(3aS,4S,6aR)-4-methoxytetrahydrofuro[3,4-b]furan-2

Off-White to Pale Yellow Solid

Synthesis of (3aS, 6a/?)-4-methoxy-tetrahvdro-furo[3, 4-b1furan-2(3l-0-one (Ml. R = Me) using aldehydes NXl (P1= PMB) and [Xl (P2 = Me) with riX1:fXl = 1 :1.5; A mixture of 345 mg L-proline (3.0 mmol), 4.51 g (25.0 mmol) p- methoxybenzyloxy-acetaldehyde ([IX], Pi = PMB), 4.35 g 4-oxobutanoic acid methylester (37.5 mmol) and 30 ml. THF were stirred for 16 h in a closed flask at 200C. Then, 50 ml. methanol was added and the mixture was concentrated in vacuo. The volatiles were further removed by coevaporation with 2 x 50 ml. methanol. 1H NMR spectroscopy showed that the R, S- and S, S-isomers of the Aldol product with formula [Xl] (Pi = PMB, P2 = Me) were present as the main products in a ratio of 2.5:1. To a solution of the crude product in 50 ml. methanol was added 5.3 ml. (0.10 mol) sulfuric acid and the mixture was stirred at 2O0C for 3 h and subsequently, slowly and under vigorous stirring, poured into a solution of 20 g KHCO3 in 80 ml. water. The slightly alkaline solution was acidified to pH = 4 with 10 wtpercent aqueous sulfuric acid. The salts were removed by filtration and rinsed with 150 ml. ethyl acetate. The methanol was removed from the filtrate by evaporation in vacuo and the resulting aqueous phase was extracted with 5 x 150 ml. ethylacetate. The combined extracts and wash layer were dried (Na2SO4) and concentrated in vacuo giving a residue. According to quantitative 1H NMR spectroscopy this contained 0.71 g of (3aS, 4S, 6aR)-4-methoxy-tetrahydro-furo[3, 4-b]furan-2(3H)-one as the main compound and (3aS, 4/?, 6aR)-4-methoxy-tetrahydro-furo[3, 4-b]furan-2(3H)- one as the minor compound, corresponding to an overall crude yield of 18percent based on p-methoxybenzyloxy-acetaldehyde ([IX], P1 = PMB). The NMR data were in line with Example 6. Synthesis of (3aS, 6a/?)-4-methoxy-tetrahvdro-furo[3, 4-b1furan-2(3H)-one (Ml. R = Me) using aldehydes NXl (Pi = TBDMS) and [Xl (P' = Me) with NXUXl = 1 :1.5; A mixture of 345 mg L-proline (3.0 mmol), 4.36 g (25.0 mmol) tert- butyldimethylsilyloxy-acetaldehyde ([IX], Pi = TBDMS), 4.35 g 4-oxobutanoic acid methylester (37.5 mmol) and 30 mL THF was stirred for 16 h in a closed flask at 200C. Example 7. Synthesis of (3aS, 4S, 6a/?)-4-methoxy-tetrahvdro-furo[3, 4-b1furan-2(3H)- one (Ml. R = Me) using aldehydes [IXl (P1= TBDMS) and [Xl (P2 = Me) with NXl=FXl = 2:1; A mixture of 0.63 g L-proline (5.47 mmol), 9.53 g (54.7 mmol) tert- butyldimethylsilyloxy-acetaldehyde ([IX], P1 = TBDMS), 3.18 g 4-oxobutanoic acid methylester (27.4 mmol) and 43 ml. THF was stirred for 94 h in a closed flask at 4°C. Then, a 1.25 M HCI solution in methanol (66 ml.) was added and the reaction mixture was stirred for another 22 h at 4°C and subsequently poured slowly under vigorous stirring into a solution of 15.2 g KHCO3 in 100 ml. water at ambient temperature. The resulting slurry was acidified to pH 4 with 10 wtpercent aqueous sulfuric acid. The salts were removed by filtration and rinsed with 200 ml. ethylacetate. THF and methanol were removed from the aqueous filtrate by evaporation in vacuo and the resulting aqueous phase was extracted with 4 x 200 ml. ethylacetate. The combined extracts and wash layer were dried (MgSO4) and concentrated in vacuo giving a yellow oil containing 3.68 g of (3aS, 4S, 6aR)-4-methoxy-tetrahydro-furo[3, 4-b]furan-2(3H)-one as the main compound as determined by quantitative 1H NMR spectroscopy, corresponding to a yield of 52percent based on te/t-butyldimethylsilyloxy-acetaldehyde ([IX], Pi = TBDMS). Besides this main (3aS, 4S, 6aR)-isomer, also a minor amount of the (3aS, 4/?, 6aR)- The crude product was dissolved in isopropanol (70 g) at 60 °C. The resulting solution was cooled to 50 °C, seeded and cooled further to 0 °C resulting in crystallization of a- (4) which was isolated by filtration, washed with cold (0 °C) isopropanol (2 x 15 mL) and dried on the air. This gave 12.3 g of a- (4) which, according to quantitative 1H NMR analysis, was 97.1 wtpercent pure and contained no p-(4). This corresponds to a (first crop) yield of 38percent based on R-3- (2, 2-dimetbyl- [l, 3] dioxolan-4-yl) -acrylic acid ethylester and a crystallization yield of 68percent (output a- (4)/ [input a- (4) + 0- (4)]). The combined mother and wash liquors of the first crystallization (108 g, containing 4.0 g P- (4) and 1.2 g a- (4)) were concentrated in vacuo to 17.9 g of a liquid. Subsequently, methanol (9.05 g) and MeSO3H (0. 91 g, 0.29 eq. ) were added and the mixture was heated up to reflux. After 2 h of reflux the epimerization reaction was complete (a- (4) : p- (4) ratio > 3). After cooling to 20 °C, triethyl amine (0.96 g, 1 eq. based on MeSO3H) was added and the mixture was concentrated in vacuo to 18.7 g of a viscous residue. The residue was redissolved in isopropatiol (13.9 g) at 50 °C. After cooling to 45 °C the mixture was seeded and cooled down to 0 °C resulting in crystallization of a- (4) which was isolated by filtration, washed with cold (0 °C) isopropanol (2 x 6 mL) and dried on the air. This gave 2.24 g a- (4) which, according to quantitative 1H NMR analysis, was 95.3 wtpercent pure and contained no ss-(4). This corresponds to a (second crop) yield of 6percent based on R-3- (2, 2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid ethylester and a crystallization yield of 43percent (output a- (4)/ [input a- (4) + 0- (4)] after the epimerization). Thus, the total a- (4) yield (crop 1 and 2) based on R-3- (2, 2- dimethyl- [1, 3] dioxolan-4-yl)-acrylic acid ethylester was 44percent. Example 6: Crystallization of pure a- (4) from a mixture of a- (4) and P- (4) with simultaneous epimerization of P- (4) A solution of light-brown a- (4) (5.0 g, 96.6 wtpercent pure, 30.6 mmol, containing no P- (4)) and MeSO3H (0.3 g, 0.1 eq. ) in methanol (200 mL) was stirred at 20 °C for 92 h resulting in epimerization to an a- (4) : (3- (4) ratio of 3.6 : 1. The reaction mixture was subsequently concentrated in vczcuo (20 mbar; 45 °C) to give 5.2 g of a sticky solid. This was taken up in methanol (50 mL) and concentrated once more in vacuo (20 mbar; 50 °C) to give 5.1 g of a dry light-brown solid which, according to quantitative 1H NMR analysis, contained a- (4) in 90 wtpercent purity (4.6 g, 29 mmol). No je- (4) was detected. Thus, nearly all (960/, o) initial a- (4) had been recovered. The mother liquor and wash liquors of the first a- (4) crystallization (totally 374 g) were concentrated in vacuo to 90.8 g, methanol (120 mL) was added and the resulting mixture concentrated to 83 g. Methanol (120 mL) was added once more and the mixture concentrated to 83 g. To the residue was added methanol (45 g) and MeSO3H (2.66 g, 0. 0277 mol, 0.2 eq. based on total a- (4) + P- (4) present in the mother liquor and wash liquors) and the solution was heated up to reflux. After 1 h at reflux (60-65°C) GC indicated that the epimerization was complete (the a- (4) : (3- (4) ratio was 3.1 : 1) and the solution was cooled to 33 °C, meutralized with triethyl amine (2.94 g, 1.05 eq. based on MeSO3H) and concentrated in vacuo. To the resulting residue was added isopropanol (120 mL) and the mixture was concentrated in vacuo to give 88 g of a residue. Subsequently, methanol (42.6 g) and MeS03H (6.06 g, 0.04 eq. ) were added and the mixture was heated up to 50 °C. After 2 h of stirring at this temperature the mixture was cooled to 20oC and stirring was continued for an additional 12h. After cooling to - 5°C, triethyl amine (6.60 g, 1.1 eq. based on MeS03H) was added and the mixture was stirred for another 2 h. The crystalline a- (4) which was isolated by filtration, washed with cold (-5'C) isopropanol (3 x 70 mL) and dried on the air. This gave 120.0 g a- (4) which, according to quantitative GC analysis, was 99.0 wtpercent pure and contained 0.09 areapercent of (3- (4). This corresponds to a yield of 51percent baseK on R-3-(2, 2-dimethyl- [1, 3] dioxolan-4-yl)-acrylic acid ethylester.The other 25 g solution as obtained after the Michael addition in example 2A was cooled to 0 °C and quenched into a solution of H2S04 (7.8 g, 96 wtpercent, 0.076 mol, 1.5 eq. ) in methanol (13.2 g) at 0 °C by dropwise addition during 40 min under vigorous stirring. The funnel was rinsed with methanol (7.7 g). The resulting reaction mixture was stirred for 4 h at 0 °C and subsequently worked up according to the procedure of example 2A giving a solid which, according to quantitative 1H NMR analysis, contained 2.8 g (0. 0175 mol) of compounds a- (4) and ss-(4), corresponding to a yield of 35percent based on R-3- (2, 2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid ethylester.To R-3- (2, 2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid ethylester (21.2 g oil, 94.5 wtpercent pure, 0.1 mol) was added nitromethane (13.0 g of a 51.7 wtpercent solution in methanol, 0.11 mol, 1. 1 eq. ) and the solution was cooled to 0'C. Subsequently, DBU (15. 2 g, 0.1 mol, 1 eq. ) was added dropwise during 25 min and the funnel was rinsed with methanol (1 g). The reaction mixture was heated up to 20 °C and stirred at that temperature for 17 h. The resulting solution (50 g) was divided in 2 equal parts; the other 25 g part was further processed as described in example 2B. The one 25 g part was cooled to 0 °C and NaOMe (10. 0 g of a 29.6 wtpercent solution in methanol, 0.055 mol, 1.1 eq. ) was added dropwise during 1 O min at 0 °C and the funnel was rinsed with methanol (1.6 g). The reaction mixture was stirred for 50 min at 0 °C and then quenched into a solution of H2S04 (17. 9 g, 96 wtpercent, 0.175 mol, 3.5 eq. ) in methanol (30.4 g) at 0-5 °C by dropwise addition during 60 min under vigorous stirring. The funnel was rinsed with methanol (2 x 4 g). The resulting reaction mixture was stirred for 2 h at 0 °C and subsequently quenched into a stirred mixture of saturated aqueous NaHCO3 (300 mL) and ethyl acetate (100 mL) at 0-5 °C by dropwise addition during 15 min. The final pH was 6.9. Another portion of ethyl acetate (50 mL) was added and the pH was adjusted to 4.2 with H2SO4 (96 wtpercent). After phase separation the aqueous phase was extracted with ethyl acetate (1 x 150 mL, 3 x 100 mL). The combined organic phases were concentrated in vacua at 40-50 °C giving 8.1 g of an orange solid. According to quantitative 1H NMR analysis this solid contained 4.2 g (0. 026 mol) of compounds a- (4) and P- (4), corresponding to a total yield of 53percent based on R-3- (2, 2- dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid ethylester. The a- (4) : ss-(4) ratio was 3.1 : 1. To R-3- (2, 2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid ethylester (47.5 g oil, 84.2 wtpercent pure, 0.2 mol) was added nitromethane (26.0 g of a 51.7 wtpercent solution in methanol, 0.22 mol, 1.1 eq. ) and the solution was cooled to 0 °C. Subsequently, TMG (23 g, 0.2 mol, 1 eq. ) was added dropwise during 20 min and the funnel was rinsed with methanol (2 g). The reaction mixture was heated up to 20 °C and stirred at that temperature for 22 h. The solution was cooled to 0 °C and NaOMe (40. 2 g of a 29.6 wtpercent solution in methanol, 0.22 mol, 1.1 eq. ) was added dropwise during 15 min at 0 °C and the funnel was rinsed with methanol (6.4 g). After stirring for another 70 min at 0 °C the mixture was quenched into a solution of H2S04 (71.6 g, 96 wtpercent, 0.7 mol, 3.5 eq. ) in methanol (121.6 g) at 0-5 °C by dropwise addition during 70 min under vigorous stirring. The funnel was rinsed with methanol (2 x 15 g). The resulting reaction mixture was stirred for 145 min at 0 °C and subsequently quenched into a stirred mixture of saturated aqueous NaHCO3 (1200 mL) and ethyl acetate (400 mL) at 0 °C by dropwise addition during 30 min. The final pH was 7.4. After adding an additional portion (200 mL) of ethyl acetate the pH was adjusted to 4.2 with H2S04 (96 wtpercent). After phase separation the aqueous phase was extracted with ethyl acetate (4 x 400 mL). The combined organic phases were concentrated in vacuo at 40-50 °C giving 38.5 g of a yellow-orange solid which, according to quantitative 1H NMR analysis, contained a- (4) (12.2 g, 0.077 mol) and 0- (4) (4.6 g, 0.029 mol) corresponding to a total yield of 53percent based on R-3- (2, 2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid ethylester and an a- (4) : ss-(4) ratio of 2.7 : 1. To R-3-(2, 2-dimethyl-[1, 3] dioxolan-4-yl) -acrylic acid ethylester (42.3 g, 94.5 wtpercent pure, 0.2 mol) was added nitromethane (26.0 g of a 51.7 wtpercent solution in methanol, 0.22 mol, 1.1 eq. ) and the solution was cooled to 0 °C. Subsequently, DBU (30.4 g, 0.2 mol, 1 eq. ) was added dropwise during 20 min and the funnel was rinsed with methanol (4 g). The reaction mixture was heated up to 20 °C, stirred for another 16.5 h at this temperature and subsequently cooled to 0 °C. Then, NaOMe (40.4 g of a 29.6 wtpercent solution in methanol, 0.22 moL 1.1 eq. ) was added dropwise during 20 min at 0 °C and the funnel was rinsed with methanol (6.4 g). The resulting solution was stirred for 50 min at 0 °C and then quenched into a solution of H2SO4 (71.6 g, 96 wtpercent, 0.7 mol, 3.5 eq. ) in methanol (121.6 g) at 0-5 °C by dropwise addition during 70 min under vigorous stirring. The funnel was rinsed with methanol (2 x 16 g) and the reaction mixture was stirred for 2 h at 0-2 °C and then quenched into a stirred mixture of saturated aqueous NaHCO3 solution (1.2 L) and ethyl acetate (400 mL) at 0-9°C by dropwise addition during 17 min. The final pH was 7.2. The funnel was rinsed with methanol (40 ml) and the pH was adjusted to 4.0 with H2S04 (96 wtpercent) at 9 °C. After the addition of ethyl acetate (200 mL) and phase separat...To R-3- (2, 2-dimethyl- [1, 3] dioxolan-4-yl)-acrylic acid ethylester (47.5 g, 84.2 wtpercent pure, 0.2 mol) in methanol (200 g) was added nitromethane (26.0 g of a 51.7 wtpercent solution in methanol, 0.22 mol, 1.1 eq. ) and the solution was cooled to 0 °C. NaOMe (40 g of a 30 wtpercent solution in methanol, 0.22 mol, 1.1 eq. ) was added and the reaction mixture was stirred for 18 h at 0 °C and then quenched into a solution of H2S04 (58 g, 96 wtpercent, 0.57 mol, 2.9 eq. ) in methanol (140 g) at-3-0 °C by dropwise addition during 75 min under vigorous stirring. The reaction mixture was stirred for 4 h at 0 °C and subsequently kept for 16 h at-30 °C. According to quantitative 1H NMR analysis the total yield (in the reaction mixture) of a- (4) and (3- (4) based on R-3- (2, 2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid ethylester was 45percent and the a- (4) : p- (4) ratio 2.5 : 1. The reaction mixture was subsequently quenched into a stirred solution of NaHC03 (80 g) in water (1 L) at 0-5 °C by dropwise addition during 90 min. At the end of the quench a solution of NaHCO3 (4 g) in water (50 mL) was added to adjust the pH to 5-5.5. After phase separation the aqueous solution was extracted with ethyl acetate (4 x 500 mL) and the combined organic phases were concentrated in vacuo at 30-40 °C giving 32 g of a red oil. According to quantitative 1H NMR analysis, this oil contained 13.2 g (0.084 mol) a- (4) and p- (4) corresponding to a total yield of 42percent based on R-3- (2, 2- dimethyl- [1, 3] dioxolan-4-yl)-acrylic acid ethylester with the a- (4) : ss-(4) ratio being 3: 1.The crude semi-solid product was dissolved in isopropanol (69.5 g) at 80°C. The resulting solution was cooled to 60 °C, seeded and cooled further to 0 °C during 2 h which resulted in crystallization of a- (4). The solids were isolated by filtration, washed with isopropanol (30 mlv, 20 °C) and dried on the air giving 12.0 g off-white crystalline product which, according to quantitative 1H NMR, consisted of 9.8 g a-(4) (31percent yield based on R-3- (2, 2-dimethyl- [1, 3] dioxolan-4-yl)-acrylic acid ethylester) and 0.38 g ss- (4) (1. 2percent yield based on R-3- (2, 2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid ethylester). This corresponds to a crystallization yield of 60percent (output a- (4)/ [input a- (4) + 0- (4)]) and an a-(4) :) ratio of 26: 1. The crude solid product was dissolved in ethyl acetate (300 mL) and the solution was washed with a mixture of saturated aqueous NaCl solution (25 mi) and water (10 mL). The organic layer which, according to GC, contained 14.1 g a- (4) and 3.4 g p- (4), was concentrated in vacuo to 42.4 g of a dreggy solid. To 38 g of this crude product was added isopropanol (62 g) and the solid was dissolved by heating to 60 °C. The resulting solution was cooled to 50 °C, seeded, and cooled further to 0°C during 2 h which resulted in crystallization of a- (4). The solids were isolated by filtration, washed with isopropanol (2 x 20 mL, 0 °C) and dried on the air giving 12.9 g off-white crystalline product which, according to GC, contained 12.2 g a- (4). This corresponds to 39percent yield based on R-3- (2, 2-dimethyl- [1, 3] dioxolan-4-yl)-acrylic acid ethylester) and a crystallization yield of 78percent (output a- (4)/ [input a- (4) + 0- (4)]). No p- (4) could be detected. The crude product was dissolved in isopropanol (70 g) at 60 °C. The resulting solution was cooled to 50 °C, seeded and cooled further to 0 °C resulting in crystallization of a- (4) which was isolated by filtration, washed with cold (0 °C) isopropanol (2 x 15 mL) and dried on the air. This gave 12.3 g of a- (4) which, according to quantitative 1H NMR analysis, was 97.1 wtpercent pure and contained no p-(4). This corresponds to a (first crop) yield of 38percent based on R-3- (2, 2-dimetbyl- [l, 3] dioxolan-4-yl) -acrylic acid ethylester and a crystallization yield of 68percent (output a- (4)/ [input a- (4) + 0- (4)]).The combined mother and wash liquors of the first crystallization (108 g, containing 4.0 g P- (4) and 1.2 g a- (4)) were concentrated in vacuo to 17.9 g of a liquid. Subsequently, methanol (9.05 g) and MeSO3H (0. 91 g, 0.29 eq. ) were added and the mixture was heated up to reflux. After 2 h of reflux the epimerization reaction was complete (a- (4) : p- (4) ratio > 3). After cooling to 20 °C, triethyl amine (0.96 g, 1 eq. based on MeSO3H) was added and the mixture was concentrated in vacuo to 18.7 g of a viscous residue. The residue was redissolved in isopropatiol (13.9 g) at 50 °C. After cooling to 45 °C the mixture was seeded and cooled down to 0 °C resulting in crystallization of a- (4) which was isolated by filtration, washed with cold (0 °C) isopropanol (2 x 6 mL) and dried on the air. This gave 2.24 g a- (4) which, according to quantitative 1H NMR analysis, was 95.3 wtpercent pure and contained no ss-(4). This corresponds to a (second crop) yield of 6percent based on R-3- (2, 2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid ethylester and a crystallization yield of 43percent (output a- (4)/ [input a- (4) + 0- (4)] after the epimerization). Thus, the total a- (4) yield (crop 1 and 2) based on R-3- (2, 2- dimethyl- [1, 3] dioxolan-4-yl)-acrylic acid ethylester was 44percent. Crystallization of a- (4) starting from crude mixtures of a- (4) and P- (4) from other solvents than isopropanol Example 5A : From tert-butanol A crude mixture (6.5 g) of a- (4) and ss-(4) as obtained in Example 2A (containing 3. 37 g of a- (4) + p- (4) in a ratio of 3.1 : 1) was dissolved in tert-butanol (16 g) at 72 °C. Cooling to 55 °C, seeding and further cooling to 25 °C resulted in the crystallization of a- (4) which was isolated by filtration, washed with isopropanol (5 mL, 20 °C) and dried in vacuo. This gave a- (4) (1.85 g) which, according to quantitative 1H NMR analysis, consisted of 82.9 wtpercent pure a- (4) corresponding to a crystallization yield of 46percent ( [output a- (4) + 0- (4)]/ [input a- (4) + P- (4)]) with an alpha-(4) : ss-(4) ratio of 30: 1. Example 5B : From tert-amvlalcohol A crude mixture (7.25 g) of a- (4) and ss-(4) (containing 3.44 g of a- (4) + p- (4) in a ratio of 2.9 : 1) was dissolved in tert-amylalcohol (15.7 g) at 70 °C. Cooling to 60°C, seeding and further cooling to 40 °C did not result in crystallization. After seeding once more at 40 °C the solution was further cooled and crystallization of a- (4) started at 27 °C. The mixture was further cooled down to 2 °C and the crystals of a- (4) were isolated by filtration, washed with tert-amylalcohol (7. 5 mL, 20 °C) and dried in ...

(3aS,4S,6aR)-Tetrahydro-4-methoxyfuro[3,4-b]furan-2(3H)-one is an impurity of Darunavir (D193500).

Molecular Weight:158.15
XLogP3:-0.2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:158.05790880
Monoisotopic Mass:158.05790880
Topological Polar Surface Area:44.8
Heavy Atom Count:11
Complexity:179
Defined Atom Stereocenter Count:3
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes