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CAS No. : | 57292-44-1 | MDL No. : | MFCD00076978 |
Formula : | C14H18ClNO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BETBOAZCLSJOBQ-LLVKDONJSA-N |
M.W : | 299.75 | Pubchem ID : | 7018791 |
Synonyms : |
|
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.43 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 76.35 |
TPSA : | 75.63 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.51 cm/s |
Log Po/w (iLOGP) : | 2.31 |
Log Po/w (XLOGP3) : | 3.69 |
Log Po/w (WLOGP) : | 2.86 |
Log Po/w (MLOGP) : | 2.49 |
Log Po/w (SILICOS-IT) : | 2.3 |
Consensus Log Po/w : | 2.73 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -3.78 |
Solubility : | 0.0494 mg/ml ; 0.000165 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.97 |
Solubility : | 0.00322 mg/ml ; 0.0000108 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -3.78 |
Solubility : | 0.0496 mg/ml ; 0.000166 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.74 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
87.3% | With triethylamine In water; acetone at 20℃; for 44 h; | The D-4-chlorophenylalanine crude product (22.0 mg, 0.110 mmol) was dissolved in water (2 mL) and acetone (1.0 mL). To the solution, a solution of (Boc)2O (40.4 mg, 0.185 mmol) in acetone (0.5 mL) and a solution of triethylamine (18.8 mg, 0.186 mmol) in acetone (0.5 mL) were added. The mixture was stirred at room temperature for 44 hours. The reaction mixture was concentrated until the volume was reduced to 2 mL or less, and then toluene (5 mL) was added thereto. To this, 4 N hydrochloric acid was added under stirring until the pH of the aqueous layer was reduced to 2 to 3. The organic layer was separated and washed with saturated brine (5 mL, twice). The organic layer was dried over magnesium sulfate, and then the solvent was removed by evaporation to give Boc-D-4-chlorophenylalanine (28.7 mg, 87.3percent, 98.6percent ee) as a white solid. (0304) HPLC analysis was conducted on the obtained compound under the following conditions. The results are shown in Table 5 and FIG. 5. <HPLC Conditions: Boc-D-4-Cl-Phe Chiral Analysis Conditions> Column: CHIRALPAK AD-RH (5 μm, 150×4.6 mm i.d.) Eluent: A:B=35:65 (0305) A=0.1percent phosphoric acid aqueous solution (0306) B=0.1percent solution of phosphoric acid in acetonitrile Flow rate: 1.0 mL/min Temperature: 35° C. Detector: UV 254 nm (0307) [table-us-00005-en] Retention time in HPLC (min) Isomer of Objective Excess ratio objective substance substance (isomer of objective Boc-L-4- Boc-D-4- substance:objective chlorophenylalanine chlorophenylalanine substance) 11.08 14.16 98.6percent ee (0.7:99.3) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.3% | With triethylamine In water; acetone at 20℃; for 44 h; | D-4- chlorophenylalanine crude product (22.0 mg, 0.110 mmol) was dissolved in water (2 mL) and acetone (1.0 mL), (Boc) 2O(40.4 mg, 0.185 mmol) acetone (0.5 mL) of solution of triethylamine (18.8 mg, 0.186 mmol) was stirred 44 hours at room temperature was added acetone (0.5 mL) solution of.After concentrated to the reaction mixture below 2 mL, it was added 4N hydrochloric acid under stirring by addition of toluene (5 mL) until the pH of the aqueous layer is 2-3.The organic layer prep to saturated brine (5 mL, 2 times) after drying washing and with magnesium sulfate, and the solvent was distilled off Boc-D-4- chloro-phenylalanine (28.7 mg, 87.3percent, 98.6 percent ee)as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In water; acetone at 25℃; for 14 h; | General procedure: L-Phenylalanine (1.0 g, 6.05 mmol) and sodium carbonate (0.71 g, 6.70 mmol) in water (10 mL) was reacted with a solution of 2 (1.89 g, 6.36 mmol) in acetone (10 mL). The reaction mixture was stirred at room temperature till the reaction completes, as monitored by TLC. The resulting solution was concentrated, to the residue was added water (10 mL) and ethyl acetate (10 mL), pH adjusted to 6.0 with 10percent KHSO4 and stirred for 5 minutes. The organic layer was removed and the aqueous layer was acidified to pH 2.0 with 10percent KHSO4 at 0-5°C and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with 5percent NaHCO3 solution, water, brine and dried over anhydrous Na2SO4. The ethyl acetate layer was concentrated and the residue was crystallized from EtOAc/ n-hexane (2:8) mixture to give the product as a white solid (1.53g, 95percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydroxide; In tetrahydrofuran; water; at 20℃;Cooling with ice; | Racemic 4-chlorophenylalanine (10.0 g, 50 mmol) and sodium hydroxide (6.0 g, 150 mmol) were dissolved in distilled water (150 mL) in a round-bottom flask equipped with a stirring bar and a dropping funnel. The reaction mixture was cooled in ice and a solution of di-tert-butyl dicarbonate (13.1 g, 60 mmol) in tetrahydrofurane (150 mL) was slowly introduced from the dropping funnel. The resulting mixture was allowed to warm to room temperature and then stirred overnight. The resulting solution was transferred into a separatory funnel and washed twice with diethyl ether (100 mL). The aqueous phase was acidified with 3 M aqueous citric acid to pH 4-5 and the obtained suspension was extracted with dichloromethane (3 * 150 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to give 4a as a white solid. Yield: 13.8 g (92%). 1H NMR (DMSO-d6): delta 1.32 (s, 9H, CMe3), 2.74-3.05 (m, 2H, CH2), 3.97-4.12 (m, 1H, CH), 7.11 (d, 3JHH = 8.5 Hz, 1H, NH), 7.27 (d, 3JHH = 8.4 Hz, 2H, C6H4); 7.33 (d, 3JHH = 8.4 Hz, 2H, C6H4), 12.64 (br s, 1H, CO2H). 13C{1H} NMR (DMSO-d6): delta 28.03 (9C, CMe3), 35.66 (CH2), 54.84 (CH), 77.98 (CMe3), 127.94 (2C), 130.90 (2C), and 136.99 (C6H4); 155.33 (C=O), 173.27 (CO2H). One of the C6H4 carbons was not found. MS (ESI-): m/z 299.1 ([M - H]-). Anal. Calcd. for C14H18ClNO4: C 56.09, H 6.05, N 4.67%. Found: C 55.99, H 6.07, N 4.60%. |
In sodium hydroxide; hexane; butan-1-ol; | (a) N-tert-Butyloxycarbonyl-4-chlorophenylalanine A solution of 54.6 g (250 mmol) of di-tert-butyl dicarbonate in 250 ml of n-butanol is added to a solution of 50 g (250 mmol) of (R,S)-4-chlorophenylalanine in 750 ml of 0.65N sodium hydroxide solution and the mixture is stirred at room temperature for 19 hours. The solution is then washed twice with ether, adjusted to pH 2 with 2N hydrochloric acid and extracted twice with ethyl acetate. The organic phases are washed with water and brine, dried with sodium sulfate and concentrated by evaporation. The crude product crystallises from hexane. M.p.: 145-146 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | [0465] To a solution of Boc-D-4-Cl-Phe (1.6 g, 5.5 mmol) in CH2Cl2 (30 ml) was added EDC (1.84 g, 9.6 mmol), HOBT (1.298 g, 9.6 mmol), NMM (1.67 g, 16.5 mmol) and followed by the oxazolidinone intermediate (1.65 g, 5 mmol). After stirring the reaction mixture overnight at room temperature, the mixture was diluted with CH2Cl2, washed with water, dilute HCl, aqueous NaHCO3 and brine. The organic layer was dried, concentrated and purified by chromatography on silica gel (10% acetone/CH2Cl2) to give 2.55 g of pure product. [0466] ESI-MS: calc. for C31H46ClN3O5: 575; Found: 576 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 1h; | Step 3: To a solution of (R)-5-methyl-4-((S)-2-methylpiperazin-l-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (32 mg, 0.14 mmol) in DCM (5 mL) were added triethylamine (1 mL), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (41 mg, 0.14 mmol) and HBTU (52 mg, 0.14 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to afford tert-butyl (R)-3-(4-chlorophenyl)-l-((S)-3-methyl-4-((R)-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin- 1 -yl)- 1 -oxopropan-2-ylcarbamate (60 mg, 88%). 1U NMR (CDCl3, 400 MHz) delta 8.44 (s, IH), 7.23-7.01 (m, 4H), 5.40-5.15 (m, IH), 4.85-4.60 (m, IH), 4.46-4.30 (m, IH), 4.20-4.00 (m, IH), 3.82-3.60 (m, IH), 3.40 (m, IH), 3.00-2.70 (m, 2H), 2.28 (m, IH), 1.70 (m, IH), 1.40 (s, 9H), 1.30-0.98 (m, 6H). MS (APCI+) [M+H] +514. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Step 6: To a solution of D-Boc-4-chlorophenyl aniline (0.033 g, 0.110 mmol), 5- methyl-4-(piperazin-l-yl)-5,7-dihydrofuro[3,4- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In dichloromethane; at 20℃; | Step 2: To a solution of D-Boc-4-chlorophenyl alanine (0.033 g, 0.110 mmol), 5- methyl-4-((S)-2-methylpiperazin-l-yl)-5,7-dihydrofuro[3,4-d]pyrimidine dihydrochloride (0.031 mg, 0.100 mmol), and triethylamine (0.033 mL, 0.220 mmol) in DCM (3 mL) was added HATU (0.042 g, 0.110 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was partitioned between water and DCM and the organic layer separated. The aqueous phase was extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine, dried with MgSO4 and concentrated. The residue was purified by column chromatography (EtOAc) to give the coupled intermediate tert-butyl(2R)-3-(4-chlorophenyl)-l-((3S)-3-methyl-4-(5-methyl- 5 ,7-dihydrofuro[3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)- 1 -oxopropan-2-ylcarbamate LCMS (APCI+) m/z 516 [M+H+]; Rt = 3.18 min as a clear oil. This material was dissolved in DCM (5 mL) to which was added excess 4N HCl in dioxane (2 mL). The mixture was stirred at room temperature overnight and then evaporated. The residue was dissolved in a minimal amount of isopropanol and titrated with ether to form a white precipitate, which was filtered to give (2i?)-2-amino-3-(4- chlorophenyl)-l-((3S)-3-methyl-4-(5-methyl-5,7-dihydrofuro[3,4-J]pyrimidin-4-yl)piperazin-l- yl)propane-l-one dihydrochloride as an off white solid (0.025 mg, 51%). 1H NMR (CD3OD, 400 MHz) delta 8.71(s, IH), 7.41-7.26 (m, 4H), 5.73-5.71 (m, IH), 5.12-5.01 (m, 2H), 4.39-4.32 (m, IH), 4.10-4.05 (m, IH), 3.95-3.81 (m, IH), 3.67-3.48 (m, 2H), 3.23-3.01 (m, 3H), 2.73-2.58 (m, IH), 1.45-1.26 (m, 6H), 1.15-1.41 (d, J= 6.0 Hz, 3H). LCMS (APCI+) m/z 416 [M+H+]; Rt = 2.18 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 2h; | Step 3: To a solution of (S)-5-methyl-4-((S)-2-methylpiperazin-l-yl)-5,7- dihydrothieno[3,4-d]pyrimidine (0.5 g, 1.5 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4- chlorophenyl)propanoic acid (0.46 g, 1.5 mmol) in DCM (30 mL) and triethylamine (5 mL) was added HBTU (0.59 g, 1.5 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue was dissolved in ethyl acetate (200 mL) and washed with water (6 x 100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with DCM/MeOH (20:1) to afford tert-butyl (R)-3-(4- chlorophenyl)-l-((S)-3-methyl-4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin- l-yl)-l-oxopropan-2-ylcarbamate (0.48 g, 70%). 1H NMR (CDCl3, 400 MHz) delta 8.52 (s, IH), 7.28- 7.09 (m, 4H), 5.43-5.18 (m, IH), 4.86-4.71 (m, 2H), 4.41-4.33 (m, IH), 4.26-4.10 (m, 2H), 3.95- 3.74 (m, IH), 3.25-2.65 (m, 2H), 1.46 (m, 12H), 1.25 (m, 3H). MS (APCI+) [M+H] + 532. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 3h; | Step 6: To a solution of 5-ethyl-4-(piperazin-l-yl)-5,7-dihydrothieno[3,4- d]pyrimidine dihydrochloride (50 mg, 0.15 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4- chlorophenyl)propanoic acid (46 mg, 0.15 mmol) in DCM (10 mL) and triethylamine (1 mL) was added HBTU (59 mg, 0.15 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was removed and the residue was purified by silica gel chromatography, eluting with DCM/ethyl acetate (1:1) to give tert-butyl (R)-3-(4-chlorophenyl)-l-(4-(5-ethyl-5,7- dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-l-yl)-l-oxopropan-2-ylcarbamate (50 mg, 60%). 1H NMR (CDCl3, 400 MHz) delta 8.53 (s, IH), 7.26-7.14 (m, 4H), 5.36 (m, IH), 4.82 (m, IH), 4.62 (m, IH), 4.14 (m, IH), 3.80-2.90 (m, 8H), 1.94 (m, IH). 1.68 (m, IH), 1.54 (m, IH), 1.42 (s, 9H), 0.94 (m, 3H). MS (APCI+) [M+H] +533. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Step 5: To a solution of 4-(piperazin-l-yl)-5,7-dihydrothieno[3,4-d]pyrimidine(0.28g, 1.3 mmol) in CH2Cl2 (20 mL) was added triethylamine (5 mL) and (R)-2-(tert- butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.38 g, 1.3 mmol). After stirring for 30 minutes, HBTU (0.57 g, 1.5 mmol) was added. The mix was stirred at room temperature for 1 hour. The solvent was removed and the residue was subject to silica gel chromatography, eluting with hexane/ethyl acetate (1:1) to give (R)-tert-butyl 3-(4-chlorophenyl)-l-(4-(5,7-dihydrothieno[3,4- d]pyrimidin-4-yl)piperazin-l-yl)-l-oxopropan-2-ylcarbamate (0.62 g, 98%). 1H NMR (CDCl3, 400 MHz) delta 8.49 (s, IH), 5.38-5.35 (m, IH), 3.70-3.50 (m, 6H), 3.27-3.13 (m, 2H), 2.98-2.92 (m, 2H), 1.42 (s, 9H). MS (APCI+) [M+H] + 505. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;benzotriazol-1-ol; In dichloromethane; at 20℃; for 16h; | To a stirred solution of Intermediate 1a(ii) (0.36 gm, 1.30 mmol), N-Boc-D-4-chlorophenylalanine (0.47 gm, 1.56 mmol), HOBt (0.21 gm, 1.56 mmol) and EDC (0.30 gm, 1.56 mmol) in dichloromethane, 10 mL was added NMM (0.50 mL, 4.55 mmol). The mixture was stirred for 16 hr at room temperature and diluted with ethyl acetate and washed with 1N HCl and saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give an intermediate that was chromatographed on silica gel using hexane-ethyl acetate (1:1) as the eluent to give the coupled product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h; | To a solution of Intermediate If (3.35 g, 9.6 mmol) in CH2Cl2 (200 mL) was added BOC-D-4-chlorophenylalanine (4.9 g, 16.3 mmol), HOBt (2.1 g, 15.4 mmol), EDC (2.9 g, 15.4 mmol) and NMM (4.75 mL, 43.2 mmol). The resultant solution was stirred at rt for 18 hr. The reaction mixture was poured into EtOAc (1L) and washed successively with 0.5M HCl, saturated aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated in vacuo. Chromatography over silica eluting with 1:2 acetone/CH2Cl2 furnished the N-BOC protected amine as a white foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate;dmap; In dichloromethane; for 16h; | To a stirred solution of Intermediate 1j(iii) (345 mg, 1.21 mmol), Boc-p-Cl-D-Phe-OH (364 mg, 1.21 mmol), PyBrop (570 mg, 1.21 mmol) and DMAP (90 mg, 0.73 mmol) in dichloromethane (2.5 mL) was added DIEA (470 mg, 3.64 mmol). The solution was stirred for 16 hr, concentrated and chromatographed directly (SiO2, 19:1 EtOAc/methanol) to provide 0.59 gm of the title compound as a white solid. ESI-MS calc. for C27H40ClN3O4: 505; Found 526 (M+H), 406 (M+H-Boc), 526 (M+H+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h; | [0436] To a solution of Intermediate 19 (1.2 g, 3.37 mmol) in dichloromethane (10 ml) was added 4-methylmorpholine (0.56 ml, 5.055 mmol), HOBt (0.5008 mg, 3.71 mmol), EDC (0.97 g, 5.06 mmol), and Boc-D-4-chlorophenylalanine (1.1 g, 3.71 mmol). The reaction mixture was stirred at room temperature for 18 hrs. Water (3 ml) was added and solvent was removed in vacuo. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water, dried over MgSO4, and concentrated to provide a white solid (2.2 g), which was purified by column chromatography on silica gel (7:1 CH2Cl2/EtOAc) to give a white solid (1.45 g). [0437] ESI-MS: calc. for C34H49ClN2O5: 601; Found: 602 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 4-methyl-morpholine; HATU; In DMF (N,N-dimethyl-formamide); at 0℃; | 2- (3-ETHYL- piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester, 34, (0.52 g, 1.6 MMOL) and Boc-D-4- chlorophenylalanine (0.5 g, 1.7 MMOL) and O-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyl- uronium HEXAFLUORO-PHOSPHATE (1.2 g, 3.2 mmol) are dissolved in anhydrous DMF (20 mL). The reaction mixture is cooled to 0 C, then N-methylmorpholine (0.35 mL, 3.2 MMOL) is added. The reaction mixture is placed in a refrigerator overnight. EtOAc (75 mL) and water (100 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3X50 mL). All organic layers are combined and washed with water (20 mL), and dried over NA2SO4. The organic layers are concentrated in vacuo to afford 1.0 g (quantitative yield) of the desired product. 1H NMR (CDCl3, 6) : 7.70-7. 65 (m, 3H), 7.52 (s, 1H), 7.35-7. 32 (m, 2H), 7.22-7. 13 (m, 4H), 7.07-7. 02 (m, 2H), 5.59 (dd, J = 13.5, 8.7 Hz, 1 H), 4.74 (q, J = 7.5 Hz, 1 H), 2.28-4. 21 (m, 1 H), 3.53 (d, J = 12.3 Hz, 3H), 3.42-3. 08 (m, 2H), 3.04-2. 81 m, 4H), 2.80 (s, 1 H), 2.75 (s, 3H), 2.64 - 2. 60 (m, 1 H), 2.46 (t, J = 10.5 Hz, 1 H), 2.20-2. 05 (m, 1 H), 1.55-1. 40 (m, 1 H), 1.18 (s, 9H), 0.54-0. 47 (m, 2H); 13C NMR, S 171.6, 170.5, 170.0, 162.9, 155.0, 150.7, 135.8, 135.2, 133.6, 132.8, 132.4, 131.1, 131.2, 128.9, 128.7, 128.6, 128. 0,127. 7,127. 6,126. 2,125. 6,124. 5,120. 4, 79.7, 68.9, 60.5, 55.8, 53.7, 51.4, 51.0, 47.4, 47.0, 41.5, 40.0, 39.0, 38.7, 38.0, 36.6, 35.3, 35.0, 31.6, 28.4, 22.8, 21.8, 21.1, 14.3, 10.5, 10.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; | To Boc-D-4-chlorophenylalanine (82 mg) in DCM (5 ml) was added the amine hydrochloride (preparation in US005536716) (62 mg), N-methylmorpholine (42 mul), HOBt (48 mg) and stirred for 20 min. EDC (72 mg) was added and stirring was continued for 1 h. An additional amount of N-methylmorpholine (20 mul) was added and stirred overnight. The reaction mixture was poured into water (5 ml) and the organic phase was separated. The aqueous phase was extracted two times with DCM. The combined organic phases were washed with 0.5 N HCl and saturated sodium bicarbonate solution, dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography yielded the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 6h; | To a solution of 4-cyclohexyl-4-[1,2,4]triazole-1-ylmethylpiperidine, 18, (2.16 g, 8.74 mmol), (R)-2-N-(tert-butoxy-carbonyl)-amino-3-(4-chloro)phenyl-propanoic acid [Boc-D-Ph(p-Cl)-OH] (2.65 g, 9.18 mmol), 1-hydroxy-benzotriazole (2.36 g, 17.5 mmol), N-methylmorpholine (35.0 mmol, 3.83 mL) in DMF (30 mL) is added in portions 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.16 g, 11.4 mmol). The reaction is allowed to stir for 6 hours after which it is quenched by adding aqueous NH4Cl. The reaction mixture is extracted with EtOAc and the combined layers are dried, concentrated in vacuo, and the resulting crude product purified over silica gel to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 6h; | To a solution of N-[3-(4-cyclohexyl-piperidin-4-yl)-propyl]-dicarbobenzyloxy-guanidine, 17, (4.67 g, 8.74 mmol), (R)-2-N-(tert-butoxy-carbonyl)-amino-3-(4-chloro)phenyl-propanoic acid [Boc-D-Ph(p-Cl)-OH] (2.65 g, 9.18 mmol), 1-hydroxy-benzotriazole (2.36 g, 17.5 mmol), N-methylmorpholine (35.0 mmol, 3.83 mL) in DMF (30 mL) is added in portions 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.16 g, 11.4 mmol). The reaction is allowed to stir for 6 hours after which it is quenched by adding aqueous NH4Cl. The reaction mixture is extracted with EtOAc and the combined layers are dried, concentrated in vacuo, and the resulting crude product purified over silica gel to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h; | To a round bottom flask equipped with a stirring bar is charged [1,4']bipiperidinyl-4'-yl-methanol, 22, (2.2 g, 11.1 mmol, 1.0 eq.) 2-(R)-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionic acid (3.648 g, 12.2 mmol), 1-hydroxybenzotriazole (2.552 g, 18.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.71 g, 18.9 mmol) in anhydrous N,N-dimethylformamide (80 mL). The mixture is cooled to 0 C. and N,N-diisopropyl-ethylamine (4.1 mL, 37.7 mmol) is added. The ice bath is removed and the reaction mixture allowed to stir overnight. The mixture is concentrated under reduced pressure and purified by preparative HPLC to afford 2.83 g (43% yield) of the desired compound as the trifluoroacetic acid salt. 1H NMR (CD3OD, 300 MHz) delta 0.85-2.13 (m, 19H), 2.65-3.82 (m, 8H), 3.90-4.10 (m, 3H), 4.48 (m, 1H), 4.76 (m, 1H), 7.22-7.48 (m, 4H). MS (ESI) m/z 480 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 2.5h; | [0535] To a round-bottomed flask equipped with stirring was added 4-{2-[(methylsulfonyl)amino]phenyl}piperidine (Step e) (400 mg, 1.38 mmol) and DMF (5 mL). The mixture was stirred for 5 min, then treated with N-Boc-p-Cl-D-PheOH (PepTech Corporation) (454 mg, 1.52 mmol), HOAT (Aldrich) (188 mg, 1.38 mmol), EDC (Aldrich) (529 mg, 2.76 mmol) and DIEA (Aldrich) (240 muL, 1.38 mmol) and stirred at RT for 2.5 h. The reaction mixture was diluted with EtOAc (15 mL) and 10% Na2CO3 (20 mL) was added. The organic layer was separated, washed with 10% Na2CO3, H2O and satd NaCl, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a white foam (655 mg). MS (ESI, pos. ion) m/z: 536 (M+1). Calc'd for C26H34ClN3O5S: 536.08. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.9% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 12h; | Examples Example 1: (2R)-2-Amino-N- [4-Cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide TFA Step A: (2R)-2- (BOC-Amino)-N- [4-Cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide To a solution of 4-cyclohexyl-4-(t-butylcarbamoyl) piperidine (HCl salt, 917 mg, 3. 30 mmol) in DMF (30 mL) were added DIPEA (1. 15 mL, 6.70 mmol), EDC (845 mg, 4.30 mmol), HOBT (668 mg, 5.00 mmol), and (2R)-N-BOC- (4-chlorophenyl) alanine, and the reaction mixture was stirred at rt for 12 h. After DMF was distilled off under reduced pressure, the residue was poured into EtOAc, and subsequently washed with a saturated aqueous NaHC03 solution and an aqueous 1N HCl solution. The organic solution was dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 2/1) to give the title compound (1.58 g, 93.9%). MS [M+H] = 520 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.9% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 12h; | To a solution of (3S)-3- [cyclohexyl (isobutyryl) amino] pyrrolidine (HC1 salt, 917 mg, 3.30 mmol) in DMF (30 mL) were added DIPEA (1.15 mL, 6.70 mmol), (2R) -N- BOC- (4-chlorophenyl) alanine (1. 00 mg, 3.30 mmol), HOBT (668 mg, 5.00 mmol), and EDC (845 mg, 4.30 mmol). After being stirred at rt for 12 h, the reaction solution was concentrated in vacuo, and the residue was diluted with a saturated NaHC03 solution and EtOAc. The organic layer was extracted with EtOAc and subsequently washed with a saturated aqueous NaHC03 solution, water and an aqueous 1N HC1 solution. The organic solution was dried over MgS04 and concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex = 1/2) to give the title compound (1. 58 g, 93.9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Preparation of {1-(R)-(4-chlorobenzyl)-2-[4-cyclohexyl-4-(thiazol-2-ylaminomethyl)-piperidin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (27): To a solution of the (4-cyclohexyl-piperidin-4-ylmethyl)-thiazol-2-yl-amine, 26, (39 mg, 0.14 mmol), 2-(R)-tert-butoxycarbonylamino-3-(4-chloro-phenyl)-propionic acid (44 mg, 0.147 mmol), 1-hydroxybenzotriazole (38 mg, 0.28 mmol), 4-methylmorpholine (0.56 mmole, 62 L) in N,N-dimethylformamide (7 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (35 mg, 0.183 mmol) and the reaction mixture stirred overnight. Aqueous ammonium chloride solution is then added and the reaction extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified over silica to afford 48 mg (61% yield) of the desired compound. MS (ESI) m/z 561 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of (D)-Boc-4-chlorophenylalanine (0.119 g, 0.396 mmol) and 5-Piperazin-1-yl-lH-indazole (0.100 g, 0.494 mmol) in DMF (5 mL) was added EDCI (0.152 g, 0.791 mmol), HOBt (0.121 g, 0.791 mmol) and triethylamine (0.110 mL, 0.791 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with aqueous NaHC03, brine, dried and concentrated. The residue was purified by column chromatography (80: 1 to 50: 1 DCM/MeOH) to give (2R)- {1- (4-chlorobenzyl)-2- [4- (lH-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert- butyl ester (0.176 g, 92%) as a white solid. lH NMR (CDC13, 400 MHz) 6 10.12 (s, 1H), 7.98 (s, 1H), 7.41 (d, J= 8.8 Hz, 1H), 7.28 (d, J= 8.4 Hz, 2H), 7.16 (d, J= 8.4 Hz, 2H), 7.12 (dd, J= 8.8 Hz, J= 2.0 Hz, 1H), 7.07 (s, 1H), 5.46 (m, 1H), 4.88 (m, 1H), 3.74 (m, 2H), 3.53 (m, 1H), 3.31 (m, 1H), 3.07 (m, 1H), 2.99 (d, J= 6.8 Hz, 2H), 2.91 (m, 2H), 2.49 (m, 1H), 1.43 (s, 9H). LCMS (APCI+) m/z 484, 486 [M+H] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.3% | With triethylamine; In water; acetone; at 20℃; for 44h; | The D-4-chlorophenylalanine crude product (22.0 mg, 0.110 mmol) was dissolved in water (2 mL) and acetone (1.0 mL). To the solution, a solution of (Boc)2O (40.4 mg, 0.185 mmol) in acetone (0.5 mL) and a solution of triethylamine (18.8 mg, 0.186 mmol) in acetone (0.5 mL) were added. The mixture was stirred at room temperature for 44 hours. The reaction mixture was concentrated until the volume was reduced to 2 mL or less, and then toluene (5 mL) was added thereto. To this, 4 N hydrochloric acid was added under stirring until the pH of the aqueous layer was reduced to 2 to 3. The organic layer was separated and washed with saturated brine (5 mL, twice). The organic layer was dried over magnesium sulfate, and then the solvent was removed by evaporation to give Boc-D-4-chlorophenylalanine (28.7 mg, 87.3%, 98.6% ee) as a white solid. (0304) HPLC analysis was conducted on the obtained compound under the following conditions. The results are shown in Table 5 and FIG. 5. <HPLC Conditions: Boc-D-4-Cl-Phe Chiral Analysis Conditions> Column: CHIRALPAK AD-RH (5 mum, 150×4.6 mm i.d.) Eluent: A:B=35:65 (0305) A=0.1% phosphoric acid aqueous solution (0306) B=0.1% solution of phosphoric acid in acetonitrile Flow rate: 1.0 mL/min Temperature: 35 C. Detector: UV 254 nm (0307) [table-us-00005-en] Retention time in HPLC (min) Isomer of Objective Excess ratio objective substance substance (isomer of objective Boc-L-4- Boc-D-4- substance:objective chlorophenylalanine chlorophenylalanine substance) 11.08 14.16 98.6% ee (0.7:99.3) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.3% | With triethylamine; In water; acetone; at 20℃; for 44h; | D-4- chlorophenylalanine crude product (22.0 mg, 0.110 mmol) was dissolved in water (2 mL) and acetone (1.0 mL), (Boc) 2O(40.4 mg, 0.185 mmol) acetone (0.5 mL) of solution of triethylamine (18.8 mg, 0.186 mmol) was stirred 44 hours at room temperature was added acetone (0.5 mL) solution of.After concentrated to the reaction mixture below 2 mL, it was added 4N hydrochloric acid under stirring by addition of toluene (5 mL) until the pH of the aqueous layer is 2-3.The organic layer prep to saturated brine (5 mL, 2 times) after drying washing and with magnesium sulfate, and the solvent was distilled off Boc-D-4- chloro-phenylalanine (28.7 mg, 87.3%, 98.6 % ee)as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; In water; acetone; at 25℃; for 14h; | General procedure: L-Phenylalanine (1.0 g, 6.05 mmol) and sodium carbonate (0.71 g, 6.70 mmol) in water (10 mL) was reacted with a solution of 2 (1.89 g, 6.36 mmol) in acetone (10 mL). The reaction mixture was stirred at room temperature till the reaction completes, as monitored by TLC. The resulting solution was concentrated, to the residue was added water (10 mL) and ethyl acetate (10 mL), pH adjusted to 6.0 with 10% KHSO4 and stirred for 5 minutes. The organic layer was removed and the aqueous layer was acidified to pH 2.0 with 10% KHSO4 at 0-5C and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with 5% NaHCO3 solution, water, brine and dried over anhydrous Na2SO4. The ethyl acetate layer was concentrated and the residue was crystallized from EtOAc/ n-hexane (2:8) mixture to give the product as a white solid (1.53g, 95% yield). |
[ 80102-23-4 ]
(R)-2-((tert-Butoxycarbonyl)amino)-3-(2-chlorophenyl)propanoic acid
Similarity: 0.95
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