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CAS No. : | 4984-22-9 | MDL No. : | MFCD01632587 |
Formula : | C4H10O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ARXJGSRGQADJSQ-SCSAIBSYSA-N |
M.W : | 90.12 | Pubchem ID : | 2733589 |
Synonyms : |
|
Num. heavy atoms : | 6 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 23.59 |
TPSA : | 29.46 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.97 cm/s |
Log Po/w (iLOGP) : | 1.64 |
Log Po/w (XLOGP3) : | -0.17 |
Log Po/w (WLOGP) : | 0.01 |
Log Po/w (MLOGP) : | -0.18 |
Log Po/w (SILICOS-IT) : | -0.04 |
Consensus Log Po/w : | 0.25 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.16 |
Solubility : | 62.4 mg/ml ; 0.692 mol/l |
Class : | Very soluble |
Log S (Ali) : | 0.01 |
Solubility : | 91.5 mg/ml ; 1.02 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.18 |
Solubility : | 60.1 mg/ml ; 0.667 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.28 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P501-P240-P210-P233-P243-P241-P242-P280-P370+P378-P303+P361+P353-P403+P235 | UN#: | 1993 |
Hazard Statements: | H225 | Packing Group: | Ⅲ |
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 |
---|---|---|
90% | With triphenylphosphine on polystyrene; di-isopropyl azodicarboxylate; In tetrahydrofuran; at 5 - 20℃; | To a 5 C. mixture of Part A compound (5 g, 15.5 mmol), <strong>[4984-22-9](R)-(-)-1-methoxy-2-propanol</strong> (2 mL, 20.4 mmol) and polymer-supported Ph3P (13.4 g of 3 mmol/g, 40.2 mmol) in THF (175 mL) was added dropwise a solution of DIAD (4.5 mL, 23.2 mmol) in THF (25 mL) over 25 min under Ar (internal temperature maintained at 5 C.). The reaction mixture was allowed to warm to RT overnight, and was then filtered. The solids were thoroughly washed with THF and CH2Cl2. The combined filtrates were concentrated in vacuo, re-dissolved in CH2Cl2 and divided in 2 equal portions. The first portion was chromatographed (330 g SiO2; elution with a continuous gradient of 0-10% EtOAc in CH2Cl2 over 40 min) to give 2.53 g of pure Part B compound as a colorless oil. Impure product fractions from this column were combined with the rest of the crude product and this mixture was chromatographed as above on 330 g SiO2, but with a continuous gradient from 0-8% EtOAc in CH2Cl2 to give Part B compound (3.02 g) as a colorless oil. The combined yield of Part B compound was 5.55 g (90%). [M+H]+=395.0; 1H-NMR (400 MHz, CDCl3): delta 7.90 (d, 2H), 7.48 (s, 1H), 7.30 (s, 1H), 7.11 (dd, 2H), 6.86 (d, 1H), 4.61 (m, 1H), 3.90 (s, 3H), 3.49-3.62 (m, 2H), 3.40 (s, 3H), 3.07 (s, 3H), 1.32 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 18h; | To a 0 C. solution of Ph3P (1.820 g, 6.94 mmol), Part A compound (1 g, 3.47 mmol), and <strong>[4984-22-9](R)-1-methoxypropan-2-ol</strong> (0.365 mL, 4.16 mmol) in dry THF (5 mL) was added DIAD (1.012 mL, 5.20 mmol). The reaction was stirred at RT for 18 h. Volatiles were removed in vacuo, and the residue was chromatographed (SiO2; EtOAc/Hexane, 1:5) to give crude Part B compound (1.7 g, 136%), which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With PS-triphenylphosphine; di-isopropyl azodicarboxylate In tetrahydrofuran for 0.5h; | Methyl 3-r (lS)-1-methyl-2-methoxv-ethoxv-5-benzvloxe-benzoate; To a solution of methyl 3-hydroxy-5- [ (phenylmethyl) oxy] benzoate (77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7g of 3 mmol/g loading, 155mmol) and (R)- (-)-1-methoxy-2-propanol (102 mmol). The stirred solution was blanketed with argon and cooled in an ice bath; a solution of diisopropyl azodicarboxylate (116 mmol) was added dropwise from a syringe over 10 minutes. After addition the solution was stirred for 20 minutes and then filtered, washing the residue with THF (500 mL); the filtrate and washings were combined and evaporated to give crude desired compound which was used in the next step without further purification. 'H NMR 8 (d6-DMSO) : 3.26 (s, 3H), 3.44 (m, 2H), 3.82 (s, 3H), 4.63 (m, 1H), 5.14 (s, 2H), 6.85 (s, 1H), 7.05 (s, 1H), 7.11 (s, 1H), 7.30-7. 47 (m, 5H) ; the spectrum also contained signals consistent with a small amount of bis (1-methylethyl) hydrazine-1,2-dicarboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 48h; | To a 0 C. solution of Part A(i) compound (1.0 g, 3.9 mmol) in THF (16.8 mL) were successively added <strong>[4984-22-9](R)-(-)-1-methoxy-2-propanol</strong> (0.5 g, 5.8 mmol) and Ph3P (1.5 g, 5.8 mmol), followed by slow addition of DIAD (1.1 mL, 5.8 mmol). The reaction mixture was warmed to RT and stirred at RT for 2 days. The reaction mixture was diluted with H2O and extracted with Et2O. The organic layer was dried [MgSO4] and concentrated in vacuo to give a thick, pale, yellow oil. This crude material was chromatographed (product eluted during the 10% EtOAc/hexane portion of a stepwise gradient of 10-30% EtOAc/hexane) to give Part A(ii) compound (1. 1 g, 85% yield) as a colorless oil. |
85% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 48h; | 11.[00189] To a O0C solution of Part A(i) compound (1.0 g, 3.9 mmol) in THF (16.8 mL) was added (R)-(-)-l-methoxy-2-propanol (0.5 g, 5.8 mmol). Ph3P (1.5 g, 5.8 mmol) was then added, followed by slow addition of DIAD (1.1 mL, 5.8 mmol). The reaction mixture was warmed to RT and was stirred for 2 days. The reaction mixture was diluted with H2O and extracted with Et2O. The organic layer was dried(MgSO4), filtered, and concentrated in vacuo to give the crude product as a thick, pale, yellow oil. The crude material was chromatographed (product eluted during the 10% EtOAc/hexane portion of a stepwise gradient of 10-30% EtOAc/hexane) to give Part A(ii) compound (1.1 g, 85% yield) as a colorless oil. |
75% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16h; | To a solution of previous compound (25 g, 96.8 mmol, 1 eq.) in anhydrousTHF (135 ml) is added under inert atmosphere successively triphenyl- 25 phosphine (38.1 g, 145.2 mmol, 1.5 eq.) and <strong>[4984-22-9](R)-(-)-1-methoxy-2-propanol</strong> 98% (10.5 g, 116.2 mmol, 1.2 eq.). The solution is chilled at 00C and DIAD (28.8 ml, 145.2 mmol, 1.5 eq.) is added dropwise. Then the reaction mixiuie is stirred at RT for 16h, water (200 rn.) is added and the residue extracted with ethyl acetate (2x200 ml). The organic phase is dried over MgSO4 and the solvent removed in vacuo. The residue is purified by column chromatography (cyclohexane/ethyl acetate 10/0 to 9/1 ) to give 24 g of the title compound as yellow oil (75%, ee=99%).35 1H-NMR (CDCI3, 300 MHz) delta [ppm] 7.44-7.23 (m, 8H), 6.76 (s, 1 H), 5.07 (s, 2H), 4.57 (m, 1 H)1 3.89 (s, 3H), 3.55 (m, 2H), 3.40 (s, 3H), 1.30 (d, 3H) |
With triphenylphosphine on polystyrene; diethylazodicarboxylate; In tetrahydrofuran; at 0℃; for 0.5h; | Methyl 3-[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylomethyl)oxy]benzoate To a solution of methyl 3-hydroxy-5- [ (phenylmethyl) oxy] benzoate (77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7g of 3 mmol/g loading, 155mmol) and (R)- (-)-l-methoxy-2-propanol (102 mmol). The stirred solution was blanketed with argon and cooled in an ice bath; a solution of diisopropyl azodicarboxylate (116 mmol) was added dropwise from a syringe over 10 minutes. After addition the solution was stirred for 20 minutes and then filtered, washing the residue with THF (500 mL) ; the filtrate and washings were combined and evaporated to give crude desired compound which was used in the next step without further purification. | |
With triphenylphosphine on polystyrene; di-isopropyl azodicarboxylate; for 0.5h; | Methyl 3-[dS)-2-methoxy-d-methylethv?oxyl-5-[phenylmethylloxylbenzoateTo a solution of methyl 3-hydroxy-5-[phenyhnethyl]oxy}benzoate (77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7g of 3 mmol/g loading, 155 mmol) and (i?)-(-)-l-methoxy-2-propanol (102 mmol). The stirred solution was blanketed with argon and cooled in an ice bath. A solution of DIAD (116 mmol) was added dropwise by syringe over 10 minutes. The solution was stirred for 20 minutes and filtered, washing the residue with THF (500 mL). The filtrate and washings were combined, and evaporated to give the desired compound which was used without further purification. 1H NMR ? (dg-DMSO): 3.26 (s, 3H), 3.44 (m, 2H), 3.82 (s, 3H), 4.63 (m, IH)5 5.14 (s, 2H), 6.85 (s, IH), 7.05 (s, IH), 7.11 (s, IH), 7.30-7.47 (m, 5H). The 1H NMR spectrum also contained signals consistent with a small amount of bis(l-methylethyl)hydrazine-l,2- dicarboxylate. | |
With di-isopropyl azodicarboxylate; In tetrahydrofuran; at 0℃; for 0.5h; | Methyl 3-benzyloxy-5-r (1 S)-2-methoxy-1-methylethoxyl-benzoate; To a solution of methyl 3-benzyloxy-5-hydroxy-benzoate (20 g, 77.4 mmol) in THF was added polymer-supported triphenyl phosphine (51.7 g of 3 mmol/g loading, 155mmol, 2.0 eq) and (R)-l-methoxy-propan-2-ol (10 ml, 102 mmol, 1.3 eq). The stirred solution was blanketed with argon and cooled in an ice bath; a solution of di-isopropyl azodicarboxylate (DIAD, 22.8 ml 116 mmol, 1. 5eq) was added dropwise from a syringe over 10 mins. After addition the solution was stirred for 20 mins and then filtered, washing the residue with THF (500 ml); the filtrate and washings were combined and evaporated to give crude methyl 3-benzyloxy-5- [(lS)-2-methoxy-1-methylethoxy]-benzoate which was used in the next step without further purification, 'H NMR (d6-DMSO) : 3.26 (s, 3H), 3.44 (m, 2H), 3. 82 (s, 3H), 4.63 (m, 1H), 5.14 (s, 2H), 6.85 (s, 1H), 7.05 (s, 1H), 7.11 (s, 1H), 7.30-7. 47 (m, 5H) ; the spectrum also contained signals consistent with a small amount of N, N' di (isopropyloxy carbonyl hydrazine). | |
With di-isopropyl azodicarboxylate; at 0℃; for 0.5h; | Methyl 3-F(I ^-2-methoxy-( 1 -methylethvDoxyl -5- { [phenylmethyl] oxy)benzoateTo a solution of methyl 3-hydroxy-5-[phenylmethyl]oxy}benzoate (77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7g of 3 mmol/g loading, 155 mmol) and (i?)-(-)-l-methoxy-2-propanol (102 mmol). The stirred solution was blanketed with argon and cooled in an ice bath. A solution of DIAD (116 mmol) was added dropwise by syringe over 10 minutes. The solution was stirred for 20 minutes and filtered, washing the residue with THF (500 mL). The filtrate and washings were combined, and evaporated to give the desired compound which was used without further purification. EPO <DP n="59"/>1H NMR delta (d6-DMSO): 3.26 (s, 3H)5 3.44 (m, 2H), 3.82 (s, 3H), 4.63 (m, IH), 5.14 (s, 2H), 6.85 (s, IH), 7.05 (s, IH), 7.11 (s, IH), 7.30-7.47 (m, 5H) The 1H NMR spectrum also contained signals consistent with a small amount of bis(l- methylethyl)hydrazine- 1 ,2-dicarboxylate. | |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; | To a mixture of 3-Benzyloxy-5-hydroxy-benzoic acid methyl ester (2.6 g, 1.3 mmol) Triphenyl phosphine (6.76 g, 25.77 mmol) and (R)-l-Methoxy-propan-2-ol (1.85 g, 20.62 mmol), in THF was added DIAD (4.16 g, 20.62 mmol) at 0C and reaction mixture was stirred overnight at room temperature. . Product formation was monitored by TLC. On completion of reaction solvent was removed in vacuo, taken into water and extracted with ethyl acetate and dried over anhydrous sodium sulfate and concentrated in vacuo. Purified by column chromatography (silica gel 100-200 mesh, 25% ethylacetate in hexanes as eluent) to afford compound. (3.3 g) NMR (DMSO-d6, 400 MHz):- delta 1.20 (d, J = 6.4 Hz, 3H), 3.27 (s, 3H), 3.40-3.50 (m, 2H), 3.83 (s, 3H), 4.60-4.70 (m, 1H), 5.15 (s, 2H), 6.87 (s, 1H), 7.06 (s, 1H), 7.12 (s, 1H), 7.30-7.45 (m, 5H).MS (EI) mlz: 331 .2 (M + 1 ). | |
With triphenylphosphine on polystyrene; di-isopropyl azodicarboxylate; In tetrahydrofuran; at 0℃; for 0.5h; | To a solution of methyl 3-hydroxy-5- ( [phenylmethyl]oxy)benzoate (77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7g of 3 mmol/g loading, 155 mmol) and (R)-(-)- I -methoxy-2-propanol (102 mmol). The stirred solution was blanketed with argon and cooled in an ice bath. A solution of DIAD (116 mmol) was added dropwise by syringe over 10 minutes. The solution was stirred for 20 minutes and filtered, washing the residue with THF . (500 mL). The filtrate and washings were combined, and evaporated to give the desired compound which was used without further purification. 'H NMR 8 (d6-DMSO) : 3.26 (s, 3H), 3.44 (m, 2H), 3.82 (s, 3H), 4.63 (m, 1H), 5.14 (s, 2H), 6.85 (s, 1 H), 7.05 (s, 1H), 7.11 (s, 1 H), 7.30-7.47 (m, 5H). The 'H NMR spectrum also contained signals consistent with a small amount ofbis( I -methylethyl)hydrazine- 1 ,2- dicarboxylate. | |
With polymer supported triphenylphosphine; di-isopropyl azodicarboxylate; In tetrahydrofuran; at 0℃; for 0.5h; | To a solution of methyl 3-hydroxy-5-[phenylmethyl]oxy}benzoate (77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7g of 3 mmol/g loading, 155 mmol) and (i?)-(-)-l-methoxy-2-propanol (102 mmol). The stirred solution was blanketed with argon and cooled in an ice bath. A solution of DIAD (116 mmol) was added dropwise by syringe over 10 minutes. The solution was stirred for 20 minutes and filtered, washing the residue with THF (500 mL). The filtrate and washings were combined, and evaporated to give the desired compound which was used without further purification. 1H NMR delta (de-DMSO): 3.26 (s, 3H), 3.44 (m, 2H), 3.82 (s, 3H), 4.63 (m, IH), 5.14 (s, 2H), 6.85 (s, IH), 7.05 (s, IH), 7.11 (s, IH), 7.30-7.47 (m, 5H) The 1H NMR spectrum also contained signals consistent with a small amount of bis(l- methylethyl)hydrazine- 1 ,2-dicarboxylate. | |
With triphenylphosphine on polystyrene; di-isopropyl azodicarboxylate; In tetrahydrofuran; at 0℃; for 0.5h;Ice bath; | To a solution of methyl 3-(benzyloxy)-5-hydroxybenzoate (77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7 g of 3 mmol/g loading, 155 mmol) and (/?)-(- )-l-methoxy-2-propanol (102 mmol). The stirred solution was blanketed with argon and cooled in an ice bath. A solution of diisopropylazodicarboxylate (116 mmol) was added dropwise by syringe over 10 minutes. The solution was stirred for 20 minutes and filtered, washing the residue with THF (500 ml). The filtrate and washings were combined, and evaporated to give the desired compound which was used without further purification. 1H NMR delta (d6-DMSO): 3.26 (s, 3H), 3.44 (m, 2H), 3.82 (s, 3H), 4.63 (m, IH), 5.14 (s, 2H), 6.85 (s, IH), 7.05 (s, IH), 7.11 (s, IH), 7.30-7.47 (m, 5H) The 1H NMR spectrum also contained signals consistent with a small amount of bis(l- methylethyl)hydrazine-l,2-dicarboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-tert-butyl-diazodicarboxylate; In tetrahydrofuran; at 18 - 25℃; | Methyl 6-{3-[(1S)-1-methyl-2-phenylethoxy]-5-[(1S)-2-methoxy 1-methylethoxyl-benzoylamino -3-pyridinecarboxylate; To a stirred suspension of methyl 6- {3- [ (lS)-l-methyl-2-phenylethoxy]-5- hydroxy-benzoylamino}-3-pyridine carboxylate (l. Og, 2.46 mmol), (R)-l-methoxy-2-propanol (0.34 ml, 3.47 mmol, 1.4 eq) and polymer-supported triphenyl phosphine (approx. 3 mmol/g, 2. 5 g, approx 3 eq) in dry THP (20 ml), under argon, was added di-tert-butyl azodicarboxylate (DTAD, 1.13g, 4.9 mmol, 2 eq), and the reaction mixture stirred overnight at ambient temperature. Most of the organic solvent was removed in vacuo, and ethyl acetate added to the residue; the suspension was filtered through celite and washed through with more ethyl acetate. The solvent was removed in vacuo, and the residue chromatographed (40g Biotage silica cartridge, eluting with hexane containing ethyl acetate, 10% increasing to 20%) to give methyl 6- {3- [ (lS)-1-methyl-2-phenylethoxy]-5- [ (lS)-2-methoxy- l-methylethoxy]-benzoylamino}-3-pyridinecarboxylate (740 mg) as a colourless gum, lH NMR (d6-DMSO) : 1.2 (2d, 6H), 2.9-3. 0 (m, 2H), 3.3 (s, 3H), 3.45 (m, 2H), 3. 85 (s, 3H), 4. 7 (m, 1H), 4.8 (m, 1H), 6.65 (s, 1H), 7.2 (m, 3H), 7.3 (m, 4H), 8.3 (s, 2H), 8. 9 (s, 1H), 11.1 (br s, 1H); m/z 479 (M+H) +, 477 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium hydride; In tetrahydrofuran; at -5 - 20℃; for 19h; | Preparation 94; 3, 5-Difluoro-4- (2-methoxv- (1 R)-methyl-ethoxy)-benzonitrile; 3,4, 5-Trifluorobenzonitrile (5g, 31. 83mmol) and (2R)-1-methoxy-propan-2-ol (3.44g, 38. 2mmol) were dissolved in tetrahydrofuran (60mL) and cooled to-5C. Sodium hydride (60% dispersion in mineral oil, 1.53g, 38. 20mmol) was slowly added and the mixture was stirred for 1 hour. The reaction vessel was then warmed to room temperature and stirring continued for a further for 18 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane (200mL) and water (200mL). The organic phase was washed with brine, dried over sodium sulfate and was concentrated in vacuo to form an oily residue. The residue was then azeotroped with pentane (x5) and dichloromethane (x5) to give the title compound as a pale yellow oil in 94% yield (6. 8g).'H NMR (CDC13, 400MHz) o : 1.38 (d, 3H), 3.37 (s, 3H), 3.53 (m, 1 H), 3.59 (m, 1 H), 4.60 (m, 1 H), 7.21 (d, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine on polystyrene; In tetrahydrofuran; at 0℃; for 0.5h; | Methyl 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-[phenylmethyl]oxy}benzoic; To a solution of methyl 3-hydroxy-5-[phenylmethyl] oxy} benzoate (77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7g of 3 mmol/g loading, 155 mmol) and (R)- (-)-l-methoxy-2-propanol (102 mmol). The stirred solution was blanketed with argon and cooled in an ice bath. A solution of DIAD (116 mmol) was added dropwise by syringe over 10 minutes. The solution was stirred for 20 minutes and filtered, washing the residue with THF (500 mL). The filtrate and washings were combined, and evaporated to give the desired compound which was used without further purification. 'H NMR 6 (d6-DMSO) : 3.26 (s, 3H), 3.44 (m, 2H), 3.82 (s, 3H), 4.63 (m, 1H), 5.14 (s, 2H), 6.85 (s, 1H), 7.05 (s, 1H), 7.11 (s, 1H), 7.30-7. 47 (m, 5H) The 1H NMR spectrum also contained signals consistent with a small amount of bis (l- methylethyl) hydrazine-1, 2-dicarboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | A stirred suspension of methyl 3-hydroxy-5-[(2-methylphenyl)methyl]oxy}benzoate (15.3 g, 56.25 mmol) and triphenyl phosphine (14.4 g, 55 mmol) in dry chloromethane (900 ml) was cooled in an ice-bath and diisopropyl azodicarboxylate (11.88 ml, 55 mmol) was added dropwise. The reaction mixture was stirred at 0-5 0C for 30 minutes and (R)-methoxy-propan- 2-ol was added dropwise. The reaction mixture was stirred at ambient temperature for 16 hours, and filtered through diatomaceous earth. The filtrate was evaporated and purified by <n="53"/>column chromatograph on silica gel eluting with 10% ethyl acetate in iso-hexane to give the desired compound (10.7 g, 55%).1H NMR (300 MHz, CDCI3) delta: 7.40 (d, 1 H), 7.25 (m, 5 H), 6.80 (s, 1 H), 5.00 (s, 2 H), 4.60- 4.55 (m, 1 H), 3.92 (s, 3 H), 3.63-3.51 (m, 2 H), 3.42 (s, 3 H), 2.41 (s, 3 H), 1.32 (d, 3 H). | |
Methyl 3-rl [{(1S)-2-methoxy-(1-methylethyl)oxy]-5-[(2-methylphenyl)methyl]oxy} benzoate; A stirred suspension of methyl 3-hydroxy-5-[(2-methylphenyl) methyl] oxy} benzoate (15.3 g) and polymer-supported triphenyl phosphine (39.2 g) in dry DCM (900 mL) was cooled in an ice-bath and diisopropyl azodicarboxylate (11.88 mL) was added drop wise. The reaction mixture was stirred at 0-5C for 30 minutes and (R)-l-methoxy-propan-2-ol was added dropwise. The reaction mixture was stirred at ambient temperature for 16 hours, filtered through diatomaceous earth and the DCM evaporated to a residue which was chromatographed on silica with 10% ethyl acetate in isohexane as eluant to give the desired compound (10.7 g). 'H NMR 8 (CDC13) : 1.3 (d, 3H), 2.4 (s, 3H), 3.4 (s, 3H), 3.5-3. 6 (m, 2H), 3.9 (s, 3H), 4.55-4. 6 (m, 1H), 5.0 (s, 2H), 6.8 (s, 1H), 7.25 (m, 5H), 7.4 (d, 1H) | ||
A stirred suspension of methyl 3-hydroxy-5-[(2-methylphenyl)methyl]oxy}benzoate (15.3 g) and polymer-supported triphenyl phosphine (39.2 g) in dry DCM (900 mL) was cooled in an ice-bath and diisopropyl azodicarboxylate (11.88 mL) was added drop wise. The reaction mixture was stirred at 0-50C for 30 minutes and <strong>[4984-22-9](R)-1-methoxy-propan-2-ol</strong> was added dropwise. The reaction mixture was stirred at ambient temperature for 16 hours, filtered through diatomaceous earth and the DCM evaporated to a residue which was chromatographed on silica with 10% ethyl acetate in isohexane as eluant to give the desired compound (10.7 g). 1H NMR delta (CDCl3): 1.3 (d, 3H), 2.4 (s,3H), 3.4 (s, 3H), 3.5- 3.6 (m, 2H), 3.9 (s, 3H), 4.55-4.6 (m, 1H), 5.0 (s,2H), 6.8 (s, 1H), 7.25 (m, 5H), 7.4 (d, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | To a stirred suspension of 33a (0.14 g, 0.5 mmol) and triphenyl phosphine (0.26 g, 1.0 mmol) in dry tetrahydrofuran (10 mL), under argon was added <strong>[4984-22-9](R)-1-methoxy-2-propanol</strong> (63.0 mul, 0.7 mmol) at room temperature. The reaction was cooled to 0 C and diisopropyl azodicarboxylate (0.20 g, 1.0 mmol) was added. The reaction mixture was stirred overnight at ambient temperature, and then water was added. The aqueous layer was extracted with ethyl acetate. And the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether, v/v, 10:90 to 50:50) to afford compound 34a as a yellow oil. (0.14 g, 80%). 1H NMR (300 MHz, CDCl3) delta 7.44 (s, 1H), 7.28 (s, 1H), 6.83 (t, J = 2.3 Hz, 1H), 6.57-6.53 (m, 3H), 4.62-5.58 (m, 1H), 3.90 (s, 3H), 3.61-3.48 (m, 2H), 3.40 (s, 3H), 1.33 (d, J = 6.3 Hz, 3H). |
75% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; | Methyl 3-[(3,5-difluorophenyl)oxy]-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate; To a solution of methyl 3- [ (3, 5-difluorophenyl) oxy] -5-hydroxybenzoate (15.0 mmol), (R)- (-)- l-methoxy-2-propanol (18.75 mmol) and triphenylphosphine (18.0 mmol) in anhydrous THF (100 mL) at 0C was added DIAD (18.0 mmol). The reaction was stirred at ambient temperature overnight, concentrated in vacuo, and the residue triturated with a 1: 1 mixture of ethyl acetate: isohexane. The solid was removed by filtration and the filtrate concentrated in vacuo, chromatographed on silica (using a Biotage Flash 75 eluting with 10-15% ethyl acetate in isohexane) to give the title compound (75% yield). 'H NMR 8 (d6-DMSO) : 1.21 (d, 3H), 3.27 (s, 3H obscured by solvent peak), 3.46 (m, 2H), 3.82 (s, 3H), 4.69 (m, 1H), 6.81 (dd, 2H), 7.01-7. 07 (m, 2H), 7.10 (s, 1H), 7.28 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | Example 47; 2-{4-(4-Chloro-phenyl)-5-[4-(2-methoxy-(1S)-methyl-ethoxy)-phenyl]-4H- [1, 2, 41triazol-3-vlmethv-2H-f 1, 2, 31triazole; The product of preparation 7 (225mg, 0. 64mmol), (2R)-1-methoxy-propan-2-ol (0.09g, 1 mmol) and triphenylphosphine (262mg, 1mmol) were dissolved in tetrahydrofuran (7mL) and the mixture was cooled to 0C. Dibenzyl azodicarboxylate (230mg, 1mmol) was added dropwise and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was concentrated to low volume in vacuo, treated with triethylsilane (10mL) and cooled to 0C. Trifluoroacetic acid (4mL) was added dropwise and the solution was stirred at room temperature for a further 18 hours. The solvent was concentrated in vacuo and the residue taken up in dichloromethane (12mL) and sodium hydrogen carbonate. The mixture was then filtered through a phase separation tube and the filtrate was concentrated in vacuo. Purification by column chromatography on silica gel, eluting with dichloromethane : methanol, 100: 0 to 99.75 : 0.25, afforded the title compound as a white foam in 22% yield (95mg). 'H NMR (CDCl3, 400MHz) No.: 1.29 (d, 3H), 3.39 (s, 3H), 3.46 (m, 1H), 3.56 (m, 1H) 4.53 (m, 1H), 5.71 (s, 2H), 6.83 (d, 2H), 7.05 (d, 2H), 7.33 (d, 2H), 7.36 (d, 2H) 7.52 (s, 2H). MS APCI+ m/z 425 [MH] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 4; 4- (4-Chloro-phenvl)-3- [4- ( (1 R)-2-methoxy-1-methyl-ethoxy)-phenvil-5-methvl-4H- rl, 2, 41triazole; The alcohol of preparation 6 (325mg, 1. 14mmol), (2R)-methoxypropan-2-ol (130muL, 1. 39mmol) and triphenylphosphine (600mg, 2. 29mmol) were dissolved in tetrahydrofuran (5mL) and the mixture was treated with a solution of dibenzyl azodicarboxylate (525mg, 2. 28mmol) in tetrahydrofuran (2.5mL). The reaction mixture was stirred at room temperature for 3 hours and then diluted with dichloromethane (10mL) and treated with triethylsilane (1mL) and trifluoroacetic acid (15mL). The mixture was stirred at room temperature for a further 18 hours and was then concentrated in vacuo. The residue was taken up in 10% sodium carbonate solution (10mL) and was extracted with dichloromethane (50mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The purification of the crude product by column chromatography on silica gel, eluting with dichloromethane : methanol : 0.88 ammonia, 100: 0: 0 to 97.5 : 2.5 : 0.25, afforded the title product, 73mg. 'H NMR (CDCI3, 400MHz) o : 1.27 (d, 3H), 2.32 (s, 3H), 3.38 (s, 3H), 3. 42-3. 48 (m, 1H), 3.51-3. 57 (m, 1H), 4.52 (m, 1H), 6.82 (m, 2H), 7.12 (m, 2H), 7.28 (m, 2H), 7.47 (m, 2H). MS ES+ m/z 358 [MH] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | PREPARATION 165 (R)-1-Methoxy-2-propanol Sodium methoxide (54 g, 1.0 mol) was added portionwise to ice-cooled methanol (1000 ml), and the resulting solution stirred for 20 minutes in an ice-bath. (R)-Propylene oxide (58 g, 1 mol) was added dropwise over 30 minutes, and once addition was complete, the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, and acidified, with ice-cooling, using (1M) ethereal hydrochloric acid, and the resulting mixture stirred for an hour, then filtered. The filtrate was dried (K2CO3), filtered and evaporated under reduced pressure. The residue was heated to 70 C. over dried calcium oxide for 30 minutes, then distilled at atmospheric pressure to afford the title compound (25.4 g, 28%) as an oil. b.p. 118-120 C. delta (CDCl3): 1.16 (3H, d), 2.28 (1H, d), 3.20 (1H, m), 3.36 (1H, m), 3.40 (3H, s), 13.97 (1H, m). [alpha]D-20.83 (c=1.02, dichloromethane) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
DIAD (1.18 mL, 6.0 mmol) was added to a stirred solution of methyl 3-hydroxy-5-[(4- methyl-5-oxo-2,3,4,5-tetrahydro-l,4-benzoxazepin-8-yl)oxy]benzoate (1.72 g, 5.0 mmol) and triphenylphosphine (2.62g, 10.0 mmol) in THF (50 mL) at 0C-5C. The mixture was stirred for 30 minutes, then treated with (i?)-l-methoxy-2-propanol (675 mg, 7.5 mmol) and the mixture stirred at RT for 18 hours. The mixture was evaporated in vacuo to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane. The residue was slurried in ether (25 mL), filtered, and the filtrates evaporated in vacuo to give the desired compound (2.41 g) with a small amount of contaminating triphenylphosphine present. The material was used in the next steps without further purification. 1H NMR delta (CDCl3): 1.25 (d, 3H), 3.15 (s, 3H), 3.3 (s, 3H), 3.4 - 3.5 (m, 2H), 3.5 (t,2H), 3.8 (s, 3H), 4.3 (t,2H), 4.5 (m, IH), 6.5 (d, IH), 6.7 (d, IH), 6.75 (d, IH), 7.2 (d, IH), 7.35 (d, IH), 7.8 (d, IH); m/z 416 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20 - 30℃; for 2.5h; | A solution of methyl 3-(4-cyanophenoxy)-5-hydroxybenzoate (5.0g, 18.6 mmol), (R)-I- methoxy-2-propanol (2.72 ml, 27.9 mmol) and triphenyl phosphine (7.30 g, 27.9 mmol) in anhydrous THF (300 ml) was treated in an argon atmosphere with diethyl azodicarboxylate (DEAD, 4.39 ml, 27.9 mmol added dropwise). The temperature rose from 2O0C to 3O0C; the pale yellow solution was stirred for 2 1A hours and then concentrated to a yellow oil. This was stirred in EtOAc/hexane (300 ml of a 1:1 mixture) over the weekend and then EPO <DP n="123"/>filtered and the filtrate concentrated to a yellow oil. This was purified by chromatography (40Og silica column, Biotage Flash 75 , gradient eluting with hexane containing 0% - 30% ethyl acetate) to give the title compound (6.35g, 100%). 1H NMR (400 MHz, DMSO) delta 1.23 (d, 3H), 3.33 (s, 3H), 3.42 - 3.54 (m, 2H), 3.86 (s, 3H), 4.66 - 4.77 (m, IH), 7.07 (t, IH), 7.12 - 7.16 (m, IH), 7.15 - 7.21 (m, 2H), 7.30 - 7.37 (m, IH), 7.84 - 7.91 (m, 2H), m/z 340 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0℃; for 0.5h; | To a solution of methyl 3-hydroxy-5-[phenylmethyl]oxy}benzoate (77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7g of 3 mmol/g loading, 155 mmol) and (i?)-(-)-l-methoxy-2-propanol (102 mmol). The stirred solution was blanketed with argon and cooled in an ice bath. A solution of DIAD (116 mmol) was added dropwise by syringe over 10 minutes. The solution was stirred for 20 minutes and filtered, washing the residue with THF (500 mL). The filtrate and washings were combined, and evaporated to give the desired compound which was used without further purification. 1H NMR delta (d6-DMSO): 3.26 (s, 3H), 3.44 (m, 2H), 3.82 (s, 3H), 4.63 (m, 1H), 5.14 (s, 2H), 6.85 (s, 1H), 7.05 (s, 1H), 7.11 (s, 1H), 7.30-7.47 (m, 5H) The 1H NMR spectrum also contained signals consistent with a small amount of bis(l- methylethyl)hydrazine- 1 ,2-dicarboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In 1,4-dioxane; at 70℃; for 6h; | Compound 120: (S)-3-methoxy-5-(3-(1-methoxypropan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy)phenyl)-1H-pyrazole ADDP (0.13 g) was added to a mixture of Compound 114 (0.09 g), <strong>[4984-22-9](R)-1-methoxypropan-2-ol</strong> (0.023 g), tributylphosphine (0.10 g), and 1,4-dioxane (10 mL) at 70 C. The whole was stirred at 70 C. for 2 h, then tributylphosphine (0.10 g) and ADDP (0.13 g) were added to the mixture. The whore was stirred at 70 C. for further 4 h. The whole was concentrated in vacuo. The residue was purified by chromatographed on SiO2 with hexane-ethyl acetate (2/1 to 1/3, v/v) then by HPLC to give the title compound as a colorless oil (0.03 g). 1H NMR (400 MHz, CHLOROFORM-d) delta 1.34 (d, J=6.32 Hz, 3H), 3.09 (s, 3H), 3.41-3.44 (m, 3H), 3.48-3.64 (m, 2H), 3.94 (s, 3H), 4.52-4.65 (m, 1H), 5.95 (br. s., 1H), 6.65 (t, J=2.15 Hz, 1H), 6.86 (t, J=1.77 Hz, 1H), 6.99-7.03 (m, 1H), 7.10-7.19 (m, 2H), 7.88-7.96 (m, 2H). [M+H] calc'd for C21H24N2O6S 433; found, 433. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | (a) (S)-4-(1-methoxypropan-2-yloxy)pyridine (91) Pyridin-4-ol (10 g, 105.15 mmol), <strong>[4984-22-9](R)-1-methoxypropan-2-ol</strong> (9.48 g, 105.15 mmol) and triphenylphosphine (30.3 g, 115.67 mmol) were added to THF (250 mL) and stirred for 10 minutes. To this was slowly added DIAD (22.49 mL, 115.67 mmol) and the reaction was stirred for 1 hour at 25 C. The solvent was evaporated and diethyl ether (100 mL) was added. To this was added a little triphenyl phosphine oxide and the reaction was stirred for 20 minutes to afford a solid, which was discarded. The solvent was evaporated and the pale yellow gum was acidified with 2.0HCl, extracted with Et2O (1*75 mL) and the aqueous was then basified with solid KOH. This was then extracted with Et2O (3*75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford yellow gum. This was purified by distillation at 0.43 mBar, collecting fractions that distilled at 80 C. to afford the desired material as a colourless oil (15.30 g, 87% yield); 1H NMR (400.132 MHz, CDCl3) delta 1.34 (3H, d), 3.40 (3H, s), 3.50 (1H, dd), 3.58 (1H, dd), 4.68-4.60 (1H, m), 6.82 (2H, d), 8.40 (2H, d); m/z (LC-MS, ESI+), RT=1.28 (M+H 168). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With trifluoroacetic acid; at 100℃; for 17.5h; | Method LXII: Compound ZZ. A suspension of the sulfone (BN)(15.8 mg), <strong>[4984-22-9](R)-1-methoxy-2-propanol</strong> (300 muL), and TFA (10 muL) was heated to 100 C. for 17.5 h. The reaction was cooled to 23 C., diluted with H2O (600 muL) and loaded directly onto a Teledyne Isco ?gold? 5.5 gram column and flashed (Eluent: 0.05% wlv aq. HCl/CH3CN 95:5?0:100), giving DR (13 mg, 76% yield) as a monohydrochloride salt. 1H NMR (CDCl3, 300 MHz): delta (ppm) 12.64 (s, 1H), 9.68 (s, 1H), 8.36 (s, 1H), 7.93 (s, 1H), 7.49-7.20 (m, 4H), 5.27 (s, broad, 2H), 4.87 (s, 2H), 4.40-4.08 (m, 5H), 3.67-3.30 (m, 4H), 3.34 (s, 3H), 2.85-2.70 (m, 2H), 2.30-2.20 (m, 2H), 2.20-2.10 (m, 2H), 1.35-1.18 (m, 6H). LCMS-ESI+: calc'd for C24H35N6O6: 503.3 (M+H+); Found: 503.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylamine hydrochloride; triethylamine; In toluene; at -5 - 8℃; for 1h;Inert atmosphere; | To a flask was added under a nitrogen atmosphere trimethylamine hydrochloride (0.1 eq), tosyl chloride (1.3 eq) and toluene (5 vols) and the reaction mixture agitated to form an oily slurry. The slurry was cooled to -5 C. (2R)-1-Methoxypropan-2-ol (1.0 eq) was added drop-wise over 30 minutes. Toluene (2.5 vols) was added as a wash followed by triethylamine (1.5 eq), which was added drop-wise via addition funnel over 30 minutes maintaining the reaction temperature <8 C. Further toluene (2.5 vols) was added as a wash and the reaction mixture held at -5 C. to 5 C. for 4.5 hours. N,N-Dimethyl-1,3-propane-diamine (0.3 eq) was added over 10 minutes at -5 C. The mixture was agitated at -5 C. to 5 C. for 30 minutes. Then 2N hydrochloric acid (0.55 eq) and 70 ml water were added. The mixture was agitated for 30 minutes at 22 C. and the aqueous layer was separated off and discarded. The mixture was washed twice more with water (10 vols each wash) and after separation of the aqueous wash, the toluene layer was distilled to an oil on the rotary evaporator. Toluene (20 vols) was added to the oil and the solution evaporated to give the title compound as a dry light brown oil. Yield (corrected for assay) 93-97%. 1H NMR (400 MHz CDCl3): delta 7.78-7.75 (d, 2H), 7.45-7.43 (d, 2H), 4.66-4.62 (m, 1H), 3.35-3.26 (m, 2H), 3.16 (s, 3H), 2.4 (s, 3H), 1.13-1.11 (d, 3H) |
82% | General procedure: A mixture of NaH (9.52g, 238mmol) in THF (200mL) was added (S)-1-methoxypropan-2-ol (21g, 233mmol) dropwise at 0C. The reaction mixture was stirred at room temperature for 1.5h, and then TosCl (45.3g, 230mmol) in THF (200mL) was added while the temperature was kept below 10C. The reaction mixture was then stirred at room temperature overnight. The resulting mixture was quenched with water (20mL) and extracted with ethyl acetate (200mL×3). The combine organic layers were concentrated and the residue was purified by silica gel flash chromatography (eluting with ethyl acetate in petroleum ether 5-15%) to give the product 55a as a yellow solid (37.1g, yield=65.1%). | |
51% | With pyridine; In dichloromethane; at 20℃; for 16h; | To a solution of (R)-l-methoxypropan-2-ol (available from Combi-block) (5 g, 55 mmol) in DCM (50 ml.) and pyridine (25 ml.) was added 4-methylbenzenesulfonyl chloride (11.6 g, 61 mmol) and the reaction mixture was stirred at room temperature for 16 h. Ice (100 g) was added and the mixture was stirred for 1 h. The organic phase was separated and washed with 10% aq. H2SO4 (4 x 25 ml_), water (30 ml_), dried (Na2S04), and then filtered through silica eluting with DCM (100 ml_). The filtrate was concentrated under reduced pressure to give the title compound (7 g, 51%) as a colourless liquid: MS ES+ve m/z 245 (M+H)+; [a]D25 -2 (c=l in CHC ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylamine hydrochloride; triethylamine; In toluene; at 5 - 12℃; for 18.83h; | To a flask was added 4-trifluoromethylsulfonylchloride (1.3 eq) and toluene (10 vols), the reaction mixture was cooled to 5 C., then <strong>[4984-22-9](2R)-1-methoxypropan-2-ol</strong> (1.0 eq) was added at 5 C. Trimethylamine hydrochloride (0.1 eq) was added at 5 C., then triethylamine (1.5 eq) added slowly drop-wise over 50 minutes maintaining the reaction temperature between 5-12 C. After holding for approximately 18 hours at 5 C., the reaction was quenched by the dropwise addition of 3-dimethylaminopropane (0.3 eq) over minutes at 5 C. The reaction mixture was stirred for 2 hours at 5 C., then water (5 vols) added at 5 C., then 5N hydrochloric acid (2 vols) was added slowly at 5 C. The reaction mixture was warmed to 20 C., water (1 vol) was added followed by toluene (10 vols). The reaction mixture was warmed to 30 C., then the aqueous layer separated off and discarded. Water (5 vols) was added and the reaction mixture agitated for 30 minutes, then the water layer separated off and discarded. 8% w/w Sodium carbonate (4 vols) was added, the reaction mixture agitated for 30 minutes, then the water layer separated off and discarded. Water (5 vols) was added, the batch agitated for 30 minutes, then the water layer separated off and discarded. This water wash was repeated twice. The organic layer was evaporated to an oil on the rotary evaporator. Toluene was added and the organic layer was evaporated to an oil on the rotary evaporator. This process was repeated to give the desired product as a yellow oil (corrected yield 97%). 1H NMR delta (400 MHz CDCl3) 8.07-8.05 (d, 2H), 7.82-7.80 (d, 2H), 4.84-4.80 (m, 1H), 3.44-3.35 (m, 1H), 3.19 (s, 3H), 1.35-1.33 (d, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In toluene; at 0 - 5℃; for 2h;Product distribution / selectivity; | Methyl 3-hydroxy-5-[(phenylcarbonyl)oxy]benzoate (1.0 eq.), <strong>[4984-22-9](R)-1-methoxy-2-propanol</strong> (1.25 eq.) and triphenylphosphine (1.25 eq.) were suspended in toluene (10 vol). Diisopropyl azodicarboxylate (1.25 eq.) was added at a batch temperature of between 0 and 5 C. over 2 h. The mixture was allowed to warm to room temperature and was stirred for further 30 min at this temperature. The resulting suspension was filtered to remove the bulk of the triphenylphosphine oxide formed and the filter cake was washed with toluene (1.5 vol). To the combined toluene fractions containing the resulting methyl 3-[(1S)-2-methoxy-1-methylethoxy]-5-[(phenylcarbonyl)oxy]benzoate was added sodium methylate (0.8 eq.) at a batch temperature of between 20 and 30 C. and the mixture was stirred to 1 h. The solution of the resulting methyl 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]-benzoate was then extracted twice with KOH 0.25 M (3.5 vol each) at a batch temperature of between 0 and 5 C. KOH was then added (1 eq.) to hydrolyse the ester moiety and the batch was stiffed for 1 h at a temperature of between 20 and 30 C. The pH of the aqueous phase is then adjusted to 1.5 using conc. hydrochloric at a batch temperature of <30 C. Crude 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid was subsequently extracted into MTBE (2×3 vol) before activated charcoal was added. The batch was stirred for 10 minutes and then filtered. The batch was reduced to 3 pot volumes by distillation at a batch temperature of <45 C. Toluene (4 vol) and heptane (1 vol) were added and vacuum distillation was continued at a batch temperature of <50 C. until no further MTBE was collected. The batch was cooled to a temperature of <40 C., seeded and further cooled to a batch temperature of between 28 and 32 C. The resulting suspension was stirred for 1 h at this temperature before being further cooled to 5 to 10 C. After 2 h stirring at 5 to 10 C. the batch was filtered and washed with cold toluene (1 vol.). Drying at <60 C. furnished 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid in >99% purity as colourless solid with a melting point of 95 C. in a typical yield between 65 and 70% from methyl 3-hydroxy-5-[(phenylcarbonyl)oxy]benzoate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triphenylphosphine; diethylazodicarboxylate; In toluene; at 0 - 20℃;Inert atmosphere;Product distribution / selectivity; | (38a) 1-Bromo-3-methoxy-5-[(1S)-2-methoxy-1-methylethoxy]benzene 3-Bromo-5-methoxyphenol (7.60 g, 37.4 mmol) synthesised in Example (1a) was dissolved in toluene (100 mL), and R-(-)1-methoxy-2-propanol (4.40 mL, 44.9 mmol) and triphenylphosphine (13.8 g, 52.6 mmol) were added, followed by dropwise addition of diethyl azodicarboxylate (2.2 mol/l toluene solution, 24 mL, 52.8 mmol) at 0C and stirring at room temperature for 1.5 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure, diethyl ether (100 mL) was added, and the deposit was filtered to be removed. The mother liquor was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-20%) to afford the desired compound (9.22 g, yield 89%) as a colorless liquid. 1H-NMR (CDCl3, 400 MHz): delta 1.30 (3H, d, J=6.3 Hz), 3.40 (3H, s), 3.47 (1H, dd, J=10.6, 4.3 Hz), 3.55 (1H, dd, J=10.4, 6.1 Hz), 3.76 (3H, s), 4.46-4.52 (1H, m), 6.42 (1H, t, J=2.2 Hz), 6.65 (1H, dd, J=2.3, 1.6 Hz), 6.69 (1H, t, J=2.0 Hz). MS (EI) m/z: 274 (M)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triphenylphosphine; diethylazodicarboxylate; In toluene; at 0 - 20℃;Inert atmosphere; | (13a) 1-Bromo-3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]benzene 3-Bromo-5-[4-(methylsulfonyl)phenoxy]phenol (4.86 g, 14.2 mmol) synthesised in Example (1c) was dissolved in toluene (100 mL), and <strong>[4984-22-9](R)-(-)-1-methoxy-2-propanol</strong> (1.77 mL, 18.1 mmol) and triphenylphosphine (4.10 g, 15.6 mmol) were added, followed by cooling to 0C. Under nitrogen atmosphere, diethyl azodicarboxylate (40% toluene solution, 7.75 mL, 17.1 mmol) was added dropwise over 10 minutes and stirring was carried out at 0C for 30 minutes, followed by raising the temperature naturally and stirring at room temperature overnight. Water (100 mL) and ethyl acetate (100 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-40%) to afford the desired compound (5.06 g, yield 86%) as a pale yellow oil. 1H-NMR (CDCl3, 400 MHz): delta 1.28 (3H, d, J=6.3 Hz), 3.05 (3H, s), 3.37 (3H, s), 3.46 (1H, dd, J= 3.9, 10.2 Hz), 3.54 (1H, dd, J=6.3, 10.2 Hz), 4.49 (1H, m), 6.56 (1H, d, J=2.0 Hz), 6.77 (1H, d, J=2.0 Hz), 6.93 (1H, d, J=2.0 Hz), 7.10 (2H, d, J=9.0 Hz), 7.89 (2H, d, J=9.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0 - 20℃;Inert atmosphere; | (1e) 2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 3-[4-(Methylsulfonyl)phenoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (13.20 g, 33.8 mmol) synthesised in Example (1d) was dissolved in tetrahydrofuran (300 mL), and <strong>[4984-22-9](R)-(-)-1-methoxy-2-propanol</strong> (3.70 mL, 37.8 mmol) and triphenylphosphine (9.78 g, 37.3 mmol) were added, and subsequently cooled to 0C. Diethyl azodicarboxylate (40% toluene solution, 16.2 mL, 37.2 mmol) was added dropwise over 10 minutes under nitrogen atmosphere and stirring was carried out at 0C for 30 minutes, followed by raising the temperature naturally and stirring at room temperature overnight. Water (300 mL) and ethyl acetate (300 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-40%) to afford the desired compound (11.94 g, yield 76%) as a colorless oil. 1H-NMR (CDCl3, 400 MHz): delta 1.31 (3H, d, J=6.7 Hz), 1.33 (12H, s), 3.05 (3H, s), 3.40 (3H, s), 3.48 (1H, dd, J=4.3, 10.2 Hz), 3.57 (1H, dd, J=5.9, 10.2 Hz), 4.58-4.62 (1H, m), 6.76 (1H, t, J=2.4 Hz), 7.05-7.09 (3H, m), 7.24 (1H, d, J=2.4 Hz), 7.87 (2H, d, J=9.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Step B Synthesis of methyl 3-{(1S)-2-methoxy-(1-methylethyl)oxy}-5-[(2-methylphenyl)methyl]oxy} benzoate: A stirred suspension of methyl 3-hydroxy-5-[(2-methylphenyl)methyl]oxy}benzoate (15.3 g, 56.25 mmol) and triphenyl phosphine (14.4 g, 55 mmol) in dry chloromethane (900 ml) was cooled in an ice-bath and diisopropyl azodicarboxylate (11.88 ml, 55 mmol) was added dropwise. The reaction mixture was stirred at 0-5 C for 30 minutes and (R)-methoxy-propan-2-ol was added dropwise. The reaction mixture was stirred at ambient temperature for 16 hours, and filtered through diatomaceous earth. The filtrate was evaporated and purified by column chromatograph on silica gel eluding with 10% ethyl acetate in iso-hexane to give the desired compound (10.7 g, 55%). 1H NMR (300 MHz, CDCl3) delta: 7.40 (d, 1 H), 7.25 (m, 5 H), 6.80 (s, 1 H), 5.00 (s, 2 H), 4.60-4.55 (m, 1 H), 3.92 (s, 3 H), 3.63-3.51 (m, 2 H), 3.42 (s, 3 H), 2.41 (s, 3 H), 1.32 (d, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
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Triphenyl phosphine (21 g, 80 mmol, 2.8 equiv.) was added to a stirring solution of Methyl 3-hydroxy-5-(4-(5-methyl-l,3,4-oxadiazol-2-yl) phenoxy)benzoate(Intermediate 7) (9.3 g, 28.52 mmol, 1 equiv.) in toluene (100 mL) under nitrogen atmosphere at room temperature. The mixture was heated to 90 0C for 30 min. A mixture of Diisopropylazadicarboxylate (DIAD) (11.52 g, 57 mmol, 2 equiv.) and (R)- (-)-l-Methoxy-propan-2-ol (3.8 g, 42.8 mmol, 1.5 equiv.) in tolunene (50 mL) was added to the above reaction mixture at 90 0C and the reaction mixture was stirred for 3 h at 100 0C. The completion of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under vacuum and purified by column chromatography to get (5)-Methyl 3-[(l-methoxypropan-2-yl)oxy]-5-[4-(5-methyl- l,3,4-oxadiazol-2-yl)phenoxy]benzoate (Intermediate 8) as thick liquid (27 g). Sodium hydroxide (3.43 g, 85.92 mmol, 3 equiv.) in water (55 mL) was added to a stirring solution of (5)-Methyl 3-[(l-methoxypropan-2-yl)oxy]-5-[4-(5-methyl- 1,3,4- oxadiazol-2-yl)phenoxy]benzoate (crude) (Intermediate 8) in methanol (110 mL) in round bottomed flask. The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After completion, methanol was removed under vacuum and water was added. The reaction mixture was filtered. Filtrate was washed with ethyl acetate. The aqueous layer was acidified and extracted with DCM twice. The combined organic layer was washed with water, brine and dried over anhydrous sodium sulphate, filtered and concentrated in vacuum to furnish title acid as thick liquid (9.5 g). 1H NMR (CDCl3, 400 MHz) delta ppm: 1.33 (d, J= 6.4 Hz, 3 H), 2.63 (s, 3 H), 3.41 (s, 3 H), 3.51-3.53 (m, 1 H), 3.57-3.61 (m, 1 H), 4.59-4.63 (m, 1 H), 6.88 (t, J= 2 Hz, 1 H), 7.10 (d, J= 8.8 Hz, 2 H), 7.35 (s, 1 H), 7.48 (s, 1 H), 8.01 (d, J= 8.8 Hz, 2 H); ESI-MS m/z (relative intensities): 385.2 (M+H)+ (100%), 407.19 (M+Na)+ (100%); UPLC Purity: 97.91 %; Ret.time.: 3.79 min. |
Yield | Reaction Conditions | Operation in experiment |
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24% | With sodium hydride; In diethyl ether; acetonitrile; mineral oil; at 0 - 20℃; | 2-Chloro-4-((R)-2-methoxy-1-methylethoxy)-5-trifluoro-methylpyrimidine A solution of 2.00 g (9.2 mmol) of 2,4-dichloro-5-trifluoromethylpyrimidine and 1.08 g (12.0 mmol) of <strong>[4984-22-9](R)-1-methoxypropan-2-ol</strong> in 24.4 ml of diethyl ether and 24.4 ml of acetonitrile were admixed at 0 C. with stirring in portions with 0.48 g of sodium hydride (55%). The mixture was slowly warmed to room temperature in an ice bath. After 3.5 hours, the mixture was admixed with ice and dilute sodium chloride solution. Extraction was carried out with ethyl acetate (2*). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The resulting residue was purified chromatographically (hexane/ethyl acetate 7:3). This gave 0.59 g (2.2 mmol; yield: 24%) of the product. 1H NMR (400 MHz, DMSO): delta=8.83 (s, 1H), 5.50 (m, 1H), 3.50 (d, 2H), 3.24 (s, 3H), 1.26 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.8% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; | Step 2: To the solution of 3-hydroxy-5-(4-(methylsulfonyl)phenoxy) benzonitrile (150 mg, 0.518 mmol), <strong>[4984-22-9](R)-1-methoxypropan-2-ol</strong> (93.4 mg, 1.04 mmol) and triphenylphosphine (408 mg, 1.55 mmol) in tetrahydrofuran (3 ml_) was added diisopropyl azodicarboxylate (0.205 ml_, 1.04 mmol). The mixture was stirred at room temperature overnight. Purification by column chromatography eluting with 0 - 30% ethyl acetate in hexane gave the title compound (S)-3-(1-methoxypropan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy) benzonitrile (170 mg, 90.8%) as an oil. 1H NMR (400 MHz, CDCI3) delta ppm 7.92 (d, J = 8.9 Hz, 2 H), 7.11 (d, J = 8.9 Hz, 2 H), 7.01 (m, 1 H), 6.86 (m, 1 H), 6.83 (m, 1 H), 4.53 (m, 1 H), 3.54 (dd, J = 10.4, 6.2 Hz, 1 H), 3.48 (dd, J = 10.4, 3.8 Hz, 1 H), 3.35 (s, 3 H), 3.04 (s, 3 H), 1.28 (d, J = 6.4 Hz, 3 H). MS (M+1 ): 362.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 25℃; for 18h;Cooling with ice; | Step 5. Synthesis of methyl A/-(te/t-butoxycarbonyl)-0-r(1 S)-2- methoxy-1 -methylethyll-2-nitro-L-tyrosinate (C7). A solution of diisopropyl azodicarboxylate (92 mL, 0.467 mol) in tetrahydrofuran (500 mL) was added over 30 minutes to a cooled (ice/water bath) solution of C6 (108 g, 0.317 mol), triphenylphosphine (123 g, 0.469 mol) and (2f?)-1 -methoxypropan-2-ol (42.1 g, 0.467 mol). An exotherm was observed, which increased the reaction temperature from 0 to 25 C. The reaction was stirred for 18 hours at RT, then partitioned between EtOAc (500 mL) and water (500 mL). The aqueous layer was extracted with EtOAc (250 mL), and the combined organic layers were washed with brine (250 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was suspended in a mixture of diethyl ether and heptane (1 :1 , 750 mL) and allowed to stand for 18 hours. The solid (a mixture of triphenylphosphine oxide and reduced diisopropyl azodicarboxylate) was removed by filtration, and the filtrate wasconcentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 40% EtOAc in heptane) afforded C7 contaminated with reduced diisopropyl azodicarboxylate (144 g). This mixture could be used in the following step with no detrimental effect on the reaction. 1H NMR (400 MHz, CDCIs) delta 1 .32 (d, J=6.3 Hz, 3H), 1 .37 (br s, 9H), 3.17 (dd, J=13.7, 8.2 Hz, 1 H), 3.41 (s, 3H), 3.44 (dd, J=13.7, 5.5 Hz, 1 H), 3.51 (dd, half of ABX pattern, J=10.3, 4.0 Hz, 1 H), 3.58 (dd, half of ABX pattern, J=10.3, 6.2 Hz, 1 H), 3.73 (s, 3H), 4.54-4.66 (m, 2H), 5.19 (br d, J=8.4 Hz, 1 H), 7.12 (dd, J=8.6, 2.6 Hz, 1 H), 7.25 (d, J=8.5 Hz, 1 H), 7.50-7.53 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.5% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h; | Step 1: 5-(2-methoxy-(1S)-methyl-ethoxy)-isophthalic acid dimethyl ester Dimethyl 5-hydroxyisophthalate (10.7 g), <strong>[4984-22-9](R)-(-)-1-methoxy-2-propanol</strong> (5.0 mL), and triphenylphosphine (16.1 g) were dissolved in tetrahydrofuran (300.0 mL). Diiso-propylazodicarboxylate (12.0 mL) was slowly added at 0 C. to the solution, which was then stirred at room temperature for 12 hours. The reaction mixture was concentrated and then purified with silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to obtain 13.6 g of the titled compound in the form of yellow liquid (Yield: 94.5%). 1H-NMR (CDCl3) delta 8.27 (t, 1H), 7.79 (d, 2H), 4.69-4.64 (m, 1H), 3.93 (s, 6H), 3.63-3.50 (m, 2H), 3.42 (s, 3H), 1.32 (d, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In tetrahydrofuran; at 60℃; for 4h; | To a tetrahydrofuran solution (10 mL) of 2-amino-5- hydroxy-3- (2-pyridin-2-ylethoxy) benzonitrile (303 mg) , tributylphosphine (0.60 mL) and (2R) -l-methoxypropane-2-ol (0.18 mL) was added 1, 1' - (azodicarbonyl) dipiperidine (600 mg) , and the mixture was stirred at 600C for 4 hr. The reaction solution was concentrated under reduced pressure, diisopropyl ether was added, and insoluble materials were filtered through Celite. The mother liquor was concentrated under reduced pressure, and purified by NH-silica gel column chromatography (hexane: ethyl acetate = 5:1 - 1:1) and silica gel column chromatography (hexane: ethyl acetate = 2:1 - 1:4) to give the title compound (405 mg, yield 100%) as a brown oily substance. MS: 328 (MH+) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; | Example 6: (2R, 75R)-2-[(l-Amino-4-fluoroisoquinolin-6-yl)amino]-7-[(25)-l- methoxypropane-2-sulfonyl]-4, 15, 17-trimethyl-13-oxa-4, 1 1- diazatricyclo[14.2.2.16' 10]henicosa-l(18),6,8, 10(21),16, 19-hexaene-3, 12-dione; trifluoroacetic acid 6A: Benzyl 2-chloro-5-nitrobenzyl(methyl)carbamate [00203] To a solution of 2-chloro-5-nitrobenzaldehyde (5 g, 26.9 mmol) in MeOH (100 mL), was added methylamine (33% in EtOH) (14.82 mL, 29.6 mmol). The mixture was stirred at rt for 1 h, cooled to 0 C and treated with NaBH4 (1.223 g, 32.3 mmol). The mixture was stirred at rt for 30 min, then was concentrated. The residue was dissolved in THF (50 mL), treated with water (20 mL) and sat. NaHC03 (20 mL). After stirring for 10 min, Cbz-Cl (4.62 mL, 32.3 mmol) was added dropwise. The mixture was stirred at rt over night. THF was removed under reduced pressure. The mixture was extracted with EtOAc (2X). The organic phase was washed with brine, dried (Na2S04) and concentrated. The crude product was purified by flash chromatography (loaded in chloroform onto a 120 g column and eluted with a gradient from 0 to 50% ethyl acetate/hexanes) to give 6A (7.39 g, 22.08 mmol, 82% yield) as a white solid. MS (ESI) m/z: 335.1 [M+l]+; H MR (400 MHz, chloroform-d) delta ppm 7.97 - 8.13 (m, 2 H) 7.55 (d, J=7.53 Hz, 1 H) 7.27 - 7.45 (m, 5 H) 5.11 - 5.26 (m, 2 H) 4.58 - 4.72 (m, 2 H) 3.03 (br. s., 3 H), 3 :2 rotamers. 6B: Benzyl 2-mercapto-5-nitrobenzyl(methyl)carbamate [00204] To a partially dissolved mixture of 6A (7.00 g, 20.91 mmol) in DMSO (40 mL), was added sodium sulfide (3.26 g, 41.8 mmol). The mixture was stirred at 50 C for 45 min. The reaction mixture was cooled to rt, poured into water (500 mL). The mixture was extracted with EtOAc (3X). The combined organic phase was washed with water and brine, filtered though a pad of S1O2 and concentrated to a red oil. The crude product was purified by flash chromatography (loaded in chloroform onto a 40 g column and eluted with a gradient from 0 to 100% ethyl acetate/hexanes). The desired fractions were collected, concentrated to give 6B (3.10 g, 9.33 mmol, 44.6% yield) as an orange solid. H NMR (400 MHz, chloroform-d) delta ppm 7.99 (d, J=7.15 Hz, 2 H) 7.27 - 7.48 (m, 6 H) 5.20 (br. s., 2 H) 4.56 (br. s., 2 H) 2.96 (br. s., 3 H); MS (ESI) m/z: 333.1 [M+l]+. 6C: (5)-Benzyl 2-((l-methoxypropan-2-yl)thio)-5-nitrobenzyl(methyl)carbamate [00205] To a solution of triphenylphosphine (355 mg, 1.354 mmol) in THF (4 mL) at 0 C, was added DIAD (0.263 mL, 1.354 mmol) dropwise. The mixture was stirred at 0 C for 10 min affording a colorless suspension. A solution of 6B (300 mg, 0.903 mmol) and (R)-l-methoxypropan-2-ol (0.133 mL, 1.354 mmol) in THF (2 mL) was added dropwise. The resultant dark red solution was stirred at 0 C for 0.5 h, then was allowed to slowly warm to rt over night. The reaction mixture was concentrated. The crude product was purified by flash chromatography (loaded in chloroform onto a 40 g column and eluted with a gradient from 0 to 40% ethyl acetate/hexanes) to afford 6C (396 mg, 108% yield) as yellow oil/semi-solid. MS (ESI) m/z: 405.2 [M+l]+; NMR (400 MHz, chloroform- d) delta ppm 8.07 (d, J=8.53 Hz, 1 H) 7.96 (d, J=18.57 Hz, 1 H) 7.32 - 7.51 (m, 6 H) 5.11 - 5.26 (m, 2 H) 4.59 (d, J=18.07 Hz, 2 H) 3.58 - 3.68 (m, 1 H) 3.47 (d, J=6.53 Hz, 2 H) 3.37 (s, 3 H) 2.99 (br. s., 3 H) 1.40 (br. s., 3 H). 6D: (5)-Benzyl 2-((l-methoxypropan-2-yl)sulfonyl)-5-nitrobenzyl(methyl)carbamate [00206] To a solution of 6C (362 mg, 0.895 mmol) in dichloromethane (8 mL) at rt was added m-CPBA (552 mg, 2.237 mmol). The mixture was stirred at rt over night, poured into 10% a2C03, extracted with dichloromethane (3X). The combined organic phase was dried ( a2S04) and concentrated. The crude product was purified by flash chromatography (loaded in chloroform onto a 40 g column and eluted with a gradient from 0 to 75% ethyl acetate/hexanes) to give a colorless viscous oil. This material contains some DIAD byproduct and thus was further purified by prep HPLC to afford 6D (330 mg, 0.756 mmol, 84% yield) as a white solid. MS (ESI) m/z: 437.1 [M+l]+. NMR (400 MHz, chloroform-d) delta ppm 8.08 - 8.27 (m, 3 H) 7.16 - 7.44 (m, 5 H) 5.08 - 5.26 (m, 2 H) 4.90 - 5.04 (m, 2 H) 3.30 - 3.74 (m, 3 H) 3.09 (s, 3 H) 3.01 - 3.18 (m, 3 H) 1.27 - 1.45 (m, 3 H) rotamers. 6E: (5)-4-(( 1 -Methoxypropan-2-yl)sulfonyl)-3 -((methylamino)methyl)aniline [00207] To a suspension of 6D (327 mg, 0.749 mmol) in MeOH (10 mL), was added 10% Pd-C (40 mg, 0.038 mmol). The mixture was evacuated and flushed with H2 (3X), then was stirred under an atmosphere of for 7.5 h. The reaction mixture was filtered and concentrated to give 6E (203 mg, 99% yield) as a colorless semisolid. MS (ESI) m/z: 273.2 [M+l]+. H NMR (400 MHz, methanol-d4) delta ppm 7.58 (d, J=8.78 Hz, 1 H) 6.69 (d, J=2.51 Hz, 1 H) 6.64 (dd, J=8.66, 2.38 Hz, 1 H) 3.78 - 3.89 (m, 2 H) 3.59 - 3.67 (m, 1 H) 3.44 - 3.55 (m, 2 H) 3.21 (s, 3 H) 2.37 (s, 3 H) 1.28 (d, J=6.78 Hz, 3 H). 6F: tert-Bu... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16.5h; | Example 37: (2R, 75R)-2-[(l-Aminoisoquinolin-6-yl)amino]-8-fluoro-7- [(25)-l- methoxypropan-2-yl]oxy } -4, 15,20-trimethyl- 13 -oxa-4, 1 1- diazatricyclo[14.2.2.16' 10]henicosa-l(18),6,8, 10(21),16, 19-hexaene-3, 12-dione; trifluoroacetic acid 37A: (5)-3-Fluoro-4-((l-methoxypropan-2-yl)oxy)-5-((methylamino)methyl)aniline dihydrochloride [00376] To a solution of 17D (556 mg, 1.852 mmol), (R)-l-methoxypropan-2-ol (367 mg, 4.07 mmol), triphenylphosphine (1068 mg, 4.07 mmol) in THF (5 mL) was added DIAD (0.81 mL, 4.07 mmol). The reaction mixture was stirred at 0 C for 30 min, and at rt for 16 h. The mixture was concentrated and purified by flash chromatography. The desired fractions were combined and concentrated. The residue was dissolved in MeOH (30 mL) and THF (10 mL). Zinc (dust) (3.47 g, 53.1 mmol) and ammonium chloride (5.68 g, 106 mmol) were added. The resulting solution was stirred at rt for 2 h. MeOH was removed under reduced pressure. a2C03 (aq, 100 mL) and EtOAc (150 mL) was added, and the suspension was stirred vigorously for 10 min. The mixture was filtered through a glass frit, solid residue was washed with EtOAc (3x150 mL). Combined EtOAc fractions were washed with std. a2C03 (aq, 2x50 mL), water (2x50 mL), brine (1x50 mL) and dried ( a2S04). EtOAc was removed under reduced pressure and the residue was dissolved in EtOAc (10 mL), treated with HC1 (4M, 8 mL) for 2 h at rt. The solvent was removed under reduced pressure to yield 37A (520mg, 1.650 mmol, 89% yield) as a yellow solid. MS (ESI) m/z: 244.3 (M+H)+. 37B: (5)-Benzyl 5-amino-3-fluoro-2-((l-methoxypropan-2- yl)oxy)benzyl(methyl)carbamate [00377] To a solution of 37A (472 mg, 1.497 mmol) and N,N-diisopropylethylamine (1.043 ml, 5.99 mmol) in DMF (10 ml), was added N-(benzyloxycarbonyloxy) succinimide (41 1 mg, 1.647 mmol). The mixture was stirred rt for 1 h, then quenched with water, extracted with EtOAc (3x30 ml). The organic layer was washed with brine, dried ( a2S04) and concentrated. The crude product was purified by flash chromatography (0-60% EtOAc in hexanes) to give 37B (520 mg, 1.381 mmol, 92% yield). MS (ESI) m/z: 377.3 (M+H)+. 37C: Benzyl 5-((((R)-2-(4-bromo-2-methylphenyl)propoxy)carbonyl)amino)-3-fluoro-2- - 1 -methoxypropan-2-yl)oxy)benzyl(methyl)carbamate [00378] To a solution of 37B (510 mg, 1.355 mmol), sodium bicarbonate (1 138 mg, 13.55 mmol) in CH2C12 (10 ml) at 0 C, was added phosgene (1340 mg, 2.71 mmol, 20% in toluene). The mixture was stirred 0 C for 30 min, rt for 1 h, filtered, and concentrated. The residue was dissolved in CH2C12 (10 ml) at 0 C, DMAP (182 mg, 1.490 mmol) and TEA (0.370 ml, 2.71 mmol) was added, followed by Intermediate 5A (310 mg, 1.355 mmol). The mixture was stirred rt for 1 h, quenched with water, and extracted with EtOAc (2x20 mL). The combined organic layer was washed with IN HC1, brine, dried (Na2S04) and concentrated. The crude product was purified by flash chromatography (0- 40% EtOAc in hexanes) to give 37C (810 mg, 1.283 mmol, 95% yield). MS (ESI) m/z: 631.3 (M+H)+. 37D : (4-((R)- 1 -(((3 -((((Benzyloxy)carbonyl)(methyl)amino)methyl)-5-fluoro-4-(((5)- 1 - methoxypropan-2-yl)oxy)phenyl)carbamoyl)oxy)propan-2-yl)-3-methylphenyl)boronic acid [00379] To a reaction tube was added 37C (480 mg, 0.76 mmol), 5,5,5',5'-tetramethyl- 2,2'-bi(l ,3,2-dioxaborinane) (206 mg, 0.912 mmol), KOAc (186 mg, 1.900 mmol), Pd(dppf)Cl2 (125 mg, 0.152 mmol) in DMSO (1.5 ml). The tube was filled with Ar, sealed and stirred at 85 C for 2 h. The mixture was quenched with water, and extracted with EtOAc. The combined organic layer was filtered though silica gel and concentrated. The crude product was purified by flash chromatography to give 37D (309 mg, 0.518 mmol, 68.2% yield). MS (ESI) m/z 597 '.4 (M+H)+. 37E: 2-((l -(Bis(tert-butoxycarbonyl)amino)isoquinolin-6-yl)amino)-2-(4-((R)-l -(((3- fluoro-4-(((5)- 1 -methoxypropan-2-yl)oxy)-5- ((methylamino)methyl)phenyl)carbamoyl)oxy)propan-2-yl)-3-methylphenyl)acetic acid [00380] 37D (309 mg, 0.518 mmol), Intermediate 1 (205 mg, 0.570 mmol), glyoxylic acid monohydrate (47.7 mg, 0.518 mmol) were dissolved in CH3CN (3 ml) and DMF (0.5 ml). The mixture was stirred at 85 C 20 h, then concentrated and purified by prep HPLC. The desired fractions were combined, concentrated. The residue was dissolved in THF (8 mL). 10% Pd/C was added and the mixture was hydrogenated at 40 psi for 3 h. The mixture was filtered, concentrated and purified by prep HPLC to give 37E (185 mg, 0.222 mmol, 42.8% yield). MS (ESI) m/z: 834.4 (M+H)+. 37F: tert-Butyl N-[(tert-butoxy)carbonyl]-N-(6- [(75R)-8-fluoro-7- { [(25)- 1 - methoxypropan-2-yl] oxy } -4, 15 ,20-trimethyl-3 , 12-dioxo- 13 -oxa-4, 1 1- diazatricyclo[ 14.2.2.16>10]henicosa- 1 (18),6,8, 10(21), 16, 19-hexaen-2- yl] amino }isoquinolin-l-yl)carbamate [00381] To a solution of BOP (196 mg, 0.444 mmol), 4-dimethylaminopyridine (136 mg, 1.109 mmol) in CH2C12 (40 mL), was added a solution of 37E (185 mg, 0.222 mmol) in DMF (10 mL) via a syringe pu... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 0 - 20℃; for 72h; | EDC (6.08 g, 0.03 mol) and 4-(dimethylamino)pyridine (0.48 g, 0.004 mol) were added to asolution of Boc-L-alanine (5g, 0.03 mol) and <strong>[4984-22-9](R)-(-)-1-methoxy-2-propanol</strong> (2.59 ml, 0.03 mol) at 0 00. The reaction mixture was left stirring on a melting ice-water bath and was then stirred atroom temperature for 72h.The reaction mixture was concentrated to 1/2 the volume, diluted with ethyl acetate (400 mL)and washed with saturated aqueous NH4CI (200 ml), 10% aqueous citric acid (50 mL) andsaturated aqueous NaHOO3 (200 mL). The organic layer was dried (Na2SO4), filtered and concentrated.The crude product was purified by silica gel column chromatography (Biotage SNAP ultra 100 g, gradient of 5-30% ethyl acetate in heptane) which gave the title compound as a clear oil (5.90 g,85%). |
85% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 0 - 20℃; for 72h; | Boc-L-alanine (5 g, 0.03 mol) at 0 CAnd <strong>[4984-22-9](R)-(-)-1-methoxy-2-propanol</strong> (2.59 ml, 0.03 mol) was added with EDC (6.08 g, 0.03 mol) and 4- (dimethylamino) pyridine ( 0.48 g, 0.004 mol).The reaction mixture was stirred on a melting ice water bath and then stirred at room temperature for 72 h.The reaction mixture was concentrated to about 1/2 volume,Dilute with ethyl acetate (400 mL) and wash with saturated aqueous NH4Cl (200 ml), 10% aqueous citric acid (50 mL), and saturated aqueous NaHCO3 (200 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (Biotage SNAP ultra 100 g, gradient of 5-30% ethyl acetate in heptane), which gave the title compound as a clear oil (5.90 g, 85%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of KHMDS in THF (IM, 43.8 ml, 43.8 mmol) was added to a solution of (R)-1- methoxypropanol (4.3 ml, 43.8 mmol) in THF (50 ml) at room temperature under a positive argon pressure. After stirring for 15 minutes at room temperature a solution of 6-amino-4- fluoronicotinonitrile (intermediate 21, 3.0 g, 21.88 mmol) in THF (30 ml) was added drop wise. Thereaction mixture was stirred for 65 h at room temperature, partitioned between aqueous NH4CI and EtOAc, extracted 2x with EtOAc, dried over Na2SO4 and evaporated. The residue was triturated with Et20 to give the title compound as a beige solid. 1H NMR (400 MHz, DMSO-d5) 58.14 (s, IH), 6.82 (s, br, 2H), 6.09 (s, IH), 4.64-4.56 (m, IH), 3.19 (s, 3H), 3.48 (d, 2H), 1.24 (d, 3H). | ||
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; | General procedure: A mixture of 6-amino-4-fluoronicotinonitrile 7 (4.11 g, 30 mmol), 2-methoxyethanamine (4.5 g, 60 mmol), and DIPEA (1.16 g, 90 mmol) in DMF (120 mL) was stirred at 60C until the reaction was completed by TLC. After quenched with water, the reaction solution was extracted with CH2Cl2 (3 ×100 mL), washed with sequentially with satd NaHCO3 (aq) and brine and then dried over anhydrous Na2SO4. Filtration, evaporation, and chromatography on silica gel afforded the product 8 (3.84 g, 67%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine; In dichloromethane; at 0 - 20℃; for 16h; | To a mixture of <strong>[4984-22-9](R)-1-methoxypropan-2-ol</strong> (2.0 g, 22.1 mmol) and triethylamine (6.70 g, 66.3 mmol) in DCM (10 mL) was added methanesulfonyl chloride (3.79 g, 33.1 mmol) dropwise at 0 C. The mixture was stirred at ii for 16 hrs. The mixture was quenched with sat. NaHCO3 solution, diluted with DCM, washed with water and dried over Na2SO4 anhydrous. The organiclayer was concentrated in vacuo to afford the title compound (3.0 g, yield 80%) as a yellow oil MS (ES+) C5H12045 requires: 168, found: 169 [M+H]. |
10.6 g | With triethylamine; In tetrahydrofuran; at 0℃; for 4h; | To a solution of <strong>[4984-22-9](R)-1-methoxypropan-2-ol</strong> (5.4 g) and TEA (12.1 g) in THF (20 mL) was added methanesulfonyl chloride (8.3 g) at 0C. The mixture was stirred at 0C for 4 hours.The solution was poured into water, and extracted with EA (2x50 mL). The combined organic layers were washed, dried, filtered and concentrated to give (R)-1-methoxypropan-2-yl methanesulfonate (10.6 g) as a light yellow solid. 1H-NMR (400 MHz, ODd3) 6 ppm 4.87-4.90 (m, 1 H), 3.42-3.55 (m, 2H), 3.39 (d, J = 1.5 Hz, 3H), 3.05 (d, J = 1.4 Hz, 3H), 1.39 (dd, J = 6.5, 1.5 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.65 g | To a stirred solution of compound (2R)-1 -methoxypropan-2-ol (0.9 g, 1 1 .0 mmol) in anhydrous THF (30 mL) was added NaH (60% in oil, 0.88 g, 22.0 mmol) at 5 C -10 C under a nitrogen atmosphere. After being stirred at room temperature for 30 min, a solution of 2-chloro-N-ethyl-6- (methylsulfanyl)pyrimidine-4-carboxamide (1-160) (1 .7 g, 7.36 mmol) in THF (10 mL) was added to the mixture. The resulting mixture was stirred at room temperature overnight. TLC (petroleum ether/EtOAc = 3/1 ) indicated the reaction was complete. The mixture was quenched with H20 (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (100 mL), dried over Na2S04 and concentrated. The residue was purified by column chromatography over silica gel eluting with petroleum ether/EtOAc (3/1) to yleld N-ethyl-2- [(2R)-1 -methoxypropan-2-yl]oxy}-6-(methylsulfanyl)pyrimidine-4-carboxamide (1-161) (1 .65 g, 78.6%) as yellow oil, which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.2% | With sodium hydride; In tetrahydrofuran; mineral oil; at 0℃;Reflux; | To a solution of R-(-)-1 -methoxy-2-propanol (3.3 g, 36.8 mmol) in THF (100 mL) was added NaH (1 .96 g, 60% dispersion in mineral oil, 49 mmol) at 0 C. 2-Chloro-6-(methylthio)-N-(2,2,2- trifluoroethyl)pyrimidine-4-carboxamide (1-164) (7 g, 24.5 mmol) was added to the solution. After addition, the reaction was heated to reflux overnight. TLC (petroleum ether : EtOAc = 5:1 ) indicated complete consumption of the starting material. The solution was concentrated in vacuo. The residue was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04 and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (petroleum ether: EtOAc = 40:1 ~10:1 ) to give (R)-2-(1 -methoxypropan-2-yloxy)-6-(methylthio)-N-(2,2,2-trifluoroethyl)pyrimidine-4- carboxamide (1-165) (5.0 g, 60.2%) as a light yellow gum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; for 0.833333h; | A solution of <strong>[4489-34-3]4,6-dichloro-2-(methylsulfonyl)pyrimidine</strong> (1-174) (200 mg, 0.881 mmol) and (2R)- 1 -methoxypropan-2-ol (79.4 mg, 0.881 mmol) in THF (5 mL) was cooled to 0 C (5 min), and LiHMDS (0.969 mL, 1 M, THF) was added in a dropwise manner. The resultant suspension was allowed to stir at 0 C for an additional 20 min. The ice-bath was removed and the mixture was allowed to warm to room temperature over 30 min. TLC (pPetroleum ether : EtOAc = 1 : 1) indicated the reaction was complete. The mixture was concentrated and taken up in EtOAc (8 mL), washed with saturated aq. NH4CI (4 mL), and brine (4 mL). The organic layer was dried over Na2S04, filtered and concentrated to give the crude 4,6-dichloro-2-[(2R)-1 - methoxypropan-2-yl]oxy}pyrimidine (1-175) (210 mg, 100 %) as a yellow oil, which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | To a mixture of (2R)-1 -methoxypropan-2-ol (3 g, 33.29 mmol) in THF (20 mL) was added NaH (2.66 g, 60% in mineral oil, 66.6 mmol) in portions over a period of 10 min. After addition, the mixture was stirred at 0 C for 1 hr. Then, cyanuric chloride (1-177) (6.14 g, 33.3 mmol) was added. After the addition, the reaction mixture was stirred at 0 C for a further hr. TLC (petroleum ether/EtOAc = 10/1 ) indicated the reaction was complete. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (3 x 50 mL).The combined organic layers were washed with water (2 x 10 mL), brine (20 mL), dried over Na2S04 and concentrated under vacuum to dryness to give a residue, which was purified by silica gel chromatography (petroleum ether/EtOAc = 10/1 to 1/1 ) to give 2,4-dichloro-6-[(2R)-1 -methoxypropan-2-yl]oxy}- 1 ,3,5-triazine (1-192) (1 .1 g, 14%) as a colorless oil, which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | To a round bottom flask submerged in an ice bath was added the (2R)-1 -methoxypropan-2-ol (98 mg, 1 .1 mmol) followed by THF (12ml) and NaH (92 mg, 60% in mineral oil, 2.17 mmol) under nitrogen. After being allowed to stir at ice bath temperature for 20 min, a suspension of 3- amino-6-[1 -(4,6-dichloro-1 ,3,5-triazin-2-yl)piperidin-4-yl]pyridine-2-carboxamide (1-178) (400 mg, 1 .09 mmol) in THF (12 mL) was added. After 10 min, LCMS indicated the reaction was complete. The reaction was quenched with saturated NaHC03 solution (0.5 mL), and concentrated in vacuo. The residue was purified by silica gel chromatography (0 - 100 % EtOAc/heptanes) to afford 3-amino-6-[1 -(4-chloro-6-[(2R)-1 -methoxypropan-2-yl]oxy}-1 ,3,5- triazin-2-yl)piperidin-4-yl]pyridine-2-carboxamide (1-179) (340 mg, 74%) as a white solid. LCMS (APC I), m/z 422.2 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | With potassium hexamethylsilazane; In tetrahydrofuran; at 50℃; for 18h; | To a solution of 4-chloro-N-cyclobutyl-6-[4-(1 /-/-pyrazolo[3,4-b]pyridin-3-yl)piperidin-1 - yl]pyrimidine-2-carboxamide (I-203) (50 mg, 0.12 mmol) in THF (3 mL) was added (2f?)-1 - methoxypropan-2-ol (32.7 mg, 0.36 mmol) in THF (1 mL) followed by the portionwise addition of solid KHMDS (121 mg, 0.61 mmol) over 5 min. Upon completion of the addition, the reaction was heated to 50 C for 18 hr. The reaction was diluted with EtOAc (10 mL), washed with saturated NH4CI solution (2 x 5 mL), brine (5 mL), and dried over MgS04. The reaction was filtered, concentrated, and the residue purified by SFC (ZymorSPHER HADP column 150 x 4.6 mm, 10 - 50% MeOH, 160 bar, 4.5 mL/min) to afford N-cyclobutyl-4-[(2f?)-1 -methoxypropan-2- yl]oxy}-6-[4-(1 /-/-pyrazolo[3,4-b]pyridin-3-yl)piperidin-1 -yl]pyrimidine-2-carboxamide (Example 108) (5 mg, 9%) as a white solid. LCMS (APCI), m/z 466.3 [M + H]+; 1H NMR (600 MHz, DMSO- d6) 8 ppm 8.56 (d, J = 8.2 Hz, 1 H), 8.47 (dd, J = 4.5, 1 .0 Hz, 1 H), 8.30 (dd, J = 8.0, 1 .0 Hz, 1 H), 7.13 (dd, J = 8.0, 4.5 Hz, 1 H), 6.17 (s, 1 H), 5.42 - 5.51 (m, 1 H), 4.53 (br. s., 2 H), 4.37 (sxt, J = 8.3 Hz, 1 H), 3.46 - 3.52 (m, 1 H), 3.34 - 3.46 (m, 2 H), 3.1 1 (t, J = 1 1 .9 Hz, 2 H), 2.55 - 2.52 (m, 3 H), 2.22 - 2.16 (m, 2 H), 2.13 (t, J = 9.4 Hz, 2 H), 2.07 (d, J=1 1 .4 Hz, 2 H), 1 .74 - 1 .86 (m, 2 H), 1 .61 - 1 .69 (m, 2 H), 1 .23 (d, J = 6.4 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | To a solution of (2R)-1 -methoxypropan-2-ol (43.0 mg, 0.477 mmol) in DMF (3 mL) was added NaH (50.8 mg, 60% in mineral oil, 1 .27 mmol) at 0 C. The mixture was stirred at 0 C for 30 min, and then 6-[4-([2-amino-5-(1 -methyl-1 /-/-1 ,2,3-triazol-4-yl)pyridin-3-yl]oxy}methyl)piperidin- 1 -yl]-2-chloro-N-ethyl pyrimidine-4-carboxamide (1-219) (150 mg, 0.318 mmol) was added. The mixture was stirred at room temperature for 1 hr, and then stirred at 50 C for 3 hr. LCMS showed the reaction was completed. The mixture was poured into water (10 mL) and extracted with CH2CI2/MeOH = 10/1 (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2S04 and concentrated in vacuo to give the crude product, which was purified by preparativeHPLC to give 6-[4-([2-amino-5-(1 -methyl-1 /-/-1 ,2,3-triazol-4-yl)pyridin-3- yl]oxy}methyl)piperidin-1 -yl]-N-ethyl-2-[(2R)-1 -methoxypropan-2-yl]oxy}pyrimidine-4- carboxamide (Example 138) (6.8 mg, 4%) as a white solid. LCMS (APCI), m/z 548.1 [M + H]+; 1H NMR (400 MHz, CDCI3) delta ppm 7.96 (s, 1 H), 7.86 - 7.94 (m, 1 H), 7.71 (s, 1 H), 7.59 (s, 1 H), 7.09 (s, 1 H), 5.33 - 5.38 (m, 1 H), 4.78 (s, 2 H), 4.44 - 4.68 (m, 2 H), 4.15 (s, 3 H), 3.98 (d, J = 6.4 Hz, 2 H), 3.66 - 3.70 (m, 1 H), 3.42 - 3.52 (m, 6 H), 2.92 - 3.09 (m, 2 H), 2.18 - 2.31 (m, 1 H), 1 .99 (d, J = 13.2 Hz, 2 H), 1 .34 - 1 .46 (m, 5 H), 1 .23 (t, J = 7.6 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61 mg | With potassium hexamethylsilazane; In tetrahydrofuran; at 20℃; for 102h; | To a mixture of 6-[4-([2-amino-5-(1 -methyl-1 /-/-imidazol-5-yl)pyridin-3-yl]oxy}methyl)piperidin-1 - yl]-2-chloro-N-ethylpyrimidine-4-carboxamide (1-221) (55 mg, 0.12 mmol) and (2R)-1 - methoxypropan-2-ol (42 mg, 0.47 mmol) in THF (2 mL) was added KHMDS (93 mg, 0.47 mmol), and the resulting suspension was stirred at room temperature for 18 hr. LCMS showed the reaction was predominantly starting material, and additional aliquots of both KHMDS (93 mg, 0.47 mmol) and (2R)-1 -methoxypropan-2-ol (22 mg, 0.23 mmol) were added. The reaction was stirred for a further 24 hr, before again additional KHMDS (200 mg, 1 .01 mmol) and (2R)-1 - methoxypropan-2-ol (95 mg, 0.94 mmol) were added. After being stirred for a further 60 hr, LCMS indicated the reaction was complete. H20 (5 ml_) was added, and the reaction extracted with EtOAc (3 x 10 ml_). The organic extracts were dried over Na2S04, filtered and concentrated in vacuo to afford the crude product, which was purified by preparative HPLC to afford 6-[4-([2- amino-5-(1 -methyl-1 /-/-imidazol-5-yl)pyridin-3-yl]oxy}methyl)piperidin-1 -yl]-N-ethyl-2-[(2R)-1 - methoxypropan-2-yl]oxy}pyrimidine-4-carboxamide (Example 141) (61 mg, 33%) as a white solid. LCMS (APCI), m/z 525.2 [M + H]+; 1H NMR (600 MHz, DMSO-c/6) 8 ppm 8.58 (t, J = 6.15 Hz, 1 H), 7.63 (s, 1 H), 7.58 (d, J = 1 .90 Hz, 1 H), 7.07 (d, J = 1 .76 Hz, 1 H), 6.95 (s, 1 H), 6.91 (s, 1 H), 5.87 (s, 2 H), 5.33 (quind, J = 6.31 , 4.17 Hz, 1 H), 3.90 (d, J = 6.29 Hz, 3 H), 3.60 (s, 3 H), 3.42 - 3.52 (m, 1 H), 3.24 - 3.30 (m, 3 H), 3.01 (br. s., 1 H), 2.07 - 2.18 (m, 1 H), 1 .93 (d, J = 12.29 Hz, 3 H), 1 .87 (s, 2 H), 1 .26 - 1 .32 (m, 2 H), 1 .21 - 1 .26 (m, 4 H), 1 .04 - 1 .1 1 (m, 4 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8 mg | To a solution of (2R)-1 -methoxypropan-2-ol (84 mg, 0.932 mmol) in DMF (8 mL) was added NaH (67.1 mg, 60% in mineral oil, 2.80 mmol) at 0 C. Then the reaction mixture was stirred at 0 C for 30 min. Then 6-[4-([2-amino-5-(1 -methyl-1 H-1 , 2,3-triazol-5-yl)pyridin-3- yl]oxy}methyl)piperidin-1 -yl]-2-chloro-N-ethylpyrimidine-4-carboxamide (I-223) (220 mg, 0.466 mmol) was added. The reaction mixture was stirred at room temperature for 30 min and then at 50 C for 2 hr. LCMS showed the reaction was completed. The mixture was poured into water (10 mL) and extracted with CH2CI2 (3 x 20 ml). The combined organic layers were washed with brine (10 mL), dried over Na2S04 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give 6-[4-([2-amino-5-(1 -methyl-1 H-1 , 2, 3-triazol-5- yl)pyridin-3-yl]oxy}methyl)piperidin-1 -yl]-N-ethyl-2-[(2R)-1 -methoxypropan-2-yl]oxy} pyrimidine- 4-carboxamide (Example 161) (20 mg, 8%) as a white solid. LCMS (APCI), m/z 526.1 [M + NH]+; 1H NMR (400 MHz, CDCI3) delta ppm 7.88 (t, J = 5.6 Hz, 1 H), 7.73 (d, J = 2.0 Hz, 1 H), 7.68 (s, 1 H), 7.10 (s, 1 H), 6.86 (d, J = 1 .6 Hz, 1 H), 5.30 - 5.35 (m, 1 H), 4.96 (s, 2 H), 4.60 (br. s., 2 H), 4.05 (s, 3 H), 3.89 - 3.91 (m, 2 H), 3.52 - 3.67 (m, 1 H), 3.47 - 3.51 (m, 6 H), 3.30 - 3.42 (m, 2 H), 2.22 (br. s. 1 H), 1 .96 - 1 .99 (m, 2 H), 1 .38 - 1 .42 (m, 5 H), 1 .21 -1 .23 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7 mg | To a suspension of (2R)-1 -methoxypropan-2-ol (90.12 mg, 55.6 mmol) in DMF (10 mL) was added NaH (30.9 mg, 60% in mineral oil, 0.77 mmol), the mixture was stirred at room temperature for 30 min, and then 6-[4-([2-amino-5-(1 ,5-dimethyl-1 /-/-1 ,2,3-triazol-4-yl)pyridin-3- yl]oxy}methyl)piperidin-1 -yl]-2-chloro-N-ethylpyrimidine-4-carboxamide (I-225) (150 mg, 0.31 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hr. The reaction was quenched with aqueous NH4CI (1 mL), and concentrated to remove DMF. The residue was purified by preparative TLC (CH2CI2/MeOH = 10/1) to give 6-[4-([2-amino-5-(1 ,5- dimethyl-1 H-1 ,2,3-triazol-4-yl)pyridin-3-yl]oxy}methyl)piperidin-1 -yl]-N-ethyl-2-[(2f?)-1 - methoxypropan-2-yl]oxy}pyrimidine-4-carboxamide (Example 162) (7 mg, 4%) as a white solid. LCMS (APCI), m/z 562.1 [M + Na]+; 1H NMR (400 MHz, CDCI3) delta ppm 7.82 - 7.88 (m, 1 H), 7.82 (s, 1 H), 7.47 (s, 1 H), 7.08 (s, 1 H), 5.30 - 5.34 (m, 1 H), 4.90 (br. s., 2 H), 4.46 - 4.76( m, 1 H), 4.01 (s, 3 H), 3.96 (d, J = 6.0 Hz, 2 H), 3.65 - 3.69 (m, 1 H), 3.41 - 3.51 (m, 2 H), 3.41 (s 3 H), 2.95 - 2.99 (m, 2 H), 2.53 (s, 3 H), 2.15 - 2.25 (m, 1 H), 1 .95 - 1 .97 (m, 2 H), 1 .30 - 1 .40 (m, 5 H), 1 .19 - 1 .20 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Intermediate 279: (S)-(R)-1-methoxypropan-2-yl 2-((tert-butoxycarbonyl)amino)-3- methylbutanoate A mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (1.0 g, 4.60 mmol), diisopropylethylamine (1.19 g, 1.608 mL, 9.21 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (846 mg, 5.52 mmol), EDC (1.06 g, 5.53 mmol), and <strong>[4984-22-9](R)-1-methoxypropan-2-ol</strong> (1.037 g, 1.127 mL, 11.5 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (15 mL) and sat'd NaHCO3 (15 mL). The organic phase was washed with 1M hydrochloric acid (15 mL), water (15 mL) and brine (15 mL). The organic phase was dried and evporated under reduced pressure to give the title compound as a colourless oil (1.2 g, 90% yield). 1H NMR (CDCl3): delta 0.89 (m, 3 H), 0.96 (m, 3 H), 1.24 (d, J = 6.6 Hz, 3 H), 1.45 (s, 9H), 2.16 (m, 1H), 3.36 (s, 3H), 3.44 (m, 2H), 4.23 (m, 1H), 5.05 (m, 1H), 5.13 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | General procedure: To a stirred suspension of 28 (0.5 mmol, 1.0 equiv.) and triphenyl phosphine (1.0 mmol, 2.0 equiv.) in dry tetrahydrofuran (200 mL), under argon was added alkyl ethanol (0.64 mmol, 1.28 equiv.) at room temperature. The reaction was cooled to 0 C and diisopropyl azodicarboxylate (1.0 mmol, 2.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature, and then water was added. The aqueous layer was extracted with ethyl acetate. And the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether, v/v, 10:90 to 25:75) to offord ester 29a-b and 29d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | General procedure: To a stirred suspension of 36 (3.0 mmol, 1.0 equiv.) and triphenyl phosphine (6.0 mmol, 2.0 equiv.) in dry tetrahydrofuran (200 mL), under argon was added alkyl ethanol (9.0 mmol, 3.0 equiv.) at room temperature. The reaction was cooled to 0 C and diisopropyl azodicarboxylate (6.0 mmol, 2.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature, and then water was added. The aqueous layer was extracted with ethyl acetate. And the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether, v/v, 90:10 to 75:25) to afford esters 37a-c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; for 48h; | 2.7 mL (11.4 mmol) of diethylazodicarboxylate is added dropwise to a solution cooled to 0 C. of 1 g (3.8 mmol) of 5-bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-methyl acetate, 0.8 mL (8 mmol) of <strong>[4984-22-9](R)-1-methoxy-propan-2-ol</strong> and 2 g (7.6 mmol) of triphenylphosphine in 20 mL of tetrahydrofuran. The reaction mixture (white suspension) is stirred at room temperature for 48 hours. The tetrahydrofuran is removed under vacuum and then the residue is taken up in ethyl acetate. The organic phase is washed once with a saturated aqueous solution of sodium hydrogen carbonate, once with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under vacuum. The crude product is purified by silica gel chromatography eluted with a heptane/ethyl acetate 60/40 mixture. 1.2 g (78%) of [5-bromo-3-((S)-2-methoxy-1-methylethyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-methyl acetate is obtained in the form of a colourless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With sodium hydride; In 1-methyl-pyrrolidin-2-one; mineral oil; at 70℃; for 16h;Inert atmosphere; | Compounds 6-amino-4-chloronicotinonitrile 18a (60 mg, 0.39 mmol), 194 <strong>[4984-22-9](R)-1-methoxypropan-2-ol</strong> (70 mg, 0.78 mmol), 52 sodium hydride (34 mg, 0.86 mmol, 60% 53 mineral oil mixture) and 54 N-methylpyrrolidone (1.5 mL) were mixed and stirred for 16 h at 70 C. The mixture was cooled to room temperature, and this mixture was quenched with 20 mL of 9 water, extracted with ethyl acetate (20 mL×2), and the organic phase was washed with saturated brine (20 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and subjected to exsolution under reduced pressure. The residuals were purified through a preparative silica gel plate (petroleum ether/ethyl acetate 1:1), to obtain the target 195 product (R)-6-amino-4-((1-methoxyprop-2-yl)oxo) nicotinonitrile 18b (17 mg, white solid), at a yield of 21%. (0297) MS m/z (ESI): 208 [M+1] (0298) 1H NMR (400 MHz, CDCl3) delta 8.17 (s, 1H), 6.00 (s, 1H), 4.94 (brs, 2H), 4.63-4.60 (m, 1H), 3.63-3.62 (m, 1H), 3.54-3.51 (m, 1H), 3.41 (s, 3H), 1.38-1.36 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99%Chromat. | With di-isopropyl azodicarboxylate; triphenylphosphine; In toluene; at 50℃; for 2h;Cooling with ice; | Into a 1L three-neck flask, add 32 g (0.1 mol) of N- (2-methyl-6-ethylphenyl) -4-nitrobenzenesulfonamide IV39.3g (0.15mol) of triphenyl phosphorus,(R) -1-methoxy-2-propanolV13.5g (0.15mol)And 320mL of anhydrous toluene,75 mL (2mol / L) of DIAD in anhydrous toluene was added dropwise under an ice bath. Remove the ice bath after the addition,Heated to 50 for 2h,Stop the reaction,Concentrated to remove the solvent,The kettle residue is used directly in the next reaction(Column chromatography separation yield: 99%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.8% | With triethylamine; In dichloromethane; at 0 - 20℃; for 4h; | (2) 250 ml of methylene chloride and 90 g (1.0 mol) of <strong>[4984-22-9](R)-1-methoxy-2-propanol</strong> at room temperature, 121.2 g (1.2 mol) of triethylamine was stirred and mixed, cooled to 0-5 C, A mixture of 126 g (1.1 mol) of methanesulfonyl chloride and 100 ml of methylene chloride was added dropwise. The reaction is exothermic, and the drop acceleration is controlled so that the temperature is not higher than 5 C. The addition is completed in about 2 hours. Remove the freezing and let it warm to room temperature for 2 hours. The reaction solution was washed successively with 200 ml of saturated sodium bicarbonate solution, 200 ml of 5% dilute hydrochloric acid solution and 200 ml of purified water. Dry over anhydrous sodium sulfate and concentrate at atmospheric pressure to remove the methylene chloride solvent to dryness. High vacuum distillation of the product gave 154.22 grams of oily product. The content is 97.89% and the yield is 91.80%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.54% | With triethylamine; In dichloromethane; at 0 - 20℃; for 4h; | (2) At room temperature, 250 ml of dichloromethane is mixed with <strong>[4984-22-9](R)-1-methoxy-2-propanol</strong> 90 g (1.0 mol), triethylamine 121.2 g (1.2 mol), cooled to 0 C A mixture of 210.6 g (1.1 mol) of p-toluenesulfonyl chloride and 300 ml of dichloromethane was added. The reaction is exothermic, and the drop acceleration is controlled so that the temperature is not higher than 5C. The addition is completed in about 2 hours. Remove the freezing and let it warm to room temperature for 2 hours. The reaction solution was washed successively with 200 ml of saturated sodium bicarbonate solution, 200 ml of 5% dilute hydrochloric acid solution and 200 ml of purified water. Dried over anhydrous sodium sulfate, Concentrate at normal pressure to remove the methylene chloride solvent to dryness. High vacuum distillation yielded 223.38 grams of oily product, with a content of 98.17% and a yield of 91.54%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.51% | In methanol; for 13.5h;Reflux; | (1) 256 g (8 mol) of methanol and 10.8 g (0.2 mol) of sodium methoxide are stirred and dissolved at room temperature. Then 116 g (2 mol) of (R) -propylene oxide was added dropwise. The reaction is exothermic. Control the drop acceleration so that the temperature is not higher than 35 C. The addition was completed in about 1.5 hours. Heat slowly to reflux. The reaction was maintained at gentle reflux for 12 hours. Cool to room temperature, add acetic acid to adjust the pH to neutral. Then recover the excess methanol to dryness by atmospheric distillation, and then distill under reduced pressure to obtain the product(R) -1-methoxy-2-propanol 155.72 g, purity 99.26% (GC detection),The yield was 86.51% (based on (R)-propylene oxide). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.51% | With sodium hydroxide; at 35 - 65℃; for 16h; | (1) 208 grams (6.5 moles) of methanol and 12 grams (0.3 moles) of sodium hydroxide are stirred and mixed at room temperature. Then 116 g (2 mol) of (R)-propylene oxide was added dropwise. The reaction is exothermic. Control the drop acceleration so that the temperature is not higher than 35 C. The addition is completed in about 1 hour. Heat slowly to 65 C. Incubate for 15 hours. Cool to room temperature and add dilute hydrochloric acid to adjust the pH to neutral. Then recover excess methanol to dryness by atmospheric distillation, then distill the product (R)-1-methoxy-2-propanol 158.63 g under reduced pressure, purity 99.19% (GC detection), Yield 88.13% (counted on (R)-propylene oxide) |
Tags: 4984-22-9 synthesis path| 4984-22-9 SDS| 4984-22-9 COA| 4984-22-9 purity| 4984-22-9 application| 4984-22-9 NMR| 4984-22-9 COA| 4984-22-9 structure
[ 642-38-6 ]
(1R,2S,3S,4S,5R,6R)-6-Methoxycyclohexane-1,2,3,4,5-pentaol
Similarity: 0.63
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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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