step 2. MS (apci) m/z = 493.3 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; In ethanol; at 45℃; for 0.833333h;Microwave irradiation; | General procedure: Following the general procedure below, the data are reported as a) mass of starting material; b) mass of pyrrolidine; c) mass of K2CO3; d) volume of ethanol; e) mass of product obtained.Following an adapted procedure of Bensen et al., ADDIN EN.CITE Bensen2012US/2012/023875163US 20120238751Bensen, D.Chen, Z.Finn, J.Lam, T.T.Lee, S.J.Li, X.Phillipson, D.W.Tari, L.W.Trzoss, M.Zhang, J.146234847025201270149441867663 to a microwave vial was added tert-butyl N-[2,4-bis(benzylsulfonyl)-6-fluoro-9H-pyrimido[4,5-b]indol-8-yl]-N-methyl-carbamate 3 (1.12 - 4.80 mmol, 1 eq), corresponding pyrrolidine (either a) tert-butyl pyrrolidin-3-ylcarbamate, b) tert-butyl methyl(pyrrolidin-3-yl)carbamate, c) N,N-dimethylpyrrolidin-3-amine or d) tert-butyl (pyrrolidin-3-ylmethyl)carbamate) (1.46 - 5.28 mmol, 1.3 eq) and potassium carbonate (1.74 - 5.76 mmol, 1.5 eq) in EtOH. The mixture was heated in a Biotage Initiator microwave reactor at 45 C for 50 min. The mixture was concentrated in vacuo and the resulting solid was dissolved in EtOAc, then washed with water then brine. The organic phase was concentrated in vacuo and purified by silica gel column chromatography (gradient = 0-100% EtOAc in petroleum ether (bp. 40-60)). The appropriate fractions were combined and concentrated in vacuo to give pyrrolidine-substituted intermediates 4a-d in good yield. tert-butyl N-[2-benzylsulfonyl-4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-6-fluoro-9H-pyrimido[4,5-b]indol-8-yl]-N-methyl-carbamate (4a)Following the general procedure above: a) 3 g; b) 3-Boc-aminopyrrolidine, 984 mg; c) 996 mg; d) 30 mL; e) 1.87 g.Yellow solid; yield 75%; LCMS: RT = 3.14 min, [M+H]+ 655.5; 1H NMR (400 MHz, CDCl3) deltaH 9.21 (s, 1H), 7.62 (dd, 3JH-F = 9.8 Hz, 4JH-H = 2.3 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.33 - 7.25 (m, 3H), 7.05 (dd, 3JH-F = 9.8 Hz, 4JH-H = 2.3 Hz, 1H), 4.79 - 4.72 (m, 3H), 4.47 - 4.32 (m, 1H), 4.23 - 4.21 (m, 1H), 4.08 - 3.95 (m, 2H), 3.84 (m, 1H), 3.34 (s, 3H), 2.37 - 2.24 (m, 1H), 2.12 - 2.05 (m, 1H), 1.49 (s, 18H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.7% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | 3-Boc-aminopyrrolidine (300 mg, 1.62 mmol) was dissolved in DMF (10 mL)Potassium carbonate (450 mg, 3.24 mmol) was added in sequenceAnd trifluoroethyl trifluoromethanesulfonate (570 mg, 2.40 mmol), stirred at room temperature overnight.The reaction solution was poured into water (100 mL), and the pH was adjusted to 6-7 with saturated ammonium chloride.It was then extracted with DCM (100 mL×3) and the organic layer was concentrated.Silica gel column chromatography,Got 300mg white solid,The yield was 62.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.6% | With pyridine; In dichloromethane; at 20℃; | 3-Boc-aminopyrrolidine (150 mg, 0.81 mmol) was dissolved in DCM (2 mL)Pyridine (78 mg, 0.99 mmol) and trifluoroacetic anhydride (192 mg, .0.90 mmol) were added dropwise, respectively.Stir at room temperature overnight, and distill off the solvent under reduced pressure.The resulting oil was dissolved in ethyl acetate (100 mL).Washed (100mL × 3), dried Na2SO4,Concentrated177mgLight yellow oil,The yield was 77.6% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.7% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 40℃; for 24h; | 3-(Boc-Amino)pyrrolidine (560 mg, 3.0 mmol) was dissolved in 10 mL of acetonitrile.DIEA (1 mL, 6.0 mmol) and bromomethylcyclopropane (470 mg, 3.4 mmol) were added.The reaction was stopped at 40 C for 1 d, the reaction was stopped, and the reaction solution was concentrated.Column chromatography (DCM: MeOH = 60:1 - 50:1)510mg,The yield was 70.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tetra-(n-butyl)ammonium iodide; acetic acid; In acetonitrile; at 20℃;Electrochemical reaction; Green chemistry; | General procedure: A 30 mL screw capped vial with a septum was inserted carbon anode and aluminum cathode (CAUTION: Electrodes should not come in contact with each other). The electrodes were connected to a cell phone charger (5V) by use of alligator clips. To the reaction vial were added benzoxazole 1 (119 mg, 1 mmol), N-Boc piperazine 2a (372 mg, 2 mmol), acetic acid (300 mg, 5 mmol, 5 equiv.) and TBAI (37 mg, 10 mol%) and the mixture was dissolved in 20mL of acetonitrile and stirred gently at room temperature. Electric current was passed through the reaction vial at room temperature for 3 h. The progress of the reaction was monitored by TLC and LC-MS. After the completion of the reaction, the solvent was removed in vacuo and the crude material was re-dissolved in ethyl acetate (25 mL) and then washed with saturated aqueous sodium carbonate solution (3×10mL). The organic layer was separated, washed with water and then dried over sodium sulfate. The product was purified by column chromatography using hexane and ethyl acetate as eluent to afford 282 mg of compound 3a (93 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With acetic acid; sodium nitrite; In water; at 0 - 20℃; for 18h;Inert atmosphere; | Dissolve tert-butylpyrrolidin-3-ylcarbamate (4.33g, 23.3mmol) in 30mL acetic acid and 10mL water,An aqueous solution (20 mL) containing sodium nitrite (3.21 g, 46.6 mmol) was slowly added dropwise at 0 C, and then the mixture was heated to room temperature under nitrogen protection and stirred for 18 hours.After the reaction was completed, it was quenched by adding water at 0 C, and extracted three times with ethyl acetate (240 mL), and filtered.Spin-dry and purify to obtain the product (1-nitrosopyrrolidin-3-yl) tert-butyl carbamate (4.58 g, yield 93%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 1h; |
Tags: 99724-19-3 synthesis path| 99724-19-3 SDS| 99724-19-3 COA| 99724-19-3 purity| 99724-19-3 application| 99724-19-3 NMR| 99724-19-3 COA| 99724-19-3 structure
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P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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