Structure of Boc-cis-5-Me-Pro-OH
CAS No.: 334769-80-1
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CAS No. : | 334769-80-1 |
Formula : | C11H19NO4 |
M.W : | 229.27 |
SMILES Code : | C[C@H]1CC[C@H](N1C(=O)OC(C)(C)C)C(O)=O |
MDL No. : | MFCD13185989 |
InChI Key : | BSAYEGDCKUEPNE-YUMQZZPRSA-N |
Pubchem ID : | 15516206 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 16 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.82 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 63.17 |
TPSA ? Topological Polar Surface Area: Calculated from |
66.84 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.21 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.66 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.48 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.03 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.32 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.34 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.04 |
Solubility | 2.08 mg/ml ; 0.00905 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.68 |
Solubility | 0.482 mg/ml ; 0.0021 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.53 |
Solubility | 67.2 mg/ml ; 0.293 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.52 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
3.03 |
* 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 |
---|---|---|
100% | With lithium hydroxide monohydrate; In ethanol; water; for 16h; | (2S,5S)-1-(Tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid To a solution of (2S,5S)-1-tert-butyl 2-ethyl 5-methylpyrrolidine-1,2-dicarboxylate (6.46 g, 25.1 mmol) in ethanol (20 mL) was added lithium hydroxide mono hydrate (2.11 g, 50.2 mmol) and deionized water (12 mL). The mixture was allowed to stir for 16 hours then partitioned between ethylacetate and a 1:1 mixture of saturated brine and 1N HCl. The aqueous layer was extracted an additional time with ethyl acetate. The organic layers were combined, dried with sodium sulfate and the solvent was removed in vacuo to yield (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid as a white solid (quant.) and was used directly in the following step. |
100% | With lithium hydroxide monohydrate; water; In ethanol; for 16h; | (2S,5S)-1-(Tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (Compound 1-6) To a solution of (2S,5S)-1-tert-butyl 2-ethyl 5-methylpyrrolidine-1,2-dicarboxylate (6.46 g, 25.1 mmol) in ethanol (20 mL) was added lithium hydroxide monohydrate (2.11 g, 50.2 mmol) and deionized water (12 mL). The mixture was allowed to stir for 16 hours then partitioned between ethylacetate and a 1:1 mixture of saturated brine and 1 N HCl. The aqueous layer was extracted an additional time with ethyl acetate. The organic layers were combined, dried with sodium sulfate and the solvent was removed in vacuo to yield (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid as a white solid (quant.) and was used directly in the following step. |
98.5% | With lithium hydroxide monohydrate; water; In ethanol; at 25℃; for 12h; | [001651 To a solution of compound 1-5 (9.11 g, 35.45 mmol) in EtOH (80 mL) was added a solution of Lithium hydroxide hydrate (2.5 g, 59.67 mmol) in 20 mL of H20 at 25 °C. The mixture was stirred at 25 °C for 12 hours. After the reaction was completed, the mixture was extracted with EtOAc (150 mL), then the EtOAc phase was discarded. The aqueous phase was adjusted to pH 2 with 6percent hydrochloric acid, then the resulting mixture was extracted with EtOAc (80 mLx3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated /n vacuo to give the title compound as a white solid (8.0 g, 98.5percent).The compound was characterized by the following spectroscopic data:MS (ESI, pos.ion) m/z: 230.3 [M+Hfb; and?H NMR (400 MHz, CD3OD): 4.24 (m, 1H), 3.56 (m, 1H), 1.75-1.97 (m, 2H), 1.45-1.69 (m, 2H), 1.40 (s, 9H), 1.32-1.34 (m, 3H) ppm. |
98.5% | With lithium hydroxide; In ethanol; water; at 25℃; for 12h; | Step 5) the Preparation of Compound 1-6 (0231) To a solution of compound 1-5 (9.11 g, 35.45 mmol) in EtOH (80 mL) was added a solution of Lithium hydroxide hydrate (2.5 g, 59.67 mmol) in 20 mL of H2O at 25° C. The mixture was stirred at 25° C. for 12 hours. After the reaction was completed, the mixture was extracted with EtOAc (150 mL), then the EtOAc phase was discarded. The aqueous phase was adjusted to pH 2 with 6percent hydrochloric acid, then the resulting mixture was extracted with EtOAc (80 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a white solid (8.0 g, 98.5percent). The compound was characterized by the following spectroscopic data: (0232) MS (ESI, pos. ion) m/z: 230.3 [M+H]+; and (0233) 1H NMR (400 MHz, CD3OD): delta 4.24 (m, 1H), 3.56 (m, 1H), 1.75-1.97 (m, 2H), 1.45-1.69 (m, 2H), 1.40 (s, 9H), 1.32-1.34 (m, 3H) ppm. |
Example 84A (3.69 g, 14.34 mmol) in 15 mL [OF ETOH] was treated with 14.3 mL of 1.7 N [LIOH] solution at room temperature. After 4 h, the mixture was concentrated, acidified with 1N [HC1] and then extracted with EtOAc (3X). The combined organic extracts were dried with [NA2S04,] and then concentrated to give the crude acid. MS (ESI) [M/Z] 228 (M-H)-. | ||
(d) (2S,5S)-5-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester A mixture of the product of the previous step (2 g, 7.77 mmol) and lithium hydroxide (466 mg, 23.3 mmol) in 3:1 methanol:water (24 mL) was stirred at RT overnight, and concentrated. The residue was dissolved in water and extracted with EtOAc (2*20 mL). The aqueous layer was adjusted to pH 2 with 1N HCl and extracted with 3:1 DCM:methanol (3*24 mL) to give the title intermediate (1.7 g) as a white crystal. | ||
With lithium hydroxide monohydrate; water; In ethanol; for 16h; | (2S,5S)-l-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid To a solution of (2S,5S)-l -tert-butyl 2-ethyl 5-methylpyrrolidine-l,2-dicarboxylate (6.46 g, 25.1 mmol) in ethanol (20 mL) was added lithium hydroxide mono hydrate (2.11 g, 50.2 mmol) and deionized water (12mL). The mixture was allowed to stir for 16 hours then partitioned between ethylacetate and a 1 : 1 mixture of saturated brine and IN HC1. The aqueous layer was extracted an additional time with ethyl acetate. The organic layers were combined, dried with sodium sulfate and the solvent was removed in vacuo to yield (2S,5S)-l -(tert-butoxycarbonyl)-5-methylpyrrolidine-2- carboxylic acid as a white solid (quant.) and was used directly in the following step. | |
To a solution of (2S,5S)-1-tert-butyl 2-ethyl 5-methylpyrrolidine-1,2-dicarboxylate (6.46 g, 25.1 mmol) in ethanol (20 mL) was added lithium hydroxide mono hydrate (2.11 g, 50.2 mmol) and deionized water (12 mL). The mixture was allowed to stir for 16 hours then partitioned between ethylacetate and a 1:1 mixture of saturated brine and 1N HCl. The aqueous layer was extracted an additional time with ethyl acetate. The organic layers were combined, dried with sodium sulfate and the solvent was removed in vacuo to yield (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid as a white solid (quant.) and was used directly in the following step. | ||
9.1 g | With lithium hydroxide monohydrate; water; In ethanol; for 16h; | In the 12g ii-5 prepared in the previous step, add 30ml of ethanol and stir to dissolve.2 g of lithium hydroxide monohydrate and 12 ml of deionized water are added. The mixture was stirred for 16 hours,Add 100ml of saturated sodium chloride solution and acidify with 1N hydrochloric acid;Then add 100ml of ethyl acetate to extract;It is extracted once more with 50 ml of ethyl acetate. The ethyl acetate extracts were combined and dried over anhydrous sodium sulfate overnight. The solid was filtered off and the filtrate was evaporated to dryness under reduced pressure.(9.1 g) of a white solid of (2S,5S)-N-(tert-butoxycarbonyl)-5-methyl-pyrrolidine-2-carboxylic acid (II) was obtained. |
9.1 g | With lithium hydroxide monohydrate; In ethanol; water; for 16h; | Step 5: In 12 g of ii-5 prepared in the previous step, add 30 ml of ethanol, stir to dissolve, add 2 g of lithium hydroxide monohydrate and12ml of deionized water. The mixture was stirred for 16 hours,Add 100ml of saturated sodium chloride solution and acidify with 1N hydrochloric acid; Then add 100ml of ethyl acetate to extract;It is extracted once more with 50 ml of ethyl acetate.The ethyl acetate extracts were combined and dried over anhydrous sodium sulfate overnight.The solid was filtered off and the filtrate was evaporated to dryness under reduced pressure.9.1 g of white solid II was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; ammonia; triethylamine; In tetrahydrofuran; 1,4-dioxane; ethyl acetate; | Example 84C (2S,5S)-2-Carbamoyl-5-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester Example 84B (2.055 g, 8.96 mmol) and Et3N (2.24 mL, 1.8 equiv.) were mixed in 15 mL of THF and then cooled to 0° C. Isobutyl chloroformate (1.51 mL, 1.3 equiv.) was added. After stirring for 35 min, 0.5 M NH3 in dioxane (35.8 mL, 2 equiv.) was added. After stirring at 0° C. for 3 h, the mixture was warmed to room temperature and stirred overnight. The volatiles were evaporated, and 1N HCl was added. The mixture was extracted with EtOAc (3*). The combined organic extracts were dried with Na2SO4 and then concentrated. The crude product was purified by chromatography (silica gel, 50percent then 75-80percent EtOAc/hexane) to give the desired amide. MS (ESI) m/z 229 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 84B (2. [055G,] 8.96 mmol) and Et3N (2.24 mL, 1.8 equiv. ) were mixed in 15 mL of THF and then cooled to [0 °C.] Isobutyl [CHLOROFORMATE] (1.51 mL, 1.3 equiv. ) was added. After stirring for 35 min, 0.5 M NH3 in dioxane [(35.] 8 mL, 2 equiv. ) was added. After stirring at [0 °C] for 3 h, the mixture was warmed to room temperature and stirred overnight. The volatiles were evaporated, and 1N [HC1] was added. The mixture was extracted with EtOAc (3X). The combined organic extracts were dried with [NA2S04] and then concentrated. The crude product was purified by chromatography (silica gel, 50percent then 75-80percent EtOAc/hexane) to give the desired amide. MS (ESI) m/z 229 (M+H) [+.] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In DMF (N,N-dimethyl-formamide);pH 6 - 7; | Example 3F 2S (2S-CARBAMOYL-4, 4-DIFLUORO-PYRROLIDINE-1-CARBONYL)-5S-METHYL-PYRROLIDINE-1- carboxylic acid ter-butyl ester The compound from Example 3E (303 mg, 0.93 mmol), 5S-methyl- pyrrolidine-1, 2S-dicarboxylic acid 1-TERT-BUTYL ester (leq, prepared as described in Example 5) AND 2-(LH-BENZOKIAZOLE-1-YL)-L, 1, 3, 3-tetramethyluronium tetrafluoroborate (TBTU, 1.4 eq. ) were mixed in 2 mL of DMF, then Et3N was added until the pH of the mixture reached 6-7 (wet pH paper). The mixture was stirred overnight and purified by reverse-phase HPLC to provide the titled compound. (170 mg, 56percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 84B (2S,5S)-5-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester Example 84A (3.69 g, 14.34 mmol) in 15 mL of EtOH was treated with 14.3 mL of 1.7 N LiOH solution at room temperature. After 4 h, the mixture was concentrated, acidified with 1N HCl and then extracted with EtOAc (3*). The combined organic extracts were dried with Na2SO4, and then concentrated to give the crude acid. MS (ESI) m/z 228 (M-H)-. | ||
Example 84B (2S,5S)-5-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester Example 84A (3.69 g, 14.34 mmol) in 15 mL of EtOH was treated with 14.3 mL of 1.7 N LiOH solution at room temperature. After 4 h, the mixture was concentrated, acidified with 1N HCl and then extracted with EtOAc (3*). The combined organic extracts were dried with Na2SO4, and then concentrated to give the crude acid. MS (ESI) m/z 228 (M+H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With triethylamine; In dichloromethane; at 0 - 25℃; for 3.5h; | [001691 To a cooled 0°C solution of compound 1-6 (5.0 g, 21.8 mmol) and compound 1-6-2 (7.28 g, 26.17 mmol) in DCM (140 mL) was added TEA (4.54 mL, 32.7 mmol) dropwise. The mixture was stirred at 25 °C for 3.5 hours. After the reaction was completed, the mixture was quenched with H20 (80 mL) and extracted with DCM (100 mLx3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a white solid (4.73 g, 52percent). The compound was characterized by the following spectroscopic data:MS (ESI, pos.ion) m/z: 426.3 [M+Hfb; and?H NMR (400 MHz, CDC13): 7.78-7.75 (m, 2H), 7.65-7.63 (m, 2H), 5.53-5.15 (m, 2H), 4.49-4.39 (m, 1H), 3.59-3.54 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85 (m, 1H), 1.45 (s, 9H), 1.12-1.13 (d,J= 6.4 Hz, 3H) ppm. |
52% | With triethylamine; In dichloromethane; at 0 - 25℃; for 3.5h; | Step 9) the Preparation of Compound 1-12 (0243) To a cooled 0° C. solution of compound 1-6 (5.0 g, 21.8 mmol) and compound 1-6-2 (7.28 g, 26.17 mmol) in DCM (140 mL) was added TEA (4.54 mL, 32.7 mmol) dropwise. The mixture was stirred at 25° C. for 3.5 hours. After the reaction was completed, the mixture was quenched with H2O (80 mL) and extracted with DCM (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=5/1) to give the title compound as a white solid (4.73 g, 52percent). The compound was characterized by the following spectroscopic data: (0244) MS (ESI, pos. ion) m/z: 426.3 [M+H]+; and (0245) 1H NMR (400 MHz, CDCl3): delta 7.78-7.75 (m, 2H), 7.65-7.63 (m, 2H), 5.53-5.15 (m, 2H), 4.49-4.39 (m, 1H), 3.59-3.54 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85 (m, 1H), 1.45 (s, 9H), 1.12-1.13 (d, J=6.4 Hz, 3H) ppm. |
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 5h; | Example M10, Step cTo a solution of acid MlOb (2.16 g, 9.42 mmol) and 2-bromo-l-(4- bromophenyl)ethanone (2.62 g, 9.42 mmol) in acetonitrile (50 mL) was added slowly diisopropylethylamine (1.645 mL, 9.42 mmol), and the reaction mixture was stirred at room temperature for 5 hr. Solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and water (1 : 1, 100 mL). The organic layer was washed with sat. aHC03, dried ( a2S04) and concentrated in vacuo to afford ketoester MlOc as white solid (3.9g), which was used in the next step without further purification. XH NMR (400 MHz , DMSO-d6, delta = 2.5 ppm): 7.92 (d, J = 8.3, 2H), 7.78 (d, J = 8.5, 2H), 5.6-5.4 (m, 2H), 4.35 (m, 1H), 3.85 (m, 1H), 2.25 (m, 1H), 2.05 (m, 2H), 1.60 (m, 1H), 1.5/1.4 (two overlapping br s, 9H), 1.18 (d, J = 6.6, 3H). LC/MS: Anal. Calcd. for [M+Na Ci9H2481BrNaN05: 450.07; found: 450.00. |
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 16h; | To a solution of 2-bromo- 1 -(4-bromophenyl)ethanone (2.425 g, 8.72 mmol) and (2S,5S)-l-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (2 g, 8.72 mmol) in acetonitrile (50 mL) was added DIEA (1.524 mL, 8.72 mmol), and the mixture was stirred at room temperature for 16 hrs. Solvent was removed in vacuo and the residue was partitioned between EtOAc (40 mL) and water (30 mL). The organic phase was washed with sat. NaHCCh and brine, and dried with a2S04. Removal of the volatile component in vacuo afforded Example 4, step d (1.74 g) as light yellow solid, which was used without further purification. 1H NMR (DMSO-d6, delta = 2.5 ppm, 400 MHz): 7.95-7.90 (m, 2H), 7.81 (m, 1H), 7.79 (m, 1H), 5.63-5.44 (m, 2H), 4.36 (m, 1H), 3.99 (m, 1H), 2.27 (m, 1H), 2.09 (m, 2H), 1.63 (m, 1H), 1.41- 1.37 (two singlet, 9H), 1.19 (m, 3H). LC/MS: Anal. Calcd. for [M+Na]+ Ci9H24BrNNa05: 448.07; found: 448.06. | |
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 16h; | Exam le QC-18.1, step dTo a solution of 2-bromo- 1 -(4-bromophenyl)ethanone (2.425 g, 8.72 mmol) and (2S,5S)-l-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (2 g, 8.72 mmol) in acetonitrile (50 mL) was added DIEA (1.524 mL, 8.72 mmol), and the mixture was stirred at room temperature for 16 hrs. Solvent was removed in vacuo and the residue was partitioned between EtOAc (40 mL) and water (30 mL). The organic phase was washed with sat. aHC03 and brine, and dried with Na2S04. Removal of the volatile component in vacuo afforded Example 18.1, step d (1.74 g) as light yellow solid, which was used without further purification. lH NMR (DMSO- d6, delta = 2.5 ppm, 400 MHz): 7.95-7.90 (m, 2H), 7.81 (m, 1H), 7.79 (m, 1H), 5.63-5.44 (m, 2H), 4.36 (m, 1H), 3.99 (m, 1H), 2.27 (m, 1H), 2.09 (m, 2H), 1.63 (m, 1H), 1.41- 1.37 (two singlet, 9H), 1.19 (m, 3H). LC/MS: Anal. Calcd. for [M+NafCi9H24Br a05: 448.07; found: 448.06. | |
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2h;Inert atmosphere; | (a) (2S,5S)-5-Methyl-pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester A mixture of the product of Preparation 41 (1.7 g, 7.41 mmol), 2-bromo-1-(4-bromo-phenyl)-ethanone (2.08 g, 7.49 mmol) and DIPEA (2.87 g, 22.23 mmol) in ACN (50 mL) was stirred under nitrogen at RT for 2 h. The reaction mixture was concentrated under reduced pressure to give the title intermediate (3.16 g). | |
In acetonitrile; at 20℃; for 5h;Inert atmosphere; | General procedure: 2, 4'-Dibromoacetophenone (24 g, 87 mmol) was added under N2 at room temperature to a solution of compound BB2-d (154 g, 87 mmol) in MeCN (100 ml) followed by slow addition of DIEA (34 g, 261 mmol). The mixture was stirred at rt for 5 h then concentrated in vacuo and the resulting residue was diluted with EtOAc, washed with 1 N HCI (2x50 ml), saturated NaHC03 (2x50 ml) and brine (2x50 ml), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography (p.ether/EtOAc 10: 1) which gave the title compound (27 g, 84percent). MS (ESI): 369 [M+H]+. | |
1.74 g | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 16h; | To a solution of 2-bromo- 1 -(4-bromophenyl)ethanone (2.425 g, 8.72 mmol) and (2S,5S)-l-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (2 g, 8.72 mmol) in acetonitrile (50 mL) was added DIEA (1.524 mL, 8.72 mmol), and the mixture was stirred at room temperature for 16 h. Solvent was removed in vacuo and the residue was partitioned between EtOAc (40 mL) and water (30 mL). The organic phase was washed with sat. aHC03 and brine, and dried with Na2S04. Removal of the volatile component in vacuo afforded Example 18.1, step d (1.74 g) as light yellow solid, which was used without further purification. 1H NMR (DMSO-d6, delta = 2.5 ppm, 400 MHz): 7.95-7.90 (m, 2H), 7.81 (m, 1H), 7.79 (m, 1H), 5.63-5.44 (m, 2H), 4.36 (m, 1H), 3.99 (m, 1H), 2.27 (m, 1H), 2.09 (m, 2H), 1.63 (m, 1H), 1.41-1.37 (two singlet, 9H), 1.19 (m, 3H). LC/MS: Anal. Calcd. for [M+Naf Ci9H24BrNNa05: 448.07; found: 448.06. |
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; | To a solution of acid MlOb (2.16 g, 9.42 mmol) and 2-bromo-l-(4- bromophenyl)ethanone (2.62 g, 9.42 mmol) in acetonitrile (50 mL) was added slowly diisopropylethylamine (1.645 mL, 9.42 mmol), and the reaction mixture was stirred at room temperature for 5 hr. Solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and water (1 :1, 100 mL). The organic layer was washed with sat. NaHCO3, dried (Na2SO4) and concentrated in vacuo to afford ketoester MlOc as white solid (3.9g), which was used in the next step without further purification. 1H NMR (400 MHz , DMSO-d6} delta - 2.5 ppm): 7.92 (d, J = 8.3, 2H), 7.78 (d, J = 8.5, 2H), 5.6-5.4 (m, 2H), 4.35 (m, IH), 3.85 (m, IH), 2.25 (m, IH), 2.05 (m, 2H), 1.60 (m, IH), 1.5/1.4 (two overlapping br s>; 9H), 1.18 (d, J - 6.6, 3H). LC/MS: Anal. Calcd. for [M+Naf Cj9H2481BrNaNO5: 450.07; found: 450.00. |
Yield | Reaction Conditions | Operation in experiment |
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79% | 1 M aq LiOH (12.3 ml, 12.3 mmol) was added to a solution of BB21-d (3 g, 12.3 mmol) in THF (10 ml) and the resulting mixture was stirred overnight. The mixture was adjusted to pH 4 with 1 N HCI and extracted with EtOAc. The organic phase was concentrated in vacuo which gave the title compound (2.2 g, 79percent). LC-MS (ESI): 230 [M+H]+. | |
Exam le M10, Step bA solution of lithium hydroxide (0.23g, 9.62 mmol) in water (5 mL) was added dropwise to a solution of ester MlOa (1.8g, 7.4 mmol) in ethanol (10 mL), and stirred at room temperature for 17 hr. Most of the solvent was evaporated, and the residue was diluted with water, 1 N HCl was added dropwise to bring it to pH 3. It was extracted with ethyl acetate (20 mL, 4x), dried (Na2S04) and evaporated in vacuo to afford a colorless oil, which yielded crystals when dissolved inEtOAc/hexanes solvent system and allowed to stand at room temperature. The white solid was filtrated and dried in vacuo (1.42g). XH NMR (CDC13, 400 MHz, d = 7.24 ppm): 4.35 (m, 1H), 3.95 (m, 1H), 2.35 (m, 1H), 2.05 (m, 2H), 1.70 (m, 1H), 1.50 (br s, 9H), 1.25 (d, J = 7.1, 3H). | ||
Example MlO, Step b; A solution of lithium hydroxide (0.23g, 9.62 mmol) in water (5 mL) was added dropwise to a solution of ester MlOa (1.8g, 7.4 mmol) in ethanol (10 mL), and stirred at room temperature for 17 hr. Most of the solvent was evaporated, and the residue was diluted with water, 1 N HCl was added dropwise to bring it to pH 3. It was extracted with ethyl acetate (20 mL, 4x), dried (Na2SO4) and evaporated in vacuo to afford a colorless oil, which yielded crystals when dissolved in EtOAc/hexanes solvent system and allowed to stand at room temperature. The white solid was filtrated and dried in vacuo (1.42g). 1H NMR (CDCl3, 400 MHz, d - 7.24 ppm): 4.35 (m, IH), 3.95 (m, IH), 235 (m, IH), 2.05 (m, 2H), 1.70 (m, IH), 1.50 (br s, 9H), 1.25 (d, J = 7.1, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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76.7% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 3h; | To a mixture of 2-bromo-1 -[4-(4-bromophenyl)phenyl]ethanone (735.3 mg, 2mmol), (2S,5S)-1 -tert-butoxycarbonyl-5-methyl-pyrrolidine-2-carboxylic acid (500 mg, 2.18 mmol) in acetonitrile (10 ml) (suspension) is added DIPEA (380 muIota_, 2.18 mmol). The reaction mixture is stirred at rt for 3 hours, diluted with EtOAc and H20. The organic phase is washed with brine, dried over Na2S04, filtered and concentrated. The residue is purified by flash column chromatography on silica gel (0 to 30percent EtOAc in Hexanes) to afford 2-[2-[4-(4- bromophenyl)phenyl]-2-oxo-ethyl]-1 -tert-butyl-(2S,5S)-5-methylpyrrolidine-1 ,2- dicarboxylate (0.8 g, 76.7percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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EEDQ (1.67 g, 6.75 mmol) was added to a solution of Example J.9g2 (1.6 g,6.75 mmol) and M.4a (1.55 g, 6.75 mmol) in DCM (100 mL) and stirred for 6h.(Note: The dianiline was not completely soluble). The reaction mixture was diluted with DCM (1 vol) and washed with half sat'd NaHC03 soln. Concentration gave a solid (2.5 g). LC/MS (Cond. J2): RT = 3.07 min. LC/MS Anal. Calcd. for[M+H]+ C2iH27BrN303: 448.13; found 448.11. The crude solid (2.5 g, 5.58 mmol) was taken up in AcOH (200 mL) and stirred for 18 h at 60 °C. Concentration under high vacuum removed the solvent. The residue was taken up in DCM, washed with sat'd aHC03 soln, and concentrated. The residue was charged (DCM) to a 80 g Thompson silica gel cartridge and gradient elution was performed from 15percent to 100percent B over 750 mL. (A/B Hex/EtOAc) to give Example J.9g (2.6 g). XH NMR (MeOD, 500 MHz, delta): 8.36-8.35 (m, 2H), 8.0 (d, J = 9Hz, 1H), 7.91 (dd, J = 9, 2 Hz, 1H), 7.87 (d, J = 9 Hz, 1H), 5.31-5.28 (m, 1H), 4.17 (br. s, 1H), 2.59-2.56 (m, 1H), 2.39-2.31 (m, 2H) 1.86-1.83 (m, 1H), 1.52-1.19 (m, 12H). LC/MS (Cond. J2): RT = 2.57 min.LC/MS Anal. Calcd. for [M+H]+ 430.12; found 430.09. |
Yield | Reaction Conditions | Operation in experiment |
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94.3% | With borane; In tetrahydrofuran; at 0 - 25℃; for 2h; | [001661 To a cooled 0 °C solution of compound 1-6 (2.24 g, 9.78 mmol) in THF (20 mL) was added a solution of borane in THF (14.6 mL, 1 mol/L). The mixture was stirred at 25 °C for 2 hours, and then to the mixture was added MeOH (8.0 mL). The THF was removed /n vacuo and the residue was dissolved in DCM (30 mL). The resulting mixture was washed with water (20 mLx3). The separated organic phase was dried over anhydrous Na2504 and concentrated /n vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give the title compound as colorless oil (1.98 g, 94.3percent). The compound was characterized by the following spectroscopic data:MS (ESI, pos.ion) m/z: 216.2 [M+Hfb; and?H NMR (400 MHz, CDC13): 3.90-3.91 (br, 2H), 3.62-3.65 (m, 2H), 3.50-3.54 (m, 1H), 1.91-1.93 (m, 2H), 1.51-1.60 (m, 2H), 1.44 (s, 9H), 1.13-1.14 (d,J= 6.2 Hz, 3H) ppm. |
93% | To a solution of <strong>[334769-80-1](2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid</strong> (5.91 g, 25.8 mmol) in tetrahydrofuran at 0° C., was added borane in dimethylsulfide (1.0 M, 3.4 mL, 34 mmol) dropwise. The reaction was stirred for 4 hours at 0° C. then 18 hours at room temperature. The mixture was then cooled to 0° C. and methanol (70 mL) was added dropwise. The reaction was warmed to room temperature and the solvents were removed in vacuo. The residue was taken up in dichloromethane (200 mL) and extracted with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and the solvent was removed in vacuo to yield (2S,5S)-tert-butyl 2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate as a clear oil (5.15 g, 23.9 mmol, 93percent) and was used directly in the following step. | |
Example 17, Step hTo a solution of (2S,5S)-l-(tert-butoxycarbonyl)-5-methylpyrrolidine-2- carboxylic acid (3.5 g, 15.27 mmol) in THF (10 mL) was added BH3.DMS (1.595 mL, 16.79 mmol) at 0 °C and then refluxed at 80 °C for 12 h. The reaction mixture was cooled to 0 °C and added slowly MeOH (10 mL). After stirring for 10 minutes the volatile components were removed under reduced pressure. The resulting residue was dissolved in EtOAc (50 mL), washed with 10percent NaHC03 (25 mL), water (25 mL), brine (10 mL), dried over Na2S04 and concentrated in vacuum. The crude was purified by flash chromatography (Silica gel 230-400, 30-40percent EtO Ac/petroleum ether) to obtain 17h (3.1 g) as a colorless liquid. LC/MS (Condition 75): Rt = 1.71 min. XH NMR (CDC13> delta = 7.26 ppm, 400 MHz): delta 4.95 (br s, 1H), 3.98-3.88 (m, 2H), 3.71-3.63 (m, 1H), 3.57-3.50 (m, 1H), 2.03-1.89 (m, 2H), 1.72-1.50 (m, 2H), 1.47 (s, 9H), 1.16 (d, J = 6.0, 3H). LC/MS: Anal. Calcd. for [M+H-Boc]+ C6H14NO: 116.10; found 116.2. |
With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 20℃; for 22h; | (2S,5S)-tert-butyl 2-(hydroxymethyl)-5-methylpyrrolidine-l-carboxylate To a solution of (2S,5S)-l -(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (5.91 g, 25.8 mmol) in tetrahydrofuran at 0 °C, was added borane in dimethylsulfide (1.0 M, 3.4 mL, 34 mmol) dropwise. The reaction was stirred for 4 hours at 0 °C then 18 hours at room temperature. The mixture was then cooled to 0 °C and methanol (70 mL) was added dropwise. The reaction was warmed to room temperature and the solvents were removed in vacuo. The residue was taken up in dichloromethane (200 mL) and extracted with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and the solvent was removed in vacuo to yield (2S,5S)-tert-butyl 2- (hydroxymethyl)-5-methylpyrrolidine-l -carboxylate as a clear oil (5.15 g, 23.9 mmol, 93percent) and was used directly in the following step. | |
With borane-THF; In tetrahydrofuran; at 0 - 25℃; for 2h; | Step 6) the Preparation of Compound 1-7 (0234) To a cooled 0° C. solution of compound 1-6 (2.24 g, 9.78 mmol) in THF (20 mL) was added a solution of borane in THF (14.6 mL, 1 mol/L). The mixture was stirred at 25° C. for 2 hours, and then to the mixture was added MeOH (8.0 mL). The THF was removed in vacuo and the residue was dissolved in DCM (30 mL). The resulting mixture was washed with water (20 mL×3). The separated organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the title compound as colorless oil (1.98 g, 94.3percent). The compound was characterized by the following spectroscopic data: (0235) MS (ESI, pos. ion) m/z: 216.2 [M+H]+; and (0236) 1H NMR (400 MHz, CDCl3): delta 3.90-3.91 (br, 2H), 3.62-3.65 (m, 2H), 3.50-3.54 (m, 1H), 1.91-1.93 (m, 2H), 1.51-1.60 (m, 2H), 1.44 (s, 9H), 1.13-1.14 (d, J=6.2 Hz, 3H) ppm |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.5h; | Example 17, Step eTo a stirred solution of 2-amino-l-(4-bromophenyl)ethanone hydrochloride (5 g, 19.96 mmol) in DMF (50 mL) was added (2S,5S)-l-(tert-butoxycarbonyl)-5- methylpyrrolidine-2-carboxylic acid (4.80 g, 20.96 mmol) at 0 °C. Then HATU (7.74 g, 20.36 mmol) was added to the reaction mixture followed by DIPEA (10.46 mL, 59.9 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. Water (100 mL) was added to the reaction mixture and extracted with EtOAc (2 x 100 mL). The organic layer was washed with brine (50 mL), dried over a2S04 and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel 60-120, 1.8percent MeOH /DCM) to yield 17e (7.9 g) as an off white solid. LC/MS (Condition 15): Rt = 1.99 min. XH NMR (CDCls, delta = 7.26 ppm, 400 MHz): delta 7.84 (d, J = 8.8, 2H), 7.65 (d, J = 8.8, 2H), 4.84-4.62 (m, 2H), 4.39 (br s, 1H), 3.94 (br s, 1H), 2.23 (br s, 1H), 2.10-2.02 (m, 2H), 1.64-1.54 (m, 1H), 1.48/1.47 (s, 9H), 1.39 (d, J = 6.0, 3H). LC/MS: Anal. Calcd. for [M-H]" Ci9H24BrN204: 424.32; found 425.0. |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; for 2h; | Example 15, Step eA solution of crude dibromide 15d (350 mg, 0.829 mmol) in ACN (5 mL) was cooled to 0 °C. Then (2S,5S)-l-(tert-butoxycarbonyl)-5-methylpyrrolidine-2- carboxylic acid (418 mg, 1.824 mmol) was added followed by drop-wise addition of DIPEA (0.579 mL, 3.32 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with saturated NH4C1 (20 mL), 10percent NaHC03 (20 mL), water (20 mL) and brine (10 mL). The organic layer was dried over Nu3/4804 and concentrated under reduced pressure. The crude was purified by Combiflash Isco (Silicycle, 40 g, silica, EtOAc: petroleum ether, 35:65) to afford diketoester 15e (300 mg) as a yellow solid. LC/MS (Condition 14): Rt = 2.36 min. 3/4 NMR (CDC13, delta = 7.26 ppm, 400 MHz): delta 8.01-7.99 (m, 2H), 7.89 (d, J = 8.4, 1H), 7.79-7.77 (m, 2H), 7.62 (d, J = 8.4, 1H), 5.60- 5.05 (m, 4H), 4.55-4.47 (m, 1H), 4.45-4.38 (m, 1H), 4.09-4.01 (m, 1H), 3.98-3.92 (m, 1H), 3.52 (br s, 4H), 2.38-2.29 (m, 4H), 2.17-2.04 (m, 2H), 1.80-1.69 (m, 2H), 1.48/1.45 (s, 18 H), 1.33 (br s, 6H). LC/MS: Anal. Calcd. for [M-H]" C4oH49N2Oio: 717.35; found 717.6. |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine;potassium iodide; In acetonitrile; at 0 - 20℃; for 2h; | Example 16, Step eTo a solution of crude 16d (350 mg, 1.008 mmol) and (2S,5S)-l-(tert- butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (462 mg, 2.016 mmol) in ACN (50 mL) was added KI (36.8 mg, 0.222 mmol) followed by DIPEA (0.704 mL, 4.03 mmol) at 0°C. Then the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NH4C1 (50 mL), 10percent NaHC03 (50 mL), brine (50 mL), dried over a2S04 and concentrated under reduced pressure. The crude was dissolved in MeOH (5 mL) and precipitated with diethyl ether:petroleum ether, 50:45 mL). The resulting precipitate was redissolved in MeOH (5 mL) and precipitated with diethyl ether:petroleum ether, 50:45 mL). This process was repeated for one more time. The precipitate was dried under high vacuum to obtain 16e (700 mg) as a yellow solid. LC/MS (Condition 10): Rt = 2.55 min. XH NMR (CDC13> delta = 7.26 ppm, 400 MHz): delta 8.14-8.12 (m, 2H), 7.85-7.82 (m, 2H), 7.70-7.65 (m, 1H), 7.59 (s, 1H), 7.59-7.56 (m, 1H), 7.08-7.04 (m, 1H), 5.89- 5.26 (m, 4H), 4.58-4.40 (m, 2H), 4.10-3.72 (m, 2H), 2.41-2.24 (m, 4H), 2.15-2.03 (m, 2H), 1.78-1.60 (m, 2H), 1.50 (br s, 18H), 1.40-1.31 (m, 6H). LC/MS: Anal. Calcd. For [M+H]+ C39H49N4O10: 733.34; found 733.4. |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 3h; | To a mixture of Example 1, step a (7.12 g, 31.1 mmol) and l, l'-(biphenyl- 4,4'-diyl)bis(2-bromoethanone) (6.0 g, 15 mmol) in acetonitrile (100 mL), z'-P^EfN (5.56 mL, 31.8 mmol) was added dropwise, and the reaction was stirred at room temperature for 3 hr. The volatile component was removed in vacuo and the residue was partitioned between (3/4(3/4 (100 mL) and sat. aq. aHC03 (100 mL). The organic layer was separated and washed with water and brine, dried ( a2S04), filtered, and concentrated in vacuo to afford Example 1, step b as white foam (9.83 g), which was used in the next step without purification. 1H NMR (500 MHz, CDC13) delta ppm 8.01 (4 H, t, J=7.32 Hz), 7.73 (4 H, d, J=6.71 Hz), 5.18 - 5.66 (4 H, m), 4.51 (1 H, t, J=7.17 Hz), 4.42 (1 H, t, J=7.32 Hz), 4.06 (1 H, d, J=3.36 Hz), 3.95 (1 H, d, J=5.19 Hz), 2.27 - 2.37 (4 H, m), 2.01 - 2.17 (2 H, m), 1.67 - 1.82 (2 H, m), 1.39 - 1.52 (18 H, m), 1.32 (6 H, t, J=6.56 Hz). LC-MS: Anal. Calcd. for [M+H]+ C38H49 2O10 693.34; found 693.34. |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 64h; | To a solution of Example 4, step a (2.58 g, 8.72 mmol) and (2S,5S)-l-(tert- butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (2.00 g, 8.72 mmol) in acetonitrile (50 mL) was added DIEA (2.285 mL, 13.08 mmol), and the mixture was stirred at room temperature for 64 hrs. Solvent was removed in vacuo and the residue was partitioned between EtOAc (40 mL) and water (30 mL). The organic layer was washed with sat. aHC03 and brine, dried with a2S04 and evaporated in vacuo to afford Example 4, step b (3.8 g) as yellow solid. 1H NMR (CDC13, 400 MHz): 7.87 (m, 1H), 7.44 (m, 2H), 5.42-5.09 (m, 2H), 4.53-4.40 (m, 1H), 4.10-3.95 (m, 1H), 2.31 (m, 2H), 2.09 (m, 1H), 1.75 (m, 1H), 1.49-1.46 (two singlet, 9H), 1.33 (m, 3H). LC/MS: Anal. Calcd. for [M+Na]+ Ci9H24BrNNa05: 466.06; found: 466.03. | |
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 64h; | Exam le QC-18.1, step bTo a solution of Example 18.1, step a (2.58 g, 8.72 mmol) and (2S,5S)-l-(tert- butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (2.00 g, 8.72 mmol) in acetonitrile (50 mL) was added DIEA (2.285 mL, 13.08 mmol), and the mixture was stirred at room temperature for 64 hrs. Solvent was removed in vacuo and the residue was partitioned between EtOAc (40 mL) and water (30 mL). The organic layer was washed with sat. aHC03 and brine, dried with Na2S04 and evaporated in vacuo to afford Example 18.1, step b (3.8 g) as yellow solid. XH NMR (CDC13, 400 MHz): 7.87 (m, 1H), 7.44 (m, 2H), 5.42-5.09 (m, 2H), 4.53-4.40 (m, 1H), 4.10-3.95 (m, 1H), 2.31 (m, 2H), 2.09 (m, 1H), 1.75 (m, 1H), 1.49-1.46 (two singlet, 9H), 1.33 (m, 3H). LC/MS: Anal. Calcd. for [M+Naf 466.06; found: 466.03. |