* 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.
With sodium tetrahydroborate In methanol at 5 - 20℃;
Sodium tetrahydroborate (1.92 g, 50.67 mmol) was added portionwise at 5°C to a solution of intermediate 1 (7.72 g, 46.06 mmol) in MeOH (80 ml). The reaction mixture was stirred at room temperature for 1 night and then poured out into water. The mixture was extracted three times with EtOAc. The organic layer was washed with water and NaCl solution, separated, dried over MgSO4, filtered and the solvent was evaporated, yielding 6.38 g (81.7percent) of intermediate 3 (50/50 mixture RS). This product was used without further purification in the next step.
With Lipase Candida Antartica B; at 20℃; for 4.0h;
.?). Preparation .of intermediate.? and intermediate 8 Intermediate 7 (S) Intermediate 8 (R)A mixture of intermediate 4 (5 g, 0.029 mol) and Lipase Candida Antartica B (2.5 g) in acetic acid ethenyl ester (50 ml) was stirred at room temperature for 4 hours. The reaction mixture was filtered over Celite. The Celite was washed with DCM. The filtrate's solvent was evaporated. The residue (6.3 g) was purified by column chromatography over silica gel (eluent: DCM/MeOH from 100/0 till 98/2; 15-40 mum). Two different product fractions were collected and the solvent of each product fraction was evaporated. Yield: 2.1 g of intermediate 7 (42 %; S-enantiomer), and 3.6 g of intermediate 8 (58 %; R-enantiomer). When desired intermediate 8 can be converted into the R enantiomer of intermediate 7 by reaction in MeOHZNH3.
42%; 58%
With Lipase Candida Antartica B; at 20℃; for 4.0h;
A mixture of <strong>[126053-15-4]4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol</strong> (5 g, 0.029 mol) and Lipase Candida Antartica B (2.5 g) in acetic acid ethenyl ester (50 ml) was stirred at room temperature for 4 hours. The reaction mixture was filtered over Celite. The Celite was washed with DCM. The filtrate's solvent was evaporated. The residue (6.3 g) was purified by column chromatography over silica gel (eluent: DCM/MeOEta from 100/0 till 98/2; 15-40 mum). Two different product fractions were collected and the solvent of each product fraction was evaporated, yielding 2.1 g of intermediate 18 (42 %; S- enantiomer), and 3.6 g of intermediate 19 (58 %; R-enantiomer). When desired intermediate 19 can be converted into the R enantiomer of intermediate 18 by reaction in MeOEta/NEta3, yielding intermediate 20.
B. Preparation of the final compoundsExample BlCompound 1 (enantiomer A; S) (chiral center indicated by *) Compound 2 (enantiomer B; R)A mixture of intermediate 6 (0.0039 mol), intermediate 4 (0.0042 mol) and HC1/2- propanol (3 drops) in CH3CN (20 ml) was stirred overnight at 65 0C. Then K2CO3 (10 %) was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (1.8 g) was purified by column chromatography over silica gel (eluent: CH2CI2ZCH3OHZNH4OH 92Z8Z0.5; 15-40 mum). The pure fractions were collected and the solvent was evaporated. The residue (0.55 g) was purified by column chromatography over Chiralpack AD (eluent: EtOHZMeOHZ2-propanol 50Z50Z0.3). Two fractions were collected and the solvent was evaporated, yielding 0.24 g of fraction 1 and 0.26 g of fraction 2. Fraction 1 was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.17 g of compound 1 (enantiomer A; S enantiomer) (11 %). Fraction 2 was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.12 g of compound 2 (enantiomer B; R enantiomer) (8 %).
4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate[ No CAS ]
[ 126053-15-4 ]
Yield
Reaction Conditions
Operation in experiment
With ammonia; In methanol; at 20℃; for 48.0h;
dchiPrepjM.atipn_rhof i.ntermeate 4 A mixture of intermediate 3 (0.04 mol) in CH3OH/NH3 (90 ml) was stirred at room temperature for 48 hours. Then the mixture was concentrated. The crude oil was dissolved in DCM and K2CO3 was added. The solution was filtered over Celite. The filtrate was extracted with DCM. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. Yield: 6.7 g of intermediate 4.
A mixture of intermediate 4 (0.0002 mol) and 4-chloro-6,7-dihydro-5/-/- cyclopenta[b]pyridin-7-ol (0.0002 mol) in HCI/dioxane 4N (14mul), CH3CN (1 ml) and EtOH (0.5ml) was stirred at 65C for 18 hours. HCI (0.2eq) and dioxane 4N (14mul) were added. The mixture was stirred at 65C for 18 hours, then cooled to room temperature, diluted in CH2CI2 and washed with K2CO3 10% aqueous solution. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (0.14g) was purified by column chromatography over Sunfire (eluent: CH2CI2/CH3OH/NH4OH 100/0/0 to 92/8/0.8; 5mum). The pure fractions were collected and the solvent was evaporated. The residue (0.072g, 50%) was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.049g (30%) of compound 5 (M. P.: 178C).
A mixture of intermediate 8a (0.0006 mol) and 4-chloro-6,7-dihydro-5/-/- cyclopenta[b]pyiotadin-7-ol (0.006 mol) in HCI/dioxane 4N (0.0001 mol), CH3CN (2 ml) and CH3OH (0.8 ml) was stirred at 65C for 18 hours then cooled at room temperature. 3N HCI (0.0025 mol) was added. The mixture was stirred at 65C for 18 hours, cooled at room temperature, diluted with CH2CI2 and washed with K2CO3 10% aqueous solution. The organic layer was decanted, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (0.36g) was purified by column chromatography over kromasil (eluent: CH2CI2/CH3OH/NH4OH 98/2/0.2 to 90/10/1 ; 3.5mum). The pure fractions (0.14g) were crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.12Og (47%) of compound 9 (M. P.: 2070C).
A mixture of intermediate 8b (0.0007 mol) and 4-chloro-6,7-dihydro-5/-/- cyclopenta[b]pyridin-7-ol (0.0008 mol) in HCI/dioxane 4N (0.0001 mol), CH3CN (2 ml) and CH3OH (0.8 ml) was stirred at 65C for 48 hours then cooled to room temperature, poured out to into K2CO3 10% aqueous solution and extracted with CH2CI2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over kromasil (eluent: CH2CI2/CH3OH/NH4OH 98/2/0.2 to 90/10/1 ; 3.5mum). The pure fractions were collected and the solvent was evaporated till <n="90"/>dryness. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.055g (17%) of compound 10 (M. P.: 237C).
A mixture of intermediate 22 (0.0015 mol) and 4-chloro-6,7-dihydro-5/-/- cyclopenta[b]pyiotadin-7-ol (0.0016 mol) in HCI/dioxane 4N (0.0003 mol), CH3CN (3 ml) and EtOH (1.2 ml) was stirred at 65C for 18 hours then cooled at room temperature, poured out into K2CO3 10% aqueous solution and extracted with CH2CI2. The organic layer was decanted, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (0.74 g) was purified by column chromatography over kromasil (eluent: CH2CI2/CH3OH/NH4OH 100 to 93/7/0.7; 5mum). The solvent was evaporated till dryness. The residue (0.445 g) was crystallized from EtOH. The residue was filtered off and dried, yielding 0.244 g (36%) of compound 49 (M. P.: 123C).
A mixture of intermediate 29 (0.00168 mol), 4-chloro-6,7-dihydro- 5H- cyclopenta[b]pyridin-7-ol (0.00168 mol) and hydrogen chloride in dioxane 4M (0.000336 mol) in a solution of CH3CN/ EtOH (25ml) was prepared. The mixture was stirred at 65C overnight. K2CO3 10% aqueous solution was added and the organic layer was extracted with CH2CI2, dried (MgSO4), filtered and the solvent was evaporated. The residu (0.9g) was purified by column chromatography over silica gel (eluent:CH2CI2/CH3OH/NH4OH gradient 97/3/0.5; 9Og 15-40mum). The pure fractions were collected and the solvent was evaporated. The residue was crystallized in CH3OH, yielding 0.16Og of intermediate 30.
A solution of intermediate 38 (0.92 mmol), 4-chloro-6,7-dihydro- 5/-/-cyclopenta[b]pyridin- 7-ol (1 mmol), hydrogen chloride in dioxane 4M (46mul) in CH3CN (10ml) was heated at 65C for 5 hours. K2CO3 10% aqueous solution and EtOAc were added. The reaction mixture was extracted, the organic layer was separated, dried over MgSO4, filtered and evaporated. The residue (0.4g) was purified by high-performance liquid chromatography (Stability Silica 5mum 150x30. Omm). Mobile phase (NH4OH 0.2%; gradient CH2CI2/CH3OH from 98/2 to 88/12), yielding 49mg compound 63 and 114mg of compound 64.
A mixture of intermediate 2 (0.0012 mol), 4-chloro-6,7-dihydro-5/-/-cyclopenta[b]pyridin-7- ol (0.0012 mol) and HCI/dioxane 4N (0.0025 mol) in CH3CN (10ml) was stirred at 65C for 18 hours, then cooled to room temperature, poured out into K2CO3 10% aqueous solution and extracted with CH2CI2/CH3OH (few). The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (0.54g) was purified by column chromatography over kromasil (eluent: CH2CI2/CH3OH/NH4OH 97/3/0.3 to88/12/1.2; 3-5mum). The pure fractions were collected and the solvent was evaporated. The residue (0.14g, 26%) was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.113g (21 %) of compound 17 (M. P.: 147C).
A mixture of intermediate 3 (0.0004 mol) and 4-chloro-6,7-dihydro- 5H- cyclopenta[b]pyridin-7-ol (0.0005 mol) was stirred at 1500C for 20 minutes, cooled to room temperature, extracted with NaHCOs/DCM/methanol (few drops) (4 times 40ml). The organic layers were combined, dried over MgSO4, filtered off and the solvent was evaporated. The residue (0.218g) was purified by column chromatography over silica <n="74"/>gel (DCM/methanol 95/5, 93/7 to 90/1 ). The pure fraction was collected and the solvent was evaporated, yielding 0.15O g (86%) of compound 1.
A mixture of intermediate 4 (0.0003 mol) and 4-chloro-6,7-dihydro- 5H- cyclopenta[b]pyridin-7-ol (0.0003 mol) was stirred at 1500C for 20 minutes, cooled to room temperature, extracted with NaHCOs/DCM/methanol (few drops). The organic layers were combined, dried over MgSO4, filtered off and the solvent was evaporated. The residue (0.174g) was purified by column chromatography over silica gel (DCM/methanol 95/5, 93/7 to 90/1 ). The pure fraction was collected and the solvent was evaporated, yielding 0.097 g (68%) of compound 2.
A mixture of intermediate 9 (0.139 mmol) and 4-chloro-6,7-dihydro- 5H- cyclopenta[b]pyridin-7-ol (0.167 mmol) in HCI/dioxane 4N (0.0278 mmol) and acetonitrile (1 ml) was heated at 65C for 18 hours. The reaction mixture was cooled to room temperature, diluted with DCM and quenched with a 10% solution of potassium carbonate. The organic layer was decanted, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by high-performance liquid chromatography (X-Terra-C18 10mum 19x150mm mobile phase: NH4HCO3 0.5%;Gradient from 40 % to 100 of acetonitrile), yielding 24mg (35%) of compound 5.
A mixture of intermediate 13 (0.000966mol), 4-chloro-6,7-dihydro- 5H- cyclopenta[b]pyridin-7-ol (0.00116mol) and HC/dioxane 4M (0.000193mol) in acetonitrile (3.3ml) and EtOH (2.6ml) was heated at 8O0C for 18 hours. The mixture was cooled to room temperature, quenched with a 10% solution of potassium carbonate and extracted with DCM. The organic layer was decanted, dried over MgSO4, filtered and evaporated till dryness. The residue (0.48g ) was purified by high- performance liquid chromatography (Spherical SiOH 10mum 6Og PharmPrep MERCK mobile phase: NH4OH 0.1%;DCM 92% MeOH 8%). The pure fractions were collected and the solvent was evaporated. The residue (0.202g) was crystallized from Et2O and dried, yielding 0.139g (32%) of compound 12.
A mixture of intermediate 19 (0.00114mol), 4-chloro-6,7-dihydro- 5H- cyclopenta[b]pyridin-7-ol (0.00137mol) and HCI 4M in dioxane (0.000228mol) in acetonitrile (3.5ml) and EtOH (2.8ml) was heated at 800C overnight. The mixture was cooled to room temperature, quenched with a 10% solution of potassium carbonate and extracted with DCM. The organic layer was decanted, dried over MgSO4, filtered and evaporated till dryness. The residue (0.56g) was purified by high-performance liquid chromatography (Spherical SiOH 10mum 6Og PharmPrep MERCK mobile phase: NH4OH 0.5%;DCM 95% MeOH 5%). The pure fractions were collected and the solvent was evaporated. The residue (200mg) was crystallized from Et2O and dried, yielding 0.164g (33%) of compound 24.
A mixture of intermediate 22 (0.68 mmol) 4-chloro-6,7-dihydro- 5H- cyclopenta[b]pyridin-7-ol (0.816 mmol) and HCI/dioxane 4N (34mul) in acetonitrile (3 ml) and EtOH (2.4 ml) was heated at 65C for 18 hours. The reaction mixture was quenched with a 10% solution of potassium carbonate and extracted with DCM. The organic layer was decanted, dried over MgSO4, filtered and evaporated to dryness. The residue (321 mg) was purified by high-performance liquid chromatography (Spherical SiOH 10mum 6Og PharmPrep MERCK mobile phase: NH4OH 0.5%; DCM94% MeOH6%). The pure fractions were collected and the solvent was evaporated. The residue (124mg) was crystallized from CH3CN/DIPE. The precipitate was filtered off and dried, yielding 93mg (32%) of compound 11.
A mixture of intermediate 25 (0.228 mmol), 4-chloro-6,7-dihydro- 5H- cyclopenta[b]pyridin-7-ol (0.274 mmol) and HCI/dioxane 4M (0.0456 mmol) in acetonitrile (1 ml) and EtOH (0.8 ml) was heated at 65C for 18 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and quenched with a 10% solution of potassium, carbonate. The organic layer was decanted, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by HPLC (H660 - kromasil 3.5mum - eluent: DCM/MeOH/NH4OH 99/1/0.1 to 93/7/0.7). The pure fractions were collected and evaporated to dryness, yielding 77mg (76%) of compound 13.
A mixture of 4-chloro-6,7-dihydro- 5/-/-cyclopenta[b]pyridin-7-ol (0.00039mol), HCI/dioxane 4M (0.0000651 mol) and intermediate 29 (0.000325mol) in acetonitrile (1 ml) and EtOH (0.8ml) was heated at 65C for 18 hours. The mixture was cooled to room temperature, quenched with a 10% solution of potassium carbonate and extracted with DCM. The organic layer was decanted, dried over MgSO4, filtered and evaporated till dryness. The residue was purified by high-performance liquid chromatography over XTerra (eluent: CH3CN/ 0.5%NaHCO3: 30/70 to 100/0). The pure fractions were evaporated till dryness, yielding 0.013g (8%) of compound 14.
A mixture of intermediate 31 (see Example A3) (0.432 mmol), 4-chloro-6,7-dihydro- 5/-/-cyclopenta[b]pyridin-7-ol (0.518 mmol) and HCI/dioxane 4N (0.0863 mmol) in acetonitrile (2 ml) and EtOH (16 ml) was heated at 65C for 18 hours. The reaction mixture was cooled to room temperature, diluted with DCM and quenched with a 10% solution of potassium carbonate. The organic layer was decanted, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by HPLC (1 Og SiO2 15/40mum - eluent: DCM/MeOH/NH4OH 95/5/0.5). The pure fractions were collected and evaporated to dryness, yielding 163mg (64%) of intermediate 32.
With hydrogenchloride; In 1,4-dioxane; ethanol; acetonitrile; at 65℃;
A mixture of intermediate 20 (0.0006 mol), 4-chloro-6,7-dihydro- 5H- cyclopenta[b]pyridin-7-ol (0.0006 mol) and HCI/dioxane 4M (0.0002 mol) in acetonitrile/EtOH 4/1 (25ml) was stirred at 65C overnight. The residue was purified by column chromatography over silica gel (eluent: DCM/MeOH/NH4OH from 96/4/0.4 to 86/13/1.2; Sunfire 5mum). The pure fractions were collected and the solvent was evaporated, yielding 0.073g of compound 10.
With dibromotriphenylphosphorane; In acetonitrile; for 3.0h;
Example A4PXQP ar ation _o_ f intermediate 14 ; Dibromotriphenyl- phosphorane (0.004 mol) was added to a solution of 4-chloro-6,7- dihydro- 5H-Cyclopenta[b]pyridin-7-ol (0.002 mol) in acetonitrile (6 ml). The mixture <n="35"/>was stirred for 3 hours, quenched with potassium carbonate 10% and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (1.6g) was purified by column chromatography over silica gel (15-40 mum) (eluent DCM 100). The pure fractions were collected and the solvent was evaporated till dryness, yielding 0.3 Ig (67%) of intermediate 14.
At 00C and under N2 atmosphere, sodium hydride (1.06 g, 44.22 mmol) was added portionwise to a solution of intermediate 3 (3.00 g, 17.70 mmol) in THF (anhydrous, 30 ml). The reaction was stirred for 15 minutes at 00C. Then at 00C, iodomethane (1.65 ml, 26.53 mmol) was added dropwise to the mixture. The reaction was stirred at room temperature for 1 night. The mixture was cooled to room temperature and cold water was added dropwise. The mixture was stirred for 1 hour and was then extracted with EtOAc three times. The organic layer was separated, dried over MgSO4, filtered and the solvent was evaporated, yielding 3.10 g (95.4%) of intermediate 4. This product was used without further purification in the next step.
(R)-4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol[ No CAS ]
[ 1113047-05-4 ]
Yield
Reaction Conditions
Operation in experiment
29.1%; 29.2%
With CHIRALPACK AD-H; In methanol; carbon dioxide;Resolution of racemate;Purification / work up;
Intermediates 18 and 20 were also alternatively prepared as follows. Sodium tetrahydroborate (1.37 g, 36.10 mmol) was added portionwise at 5C to a solution of intermediate 1 (5.50 g, 32.82 mmol) in MeOH (50 ml). The reaction mixture was stirred at room temperature for 1 night and then poured out into water and the mixture was extracted three times by EtOAc. The organic layer was washed by water and NaCl solution in water, separated, dried over MgSO4, filtered and the solvent was evaporated. The residue (4.42 g) was purified by chiral Super critical fluid chromatography on CHIRALPAK AD-H 5mum 250x20mm. Mobile phase : 85% CO2, 15% MeOH.The pure fractions were collected and the solvent was evaporated, yielding 1.625 g of (29.2%) of compound 18 (S-enantiomer) (DMF, 200C, concentration 0.33w/v%, 589 nm : -77.58) and 1.620 g (29.1%) of compound 20 (R-enantiomer) (DMF, 200C, concentration 0.33w/v%, 589 nm : +76.74).
With manganese(IV) oxide; In dichloromethane; at 20℃; for 24.0h;
Manganese oxide (33.3 Ig, 13Eq, 0.3832 mol) was added portionwise to a solution of 4- chloro-6,7-dihydro- 5H-Cyclopenta[b]pyridin-7-ol (intermediate 3) [CAS 126053-15-4] (5g, IEq, 0.029 mol) in DCM (50ml). The mixture was stirred at room temperature for 24 hours and then filtered over celite. The solvent was evaporated, yielding 3.25g (66%) of intermediate 1.
40%
With manganese(IV) oxide; In dichloromethane; at 20℃; for 20.0h;
To a solution of 12.5 g (73.7 mmol, 1.0 eq.) of 4-chloro-6,7-dihydro-5H-cyclopenta[b] pyridin-7-ol (LXVIIa) in 250 mL of methylene chloride was added 96.1 g (1.1 mol, 15.0 eq.)of manganese dioxide and the mixture was stirred at room temperature for 20 h. The mixturewas filtered through CELITE and the pad was washed with 250 mL of methylene chloride.The solvent was removed in vacuo and the residue was purified by flash chromatography(Si02, eluting with a linear gradient of 0-30% ethyl acetate/petroleum ether) to provide 4.9 g(29.2 mmol, 40%) of 4-chloro-5H-cyclopenta[b]pyridin-7(61])-one (LXVIIIa). ?H NIVIR(500 IVIFIz, CDC13): 2.80-2.82 (t, 2H), 3.16-3.19 (t, 2H), 7.48-7.49 (d, 1H), 8.67-8.68 (d,1H).
With Dess-Martin periodane; In dichloromethane; at 20℃;Inert atmosphere;
[0223] To a solution of <strong>[126053-15-4]4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol</strong> (900 mg, 5.31 mmol) in anhydrous CH2C12 (10 ml), Dess-Martin periodinane (4501 mg, 10.61 mmol) was added. The reaction mixture was stirred at room temperature under N2 atmosphere overnight. The mixture was quenched with NaHC03 (aq.), extracted with DCM. And the DCM phase was washed with brine, dried over Na2S04, filtered and concentrated to give crude product. The crude product was purified by silica column chromatography, eluting with hexane: ethyl acetate=3: l to give 4-chloro-5H-cyclopenta[b]pyridin-7(6H)- one as a solid. LC/MS = 168 [M+l].
Intermediate 27 (0.41mmol) and <strong>[126053-15-4]4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol</strong> (0.46mmol) were heated at 125C for 2 hours. The residue was purified by column chromatography over silica gel (eluent 90/10/0.1 DCM/MeOEta/NEta4OEta). The pure fractions were collected and the solvent was evaporated, yielding 58mg of compound 9.
Intermediate 32 (2.6g, 4.2mmol), 4-chloro-6,7-dihydro- 5H-cyclopenta[b]pyridin-7-ol (0.78g, 4.6mmol), HCl 4M in dioxane (0.21ml, 0.8mmol) in acetonitrile (28ml) and EtOH (7ml) were heated at 650C for 72 hours. After cooling down to room temperature, water and potassium carbonate powder were added and the mixture was extracted twice with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered and evaporated. The residue was purified by high-performance liquid chromatography (Irregular SiOH 20-45mum 45Og MATREX). Mobile phase (NH4OH 0.5%;dichloromethane 95%; MeOH 5%) . The pure fractions were collected and the solvent was evaporated, yielding 2.35g of intermediate 33.
A mixture of intermediate 41 (0.0018 mol), 4-chloro-6,7-dihydro- 5H- cyclopenta[b]pyridin-7-ol (0.33g) and EtaCl/isopropanol (5 drops) in acetonitrile (20ml) was stirred at 65C for 24 hours. Potassium carbonatelO% was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (l.lg) was purified by column chromatography over silica gel (eluent: DCM/MeOEta/NEta4OEta 95/5/0.1). The pure fractions were collected and the solvent was evaporated, yielding 0.054g of intermediate 42.
With sodium tetrahydroborate; In methanol; at 5 - 20℃;
Sodium tetrahydroborate (1.92 g, 50.67 mmol) was added portionwise at 5C to a solution of intermediate 1 (7.72 g, 46.06 mmol) in MeOH (80 ml). The reaction mixture was stirred at room temperature for 1 night and then poured out into water. The mixture was extracted three times with EtOAc. The organic layer was washed with water and NaCl solution, separated, dried over MgSO4, filtered and the solvent was evaporated, yielding 6.38 g (81.7%) of intermediate 3 (50/50 mixture RS). This product was used without further purification in the next step.