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USD 80+
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Structure of 6342-56-9 * Storage: {[proInfo.prStorage]}
* 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.
Reference：
[1] European Journal of Organic Chemistry, 2009, # 9, p. 1417 - 1426
[2] Journal of the Chemical Society, 1955, p. 3337,3339
[3] Heterocycles, 2007, vol. 74, # C, p. 211 - 218
6
[ 67-56-1 ]
[ 1186-47-6 ]
[ 6342-56-9 ]
Reference：
[1] Journal of the American Chemical Society, 1986, vol. 108, p. 7812
7
[ 18664-32-9 ]
[ 6342-56-9 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 8, p. 2239 - 2243
Reference：
[1] Journal of Organic Chemistry, 1977, vol. 42, p. 525 - 527
22
[ 6342-56-9 ]
[ 4637-24-5 ]
[ 67751-23-9 ]
Yield
Reaction Conditions
Operation in experiment
91%
at 110℃; for 3 h;
1,1-dimethoxy-N,N-dimethylmethanamine (100 g, 839 mmol, 1.02 equiv.) and 1,1-dimethoxypropan-2-one (97 g, 821 mmol) were added and stirred at 110° C. for 3 hours. The produced methanol was removed by a Dean-Stark apparatus. After the solution was cooled to room temperature, the remaining volatile materials were removed in vacuo to provide 130 g of the crude product, (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1) (130 g, 143 g theoretical, 91percent). LC-MS m/z 283 (M+1). Reference: WO 2006/0097341A1 (incorporated by reference), pg 67.
68%
for 20 h; Reflux
(3E)-4-(Dimethylamino)-1,1-dimethoxybut-3-en-2-one (C10) A solution of N,N-dimethylformamide dimethyl acetal (147 g, 1.23 mol) and 1,1-dimethoxyacetone (146 g, 1.24 mol) in 2-butanol (1 L) was heated at reflux for 20 hours. After removal of solvent in vacuo, the residue was distilled under vacuum to provide the product as an oil. Yield: 145 g, 0.837 mol, 68percent. Boiling point: 132-140° C./0.15 torr. NMR and MS data were obtained using the product of a reaction run under similar conditions. LCMS m/z 174.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.77 (br s, 3H), 3.02 (br s, 3H), 3.30 (s, 6H), 4.47 (s, 1H), 5.23 (br d, J=12.6 Hz, 1H), 7.63 (d, J=12.6 Hz, 1H).
68%
at 110℃; for 3 h; Inert atmosphere
A stuffed solution of 1,1-dimethoxy-N,N-dimethylmethanamine (5 g, 42 mmol) was mixed with 1,1-dimethoxypropan-2-one (4.95 g, 42 mmol) under nitrogen atmosphere. The reaction mixture was heated to 110 °C for 3 h. The methanol produced was removed by Dean-Stark apparatus. After completion the solution was cooled to rt and volatiles were removed under reduced pressure to obtain oily residue. The crude material was purified by column chromatography (60-120 silica gel, 0-5percent Methanol/DCM) to afford 2.3g of the title compound (68percent). LCMS: mlz=174 [M+1]. ‘H-NMR (400MHz, CDC13) ö: 7.6 1-7.58 (d, 1H), 5.19-5.16 (d, 1H), 4.43 (s, 1H), 3.26 (s, 6H), 3.10-3.08 (d, 3H), 2.79 (s, 3H), 1.15 (s, 6H).
Reference：
[1] European Journal of Medicinal Chemistry, 1993, vol. 28, # 2, p. 129 - 140
[2] Patent: CN107235982, 2017, A,
27
[ 6342-56-9 ]
[ 4637-24-5 ]
[ 111573-59-2 ]
Reference：
[1] Chinese Journal of Catalysis, 2016, vol. 37, # 9, p. 1446 - 1450
28
[ 6342-56-9 ]
[ 50-01-1 ]
[ 4637-24-5 ]
[ 165807-05-6 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: at 110℃; for 15 h; Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide at 110℃; for 36 h;
Pyruvic aldehyde dimethyl acetal (10 g, 84 mmol) and N, N’-dimethyl formamide dimethyl diacetal (10 g, 84 mmol) in DMF (30 ml) were heated in a round bottom flask at 110 °C for 15 h. Guanidine hydrochloride (12 g, 127 mmol) and NaOH (6.7 g, 169 mmol) in water were then added to the reaction mixture. The mixture was refluxed for further 36 h. The reaction mass was then cooled and filtered. The product was recrystallized from hot ethyl acetate to yield white crystalline solid 2 (10 g, 70percent).
36%
Stage #1: at 100℃; for 16 h; Stage #2: With sodium hydroxide In water at 20℃; for 48 h;
Procedure H: Intermediate 8 (1-8) - 2-Aminopyrimidine-4-carboxaldehyde dimethylacetal.; [0093] A solution of 5.5 mL (41 mmol, 1.0 eq.) of dimethylformamide dimethyl acetal and 5.0 mL (41 mmol, 1.0 eq.) pyruvric aldehyde dimethyl acetal was heated at 100 0C for 16 h. Methanol was removed in vacuo to afford a brown oil. A solution of 1.8 g (45 mmol, 1.1 eq.) of sodium hydroxide in 5 mL of water was added to a solution of 4.3 g (45 mmol, 1.1 eq.) of guanidine HCl in 10 mL of water. The resulting solution was added to the above described oil. The resulting mixture was stirred at room temperature for 48 h. The mixture was filtered to provide 2.5 g (15 <n="38"/>mmol, 36percent) of 2-aminopyrimidine-4-carboxaldehyde dimethyl acetal (1-8).
50%
With sodium hydroxide In water
a) 2-Aminopyrimidine-4-carboxaldehyde dimethyl acetal Dimethylformamide dimethyl acetal (55 mL, 0.41 mol), and pyruvic aldehyde dimethyl acetal (50 mL, 0.41 mol) were combined and heated to 100° for 18 h. Methanol was removed in vacuo to afford an oil. A solution of NaOH (18 g, 0.45 mol) in H2 O (50 mL) was added to guanidine HCl (43 g, 0.45 mol) in H2 O (100 mL), and the resulting solution was added to the above described oil. The resulting mixture was stirred at 23° for 48 h. Filtration afforded 25 g (50percent) of the title compound.
Reference：
[1] Tetrahedron Letters, 2013, vol. 54, # 28, p. 3715 - 3717
[2] Patent: EP1227092, 2002, A2, . Location in patent: Page 25
[3] Patent: EP1229035, 2002, A1, . Location in patent: Page 25
[4] Patent: EP1227091, 2002, A2, . Location in patent: Page 25
[5] Patent: WO2007/104053, 2007, A2, . Location in patent: Page/Page column 36-37
[6] Patent: US5593992, 1997, A,
[7] Patent: US5670527, 1997, A,
With sodium methylate; thiourea; methyl iodide In methanol
a 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask and heated at 100° C. After 4.5 h the flask was removed from the heat, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. percent solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65° C. After 18 h the solution was cooled to 25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic). After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3*100 mL). The organics were combined, dried over Na2 SO4 and concentrated to give the title compound (26.8 g, 93percent) as a brown oil.
93%
With sodium methylate; thiourea; methyl iodide In methanol
a) 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask and heated at 100° C. After 4.5 h the flask was removed from the heat, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. percent solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65° C. After 18 h the solution was cooled to 25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic). After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3 X 100 mL). The organics were combined, dried over Na2 SO4 and concentrated to give the title compound (26.8 g, 93percent) as a brown oil.
93%
With sodium methylate; thiourea; methyl iodide In methanol
a) 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask and heated at 100° C. After 4.5 h the flask was removed from the heat, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. percent solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65° C. After 18 h the solution was cooled to 25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic). After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3*100 mL). The organics were combined, dried over Na2 SO4 and concentrated to give the title compound (26.8 g, 93percent) as a brown oil.
93%
With sodium methylate; thiourea; methyl iodide In methanol
a 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask. After heating at 100° C. 4.5 h, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. percent solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65° C. After 18 h, the solution was cooled to 25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic). After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3*100 mL). The organics were combined, dried (Na2 SO4) and concentrated to give the title compound (26.8 g, 93percent) as a brown oil.
Reference：
[1] Patent: US5593991, 1997, A,
[2] Patent: US5593992, 1997, A,
[3] Patent: US5670527, 1997, A,
[4] Patent: US5739143, 1998, A,
[5] Patent: US5658903, 1997, A,
31
[ 6342-56-9 ]
[ 4637-24-5 ]
[ 74-88-4 ]
[ 180869-36-7 ]
Yield
Reaction Conditions
Operation in experiment
82%
With sodium methylate; thiourea In methanol
a 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvic aldehyde dimethyl acetal (60 mL, 459 mmol) and N,N-dimethyl formamide dimethyl acetal (60 mnL, 459 mmol) were stirred together at 100° C. for 18 h. The mixture was cooled. Methanol (300 mL), thiourea (69.6 g) and sodium methoxide (231 mL, 25 wt percent in MeOH) were added to the above mixture and stirred at 70° C. for 2 h. After cooling, iodomethane (144 mL) was added dropwise and the mixture was stirred 3 h. at room temp. After diluting with EtOAc and H2 O, the organic phase was separated, dried (Na2 SO4),and concentrated to yield the title compound as a brown oil (75.5 g, 82percent yield). 1 H NMR (CDCl3): d 8.17 (d, 1H), 6.77 (d, 1H), 5.15 (s, 1H), 3.40 (s, 6H).
82%
With sodium methylate; thiourea In methanol
a 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvic aldehyde dimethyl acetal (60 milliliter (hereinafter "mL"), 459 millimole (hereinafter "mmol")) and N,N-dimethyl formamide dimethyl acetal (60 mL, 459 mmol) were stirred together at 100° C. for 18 hours (hereinafter "h"). The mixture was cooled. Methanol (300 mL), thiourea (69.6 g) and sodium methoxide (231 mL, 25 wt percent in MeOH) were added to the above mixture and stirred at 70° C. for 2 h. After cooling, iodomethane (144 mL) was added dropwise and the mixture was stirred 3 h. at room temp. After diluting with EtOAc and H2 O, the organic phase was separated, dried (Na2 SO4), and concentration to yield the title compound as a brown oil (75.5 gram (hereinafter "g"), 82percent yield). 1 H NMR (CDCl3): d 8.17 (d, 1H), 6.77 (d, 1H), 5.15 (s, 1H), 3.40 (s, 6H).
82%
With sodium methylate; thiourea In methanol
a 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvic aldehyde dimethyl acetal (60 mL, 459 mmol) and N,N-dimethyl formamide dimethyl acetal (60 mL, 459 mmol) were stirred together at 100° C. for 18 h. The mixture was cooled. Methanol (300 mL), thiourea (69.6 g) and sodium methoxide (231 mL, 25 wt percent in MeOH) were added to the above mixture and stirred at 70° C. for 2 h. After cooling, iodomethane (144 mL) was added dropwise and the mixture was stirred 3 h. at room temp. After diluting with EtOAc and H2 O, the organic phase was separated, dried (Na2 SO4),and concentrated to yield the title compound as a brown oil (75.5 g, 82percent yield). 1 H NMR (CDCl3): d 8.17 (d, 1H), 6.77 (d, 1H), 5.15 (s, 1H), 3.40 (s, 6H).
Reference：
[1] Patent: US5977103, 1999, A,
[2] Patent: US6046208, 2000, A,
[3] Patent: US5756499, 1998, A,
32
[ 6342-56-9 ]
[ 4637-24-5 ]
[ 180869-36-7 ]
Yield
Reaction Conditions
Operation in experiment
93%
With sodium methylate; thiourea; methyl iodide In methanol; water
a) 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask. After heating at 100° C. 4.5 h, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. percent solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65° C. After 18 h, the solution was cooled to 25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic). After 3 h, the solution was diluted with 250 mL of H2O and extracted with EtOAc (3*100 mL). The organics were combined, dried (Na2SO4) and concentrated to give the title compound (26.8 g, 93percent) as a brown oil.
Reference：
[1] Patent: US6218537, 2001, B1,
33
[ 6342-56-9 ]
[ 4637-24-5 ]
[ 17356-08-0 ]
[ 74-88-4 ]
[ 180869-36-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1067 - 1088
[2] Patent: WO2016/7966, 2016, A2, . Location in patent: Paragraph 0024
[3] Patent: US2003/225082, 2003, A1, . Location in patent: Page 8-9
With sodium hydroxide In ethanol; water at 6 - 20℃; for 1 h;
To a cold (6°C) solution of 2-amino-3-formylpyridine 1-3 (40 g, 0.3 16 mol), ethanol (267 ml), water (41 ml), and pyruvic aldehyde dimethyl acetal (51.3 ml, 0.411 mol) was added 5 M NaOH (82.3 ml, 0.4 11 mol) at a rate such that the internal temperature was lowerthan 20°C. After stirring at ambient temperature for 1 hour, the ethanol was removed under vacuum, and iPAc (100 mL) and NaC1 (55 g) were added. The layers were separated and the aqueous layer was extracted with iPAc (2 x 100 ml). The organic layers were combined, filtered through a silica gel bed (90 g), followed by rinse with iPAc (1 L). The fractions were combined and concentrated to 200 ml at 3 8°C. To the solution was slowly added hexane (400 ml). Theresulting suspension was cooled to 10°C and aged for 30 mm before filtration. The suspension was filtered and dried under vacuum to give the product 1-4 (54.2 g; 84percent) as colorless crystals; m.p. 53.5-55.5°C. To the mother liquors was added additional hexane (100 mL), and another 7.2 g (11percent) of 1-4 was isolated after filtration.‘H NIVIR (300 MHz; CDC13): ö 8.89 (dd, J= 4.3 and 2.0 Hz, 1H), 8.03 (d, J= 8.4 Hz, 1H), 7.98(dd, J= 8.1 and 2.0 Hz, 1H), 7.56 (d, J= 8.4 Hz, 1H), 7.26 (dd, J= 8.1 and 4.3 Hz, 1H), 5.28 (s,1H), and 3.30 (s, 6H).‘3CNI\’IR(75.5 IVIHz; CDC13): ö 161.3, 155.0, 153.5, 137.9, 136.8, 122.5, 122.3, 119.4, 105.9, and 54.9.
Stage #1: Pyruvic aldehyde dimethyl acetal; methylamine hydrochloride With titanium(IV) isopropylate; triethylamine In ethanol at 10 - 20℃; for 15h; Inert atmosphere;
Stage #2: With sodium tetrahydroborate; ethanol at 10 - 20℃; for 6h;
13.1 Procedure for synthesis of 1 ,1 -dimethox -N-methyl-propan-2 -amine (Step 1)
Procedure for synthesis of 1 ,1 -dimethox -N-methyl-propan-2 -amine (Step 1) Ti(0-iPr)4 (34.3 g, 2 equiv.) was cooled to 10°C under a nitrogen atmosphere then ethanol (89 mL) was added followed by 1 , 1-dimethoxypropan-2-one (7.14 g , 1 equiv), methylamine hydrochloride (8.16 g, 2 equiv.) and triethylamine (16.8 mL, 2 equiv.). The reaction was stirred at room temperature for 15h. The reaction was cooled to 10°C and then NaBH4 (3.43 g, 1 .5 equiv.) was added and the reaction was stirred at room temperature for 6h. The reaction was cooled to 10°C, then carefully over 10 minutes poured into ice cold aqueous ammonia (180 mL, 2M). The mixture was filtered, washing through with DCM (300 mL). The layers were separated and then the aqueous layer was extracted with further DCM (3 x 100 mL). The combined DCM layers were dried (Na2S04), filtered and evaporated with care as to not lose any of the volatile product. This crude material was distilled on a Kugelrohr (70 to 1 10°C 14mBar) to give product (4.41 g) as a colourless oil, which was used without further purification. 1 H NMR (CDCI3): 4.1 1 (d, 1 H), 3.41 (s, 6H), 2.69 (pentet, 1 H), 2.43 (s, 3H), 1.06 (d, 3H).
4.41 g
Stage #1: Pyruvic aldehyde dimethyl acetal; methylamine hydrochloride With titanium(IV) isopropylate; triethylamine In ethanol at 10 - 20℃; for 15h; Inert atmosphere;
Stage #2: With sodium tetrahydroborate In ethanol at 10 - 20℃; for 6h;
1.1 Procedure for synthesis of 1,1-dimethox -N-methyl-propan-2 -amine (Step 1)
Procedure for synthesis of 1,1-dimethox -N-methyl-propan-2 -amine (Step 1) Ti(0-iPr)4 (34.3 g, 2 equiv.) was cooled to 10°C under a nitrogen atmosphere then ethanol (89 mL) was added followed by 1 , 1-dimethoxypropan-2-one (7.14 g , 1 equiv), methylamine hydrochloride (8.16 g, 2 equiv.) and triethylamine (16.8 mL, 2 equiv.). The reaction was stirred at room temperature for 15h. The reaction was cooled to 10°C and then NaBH4 (3.43 g, 1 .5 equiv.) was added and the reaction was stirred at room temperature for 6h. The reaction was cooled to 10°C, then carefully over 10 minutes poured into ice cold aqueous ammonia (180 mL, 2M). The mixture was filtered, washing through with DCM (300 mL). The layers were separated and then the aqueous layer was extracted with further DCM (3 x 100 mL). The combined DCM layers were dried (Na2S04), filtered and evaporated with care as to not lose any of the volatile product. This crude material was distilled on a Kugelrohr (70 to 1 10°C 14mBar) to give product (4.41 g) as a colourless oil, which was used without further purification. H NMR (CDCI3): 4.1 1 (d, 1 H), 3.41 (s, 6H), 2.69 (pentet, 1 H), 2.43 (s, 3H), 1 .06 (d, 3H).
4.41 g
Stage #1: Pyruvic aldehyde dimethyl acetal; methylamine hydrochloride With titanium(IV) isopropylate; triethylamine In ethanol at 10 - 20℃; for 15h; Inert atmosphere;
Stage #2: With sodium tetrahydroborate In ethanol at 10 - 20℃; for 6h;
1.1 Procedure for synthesis of 1,1 -dimethoxy-N-methyl-propan-2-amine (Step 1)
Ti(O-iPr)4 (34.3 g, 2 equiv.) was cooled to 10°C under a nitrogen atmosphere then ethanol (89 mL) was added followed by 1,1-dimethoxypropan-2-one (7.14 g, 1 equiv), methylaminehydrochloride (8.16 g, 2 equiv.) and triethylamine (16.8 mL, 2 equiv.). The reaction was stirred at room temperature for 15 h. The reaction was cooled to 10°C and then NaBH4 (3.43 g, 1.5 equiv.) was added and the reaction was stirred at room temperature for 6 h. The reaction was cooled to 10°C, then carefully over 10 minutes poured into ice cold aqueous ammonia (180 mL, 2M). The mixture was filtered, washing through with DCM (300 mL). The layers were separated and thenthe aqueous layer was extracted with further DCM (3 x 100 mL). The combined DCM layers weredried (Na2SO4), filtered and evaporated with care as to not lose any of the volatile product. This crude material was distilled on a Kugelrohr (70 to 110°C 14 mBar)to give product (4.41 g) as a colourless oil, which was used without further purification.1H NMR (400 MHz, CDCI3) ö 4.11 (d, 1H), 3.41 (s, 6H), 2.69 (pentet, 1H), 2.43 (s, 3H), 1.06 (d,3H).
4.41 g
Stage #1: Pyruvic aldehyde dimethyl acetal; methylamine hydrochloride With titanium(IV) isopropylate; triethylamine In ethanol at 20℃; for 15h; Inert atmosphere;
Stage #2: With sodium tetrahydroborate In ethanol at 10 - 20℃; for 6h;
2.1; 5.1 Procedure for synthesis of 1 ,1 -dimethox -N-methyl-propan-2 -amine (Step 1)
Ti(0-iPr)4 (34.3 g, 2 equiv.) was cooled to 10°C under a nitrogen atmosphere then ethanol (89 mL) was added followed by 1 , 1 -dimethoxypropan-2-one (7.14 g , 1 equiv), methylamine hydrochloride (8.16 g, 2 equiv.) and triethylamine (16.8 mL, 2 equiv.). The reaction was stirred at room temperature for 15h. The reaction was cooled to 10°C and then NaBH4 (3.43 g, 1 .5 equiv.) was added and the reaction was stirred at room temperature for 6h. The reaction was cooled to 10°C, then carefully over 10 minutes poured into ice cold aqueous ammonia (180 mL, 2M). The mixture was filtered, washing through with DCM (300 mL). The layers were separated and then the aqueous layer was extracted with further DCM (3 x 100 mL). The combined DCM layers were dried (Na2S04), filtered and evaporated with care as to not lose any of the volatile product. This crude material was distilled on a Kugelrohr (70 to 1 10°C 14mBar) to give product (4.41 g) as a colourless oil, which was used without further purification. 1 H NMR (CDCI3): 4.1 1 (d, 1 H), 3.41 (s, 6H), 2.69 (pentet, 1 H), 2.43 (s, 3H), 1 .06 (d, 3H).
Stage #1: Pyruvic aldehyde dimethyl acetal; methylamine hydrochloride With titanium(IV) isopropylate; triethylamine In ethanol at 10 - 20℃; for 15h; Inert atmosphere;
Stage #2: With sodium tetrahydroborate In ethanol at 10 - 20℃; for 6h; Inert atmosphere;
2.1 Procedure for synthesis of 1,1-dimethoxy-N-methyl-propan-2-amine (Step 1)
Procedure for synthesis of 1,1-dimethoxy-N-methyl-propan-2-amine (Step 1) Ti(O-iPr)4 (34.3 g, 2 equiv.) was cooled to 10° C. under a nitrogen atmosphere then ethanol (89 mL) was added followed by 1,1-dimethoxypropan-2-one (7.14 g, 1 equiv), methylamine hydrochloride (8.16 g, 2 equiv.) and triethylamine (16.8 mL, 2 equiv.). The reaction was stirred at room temperature for 15 h. The reaction was cooled to 10° C. and then NaBH4 (3.43 g, 1.5 equiv.) was added and the reaction was stirred at room temperature for 6 h. The reaction was cooled to 10° C., then carefully over 10 minutes poured into ice cold aqueous ammonia (180 mL, 2M). The mixture was filtered, washing through with DCM (300 mL). The layers were separated and then the aqueous layer was extracted with further DCM (3*100 mL). The combined DCM layers were dried (Na2SO4), filtered and evaporated with care as to not lose any of the volatile product. This crude material was distilled on a Kugelrohr (70 to 110° C. 14 mBar) to give product (4.41 g) as a colourless oil, which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 4.11 (d, 1H), 3.41 (s, 6H), 2.69 (pentet, 1H), 2.43 (s, 3H), 1.06 (d, 3H).
1,1-dimethoxy-N,N-dimethylmethanamine (100 g, 839 mmol, 1.02 equiv.) and 1,1-dimethoxypropan-2-one (97 g, 821 mmol) were added and stirred at 110 C. for 3 hours. The produced methanol was removed by a Dean-Stark apparatus. After the solution was cooled to room temperature, the remaining volatile materials were removed in vacuo to provide 130 g of the crude product, (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1) (130 g, 143 g theoretical, 91%). LC-MS m/z 283 (M+1). Reference: WO 2006/0097341A1 (incorporated by reference), pg 67.
79%
In iso-butanol;
(a) (E)-4-(Dimethylamino)-l,l-dimethoxybut-3-en-2-one - prepared as described in Maury ei al, J. Heterocyclic Chem., 1978, 15, p. 1041
68%
In iso-butanol; for 20h;Reflux;
(3E)-4-(Dimethylamino)-1,1-dimethoxybut-3-en-2-one (C10) A solution of N,N-dimethylformamide dimethyl acetal (147 g, 1.23 mol) and 1,1-dimethoxyacetone (146 g, 1.24 mol) in 2-butanol (1 L) was heated at reflux for 20 hours. After removal of solvent in vacuo, the residue was distilled under vacuum to provide the product as an oil. Yield: 145 g, 0.837 mol, 68%. Boiling point: 132-140 C./0.15 torr. NMR and MS data were obtained using the product of a reaction run under similar conditions. LCMS m/z 174.0 (M+1). 1H NMR (400 MHz, CDCl3) delta 2.77 (br s, 3H), 3.02 (br s, 3H), 3.30 (s, 6H), 4.47 (s, 1H), 5.23 (br d, J=12.6 Hz, 1H), 7.63 (d, J=12.6 Hz, 1H).
68%
at 110℃; for 3h;Inert atmosphere;
A stuffed solution of 1,1-dimethoxy-N,N-dimethylmethanamine (5 g, 42 mmol) was mixed with 1,1-dimethoxypropan-2-one (4.95 g, 42 mmol) under nitrogen atmosphere. The reaction mixture was heated to 110 C for 3 h. The methanol produced was removed by Dean-Stark apparatus. After completion the solution was cooled to rt and volatiles were removed under reduced pressure to obtain oily residue. The crude material was purified by column chromatography (60-120 silica gel, 0-5% Methanol/DCM) to afford 2.3g of the title compound (68%). LCMS: mlz=174 [M+1]. ?H-NMR (400MHz, CDC13) oe: 7.6 1-7.58 (d, 1H), 5.19-5.16 (d, 1H), 4.43 (s, 1H), 3.26 (s, 6H), 3.10-3.08 (d, 3H), 2.79 (s, 3H), 1.15 (s, 6H).
at 100℃; for 16h;
Step 1: (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one, 57 is prepared as follows: N,N-dimethylformamide dimethylacetal (67.21 g) and 1,1-dimethoxypropan-2-one (66.62 g), are heated together at 100 C. for 16 h. Residual methanol is removed in vacuo and the product used crude in the next step.
at 100℃; for 16h;
2-Aminopyrimidine-4-carboxaldehyde dimethylacetal.; A solution of 5.5 ml (41 mmol, 1 eq.) of dimethylformamide dimethyl acetal and 5.0 ml (41 mmol, 1 eq.) pyrvuric aldehyde dimethyl acetal was heated at 100 C. for 16 h. Methanol was removed in vacuo to afford an oil. A solution of NaOH (1.8 g, 45 mmol, 1.1 eq.) in 5 mL of H2O was added to a solution of 4.3 g (45 mmol, 1.1 eq.) of guanidine HCl in 10 mL of H2O. The resulting solution was added to the above described oil. The resulting mixture was stirred at r.t. for 48 h. Filtration afforded 2.5 g (50%) of 2-aminopyrimidine-4-carboxaldehyde dimethylacetal.
at 80℃;
Equimolar amounts of dimethyformamide dimethylacetal (15 mL, 0.11 mol) and 1,1- Dimethoxy-propan-2-one (14 mL, 0.11 mol) were combined and heated to 80 C overnight. After cooling to room temperature, volatile materials were evaporated. 4-Dimethylamino-l,l- dimethoxy-but-3-en-2-one resulted as a dark brown liquid (20 g) without further purifications. 1HNMR: (300 MHz, CDCl3), delta 7.70 (d, IH), 5.30 (d, IH), 4.54 (s, IH), 3.37 (s, 6H), 3.08 (s, 3H), 2.83 (s, 3H). [0115] To a solution of the above compound (15g, 86.6 mmol) in ethanol (50 mL) was added trifluoroacetamidine (10.7 g, 95.2 mmol) and heated to reflux overnight. It was then cooled down to room temperature and concentrated in vacuo. The residue was purified on silica gel column with 100% CH2Cl2 to give 4-dimethoxymethyl-2-trifluoromethyl-pyrimidine as a light yellow liquid (8.5 g) as (Rf=0.2 using 100% CH2Cl2). 1HNMR: (300 MHz, CDCl3), delta 8.94 (s, IH), 7.75 (s, IH), 5.33 (s, IH), 3.46 (s, 6H).
at 100℃; for 18h;
Protocol F: (Scheme 6) A mixture of pyruvaldehyde dimethylacetal (125 mmol) and dimethylformamide dimethylacetal (437.5 mmol) was stirred under nitrogen atmosphere at 100C for 18 hours. The reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure.
at 110℃; for 3h;
Example 1 (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1): 1,1-dimethoxy-N,N-dimethylmethanamine (100 g, 839 mmol, 1.02 equiv.) and 1,1-dimethoxypropan-2-one (97 g, 821 mmol) were added and stirred at 110 C. for 3 hours. The produced methanol was removed by a Dean-Stark apparatus. After the solution was cooled to room temperature, the remaining volatile materials were removed in vacuo to provide 130 g of the crude product, (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1) (130 g, 143 g theoretical, 91%). LC-MS m/z 283 (M+1). Reference: WO 2006/0097341A1, pg 67.
at 110℃; for 3h;
1, l -dimethoxy-N,N- dimethylmethanamine ( 100 g, 839 mmol, 1 .02 equiv.) and l , l -dimethoxypropan-2-one (97 g, 821 mmol) were added and stirred at 1 10C for 3 hours. The produced methanol was removed by a Dean-Stark apparatus. After the solution was cooled to room temperature, the remaining volatile materials were removed in vacuo to provide 1 30 g of the crude product, (E)-4-(dimethylamino)-l ,l -dimethoxybut-3-en-2-one (1 ) ( 1 30 g, 143 g theoretical, 91 %). LC-MS m/z 283 (M+ I ). Reference: WO20060097341 A I , pg 67.
at 100℃; for 5h;
Step 1 (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one A solution of 1,1-dimethoxypropan-2-one (12 g, 101.58 mmol, 1.00 equiv) and (dimethoxymethyl)dimethylamine (12 g, 100.70 mmol, 0.99 equiv) was stirred at 100 C. for 5 h. The reaction mixture was cooled to room temperature and used in the next step directly. LCMS (method D, ESI): RT=0.94 min, m/z=174.0 [M+H]+.
at 105℃; for 3h;
502.1 g l,l-dimethoxypropan-2-one (4,25 mol) and 506.4 g l,1-dimethoxy-N,N-dimethyl-methanamine (4.25 mol) were mixed in a 2 L flask and stirred at 105C for 3 hours. The formed McOH was removed continuously via distillation. When MeOll formation stopped (at 65C head temperature) the reaction mixture was vacuum distilled (decreasing the pressure slowly to 30 mbar) to remove side products and unreacted starting materials. The crude product was distilled at 0.1 mbar. Fractions were collected between 107-118C headtemperature (bath temperature 160-165C) to give a yellow oil.?H NMR (500 MHz, DMSO-d6): 7.59 (d, 1H), 5.17 (d, lH), 4.42 (s, 1H), 3.25 (s, 6H), 3.09 (s, 3H), 2,78 (s, 3H).
at 105℃; for 3h;
502.1 g l,l-dimethoxypropan-2-one (4.25 mol) and 506.4 g l ,l-dimethoxy-N,N-dimethyl- methanamine (4.25 mol) were mixed in a 2 L flask and stirred at 105 C for 3 hours. The formed MeOH was removed continuously via distillation. When MeOH formation stopped (at 65 C head temperature) the reaction mixture was vacuum distilled (decreasing the pressure slowly to 30 mbar) to remove side products and unreacted starting materials. The crude product was distilled at 0.1 mbar. Fractions were collected between 107-118 C head temperature (bath temperature 160-165 C) to give a yellow oil. 1H NMR (500 MHz, DMSO-dg): 7.59 (d, 1H), 5.17 (d, 1H), 4.42 (s, 1H), 3.25 (s, 6H), 3.09 (s, 3H), 2.78 (s, 3H)
at 105℃; for 3h;
502.1 g 1,1 -dimethoxypropan-2-one (4.25 mo 1) and 506.4 g 1,1 -dimethoxy-N,N-dimethyl25 methanamine (4.25 mol) were mixed in a 2 L flask and stirred at 105 C for 3 hours. The formed MeOH was removed continuously via distillation. When MeOH formation stopped (at 65 C head temperature) the reaction mixture was vacuum distilled (decreasing the pressure slowly to 30 mbar) to remove side products and unreacted starting materials. The crude product was distilled at 0.1 mbar. Fractions were collected between 107-118 C headtemperature (bath temperature 160-165 C) to give a yellow oil. 1H NMR (500 MHz, DMSO-d6) oe: 7.59 (d, 1H), 5.17 (d, 1H), 4.42 (s, 1H), 3.25 (s, 6H), 3.09 (s, 3H), 2.78 (s, 3H)
at 105℃; for 3h;
502.1 g l,l-dimethoxypropan-2-one (4.25 mol) and 506.4 g l ,l-dimethoxy-N,N-dimethyl- methanamine (4.25 mol) were mixed in a 2 L flask and stirred at 105 C for 3 hours. The formed MeOH was removed continuously via distillation. When MeOH formation stopped (at 65 C head temperature) the reaction mixture was vacuum distilled (decreasing the pressure slowly to 30 mbar) to remove side products and unreacted starting materials. The crude product was distilled at 0.1 mbar. Fractions were collected between 107-118 C head temperature (bath temperature 160-165 C) to give a yellow oil. 1H NMR (500 MHz, DMSO-de) delta: 7.59 (d, 1H), 5.17 (d, 1H), 4.42 (s, 1H), 3.25 (s, 6H), 3.09 (s, 3H), 2.78 (s, 3H)
at 105℃; for 3h;
Step M: (E)-4-(Dimethylamino)- 1 , 1 -dimethoxy-but-3-en-2-one (0190) 502.1 g l,l-dimethoxypropan-2-one (4.25 mol) and 506.4 g 1 ,1-dimethoxy-NN-dimethyl- methanamine (4.25 mol) were mixed in a 2 L flask and stirred at 105 C for 3 hours. The formed methanol was removed continuously via distillation. When methanol formation stopped (at 65 C head temperature) the reaction mixture was vacuum distilled (decreasing the pressure slowly to 30 mbar) to remove side products and unreacted starting materials. (0191) The crude product was distilled at 0.1 mbar. Fractions were collected between 107-118 C head temperature (bath temperature 160-165 C) to give a yellow oil. 1H NMR (500 MHz, (0192) DMSO-de) delta: 7.59 (d, 1H), 5.17 (d, 1H), 4.42 (s, 1H), 3.25 (s, 6H), 3.09 (s, 3H), 2.78 (s, (0193) 3H)
at 100℃; for 2h;Large scale;
14.8 Kg Compound 1 was dissolved in 14.9 KgDimethylformamide dimethyl acetal.The mixture was magnetically stirred at 100 degrees Celsius for 2 hours.The reaction was concentrated in vacuo to give 20.4 Kg of crude compound 2 which was used directly in the next step.
at 110℃; for 3h;
Example 100A (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one 1,1-Dimethoxy-N,N-dimethylmethanamine (15 g) and 1,1-dimethoxypropan-2-one (14.9 g) were mixed in a 250 mL flask and the mixture was stirred at 110 C. for 3 hours. Thin layer chromatography showed the starting material was consumed. The formed methanol was removed continuously via distillation. The reaction mixture was distilled under high vacuum (decreasing the pressure slowly to 30 mbar) to remove by-products and starting materials. The remaining crude product was distilled at 0.1 mbar. Fractions were collected between 107-118 C. head temperature (bath temperature 160-165 C.) to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) delta ppm 2.78 (s, 3H), 3.09 (s, 3H), 3.26 (s, 6H), 4.42 (s, 1H), 5.18 (d, J=12.35 Hz, 1H), 7.59 (d, J=12.79 Hz, 1H).
at 90℃; for 16h;
A mixture of l,l-dimethoxypropan-2-one II-l (10 g, 85 mmol) and l,l-dimethoxy-A,iV- dimethylmethanamine III-l (10.1 g, 85 mmol) was heated at 90 C for 16 h. After completion of the reaction, the reaction mass was concentrated and the crude product (£)-4-(dimethylamino)-l,l- dimethoxybut-3-en-2-one (11 g, 63.5 mmol, 75 % yield) obtained after concentration was used in next step without any purification. -NMR (400 MHz, CHLOROFORM-D) d 7.72 (d, J = 12.8 Hz, 1H), 5.33 (d, J = 12.2 Hz, 1H), 4.57 (s, 1H), 3.36-3.43 (m, 6H), 3.05-3.10 (m, 3H), 2.86 (d, J = 6.1 Hz, 3H).
(2-[1,3]dioxolan-2-yl-ethylidene)-triphenyl-λ5-phosphane[ No CAS ]
N-cyclohexyl-3-methylpyridinium chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
Stage #1: Pyruvic aldehyde dimethyl acetal; (2-[1,3]dioxolan-2-yl-ethylidene)-triphenyl-λ5-phosphane In tetrahydrofuran; hexane at -20 - 20℃; for 16h;
Stage #2: With silica gel; iron(III) chloride In dichloromethane for 0.0833333h;
Stage #3: cyclohexylamine hydrochloride With triethylamine In dichloromethane; butan-1-ol for 16h; Heating;
Stage #1: Pyruvic aldehyde dimethyl acetal; methylamine With titanium(IV) isopropylate In methanol at 20℃; for 5h;
Stage #2: With sodium tetrahydroborate In methanol at 20℃; for 2h;
With sodium hydroxide; In ethanol; water; at 6 - 20℃; for 1.0h;
To a cold (6C) solution of 2-amino-3-formylpyridine 1-3 (40 g, 0.3 16 mol), ethanol (267 ml), water (41 ml), and pyruvic aldehyde dimethyl acetal (51.3 ml, 0.411 mol) was added 5 M NaOH (82.3 ml, 0.4 11 mol) at a rate such that the internal temperature was lowerthan 20C. After stirring at ambient temperature for 1 hour, the ethanol was removed under vacuum, and iPAc (100 mL) and NaC1 (55 g) were added. The layers were separated and the aqueous layer was extracted with iPAc (2 x 100 ml). The organic layers were combined, filtered through a silica gel bed (90 g), followed by rinse with iPAc (1 L). The fractions were combined and concentrated to 200 ml at 3 8C. To the solution was slowly added hexane (400 ml). Theresulting suspension was cooled to 10C and aged for 30 mm before filtration. The suspension was filtered and dried under vacuum to give the product 1-4 (54.2 g; 84%) as colorless crystals; m.p. 53.5-55.5C. To the mother liquors was added additional hexane (100 mL), and another 7.2 g (11%) of 1-4 was isolated after filtration.?H NIVIR (300 MHz; CDC13): oe 8.89 (dd, J= 4.3 and 2.0 Hz, 1H), 8.03 (d, J= 8.4 Hz, 1H), 7.98(dd, J= 8.1 and 2.0 Hz, 1H), 7.56 (d, J= 8.4 Hz, 1H), 7.26 (dd, J= 8.1 and 4.3 Hz, 1H), 5.28 (s,1H), and 3.30 (s, 6H).?3CNI?IR(75.5 IVIHz; CDC13): oe 161.3, 155.0, 153.5, 137.9, 136.8, 122.5, 122.3, 119.4, 105.9, and 54.9.
With sodium hydroxide; In ethanol; water; at 20℃;
A solution of 2-amino-3-pyridine carboxaldehyde (13a, 50 mg, 4.1 mmol), pyruvic aldehyde dimethyl acetal (641 muL, 5.3 mmol), 3N sodium hydroxide (1.8 mL, 5.3 mmol), ethanol (50 mL) and water (5 mL) was allowed to stir at room temperature overnight. The mixture was concentrated and the residue partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated to obtain 13b.
With L-proline; In methanol; for 16.0h;Heating / reflux;
2-Dimethoxymethyl-[1,8]naphthyridine. A mixture containing 2-amino-3-formylpyridine (30 g, 0.245 mol) (prepared as described in J. Org. Chem., 1983, vol. 48, p. 3401), pyruvaldehyde dimethylacetal (87 g, 0.737 mol), and L-proline (7.0 g, 0.062 mol) in MeOH (300 mL) was refluxed under argon for 16 h. The cooled solution was filtered, evaporated and the residue dissolved in CH2Cl2 (500 mL) and washed with water and brine then dried and concentrated to a volume of ca. 100 mL. Hexane (300 mL) was added and the mixture was kept at 0 C. for 3 h, then filtered affording 2-dimethoxymethyl-[1,8]naphthyridine as an off-white crystalline solid. 1H NMR (300 MHz, CDCl3) delta 9.14 (d, J=2.2 Hz, 1H); 8.26 (d, J=8.7 Hz, 1H); 8.21 (dd, J=8.7, 2.2 Hz, 1H); 7.8 (d, J=8.3 Hz, 1H); 7.5 (m, 1H); 5.48 (s, 1H); 3.53 (s, 6H).
With sodium hydroxide; In ethanol; water; at 20℃;
A solution of 2- amino-3-pyridine carboxaldehyde (13a, 50 mg, 4.1 mmol), pyruvic aldehyde dimethyl acetal (641 mul_, 5.3 mmol), 3N sodium hydroxide (1.8 mL, 5.3 mmol), ethanol (50 mL) and water (5 mL) was allowed to stir at room temperature overnight. The mixture was concentrated and the residue partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated to obtain 13b.
With sodium hydroxide; In ethanol; water; at 0 - 20℃; for 3.0h;
[0570] The procedure described in J. Org. Chern., 2004, 69(6), pp 1959-1966 was used. Into a 20 I 4-necked roundbottomflask was placed 2-aminopyridine-3-carbaldehyde(1000 g, 8.19 mol), 1,1-dimethoxypropan-2-one (1257 g,10.64 mol), ethanol (1 0 1), and water (2 1). This was followedby the addition of a solution of sodium hydroxide (409.S g,10.24 mol) in water (1000 ml) drop wise with stirring at 0-15C. The solution was stirred for 3 h at 0-20 C. and thenconcentrated under vacuum. The resulting solution wasextracted with 3x1200 ml of ethyl acetate and the organiclayers were combined. The mixture was dried over sodiumsulfate and concentrated under vacuum. The residue waswashed with 3x300 ml of hexane and the solid was collectedby filtration. This resulted in the title compound as a yellowsolid. 1H-NMR (400 MHz, DMSO-d6) ll9.11 (dd, lH), S.53(d, lH), S.50 (dd, lH), 7.73 (d, lH), 7.67 (dd, lH), 5.44 (s,lH), 3.41 (s, 6H).
With sodium hydroxide; In ethanol; water; at 0 - 20℃; for 3.0h;
The procedure described in J. Org. Chem., 2004, 69 (6), pp 1959-1966 was used. Into a 20 I 4- necked round-bottom flask was placed 2-aminopyridine-3-carbaldehyde (1000 g, 8.19 mol), 1,1-dimethoxypropan-2-one (1257 g, 10.64 mol), ethanol (10 I), and water (2 I). This was followed by the addition of a solution of sodium hydroxide (409.8 g, 10.24 mol) in water (1000 ml) drop wise with stirring at 0-15 C. The solution was stirred for 3 h at 0-20 C and then concentrated under vacuum. The resulting solution was extracted with 3x1200 ml of ethyl acetate and the organic layers were combined. The mixture was dried over sodium sulfate and concentrated under vacuum.The residue was washed with 3x300 ml of hexane and the solid was collected by filtration. This resulted in the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) 5 9.11 (dd, I H), 8.53 (d, I H), 8.50 (dd, I H), 7.73 (d, I H), 7.67 (dd, I H), 5.44 (s, I H), 3.41 (s, 6H).
With sodium hydroxide; In ethanol; water; at 0 - 20℃; for 3.0h;
The procedure described in J. Org. Chem. , 2004, 69 (6), pp 1959-1966 was used. Into a 20 I 4-necked round-bottom flask was placed 2-aminopyridine-3-carbaldehyde (1000 g, 8.19 mol), 1 ,1 -dimethoxypropan-2-one (1257 g, 10.64 mol), ethanol (10 I), and water (2 I). This was followed by the addition of a solution of sodium hydroxide (409.8 g, 10.24 mol) in water (1000 ml) drop wise with stirring at 0-15 C. The solution was stirred for 3 h at 0-20 C and then concentrated under vacuum. The resulting solution was extracted with 3x1200 ml of ethyl acetate and the organic layers were combined. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was washed with 3x300 ml of hexane and the solid was collected by filtration. This resulted in the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-c/6) delta 9.1 1 (dd, 1 H), 8.53 (d, 1 H), 8.50 (dd, 1 H), 7.73 (d, 1 H), 7.67 (dd, 1 H), 5.44 (s, 1 H), 3.41 (s, 6H).
With sodium hydroxide; In ethanol; water; at 0 - 20℃; for 3.0h;
The procedure described in J. Org. Chem., 2004, 69 (6), pp 1959-1966 was used. Into a 20 L 4- necked round-bottom flask was placed 2-aminopyridine-3-carbaldehyde (1000 g, 8.19 mol), 1 , 1- dimethoxypropan-2-one (1257 g, 10.64 mol), ethanol (10 L), and water (2 L). This was followed by the addition of a solution of sodium hydroxide (409.8 g, 10.24 mol) in water (1000 mL) drop wise with stirring at 0-15 C. The solution was stirred for 3 h at 0-20 C and then concentrated under vacuum. The resulting solution was extracted with 3x1200 mL of ethyl acetate and the organic layers were combined. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was washed with 3x300 mL of hexane and the solid was collected by filtration. This resulted in the title compound as a yellow solid. 1 H-NMR (400 MHz, DMSO-cf6) delta 9.1 1 (dd, 1 H), 8.53 (d, 1 H), 8.50 (dd, 1 H), 7.73 (d, 1 H), 7.67 (dd, 1 H), 5.44 (s, 1 H), 3.41 (s, 6H).
42.3 g
With sodium hydroxide; In ethanol; water; at 20℃; for 3.0h;
Step 1: Preparation of 2-(dimethoxymethyl)-1,8-naphthyridine 2-Aminonicotine aldehyde (25.0 g, 205 mmol) and 1,1-dimethoxypropan-2-one (31.4 g, 266 mmol) were mixed and dissolved in a mixed solvent of ethanol (500 mL) and water (50 mL), followed by addition of NaOH aqueous solution (3 M, 88.7 mL, 266 mmol). The reaction solution was stirred at room temperature for 3 hours, and then concentrated. The resulting residue was dissolved in EtOAc, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 2-(dimethoxymethyl)-1,8-naphthyridine (42.3 g) which was used in the next step directly.
With sodium hydroxide; In ethanol; water; at 20℃; for 3.0h;Inert atmosphere;
2-Aminonicotine aldehyde (25.0 g, 205 mmol) and 1,1-dimethoxypropan-2-one (31.4 g, 266 mmol) were mixedand dissolved in a mixed solvent of ethanol (500 mL) and water (50 mL), followed by addition of aqueous NaOH solution(3M, 88.7 mL, 266 mmol). The reaction solution was stirred at room temperature for 3 hours, and then concentrated.The resulting residue was dissolved in EtOAc, washed twice with saturated brine, dried over anhydrous sodium sulfate,and concentrated to obtain the title compound 2-(dimethoxymethyl)-1,8-naphthyridine (42.3 g) which was directly usedin the next step.
To a 12 L 3-neck flask under inert atmosphere is charged N,N-dimethyl-formamide dimethyl acetyl (801 g) and pyruvic aldehyde dimethyl acetal (779 g). The mixture is heated to reflux for 18 hours during which time the temperature decreases from about 109 C. to about 80 C. The solution is cooled and methanol (4 L) is added to dissolve the crude residue. The solution is then cooled to 20 C. and thiourea (892 g, 11.7 mol) is added. After allowing the mixture to stir about 15 minutes, sodium methoxide (741 g, 13.7 mol) is added in 4 equal portions over 1 hour while maintaining the solution temperature in the range of 18-28 C. The mixture is stirred for 5 hours at room temperature, cooled to 20 C., then methyl iodide (2 kg) is added over 1.25 hours while maintaining the reaction temperature in the range of 17-29 C. Stirring is continued for 18 hours at room temperature. The methanol and unreacted methyl iodide is removed by heating the solution at 35 C. (at) 40 torr to produce about 4.46 kg of a dark residue which is partitioned between 14 L of water and 5 L of ethyl acetate. The water fraction is extracted a second time with ethyl acetate, the organic layers combined and concentrated in vacuo too afford 685 g of an oil which is purified over silica to 522 g of 4-dimethoxymethyl-2-methylsulfanyl-pyrimidine.
To a solution of <strong>[46004-37-9]4-amino-2-chloro-benzoic acid methyl ester</strong> (12.27 g, 66.11 mmol) and pyruvic aldehyde dimethyl acetal (15.62 g, 132.22 mmol) in 260 mL glacial acetic acid was added anhydrous Na2SO4 (93.9 g, 661.1 mmol). The reaction mixture was stirred at room temperature for 3 hours. Powered sodium triacetoxy borohydride (42 g, 198.33 mmol) was then added in portions for a period of 10 min. Stirring was continued overnight. After the acetic acid was removed under reduced pressure, the remaining residue was made basic by adding a sufficient amount of saturated Na2CO3 solution. The product was then extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and concentrated in vacuo. Flash column chromatography separation (30% ethyl acetate/hexane) then afforded 16.5 g product as colorless oil (87%). M+H+(288).
a 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvic aldehyde dimethyl acetal (60 mL, 459 mmol) and N,N-dimethyl formamide dimethyl acetal (60 mnL, 459 mmol) were stirred together at 100 C. for 18 h. The mixture was cooled. Methanol (300 mL), thiourea (69.6 g) and sodium methoxide (231 mL, 25 wt % in MeOH) were added to the above mixture and stirred at 70 C. for 2 h. After cooling, iodomethane (144 mL) was added dropwise and the mixture was stirred 3 h. at room temp. After diluting with EtOAc and H2 O, the organic phase was separated, dried (Na2 SO4),and concentrated to yield the title compound as a brown oil (75.5 g, 82% yield). 1 H NMR (CDCl3): d 8.17 (d, 1H), 6.77 (d, 1H), 5.15 (s, 1H), 3.40 (s, 6H).
82%
With sodium methylate; thiourea; In methanol;
a 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvic aldehyde dimethyl acetal (60 milliliter (hereinafter "mL"), 459 millimole (hereinafter "mmol")) and N,N-dimethyl formamide dimethyl acetal (60 mL, 459 mmol) were stirred together at 100 C. for 18 hours (hereinafter "h"). The mixture was cooled. Methanol (300 mL), thiourea (69.6 g) and sodium methoxide (231 mL, 25 wt % in MeOH) were added to the above mixture and stirred at 70 C. for 2 h. After cooling, iodomethane (144 mL) was added dropwise and the mixture was stirred 3 h. at room temp. After diluting with EtOAc and H2 O, the organic phase was separated, dried (Na2 SO4), and concentration to yield the title compound as a brown oil (75.5 gram (hereinafter "g"), 82% yield). 1 H NMR (CDCl3): d 8.17 (d, 1H), 6.77 (d, 1H), 5.15 (s, 1H), 3.40 (s, 6H).
82%
With sodium methylate; thiourea; In methanol;
a 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvic aldehyde dimethyl acetal (60 mL, 459 mmol) and N,N-dimethyl formamide dimethyl acetal (60 mL, 459 mmol) were stirred together at 100 C. for 18 h. The mixture was cooled. Methanol (300 mL), thiourea (69.6 g) and sodium methoxide (231 mL, 25 wt % in MeOH) were added to the above mixture and stirred at 70 C. for 2 h. After cooling, iodomethane (144 mL) was added dropwise and the mixture was stirred 3 h. at room temp. After diluting with EtOAc and H2 O, the organic phase was separated, dried (Na2 SO4),and concentrated to yield the title compound as a brown oil (75.5 g, 82% yield). 1 H NMR (CDCl3): d 8.17 (d, 1H), 6.77 (d, 1H), 5.15 (s, 1H), 3.40 (s, 6H).
2-dimethoxymethyl-2-methyl-4-oxo-6-cyano-3,4-dihydro-2H-1-benzopyran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With hydrogenchloride; In water; toluene;
Step 1) Synthesis of 2-dimethoxymethyl-2-methyl-4-oxo-6-cyano-3,4-dihydro-2H-1-benzopyran In 100 ml of toluene were dissolved 8.06 g (50 mmole) of <strong>[35794-84-4]3-acetyl-4-hydroxybenzonitrile</strong> and 7.68 g (65 mmole) of pyruvic aldehyde dimethyl acetal; and, then 1.67 ml (20 mmole) of pyrrolidine was added thereto at room temperature. 30 minutes thereafter, the reactants were heated to reflux for 8 hours using Dean-Stark apparatus; the solvent was removed under reduced pressure; and, 50 ml of 2N HCl solution was added thereto. The resultant solution was stirred for 30 minutes at room temperature, extracted with ethyl acetate (100 ml*2), washed with 50 ml of water and with 50 ml of saturated sodium chloride aqueous solution, and purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (4:1) as an eluent to obtain 11.19 g (yield 86%) of the title compound in the form of a white solid.
86%
With hydrogenchloride; In hexane; water; ethyl acetate; toluene;
Step 1) Synthesis of 2-dimethoxymethyl-2-methyl-4-oxo-6-cyano-3,4-dihydro-2H-1-benzopyran In 100 ml of toluene were dissolved 8.06 g (50 mmole) of <strong>[35794-84-4]3-acetyl-4-hydroxybenzonitrile</strong> and 7.68 g (65 mmole) of pyruvic aldehyde dimethyl acetal; and, 1.67 ml (20 mmole) of pyrrolidine was added at room temperature thereto. 30 Minutes thereafter, the reactants were heated to reflux for 8 hours using Dean-Stark apparatus. The solvent was removed under reduced pressure; and, 50 ml of 2N HCl solution was added to the residue so obtained. The resultant solution was stirred for 30 minutes at room temperature, extracted with ethyl acetate (100 ml*2), washed with 50 ml of water and then with 50 ml of saturated sodium chloride aqueous solution and purified by silica gel column chromatography using as an eluent a mixture of hexane and ethyl acetate (4:1) to obtain 11.19 g (yield 86%) of the title compound as a white solid.
86%
With hydrogenchloride; In toluene;
Step 1) Synthesis of 2-dimethoxymethyl-2-methyl-4-oxo-6-cyano-3,4-dihydro-2H-1-benzopyran In 100ml of toluene were dissolved 8.06g(50mmole) of <strong>[35794-84-4]3-acetyl-4-hydroxybenzonitrile</strong> and 7.68g(65mmole) of pyruvic aldehyde dimethyl acetal; and, then 1.67ml(20mmole) of pyrrolidine was added thereto at room temperature. 30 minutes thereafter, the reactants were heated to reflux for 8 hours using Dean-Stark apparatus; the solvent was removed under reduced pressure; and, 50ml of 2N HCl solution was added thereto. The resultant solution was stirred for 30 minutes at room temperature, extracted with ethyl acetate (100ml x 2), washed with 50ml of water and with 50ml of saturated sodium chloride aqueous solution, and purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (4:1) as an eluent to obtain 11.19g(yield 86%) of the title compound in the form of a white solid.
86%
With hydrogenchloride; In hexane; ethyl acetate; toluene;
Step 1) Synthesis of 2-dimethoxymethyl-2-methyl-4-oxo-6-cyano-3,4-dihydro-2H-1-benzopyran In 100ml of toluene were dissolved 8.06g(50mmole) of <strong>[35794-84-4]3-acetyl-4-hydroxybenzonitrile</strong> and 7.68g(65mmole) of pyruvic aldehyde dimethyl acetal; and, 1.67ml(20mmole) of pyrrolidine was added at room temperature thereto. 30 Minutes thereafter, the reactants were heated to reflux for 8 hours using Dean-Stark apparatus. The solvent was removed under reduced pressure; and, 50ml of 2N HCl solution was added to the residue so obtained. The resultant solution was stirred for 30 minutes at room temperature, extracted with ethyl acetate(100ml x 2), washed with 50ml of water and then with 50ml of saturated sodium chloride aqueous solution and purified by silica gel column chromatography using as an eluent a mixture of hexane and ethyl acetate(4:1) to obtain 11.19g(yield 86%) of the title compound as a white solid.
Pyruvic aldehyde dimethyl acetal (10 g, 84 mmol) and N, N?-dimethyl formamide dimethyl diacetal (10 g, 84 mmol) in DMF (30 ml) were heated in a round bottom flask at 110 C for 15 h. Guanidine hydrochloride (12 g, 127 mmol) and NaOH (6.7 g, 169 mmol) in water were then added to the reaction mixture. The mixture was refluxed for further 36 h. The reaction mass was then cooled and filtered. The product was recrystallized from hot ethyl acetate to yield white crystalline solid 2 (10 g, 70%).
36%
Procedure H: Intermediate 8 (1-8) - 2-Aminopyrimidine-4-carboxaldehyde dimethylacetal.; [0093] A solution of 5.5 mL (41 mmol, 1.0 eq.) of dimethylformamide dimethyl acetal and 5.0 mL (41 mmol, 1.0 eq.) pyruvric aldehyde dimethyl acetal was heated at 100 0C for 16 h. Methanol was removed in vacuo to afford a brown oil. A solution of 1.8 g (45 mmol, 1.1 eq.) of sodium hydroxide in 5 mL of water was added to a solution of 4.3 g (45 mmol, 1.1 eq.) of guanidine HCl in 10 mL of water. The resulting solution was added to the above described oil. The resulting mixture was stirred at room temperature for 48 h. The mixture was filtered to provide 2.5 g (15 <n="38"/>mmol, 36%) of 2-aminopyrimidine-4-carboxaldehyde dimethyl acetal (1-8).
27%
1,1-dimethoxy-N,N-dimethyl methylamine 8a (4.90 g, 41.36 mmol) was mixed with 65 1,1-dimethoxypropan-2-one (4.90 g, 41.36 mmol). The mixture was stirred for 16 h at 100 C., and subjected to exsolution under reduced pressure. The residuals were mixed with 66 guanidine hydrochloride (4.30 g, 45.00 mmol), 67 sodium hydroxide (1.80 g, 45.00 mmol) and 9 water (15 mL), and stirred for 48 h at room temperature. Filtration was carried out to obtain the target 68 product 4-(dimethoxymethyl)pyrimidin-2-amine 8b (2.00 g, white solid), at a yield of 27%. (0172) MS m/z (ESI): 170 [M+1] (0173) 1H NMR (400 MHz, CDCl3) delta 8.36 (d, J=4.8 Hz, 1H), 6.87 (d, J=5.2 Hz, 1H), 5.16 (s, 1H), 5.15 (brs, 2H), 3.42 (s, 6H).
25 g (50%)
With sodium hydroxide; In water;
a) 2-Aminopyrimidine-4-carboxaldehyde dimethyl acetal Dimethylformamide dimethyl acetal (55 mL, 0.41 mol), and pyruvic aldehyde dimethyl acetal (50 mL, 0.41 mol) were combined and heated to 100 for 18 h. Methanol was removed in vacuo to afford an oil. A solution of NaOH (18 g, 0.45 mol) in H2 O (50 mL) was added to guanidine HCl (43 g, 0.45 mol) in H2 O (100 mL), and the resulting solution was added to the above described oil. The resulting mixture was stirred at 23 for 48 h. Filtration afforded 25 g (50%) of the title compound.
With sodium methylate; thiourea; methyl iodide; In methanol;
a 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask and heated at 100 C. After 4.5 h the flask was removed from the heat, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. % solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65 C. After 18 h the solution was cooled to 25 C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic). After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3*100 mL). The organics were combined, dried over Na2 SO4 and concentrated to give the title compound (26.8 g, 93%) as a brown oil.
93%
With sodium methylate; thiourea; methyl iodide; In methanol;
a) 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask and heated at 100 C. After 4.5 h the flask was removed from the heat, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. % solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65 C. After 18 h the solution was cooled to 25 C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic). After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3 X 100 mL). The organics were combined, dried over Na2 SO4 and concentrated to give the title compound (26.8 g, 93%) as a brown oil.
93%
With sodium methylate; thiourea; methyl iodide; In methanol;
a) 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask and heated at 100 C. After 4.5 h the flask was removed from the heat, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. % solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65 C. After 18 h the solution was cooled to 25 C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic). After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3*100 mL). The organics were combined, dried over Na2 SO4 and concentrated to give the title compound (26.8 g, 93%) as a brown oil.
93%
With sodium methylate; thiourea; methyl iodide; In methanol;
a 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask. After heating at 100 C. 4.5 h, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. % solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65 C. After 18 h, the solution was cooled to 25 C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic). After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3*100 mL). The organics were combined, dried (Na2 SO4) and concentrated to give the title compound (26.8 g, 93%) as a brown oil.
Step 1 4-dimethylamino-1,1-dimethoxy-3-buten-2-one 1,1-dimethoxyacetone (pyruvic aldehyde dimethyl acetal, Aldrich Chemical Co.) (3 cm3) was added dropwise with stirring to tert-butoxy-bis(dimethylamino)methane (Fluka Chemie AG) (5 cm3) and stirring continued at ambient temperature for 16 hours. The low-boiling impurities were removed by evaporation under reduced pressure. This left an orange oil (5.82 g) (1 H NMR (CDCl3): delta2.88(3H,br s); 3.10(3H,br s); 3.40(6H,s); 4.58(1H,s); 5.34(1H,d); 7.76(1H,d)).
With sodium methylate; thiourea; methyl iodide; In methanol; water;
a) 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask. After heating at 100 C. 4.5 h, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. % solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65 C. After 18 h, the solution was cooled to 25 C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic). After 3 h, the solution was diluted with 250 mL of H2O and extracted with EtOAc (3*100 mL). The organics were combined, dried (Na2SO4) and concentrated to give the title compound (26.8 g, 93%) as a brown oil.
With sodium methylate; thiourea; In hydrogenchloride; methanol; water; ethyl acetate;
To a 12 L 3-neck flask under inert atmosphere is charged N,N-dimethyl-formamide dimethyl acetyl (801 g) and pyruvic aldehyde dimethyl acetal (779 g). The mixture is heated to reflux for 18 hours during which time the temperature decreases from about 109 C. to about 80 C. The solution is cooled and methanol (4 L) is added to dissolve the crude residue. The solution is then cooled to 20 C. and thiourea (892 g, 11.7 mol) is added. After allowing the mixture to stir about 15 minutes, sodium methoxide (741 g, 13.7 mol) is added in 4 equal portions over 1 hour while maintaining the solution temperature in the range of 18-28 C. The mixture is stirred for 5 hours at room temperature, cooled to 20 C., then methyl iodide (2 kg) is added over 1.25 hours while maintaining the reaction temperature in the range of 17-29 C. Stirring is continued for 18 hours at room temperature. The methanol and unreacted methyl iodide is removed by heating the solution at 35 C. a 40 torr to produce about 4.46 kg of a dark residue which is partitioned between 14 L of water and 5 L of ethyl acetate. The water fraction is extracted a second time with ethyl acetate, the organic layers combined and concentrated in vacuo too afford 685 g of an oil which is purified over silica to 522 g of 4-dimethoxymethyl-2-methylsulfanyl-pyrimidin. The dimethyl acetal obtained above is then hydrolyzed to the free aldehyde by heating to 60 C. for 3 hours in 1 M HCl. Workup for neutral using ethyl acetate to extract the product affords 347 g crude product which is purified over silica to afford 401 g of 2-methylsulfanyl-pyrimidin-4-carbaldehyde, 1.
With sodium methylate; thiourea; In hydrogenchloride; methanol; water; ethyl acetate;
To a 12 L 3-neck flask under inert atmosphere is charged N,N-dimethyl-formamide dimethyl acetyl (801 g) and pyruvic aldehyde dimethyl acetal (779 g). The mixture is heated to reflux for 18 hours during which time the temperature decreases from about 109 C. to about 80 C. The solution is cooled and methanol (4 L) is added to dissolve the crude residue. The solution is then cooled to 20 C. and thiourea (892 g, 11.7 mol) is added. After allowing the mixture to stir about 15 minutes, sodium methoxide (741 g, 13.7 mol) is added in 4 equal portions over 1 hour while maintaining the solution temperature in the range of 18-28 C. The mixture is stirred for 5 hours at room temperature, cooled to 20 C., then methyl iodide (2 kg) is added over 1.25 hours while maintaining the reaction temperature in the range of 17-29 C. Stirring is continued for 18 hours at room temperature. The methanol and unreacted methyl iodide is removed by heating the solution at 35 C.a40 torr to produce about 4.46 kg of a dark residue which is partitioned between 14 L of water and 5 L of ethyl acetate. The water fraction is extracted a second time with ethyl acetate, the organic layers combined and concentrated in vacuo too afford 685 g of an oil which is purified over silica to 522 g of <strong>[180869-36-7]4-dimethoxymethyl-2-methylsulfanyl-pyrimidine</strong>. The dimethyl acetal obtained above is then hydrolyzed to the free aldehyde by heating to 60 C. for 3 hours in 1 M HCl. Workup for neutral using ethyl acetate to extract the product affords 347 g crude product which is purified over silica to afford 401 g of 2-methylsulfanyl-pyrimidine-4-carbaldehyde, 1.
To a 12 L 3-neck flask under inert atmosphere is charged N,N-dimethyl-formamide dimethyl acetyl (801 g) and pyruvic aldehyde dimethyl acetal (779 g). The mixture is heated to reflux for 18 hours during which time the temperature decreases from about 109 C. to about 80 C. The solution is cooled and methanol (4 L) is added to dissolve the crude residue. The solution is then cooled to 20 C. and thiourea (892 g, 11.7 mol) is added. After allowing the mixture to stir about 15 minutes, sodium methoxide (741 g, 13.7 mol) is added in 4 equal portions over 1 hour while maintaining the solution temperature in the range of 18-28 C. The mixture is stirred for 5 hours at room temperature, cooled to 20 C., then methyl iodide (2 kg) is added over 1.25 hours while maintaining the reaction temperature in the range of 17-29 C. Stirring is continued for 18 hours at room temperature. The methanol and unreacted methyl iodide is removed by heating the solution at 35 C.@40 torr to produce about 4.46 kg of a dark residue which is partitioned between 14 L of water and 5 L of ethyl acetate. The water fraction is extracted a second time with ethyl acetate, the organic layers combined and concentrated in vacuo too afford 685 g of an oil which is purified over silica to 522 g of 4-dimethoxymethyl-2-methylsulfanyl-pyrimidine
With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 14h;
123.123A
4-Fluorobenzylamine (3.00 mL, 26.2 mmol), pyruvic aldehyde dimethyl acetal (3.11 mL, 26.2 mmol), DCE (87 mL), and sodium triacetoxyborohydride (7.79 g, 36.7 mmol) were stirred at ambient temperature. After 14 hours, the reaction was complete as indicated by LCMS. To the reaction mixture was added 30% aqueous K3PO4 (pΗ = 14; 60 mL). The layers were partitioned and the aqueous layer was, extracted with EtOAc (2 x 50 mL), and washed with brine (60 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give the title compond (5.83 g, 25.7 mmol, 98% yield). MS (DCI/NΗ3) m/z 228 (M+H)+.
98%
With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 14h;
123.123A
4-Fluorobenzylamine (3.00 mL, 26.2 mmol), pyruvic aldehyde dimethyl acetal (3.11 mL, 26.2 mmol), DCE (87 mL), and sodium triacetoxyborohydride (7.79 g, 36.7 mmol) were stirred at ambient temperature. After 14 hours, the reaction was complete as indicated by LCMS. To the reaction mixture was added 30% aqueous K3PO4 (pΗ = 14; 60 mL). The layers were partitioned and the aqueous layer was, extracted with EtOAc (2 x 50 mL), and washed with brine (60 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give the title compond (5.83 g, 25.7 mmol, 98% yield). MS (DCI/NΗ3) m/z 228 (M+H)+.
Procedure J: Intermediate 8 (1-10) - 2-Methylaminopyrimidine-4- carboxaldehyde dimethyl acetal; [0097] A solution of 5.5 mL (41 mmol, 1.0 eq.) of dimethylformamide dimethyl acetal and 5.0 mL (41 mmol, 1.0 eq.) of pyruvic aldehyde dimethyl acetal was heated at 100 0C for 16 h. Methanol was removed in vacuo to afford a brown oil. To a solution of 15 mL of sodium ethoxide (21% in ethanol, 41 mmol, 1.0 eq.) was added 4.5 g (41 mmol, 1.0 eq.) of methyl guanidine HCl. The mixture was stirred for 10 min before a solution of the above described oil in 15 mL anhydrous ethanol was added. The mixture was heated to reflux for 24 h, allowed to cool to room <n="39"/>temperature and filtered. The solvent was removed in vacuo to afford 2- methylaminopyrimidine-4-carboxaldehyde dimethyl acetal (I- 10) as a dark brown oil which was used in the next step without further purification
With pyrrolidine In ethanol at 60℃; for 20h; Molecular sieve; Inert atmosphere;
5
l,l-Dimethoxypropan-2-one (8.6 niL, 72.30 mmol, 1.1 eq), 3 A molecular sieves (10 g) and pyrrolidine (16.3 mL, 197.17 mmol, 3 eq) were added to 2',5'-dihydroxyacetophenone (10.0 g, 65.72 mmol, 1 eq) in absolute EtOH (66 mL) under argon. The reaction mixture was heated at 600C for 20 h. The reaction mixture was then quenched with H2O (200 mL) and the pH was adjusted to 3 with HCl IN. The aqueous phase was extracted 3 times with CH2Cl2 (3*200 mL). The combined organic layers were washed with HCl IN, with H2O, dried over MgSO4 and concentrated in vacuo. The red oil was purified by silica gel flash chromatography (heptanes / AcOEt: 7/3) to afford 14.59 g (88%) of a white solid 9a.Molecular Weight: 252.26 (Ci3Hi6O5).1H-NMR δ (CDCl3, 300 MHz) ppm (Jin Hz): 1.36 (s, 3H, H-2a), 2.61 (d, IH, J=16.8, H-3), 3.00 (d, 1H, J=16.8, H-3), 3.48 (s, 3H, MeO), 3.51 (s, 3H, MeO), 4.27 (s, IH, H-I '), 6.84 (d, 1H, J=8.9, H-8), 7.04 (dd, 1H, J=8.9, 3.1, H-7), 7.32 (d, 1H, J=3.1, H-5).13C-NMR δ (CDCl3, 75 MHz) ppm: 19.8 (C-2a), 42.6 (C-3), 57.8 (MeO), 58.0 (MeO), 82.9 (C-2), 108.4 (C-5), 110.6 (C-I '), 119.2 (C-8), 120.4 (C-4a), 124.8 (C-7), 150.0 (C-8a), 153.6 (C-6), 192.8 (C-4).
Stage #1: Pyruvic aldehyde dimethyl acetal; (2-chloro-3-fluorophenyl)methanamine With sodium tris(acetoxy)borohydride at 20℃; for 16h;
Stage #2: With chlorosulfonic acid at 100℃; for 0.166667h;
4-(4-chlorophenyl)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxypentan-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; at 25℃; for 1h;
To a mixture of 1,1-dimethoxyacetone (0.295 mL, 2.5 mmol) and phenyl trifluoromethyl ketone (70.21iL, 0.5 mmol) was added DBU (7.45 1iL, 0.05 mmol), and the mixture was stirred at RT (25 C) until 1 was consumed (monitored by TLC), 1.5h. The reaction mixture was diluted with hexane-EtOAc and purified by silica gel flash column chromatography (hexane/EtOAc = 8:1 to 4:1) to give 3a (122.5 mg, 84%). To a mixture of 1,1-dimethoxyacetone (2.95 mL, 25.0 mmol) and phenyl trifluoromethyl ketone (7021iL, 5.0 mmol) was added DBU (74.5 1iL, 0.5 mmol), and the mixture was stirred at RT (25 C) until 1 was consumed (monitored by TLC), 1.5h. The reaction mixture was diluted with hexane-EtOAc and purified by silica gel flash column chromatography (hexane/EtOAc = 8:1 to 4:1) to give 3a (1.38 g, 94%).
copper(II) bis(5,5,6,6-tetrafluoro-1,1-dimethoxy-2,4-hexanedionate)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: Pyruvic aldehyde dimethyl acetal; methyl 2,2,3,3-tetrafluoropropionate With calcium hydride In methanol at 20℃; for 24h;
Stage #2: copper(II) acetate monohydrate With acetic acid; calcium chloride In methanol for 3h;
4.3. Reaction of 1,1-dimethoxyacetone 6 with esters ofpolyfluorocarboxylic acid in the presence of CaH2
General procedure: A mixture of 1,1-dimethoxyacetone (6, 11.81 g, 0.1 mol) and ester of polyfluorocarboxylic acid (0.12 mol) in MeOH (50 mL) was addeddropwise (2 h) to a vigorously stirred suspension of CaH2 (3.15 g,0.075 mol) in MeOH (100 mL) at r.t. The reaction mixture was stirredfor 24 h and acetic acid (6.00 g, 0.1 mol) was added. Then anhydrousCaCl2 (2.22 g, (0.02 mol) and fine powdered Cu(CH3COO)2·H2O(15.00 g, 0.075 mol) were added stepwise and obtained mixture wasstirred for 3 h. The solvent (∼ half in volume) was evaporated, theresidue was diluted with water (∼ 200 mL), and solid complex 8 wasfiltered off, washed with water, and dried on air. The complex wasdissolved in acetone and filtered to remove a possible copper or calciumcarbonates. The solvent was removed and a residue was crystallized asindicated above (Section 4.1). The yields are presented in Table 1.
copper(II) bis(1,1,1-trifluoro-5,5-dimethoxy-2,4-pentanedionate)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
General procedure: A mixture of 1,1-dimethoxyacetone (6, 11.81 g, 0.1 mol) and ester of polyfluorocarboxylic acid (0.12 mol) in MeOH (50 mL) was addeddropwise (2 h) to a vigorously stirred suspension of CaH2 (3.15 g,0.075 mol) in MeOH (100 mL) at r.t. The reaction mixture was stirredfor 24 h and acetic acid (6.00 g, 0.1 mol) was added. Then anhydrousCaCl2 (2.22 g, (0.02 mol) and fine powdered Cu(CH3COO)2·H2O(15.00 g, 0.075 mol) were added stepwise and obtained mixture wasstirred for 3 h. The solvent (? half in volume) was evaporated, theresidue was diluted with water (? 200 mL), and solid complex 8 wasfiltered off, washed with water, and dried on air. The complex wasdissolved in acetone and filtered to remove a possible copper or calciumcarbonates. The solvent was removed and a residue was crystallized asindicated above (Section 4.1). The yields are presented in Table 1.
With pyrrolidine; In dichloromethane; at 0℃; for 5h;
Acetaldehyde dimethyl acetal (71 g, 0.6 mol, 1 eq)And tetrahydropyrrole (43 g, 0.6 mol, 1 eq) were dissolved in about 200 ml of DCM,Ice bath to 0 C,After benzofuroxan (82g, 0.6mol, 1eq) in DCM over 1 hour with stirring was added dropwise,While maintaining the temperature of the solution at 0 C.After completion of the dropwise addition, the reaction was continued for 4 hours under an ice bath,TLC shows that the basic reaction of benzofurazine is complete.Spin dry solvent DCM,Get viscous liquid,Ice bath to cool the product,Add petroleum ether to the reaction flask,There is solid precipitation,Filter with a sand core funnel,The filter cake was washed with ethanol (250 ml * 3)To give a pale yellow solid (2- (dimethoxymethyl) quinoxaline-1,4-dioxide) 66g.Yield: 46.6%.
3-methyl-4,4-dimethoxy-2-buten-1-phosphonic acid diethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With potassium <i>tert</i>-butylate In toluene at 20℃; for 0.5h; Inert atmosphere;
B B.2,6,11,15-tetramethyl-2,4,6,8,10,12,14-hexadecahedra dialdehyde "batch process" Preparation
Under a nitrogen atmosphere, 150 ml of toluene and 16.8 g (0.15 mol) of potassium tert-butoxide solid were successively added into a dry 500 ml three-necked flask and uniformly stirred. A solution of 36.3 g (0.12 mol) of tetraethyl ethylene diphosphate, g (0.1mol) acetone aldehyde dimethyl acetal and 100ml of toluene mixed solution prepared about 0.5h addition was completed, then reacted at room temperature. After the conversion of pyruvic aldehyde dimethanol was completed by gas phase detection, saturated solution of ammonium chloride (100ml) was added to the reaction mixture to quench the solvent. The organic layer was taken to recover the solvent, washed with 50ml of 10% aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure get19.8 g of 3-methyl-4,4-dimethoxy-2-buten-1-phosphonic acid diethyl ester,Yield 74%
General procedure: To a solution of 4-hydroxy-1-cyclohexanone (8) (200 mg, 1.75 mmol) in dry CH2Cl2 (15 ml) at -35 C was added separately a solution of TiCl4 (0.29 ml, 2.62 mmol) and tributylamine (1.25 ml, 5.25 mmol) in CH2Cl2 (2 ml each). The reaction mixture was stirred at the same temperature for half an hour and after which a solution of 1,1-dimethoxyacetone (0.42 ml, 3.5 mmol) in CH2Cl2 (2 ml) was added to it. Reaction mixture was allowed to attain room temperature on its own and left to stir for 3 hours. Water (20 ml) was added to quench the reaction mixture. Extraction was done with CH2Cl2 (3 x 15 ml) and the combined organic layer was washed with brine (40 ml), dried over anhydrous Na2SO4 (2 g) and evaporated to dryness under reduced pressure. Crude product was purified with column chromatography using ethyl acetate/hexanes (5:95). The product was obtained as a colorless liquid in 78% yield (180 mg).
To a solution of 4-hydroxy-1-cyclohexanone (8) (200 mg, 1.75 mmol) in dry CH2Cl2 (15 ml) at -35 C was added separately a solution of TiCl4 (0.29 ml, 2.62 mmol) and tributylamine (1.25 ml, 5.25 mmol) in CH2Cl2 (2 ml each). The reaction mixture was stirred at the same temperature for half an hour and after which a solution of 1,1-dimethoxyacetone (0.42 ml, 3.5 mmol) in CH2Cl2 (2 ml) was added to it. Reaction mixture was allowed to attain room temperature on its own and left to stir for 3 hours. Water (20 ml) was added to quench the reaction mixture. Extraction was done with CH2Cl2 (3 x 15 ml) and the combined organic layer was washed with brine (40 ml), dried over anhydrous Na2SO4 (2 g) and evaporated to dryness under reduced pressure. Crude product was purified with column chromatography using ethyl acetate/hexanes (5:95). The product was obtained as a colorless liquid in 78% yield (180 mg). IR (neat) 3054, 2930, 1588, 1449, 1281, 1184, 1086, 855, 742 cm-1; 1H NMR (CDCl3, 500 MHz): delta 2.21 (s, 3H), 7.20-7.28 (m, 2H), 7.37 (s, 1H), 7.43 (d, 1H, J = 8.0 Hz), 7.49 (d, 1H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz): delta 8.0, 111.4, 115.7, 119.5, 122.3, 124.2, 129.1, 141.4, 155.4; HRMS calcd. for C9H8ONa [M+Na]+: 155.0473. Found 155.0477.
Stage #1: 4-phenyl-3-cyclohexen-1-one With tributyl-amine; titanium tetrachloride In dichloromethane at -35℃; for 0.5h;
Stage #2: Pyruvic aldehyde dimethyl acetal In dichloromethane at -35 - 20℃; for 2h;
3-Methyl-5-phenylbenzofuran (18a).
To a solution of 4-phenylcyclohex-3-enone, 22 (100 mg, 0.58 mmol) at -35 °C in dry CH2Cl2 (10 ml) was added a solution of TiCl4 (0.1 ml, 0.91 mmol) in CH2Cl2 (1 ml) followed by an immediate addition of a solution of tributylamine (0.41 ml, 1.75 mmol) in CH2Cl2 (1.5 ml). After stirring the reaction mixture for half an hour, a solution of 1,1-dimethoxyacetone (0.14 ml, 1.19 mmol) in CH2Cl2 (1 ml) was added. Reaction mixture was allowed to attain room temperature slowly and further stirred for 2 hours. After completion of the reaction (monitored by TLC), water (10 ml) was added to quench the reaction mixture. Extraction was done with CH2Cl2 (2 x 10 ml) and the combined organic layer was washed with brine (20 ml), dried over anhydrous Na2SO4 (2 g) and solvent removed under low pressure. Column chromatography of the crude extract was done with ethyl acetate / hexane (5:95). The product was obtained in 82% yield. Its physical and spectral data has been already mentioned above.
General procedure: beta-tetralone 26 (100 mg, 0.68 mmol) was dissolved in dry CH2Cl2 (12 ml) and cooled to -35 C. A solution of TiCl4 (0.11 ml, 1.0 mmol) in CH2Cl2 (1 ml) followed by a solution of tributylamine (0.48 ml, 2.04 mmol) in dichloromethane (1.5 ml) were added sequentially. The reaction mixture was stirred for 30 minutes, a solution of 1,1-dimethoxyacetone (0.16 ml, 1.36 mmol) in CH2Cl2 (2 ml) was added and the reaction mixture was allowed to stir for 2 hours at room temperature. After completion of reaction, water (15 ml) was added and extraction was done with diethyl ether (2 x 15 ml). Combined organic layer was washed with bine (25 ml), dried over sodium sulphate (2 g) and evaporated to dryness under reduced pressure. Column chromatography was done with ethylacetate/hexanes (5:95). The product was obtained as a gummy liquid in 92% (114 mg).
1-(1-benzyl-1H-pyrazol-3-yl)-4-methyl-1H-1,2,3-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
Stage #1: Pyruvic aldehyde dimethyl acetal With toluene-4-sulfonic acid hydrazide In dimethyl sulfoxide at 20℃; for 1h;
Stage #2: 1-benzyl-1H-pyrazol-3-amine In dimethyl sulfoxide at 80℃; for 4h;
General Procedure A:
General procedure: To a solution of α-ketoacetal (1.65 mmol, 1.00 eq.) in DMSO (2.0 mL) was added 4-methylbenzenesulfonylhydrazide (1.65 mmol, 1.00 eq.), and the reaction was stirred at rt for 1h. The primary amine (1.74 mmol, 1.05 eq.) was added, and the reaction was stirred at 80 °C for 4h. The reaction mixture was purified by SFC.
(E)-N-(2-bromo-5-fluorobenzyl)-1,1-dimethoxypropan-2-imine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With magnesium sulfate; In dichloromethane; at 20℃; for 15h;
A mixture of <strong>[747392-34-3](2-bromo-5-fluorophenyl)methanamine</strong> (29g, 142 mmol), 1,1- dimethoxypropan-2-one (19.78 ml, 163 mmol) and magnesium sulfate (17.11 g, 142 mmol) in DCM (150 ml) was stirred at rt for 15h. The resulting mixture was filtered through celite and the filtrate was evaporated in vacuo to give (41g, 95%) of the title compound, which was directly used for next step without further purification.
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