(3R)-3-methoxyoxan-4-one

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: reacting said 4,4-dimethoxytetrahydro-2H-pyran-3-ol in the presence of THF, NaOt-Bu, Me2SO4, and an acid to form (3R)-3-methoxytetrahydro-4H-pyran-4-one.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3.83 g (13.3 mmol) of benzyl (1R,4S)-4-amino-1-(1-hydroxycyclobutyl)cyclopent-2-ene-1-carboxylate (Preparation SRT-0235) and 1.89 g (14.5 mmol) of (3R)-3-methoxytetrahydro-4H-pyran-4-one in 26 mL of dichloromethane was stirred with activated 3 A molecular sieves for 10 min, then cooled to 0 C. Sodium triacetoxyborohydride (3.35 g, 15.8 mmol) was added in several portions over 10 min, and the mixture was stirred for 1.5 h. The cloudy mixture was added to dichloromethane and aqueous NaHCO3+NaOH (pH ˜14), and the aqueous phase was extracted with several additional portions of dichloromethane. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 3-5% methanolic ammonia (7M) in dichloromethane afforded 3.94 g (74%) of the title compound as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41-1.52 (m, 1H) 1.55-1.64 (m, 1H) 1.64-1.79 (m, 2H) 1.86-2.09 (m, 5H) 2.19-2.29 (m, 1H) 2.41 (dd, J=14.2, 7.7 Hz, 1H) 2.84-2.91 (m, 1H) 3.17-3.44 (m, 4H) 3.34 (s, 3H) 3.88-3.96 (m, 2H) 4.00 (dd, J=12.3, 4.4 Hz, 1H) 5.10-5.20 (m, 2H) 5.88-5.93 (m, 1H) 6.00 (dd, J=5.6, 1.9 Hz, 1H) 7.28-7.39 (m, 5H). TLC Rf 0.41 (4% 7M methanolic ammonia in dichloromethane). LC-MS ES+ 402.1. cooled to 0 C the aqueous phase was extracted with several additional portions of dichloromethane The organic phase was dried (Na2SO4) concentrated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 0° C. solution of tert-butyl (1S,4S)-5-{[(1S,3R)-3-amino-1-(2,2-difluoroethyl)cyclopentyl]carbonyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.45 g, 9.2 mmol) in dichloromethane (50 ml) was treated with sodium triacetoxyborohydride (5.34 g, 25.2 mmol) and (3R)-3-methoxytetrahydro-4H-pyran-4-one (2.31 g, 17.8 mmol). The reaction was stirred under nitrogen at 0° C. for 30 minutes then allowed to warm to room temperature and stirred for 47 hours. The reaction was treated with 2.5N NaOH (35 mL) and stirred for 10 minutes. The reaction was diluted with water and the layers separated. The aqueous layer was extracted twice with ethyl acetate. The dichloromethane layer was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic layers were combined, washed with brine, dried over MgSO4, concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give 1,5-anhydro-3-{[(1R,3S)-3-{[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(2,2-difluoroethyl)cyclopentyl]amino}-2,3-dideoxy-4-O-methyl-D-erythro-pentitol (2.13 g, 47%) which was used without further purification in the next step. to warm to room temperature stirred for 47 hours stirred for 10 minutes the layers separated The aqueous layer was extracted twice with ethyl acetate The dichloromethane layer was concentrated under reduced pressure partitioned between ethyl acetate and water washed with brine dried over MgSO4 concentrated under reduced pressure purified with the Biotage (0-100% methanol/ethyl acetate, 15 column volumes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3.83 g (13.3 mmol) of benzyl (1R,4S)-4-amino-1-(1-hydroxycyclobutyl)cyclopent-2-ene-1-carboxylate (Preparation SRT-0235) and 1.89 g (14.5 mmol) of (3R)-3-methoxytetrahydro-4H-pyran-4-one in 26 mL of dichloromethane was stirred with activated 3 A molecular sieves for 10 min, then cooled to 0 C. Sodium triacetoxyborohydride (3.35 g, 15.8 mmol) was added in several portions ever 10 min, and the mixture was stirred for 1.5 h. The cloudy mixture was added to dichloromethane and aqueous NaHCO3+NaOH (pH ˜14), and the aqueous phase was extracted with several additional portions of dichloromethane. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 3-5% methanolic ammonia (7 M) in dichloromethane afforded 3.94 g (74%) of the title compound as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41-1.52 (m, 1H) 1.55-1.64 (m, 1H) 1.64-1.79 (m, 2H) 1.86-2.09 (m, 5H) 2.19-2.29 (m, 1H) 2.41 (dd, J=14.2, 7.7 Hz, 1H) 2.84-2.91 (m, 1H) 3.17-3.44 (m, 4H) 3.34 (s, 3H) 3.88-3.96 (m, 2H) 4.00 (dd, J=12.3, 4.4 Hz, 1H) 5.10-5.20 (m, 2H) 5.88-5.93 (m, 1H) 6.00 (dd, J=5.6, 1.9 Hz, 1H) 7.28-7.39 (m, 5H). TLC Rf 0.41 (4% 7 M methanolic ammonia in dichloromethane). LC-MS ES+ 402.1. cooled to 0 C the aqueous phase was extracted with several additional portions of dichloromethane The organic phase was dried (Na2SO4) concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from the reaction of the product of Step E and (R)-3-methoxydihydro-2H-pyran-4(3H)-one (Intermediate 1) following the procedure described in Example 1, Step H. 1H NMR (CHLOROFORM-d) δ: 7.42 (d, J=8.6 Hz, 1H), 7.36 (br. s., 1H), 6.95 (d, J=8.1 Hz, 1H), 5.43 (br. s., 2H), 4.96-5.11 (m, 1H), 4.82 (br. s., 2H), 3.84-4.15 (m, 3H), 3.68 (d, J=7.1 Hz, 1H), 3.55 (br. s., 1H), 3.32-3.45 (m, 4H), 3.20-3.32 (m, 2H), 2.69-2.84 (m, 1H), 2.39 (br. s., 1H), 2.12-2.25 (m, 2H), 1.99-2.12 (m, 1H), 1.78-1.99 (m, 1H), 1.46-1.78 (m, 4H). Calculated for C23H29F3N2O5: 471.2 (M+1). found: 471.2.

Conditions: temp:16.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of the product of Step K (the free base) (619.7 g, 1.74 mol) in 1,2-dichloroethane/CH2Cl2 (˜10 L) was added acetic acid (glacial, 180 mL) and the mixture was cooled to 16° C. Solid Na(OAc)3BH (463 g, 2.18 mol) was added and the suspension was stirred for 5-10 min. A solution of (R)-3-methoxydihydro-2H-pyran-4(3H)-one (prepared as described in Intermediate 1, 213 g, 1.63 mol) in 1,2-dichloroethane (1.75 L) was added over 20 min and the resulting mixture was stirred at rt overnight. Additional acetic acid, (R)-3-methoxytetrahydro-4H-pyran-4-one (28 g) and Na(AcO)3BH were added until TLC showed the reaction was complete. The reaction was quenched with saturated aqueous NaHCO3, the organic layer was separated and the aqueous layer was back-extracted with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. Purification was affected by chromatography with MeOH (7N NH3) in CH2Cl2. The collected enriched isomer was further purified using chiral chromatography on chiralpak AD column using a mixture of heptanes/EtOH/isopropyl alcohol to provide the product of Step L. the resulting mixture was stirred at rt overnight The reaction was quenched with saturated aqueous NaHCO3 the organic layer was separated the aqueous layer was back-extracted with CH2Cl2 The combined organic layers were washed with brine dried (Na2SO4) evaporated under reduced pressure Purification was further purified a mixture of heptanes/EtOH/isopropyl alcohol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The product of Step H was prepared from the reaction of the product of Step G and (R)-3-methoxydihydro-2H-pyran-4(3H)-one (Intermediate 1) following the procedure described in Example 1, Step H. Calculated for C26H37N3O6: 488.3 (M+1). found: 488.1.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of (R)-3,4,4-trimethoxytetrahydro-2H-pyran (as prepared in the previous step, 141 g, 0.80 mol), in THF (3.6 L) and H2O (1.1 L) in an ice/acetone bath at <0° C., was treated with a solution of HCl (conc., 595 mL, 7.21 mol) added via addition funnel over 45 min while keeping temperature <3° C. After the addition was complete, the reaction was allowed to stir for 1.5 h at 0° C. The reaction was evaporated until ˜1.9 L of concentrate remained. The concentrated was transferred to a separatory funnel and extracted with CH2Cl2 (3×1 L). The combined organic fractions were washed with sat. NaHCO3 (1 L), brine (1 L), dried over MgSO4, filtered and evaporated to afford the title compound (71.4 g, 69%, Chiral GC 92% ee) as an oil which solidified upon standing. Optical Rotation: [α]25(D) −6.97° (c=0.8222, MeOH); Elemental Analysis calc for C6H10O3: C, 53.59; H, 7.58. Found: C, 53.64; H, 7.65. added via addition funnel over 45 min temperature <3° C After the addition The reaction was evaporated until ˜1.9 L of concentrate The concentrated was transferred to a separatory funnel extracted with CH2Cl2 (3×1 L) The combined organic fractions were washed with sat. NaHCO3 (1 L), brine (1 L) dried over MgSO4 filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: reacting said 4,4-dimethoxytetrahydro-2H-pyran-3-ol in the presence of THF, NaOt-Bu, Me2SO4, and an acid to form (3R)-3-methoxytetrahydro-4H-pyran-4-one.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Example 8C (50 mg, 0.12 mmol) in isopropyl acetate (5 mL) was cooled with an ice bath. Tributyl amine (11 mg, 0.06 mmol) followed by addition of isopropyl alcohol (16.8 mg, 0.28 mmol) was added to the solution. Sodium triacetoxyborohydride (59 mg, 0.28 mmol) was added at 5° C. After stirring for 1 hour, a solution of Example 1I (23.4 mg, 0.18 mmol) in dichloromethane was added to the reaction mixture. Then the mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried in vacuo and concentrated to provide a diastereomeric mixture. The diastereomeric mixture was separated by chiral SFC (Column: AD 250 mm*30 mm, 5 μm; Mobile phase:A, supercritical CO2; B, isopropyl alcohol with 0.1% diethylamine, A:B=80:20 with a flow rate of 70 mL/min) to afford the title compound (peak 1, retention time: 7.11 minutes) and Example 41 (peak 2, retention time: 7.94 minutes); MS (ESI) m/z 523 (M+H)+. was added to the solution Then the mixture was stirred at room temperature overnight The reaction mixture was quenched with saturated sodium bicarbonate extracted with ethyl acetate The combined organic fractions were washed with brine dried in vacuo concentrated to provide a diastereomeric mixture The diastereomeric mixture was separated by chiral SFC (Column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the product from step 3 (9.5 g, 64.68 mol) in tetrahydrofuran (300 mL) was added sodium tert-butoxide (9.3 g, 97.02 mmol) at ice bath. Then dimethyl sulfate (13.4 g, 106 mmol) was added over 20 minutes, maintaining an internal temp below 36° C. After addition, the reaction mixture was stirred for 4 hours at room temperature. Water (200 mL) was added followed by addition of 2N HCl (100 mL). The apparent pH was below 1. After 16 hours of reaction, NaHCO3 (20 g) was added and the mixture was extracted with ethyl acetate (4×300 mL), dried over Na2SO4, filtered, and concentrated to an oil (6 g, yield: 71%). maintaining an internal temp below 36° C After addition was added the mixture was extracted with ethyl acetate (4×300 mL) dried over Na2SO4 filtered

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: reacting said 4,4-dimethoxytetrahydro-2H-pyran-3-ol in the presence of THF, NaOt-Bu, Me2SO4, and an acid to form (3R)-3-methoxytetrahydro-4H-pyran-4-one.