* 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.
Stage #1: With dimethyl sulfoxide; N-ethyl-N,N-diisopropylamine In dichloromethane at -5 - 0℃; for 0.5 h; Stage #2: With pyridine; sulfur trioxide pyridine complex; dimethyl sulfoxide In dichloromethane at -5 - 20℃; for 1.16667 h;
(4R-cis)-6-(hydroxymethyl)-2,2-dimethyl- 1 ,3 -dioxane-4-acetic acid, 1 , 1 -dimethyl ethyl ester (10.0 g ,0.0385 mol) mol) was dissolved in dimethyl sulfoxide (15.0 g , 0.192 mol) and dichloromethane (100 ml) followed by cooling at 0 to -5 0C. The reaction mass was cooled for 15 min at 0 to -5 0C followed by addition of Diisopropylethyl amine( 17.42 g ,0.1347 mol) at 0 to -5 0C and continued stirring for 15 min at 0 to -5 0C. In another flask, charged pyridine-sulfur trioxide complex (12.25 g, 0.077 mol), pyridine (6.09 g, 0.077 mol) and dimethyl sulfoxide (15.0 g, 0.192 mol) at room temperature followed by stirring for 10 min. Resulting suspension was added to the above alcohol solution in dichloromethane at 0 to -5 0C and continued stirring for 1 hr at 0 to -5 0C. After the completion of reaction, water (50.0 ml) was added and stirred for 10 min. This was followed by layer separation. Aqueous layer was extracted with dichloromethane (2 x 20 ml).Dichloromethane layer was washed with water ( 3 x 100.0 ml ) followed by drying over sodium sulfate and distilled dichloromethane under vacuum at 40 to 45.0 °C.Degased mass for 1 hr at 40 to 45.0 0C under reduced pressure to obtain tertiary butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl] acetate, compound of formula II (9.22 g, 93.0percent).
86%
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide In dichloromethane; acetonitrile at 0 - 25℃; for 5.5 h; Molecular sieve
(6-Formyl-2, 2-dimethyl- [1, 3] dioxan-4-yl)-acetic acid tert-butyl ester To a solution of (6-hydroxymethyl-2. 2-dimethyl-11, 3] dioxan-4-yl)-acetic acid tert- butyl ester (30.0 g, 115 mmol) at 0 °C in DCM: MeCN (10: 1,225 mL) was added 4 A molecular sieves (55 g), 4-methylmorpholine N-oxide (20. 3 g, 172.9 mmol) and tetrapropylammonium perruthenate (0.41 g, 1. 15 mmol). The reaction was warmed from 0 °C to 25 °C over 0.5 hr and then stirred at that temperature for 5 hrs. Once complete, as determined by TLC, the reaction mixture was filtered through celite and the filtrate was concentrated to a brown oil that was purified by silica gel chromatography (20-70 percent EtOAc/Hexane) to provide (6-formyl-2, 2-dimethyl- [1, 3] dioxan-4-yl)-acetic acid tert-butyl ester (25.5 g, 86percent): H-NMR (CDCI3) 09. 54 (s, 1 H), 4.30-4. 26 (m, 2 H), 2.45-2. 39 (m, 1 H), 2.33-2. 27 (m, 1 H), 1.81-1. 77 (m, 1 H), 1.46-1. 41 (m, 16 H), 1.28-1. 20 (m, 1 H).
85.9%
With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hypochlorite; sodium hydrogencarbonate; potassium bromide In dichloromethane at -15 - 0℃;
(2) step (1) to obtain compound II of the methylene chloride solution, adding 0.15g (0.99mmol) TEMPO, 2.36g (0.0198mol) potassium bromide and 16.6g (0.198mol) sodium bicarbonate, stirring and mixing after cooling to -15 °C, dropping pre-adjusting the pH to 10 sodium hypochlorite solution (175.9g (0.238mol) sodium hypochlorite solution (content 10.9percent) in terms of mass percentage concentration is 5percent sulfuric acid adjusted to pH 10), control reaction solution temperaturethe <0 °C.drop finishes, 0 °C stirring for reaction, GC tracking of the reaction, the response finishes (compound III less than0.2percent)adding quality percentage concentration is 10percent aqueous solution of sodium thiosulfate 156.5g stirring quenching reaction, the resulting organic phase after transferring, to 300g × 2 washing, to obtain light yellow clear solution, adding 50g drying by anhydrous sodium sulfate, filter, to 20g dichloromethane wash the filter cake, the spin vaporization (40 °C, -0.09 MPa) unless the solvent to obtain strawcoloured solid 46.0g, yield 90.1percent, GC purity 98.7percent, crude I is compound;
83%
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; potassium bromide In dichloromethane; water at -15 - 5℃; for 1 h; Large scale
0.02 g of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy free radical), 0.96 g of potassium bromide, 18.6 g of sodium hydrogencarbonate and 50 ml of methylene chloride were placed in a 500 ml flask, Stirred at ~ 5 ° C.After dissolving 11.64 g (44.71 mmol) of t-butyl 2 - [(4R, 6S) -6-hydroxymethyl-2,2-dimethyl- 1,3-dioxane- 4-yl] acetate in 50 ml of methylene chloride , Added to the above reaction. After cooling the reaction product to -15 ° C. or lower, 36.6 ml (53.65 mmol, 1.2 equivalent) of a 10.9percent (w / w) sodium hypochlorite aqueous solution was added dropwise at once. After the dropwise addition, stirring was carried out at 0 ° C. for 1 hour, the reaction progress degree was checked by gas chromatography (GC), the reaction product was filtered under reduced pressure, 10percent sodium thiosulfate solution (10 w / wpercent sodium thiosulfate solution) 100 ml was added and the organic layer was separated. 100 ml of a saturated sodium chloride solution was added to the organic layer, and the organic layer was further separated. After adding 150 ml of water to the organic layer and stirring for 10 minutes, the stagnant organic layer was separated, dried over anhydrous magnesium sulfate, filtered, methylene chloride as an organic solvent was distilled under reduced pressure at 40 ° C. and 3 cmHg for 10 minutes To obtain a concentrated residue 1 as an oil phase (step A).The concentrated residue 1 was adjusted to a pressure of 3 cmHg in a vacuum vacuum dryer and dried for 30 minutes at 80 ° C. without separately adjusting the humidity to obtain the title compound as pale brown crystals (Step B) . (The XRD graph of the product is shown in Figure 1 and its value is as shown in Figure 2. The DSC value of the product is shown in Figure 3.) Yield of product 83percent (8.2kg)
54%
With sodium hypochlorite; TEMPOL; sodium hydrogencarbonate; potassium bromide In water; ethyl acetate at -10 - 5℃; for 1 h; Inert atmosphere
Reference Example 2: tert-Butyl 2-[(4R,6S)-6-formyl-2,2-dimeihyl-1, 3-dioxane-4-yl] acetate [Show Image] To a dispersion of tert-butyl 2-[(4R,6S)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-yl] acetate (15 g, 57.6 mmol), sodium hydrogencarbonate (13.6 g, 161.3 mmol), potassium bromide (1.37 g, 11.5 mmol) and 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine-1-oxyl free radical (248 mg, 1.44 mol) in ethyl acetate (150 ml), an aqueous solution of sodium hypochlorite (44.2 g, 16.7wtpercent, 70.2 mmol) was added under nitrogen stream at -10°C carefully dropwise to keep the inner temperature within 5°C. After the dropwise addition, the mixture was stirred at 0°C for 1 hour and the aqueous layer was separated. The organic layer was further diluted with ethyl acetate (100 ml), and sequentially washed with a 5percent sodium thiosulfate aqueous solution (75 ml) and water (40 ml .x. 2). Then, the organic layer was dried with anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained crude product was purified with silica gel column chromatography (silica gel: 200 g, developing solvent: hexane / ethyl acetate = 2 / 1 by volume) to obtain the title compound (8.0 g, yield: 54percent) as white crystals. 1H-NMR (CDCl3): δ1.35(1H, q, J=12.7Hz), 1.45 (9H, s), 1.46 (3H, s), 1.49(3H, s), 1.83(1H, dt, J=2.7Hz, 12.9Hz), 2.35(1H, dd, J=5.9Hz, 15.4Hz), 2.46(1H, dd, J=7.1Hz, 15.4Hz), 4.33(1H, m), 9.58 (1H, s)
19.2 g
Stage #1: With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; potassium bromide In dichloromethane at 0 - 5℃; for 0.25 h; Stage #2: With sodium hypochlorite; sodium hydrogencarbonate In dichloromethane; water at 0 - 5℃; for 1.66667 h;
Preparation of Tert-Butyl 3,5-Dideoxy-2,4-O-(1-Methylethylidene)-L-Erythro-Hexuronate tert-Butyl 2,4-dideoxy-3,5-O-(1-methylethylidene)-D-erythro-hexonate (commercially available; 20 g) was added to a pre cooled (0° C. to 5° C.) mixture of 2,2,6,6-tetramethylpiperidine-1-oxyl (0.04 g), potassium bromide (1.92 g), and sodium bicarbonate (18 g) in dichloromethane (120 mL) and stirred at 0° C. to 5° C. for 15 minutes. Aqueous sodium hypochlorite (10percent; 40 mL) was added slowly to the resulting mixture and stirred at 0° C. to 5° C. for 30 minutes. Sodium bicarbonate (18 g) was added to the mixture and stirred at 0° C. to 5° C. for 10 minutes, followed by the slow addition of aqueous sodium hypochlorite (10percent; 40 ml) in 30 minutes at 0° C. to 5° C. The reaction mixture was stirred at 0° C. to 5° C. for 30 minutes. After completion of the reaction, the reaction mixture was filtered through hyflo bed and washed with dichloromethane (20 mL). The filtrate was washed with aqueous sodium thiosulphate (10percent; 100 mL). The organic layer was separated and washed with de-ionized water (100 mL) and finally washed with aqueous solution of sodium chloride (10percent; 100 mL). The organic layer was separated and concentrated under vacuum at 40° C. to give tert-butyl 3,5-dideoxy-2,4-O-(1-methylethylidene)-L-erythro-hexuronate. Dry weight: 19.2 g.
Reference：
[1] Tetrahedron Letters, 1990, vol. 31, # 18, p. 2545 - 2548
[2] Patent: WO2008/59519, 2008, A2, . Location in patent: Page/Page column 12; 18; 23
[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2015, vol. 54B, # 10, p. 1247 - 1251
[4] Patent: WO2005/56004, 2005, A1, . Location in patent: Page/Page column 52; 145-146
[5] Patent: CN105503816, 2016, A, . Location in patent: Paragraph 0066; 0067; 0068
[6] Patent: JP2015/518881, 2015, A, . Location in patent: Paragraph 0041
[7] Synthetic Communications, 2003, vol. 33, # 13, p. 2275 - 2283
[8] Patent: KR101566536, 2015, B1, . Location in patent: Paragraph 0114-0115
[9] Patent: EP2351762, 2011, A1, . Location in patent: Page/Page column 9-10
[10] Tetrahedron, 2007, vol. 63, # 34, p. 8124 - 8134
[11] Patent: US2006/4200, 2006, A1, . Location in patent: Page/Page column 2-3
[12] Patent: WO2011/86584, 2011, A2, . Location in patent: Page/Page column 35
[13] Patent: US2012/323005, 2012, A1, . Location in patent: Page/Page column 15
[14] Patent: US2013/150579, 2013, A1, . Location in patent: Paragraph 0063
[15] Patent: WO2014/203045, 2014, A1, . Location in patent: Page/Page column 45; 46
[16] Journal of the American Chemical Society, 2015, vol. 137, # 45, p. 14313 - 14318
[17] Asian Journal of Chemistry, 2017, vol. 29, # 5, p. 1018 - 1022
2
[ 147489-02-9 ]
[ 124752-23-4 ]
Reference：
[1] Tetrahedron Letters, 1993, vol. 34, # 3, p. 513 - 516
[2] Bulletin of the Chemical Society of Japan, 1995, vol. 68, # 1, p. 364 - 372
With potassium carbonate In dimethyl sulfoxide at 20 - 70℃; Inert atmosphere
1) Preparation of the crude product containing the intermediate of formula (III)Under nitrogen atmosphere, 8.76 g of the compound of formula (II) was placed in a four-neck reaction flask at room temperature,Add 70mL dimethyl sulfoxide,Stirring completely dissolved, followed by the addition of 20g compound of formula (I) and 12.2g of anhydrous potassium carbonate powder,The solution was heated to 70 reaction, TLC detection and tracking, the reaction was completed, the solution was cooled to room temperature,To the solution was added 200mL of ethyl acetate and stirred for a few minutes, filtered,The filtrate was washed with pure water (100mL wash 3 times), saturated brine (100mL wash 2 times),The organic phase was separated, dried over anhydrous magnesium sulphate, filtered, the filtrate was concentrated to dryness under reduced pressure,17 g of crude product containing the intermediate of formula (III) was obtained.2) Purification of the crude product containing the intermediate of formula (III)Mass ratio of 1: 11 mass ratio of the solid obtained in step (1) was added 187mL of ethanol and n-hexane mixedSolution, absolute ethanol and n-hexane volume ratio of 1: 1,Heated to reflux, completely dissolved, stop heating, water bath down to room temperature,Then cooled in an ice bath to 0 ~ 10 ° C, filtered, the solid was dried to give a white solid 15.4g,Yield 89percent, HPLC purity of 99.41percentThe cis-isomer content is less than 0.1percent.
80%
With potassium carbonate In dimethyl sulfoxide at 20℃; for 2.16 h;
The compound prepared in Preparation Example 2 (11 g, 16.2 mmol) and the compound prepared in Preparative Example 1 (5.01 g, 19.4 mmol) were dissolved in 30 ml of dimethylsulfoxide, and the mixture was stirred at room temperature for 10 minutes, Potassium carbonate (3.35 g, 24.3 mmol)And the mixture was stirred at 70 ° C for 2 hours.After completion of the reaction, the temperature was maintained, 90 ml of isopropyl alcohol was added, 60 ml of H 2 O was added, refluxed at 70 to 80 ° C. for 20 minutes, and then slowly cooled to form crystals.Stir at room temperature for 30 minutes and filter the precipitate under reduced pressure.(7.48 g, yield: 80percent, HPLC: 99.5percent, white solid)
76%
With potassium carbonate In toluene at 95℃; for 6 h;
Adding a compound to a three-neck bottle4-(4-fluorophenyl)-5-triphenylphosphonium bromide-6-isopropyl-2-[(N-methyl-N-methylsulfonamido)]-pyrimidine 50 g,Further added 350 ml of toluene and (4R-cis)-6-[(acetoxy)methyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester 38.06 g, carbonic acid Potassium 30 grams,The temperature is raised at 95 ° C for 4.5 hours, and the temperature is lowered to room temperature.The potassium carbonate was filtered, and the solvent was evaporated to give a crude material.The crude product was refined with ethanol to give a product of 32.3 g.The yield was 76percent and the purity was 99.2percent.
75%
With potassium carbonate In dimethyl sulfoxide at 25 - 75℃; for 2 h;
Into a 2 L 4-necked round bottom flask, DMSO (600 ml), potassium carbonate (104 g), TPPBr (170 g) of Example 1 and BFA (65 g) were added at a temperature in the range of from about 25° C. to about 35° C. under stirring. The reaction mixture was heated to a temperature in the range of from about 70° C. to about 75° C. for about 2 hours. After completion of the reaction as determined by TLC, the reaction mixture was cooled to a temperature in the range of from about 25° C. to about 35° C. Toluene (1000 ml) was added for dilution of the reaction mixture under stirring for about 30 minutes at a temperature in the range of from about 25° C. to about 35° C. The reaction mixture was filtered, and the insoluble cake was separated. The organic layer was added to water (1000 ml) under stirring at a temperature in the range of from about 25° C. to about 35° C. and maintained for about 30 minutes. The organic layer was separated and washed twice with water (2.x.1000 ml). The organic layer was distilled in rotavapor bath at a temperature in the range of from about 50° C. to about 70° C. under in a vacuum. After distillation, methanol (750 ml) was added to the residue at a temperature in the range of from about 55° C. to about 60° C. and maintained for about 30 minutes. The reaction mixture was brought to a temperature in the range of from about 25° C. to about 30° C. by slowly Circulating water. During this time, a product precipitated out. The precipitated mass was further cooled to a temperature of about 11° C. for about 30 minutes and then filtered. The cake was washed with prechilled methanol (100 ml at a temperature of about 10° C.). The product was dried in an oven at a temperature of about 55 at a temperature of about 10° C. until the moisture content was about 1percent. The dried product appeared as an off-white crystalline solid weighing about 108 g to about 110 g. The yield was about 75percent to about 76percent, having a m.p. of 150-154° C. The IR (KBr) spectrum shows the absorption bands at 3100 cm-1 (C-H str), 2900 (C-H str), 1720 (-COO str), 1605 (-CC-str), 1150 (SO2str). The 1HNMR (CDCl3) TMS as internal standard shows the following signals δ 7.65 [m,2H,Ar-H], 7.09 [m,2H,Ar-H], 6.52 [dd,1H,ArCHCH], 5.47 [dd,1H,ArCHCH], 3.57, 3.50 [2.x.s,6H,NCH3,SO2CH3], 3.38 [hept,1H,Ar-CHMe2], 2.45-2.30 [2.x.dd,2H,CH2CO2 t-Bu], 1.55, 7.3 [dt,dd,2H,acetonide,CH2], 1.50, 1.40 [2.x.s,6H,acetonide C(CH3)2], 1.45 [s,9H,CO2C(CH3)3], 1.27 [dd,6H,ArCH(CH3)2]. The CI mass shows m/z 578 (base peak). The elemental analysis shows calculated percent C 60.29; percent H 6.98; percent N 7.27; observed percent C 60.12; percent H 6.89; percent N 7.17.
75%
With potassium carbonate In dimethyl sulfoxide at 70 - 75℃; for 2 h;
600 ml of dimethyl sulfoxide, 104 grams (0.75 mole) of potassium carbonate, 170 g (0.25 mol) [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl sulfo ) amino] pyrimidin-5-yl - methyl] triphenylphosphonium bromine and 65 g (0.26mol) (4R-cis) -6- aldehyde dimethyl-1,3-dioxane ring -4- acetate mixture was stirred and heated to 70-75 degrees for two hours. 1L of toluene was added, and then cooled and filtered to remove most of the inorganic impurities and phosphorus oxide. The organic phase was washed with 1L with water and then vacuum distilled to dryness and 750 ml of methanol was added to the residue, and then heated to boiling. At 25-30 degrees crystallized product. Cooled further to 11 degrees, the product isolated to give 108 g (75percent yield).
With potassium carbonate In dimethyl sulfoxide at 25 - 75℃; for 5 - 7 h;
In a 250 mL 4-necked round bottom flask, DMSO (150 ml), potassium carbonate (33.54 g), TBPBr (50 g) of Example 2 and BFA (20.87 g) were added at a temperature in the range of about 25° C. to about 35° C. under stirring. The reaction mixture was heated to a temperature of about 70° C. to about 75° C. for about 5 to about 7 hours. After the completion of the reaction as determined by TLC, the reaction mixture was cooled to a temperature in the range of about 25° C. to about 35° C. Toluene (250 ml) was added for dilution of the reaction mixture and stirred for about 30 minutes. The organic layer was added to water (100 ml) under stirring and maintained for 30 minutes. The organic layer was separated and washed with water (2.x.100 ml) in the same manner as described above. The organic layer was distilled in Rota vapor bath at temperature in the range of from about 50° C. to about 60° C. under vacuum. After distillation, EPA (100 ml) was added to the residue at a temperature of about 55° C. to about 60° C. and the mixture was maintained for about 30 minutes. The reaction mixture was brought to a temperature in the range of from about 25° C. to about 30° C. by Circulating room temperature water slowly. In this period, the product precipitates and the precipitated mass was further cooled to a temperature of about 10° C. for about 30 minutes, and then filtered. The cake was washed with prechilled (at a temperature of about 10° C.) IPA (50 ml). The product was dried in an oven at a temperature of about 55° C. until the moisture content was about 1percent. The dried product appeared as an off-white crystalline solid weighing about 44 g to about 45 g. The yield was about 88percent to about 90percent, and having a m.p. of 150-154° C. The IR (KBr) spectrum shows the absorption bands at 3100 cm-1 (C-H str), 2900 (C-H str), 1720 (-COO str), 1605 (-CC-str), 1150 (SO2str). The 1HNMR (CDCl3) TMS as internal standard shows the following signals δ 7.65 [m,2H,Ar-H], 7.09 [m,2H,Ar-H], 6.52 [dd,1H,ArCHCH], 5.47 [dd,1H,ArCHCH], 3.57, 3.50 [2.x.s,6H,NCH3,SO2CH3], 3.38 [hept,1H,Ar-CHMe2], 2.45-2.30 [2.x.dd,2H,CH2CO2t-Bu], 1.55, 7.3 [dt,dd,2H,acetonide,CH2], 1.50, 1.40 [2.x.s,6H,acetonideC(CH3)2], 1.45 [s,9H,CO2C(CH3)3], 1.27 [dd,6H,ArCH(CH3)2]. The CI mass shows m/z 578 (base peak). The elemental analysis shows calculated percent C 60.29; percent H 6.98; percent N 7.26; observed percent C 60.17; percent H 6.93; percent N 7.21.
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at -76 - -74℃; for 1.16667 h; Stage #2: at -76 - 10℃; for 2.08333 h;
A mixture of DPPO (19.17 g) and THF (227 ml) were warmed briefly to 40 C. until a clear solution had formed then inerted by the sequential application of vacuum and nitrogen (5 cycles). The mixture was immersed in an acetone/CO2 bath cooling the contents to -75 C. Sodium bis(trimethylsilyl)amide (37.4 ml of 1.0 M solution in THF) was added to the reaction mixture over 10 minutes from a pressure equalising dropping funnel maintaining the temperature below -74 C and forming a red solution of the anion. THF (10 ml) was rinsed through the dropping funnel into the mixture and the mixture stirred a further 1 hour at -76 C forming a red suspension. BFA (80 ml of 13.5percent w/w toluene solution) was added in portions to the suspension over 20 minutes from a pressure equalising dropping funnel maintaining the temperature below -73 C. Toluene (20 ml) was rinised through the dropping funnel into the mixture and the mixture stirred a further 15 minutes at -76 C. The chilling bath was lowered and the suspension allowed to warm to 10 C over 1.5 hours. Glacial acetic acid (3.21 g) in water (15 g) was added in one portion raising the temperature to 18 C and dissolving all solids and the mixture was stirred a further 5 minutes. The mixture was concentrated by distillation at atmospheric pressure (jacket 110 C) to a temperature of 94 C collecting a total of 274 ml distillates. The concentrated mixture was cooled to 40 C, water (40 ml) was added and the mixture stirred for 5 minutes then allowed to settle for 15 minutes. The lower aqueous phase was discarded. Sodium hydrogen carbonate (2.99 g) in water (40 ml) was added and the mixture stirred for 5 minutes then allowed to settle for 15 minutes. The lower aqueous phase was discarded. Water (30 ml) was added and the mixture stirred for 5 minutes then allowed to settle for 15 minutes. The lower aqueous phase was discarded. The organic phase was transferred to a distillation apparatus with toluene (20 ml) and concentrated by distillation at atmospheric pressure (jacket 125-130 C) to a temperature of 116 C collecting 85 ml distillates. Vacuum was applied (400-500 mbar) and a further 16.5 ml distillates collected to a temperature of 111 C. The vacuum was released and the concentrated mixture allowed to cool to 80 C. Warm MeOH (140 ml, 50 C) was added with rapid stirring and the batch allowed to self-cool to 20 C over 30 minutes during which time a solid was deposited. The suspension was further cooled to 2 C for 30 minutes then the solid was collected by filtration on a sinter and pulled as dry as possible. The solid was washed with cold MeOH (60 ml, 2C.) and again pulled as dry as possible then transferred to a vacuum oven and dried overnight (50 C, 200 mbar); giving BEM (14.01 g, 67.7percent). 1H NMR (CDCl3, 270 MHz) 7.65 [m, 2H, ArH], 7.09 [m, 2H, ArH], 6.52 [dd, 1H, ArCH=CH], 5.47 [dd, 1H, ArCH=CH], 3.57, 3.50 [2 x s, 6H, NCH3, SO2CH3], 3.38 [hept., 1H, ArCHMe2], 2.45, 2.30 [2x dd, 2H, CH2CO2tBu], 1.55, 1.13 [dt, dd, 2H, acetonide CH2], 1.50, 1.40 [2x s, 6H, acetonide C(CH3)2], 1.45 [s, 9H, CO2C(CH3)3], 1.27 [dd 6H, ArCH(CH3)2]
61%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at -74℃; for 1 h; Stage #2: at -74 - 10℃; for 3 h; Stage #3: With acetic acid In tetrahydrofuran; water; toluene at 10 - 40℃; for 0.166667 h;
Sodium bis (trimethylsilyl) amide (1 M in tetrahydrofuran, 23 mi) is added dropwise, AT-74°C, to a suspension of the compound of formula (38) (12 g, 22.3 MMOL) in tetrahydrofuran (130 M .). STIRRING is carried out at-74°C for 1 hour and then a solution of the compound of formula (40) (6.9 g, 26.8 MMOI) in toluene (28 ML) is added dropwise. Stirring is then carried out AT-74°C for 1 hour, then warming to 10°C over the course of 1 hour and stirring for a further 1 hour at that temperature. A mixture of acetic acid (2 ml) and water (8.4 ML) is added, at 10°C, to the resulting yellow suspension and stirring is carried out at room temperature for 5 minutes. The tetrahydrofuran is then distilled off, and, at 40°C, 45 ml of water are added to the reaction mixture and vigorous stirring is carried out for 5 minutes. The aqueous phase is separated off and a solution of sodium hydrogen carbonate (2.27 G) in water (45 ml) is added to the organic phase. Vigorous stirring is again carried out for 5 minutes and then the aqueous phase is removed again. The organic phase is diluted with 250 ML of toluene, washed successively with water and saturated sodium chloride solution and dried (using NA2SO4). The salt mixture is filtered off and the filtrate is concentrated by evaporation. The concentrated residue is then purified by column chromatography on silica gel (hexane: ethyl acetate 8: 1). 2.59 G (61 percent) of the desired product (39) can be obtained in the form of colourless crystals. 'H NMR (300 MHz, CDCI3) : 0.91-1. 08 (m, 1H) ; 1.20 (d, J = 6. 7 HZ, 6H); 1. 24 (S, 3H); 1. 38 (S, 9H); 1.41 (S, 3H); 1.41-1. 56 (m, 1 H) ; 2.21 (dd, J = 15. 2, 7. 9, 1 H) ; 2. 35 (dd, J = 15. 0, 5. 0 HZ, 1H) ; 3. 27-3. 37 (m, 1H) ; 3. 43 (S, 3H); 3.52 (S, 3H); 4.17-4. 24 (m, 1H) ; 4. 47-4. 53 (m, 1H) ; 5.43 (dd, J = 16.4, 5.5 Hz, 1H) ; 6.55 (dd, J = 16.1, 0.8 Hz, 1H) ; 7.24 (dd, J = 8.8, 8.8 HZ, 2H); 7.65 (dd, J = 8.8, 5.6 Hz, 2H). 13C NMR (75 MHz, CDCI3) : 18.7, 20.6, 20.7, 27.0, 29.0, 30.9, 32.0, 35.0, 41.3, 41.4, 64.8, 68.1, 79.6, 97.7, 113.7 (JCF = 21.7 Hz), 120.0, 122.0, 131. 0 (JCF = 8.4 Hz), 133.2 (JCF = 3.2 Hz), 136.3, 156.0, 162.0 (JCF = 249 Hz), 162.2, 168.8, 173.6.
With lithium carbonate; sodium hydride In tetrahydrofuran at 0 - 35℃; for 4.83333 h; Inert atmosphere
50 g of compound 1, 300 ml of anhydrous THF, and 0.16 g of lithium carbonate were placed in a reaction flask, protected with nitrogen, and stirred.The temperature was lowered to 0-5 ° C, and 4.6 g of NaH (60percent) was added.30 g of compound 3 ((4R-CIS)-6-formaldehyde-2,2 dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester) was dissolved in 80 ml of anhydrous T HF,It was added dropwise to the above reaction solution, and the addition was completed in 50 minutes.The reaction was kept at 0-5 ° C for 1-2 hours, and the temperature was raised to 30-35 ° C for 4 hours.TLC detection, after the reaction is completed, the temperature is lowered to 0-5 ° C,Acetic acid was slowly added dropwise to pH = 7-7.5, and 100 ml of water was added.Static, liquid separation, collecting the upper organic phase. The organic phase is washed 1-2 times with water, dried over anhydrous sodium sulfate, and filtered to remove the desiccant.The THF was distilled off under reduced pressure to give 56.6 g of a yellow oil.The crude product yield was 92.6percent. Add 125 ml of isopropanol to the above crude product, start stirring, warm up to 70 ° C until the solution is cleared, and then start to cool down after 30 minutes of heat preservation, and cool down to 5 ° C through 3 hours.Incubate for 1 hour, suction filtration, filter cake with a small amount of ice isopropanol, yield cake, dry,Obtained 53.2 g of Compound A as a white solid.HP LC = 99.2percent (E configuration) with a total yield of 87.3percent.
Reference：
[1] Patent: CN108822090, 2018, A, . Location in patent: Paragraph 0052-0055; 0062-0065; 0072-0075; 0082-0085
22
[ 124752-23-4 ]
[ 289042-12-2 ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at -70 - -65℃; for 2 h; Stage #2: at -70 - -65℃; for 2 h;
(1) Preparation of tert-butyl 6-[(1E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methane sulfonyl)amino]-5-pyrimidinyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-acetate (compound III) To a 5 L four-necked flask, 2 L (8 mL/g) of tetrahydrofuran and 250 g (1 mol) of N-(5-((4,4'-tolylphosphono)-methyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methyl methane sulfonamide (compound I) were sequentially added, and stirred to clearness. The mixture was cooled down to -70˜-65° C., followed by adding 486.2 mL (1.1 mol, calculated from virtually titrated content) of sodium hexamethyldisilazide. The system was kept at -70˜-65° C. for 2 hours, followed by adding dropwise a solution of 132.4 g (1.1 mol) of tert-butyl (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetate in 500 mL of tetrahydrofuran (2 mL/g). After the addition was completed, the system was stirred at the same temperature for 2 hours, followed by warming up to about 10° C. and reacting until compound I was completely consumed. The reaction system was then quenched with 1 L (4 mL/g) of purified water. The liquid was separated. The aqueous phase was extracted twice with 1.25 L (5 mL/g) of n-heptane. The organic phase was combined, washed with 750 mL (3 mL/g) of saturated brine, and concentrated to dryness. To the concentrated system was added 500 mL (2 mL/g) of methanol, leading to crystallization to give compound III with a purity of about 98percent, a stereo-selectivity of E/Z=99.8:0.2, and a yield of 82percent. 1H NMR (400 MHz, CDCl3) δ: 0.88 (t, J=7.4 Hz, 3H); 1.09˜1.25 (m, 7H); 1.39˜1.52 (m, 13H); 1.77 (q, J=7.3 Hz, 2H); 2.30 (dd, J1=15.1 Hz, J2=5.9 Hz, 1H); 2.45 (dd, J1=15.3 Hz, J2=7.0 Hz, 1H); 3.35˜3.39 (m, 1H); 3.51 (s, 3H); 3.56 (s, 3H); 4.28 (br, 1H); 4.41˜4.43 (br, 1H); 5.46 (dd, J1=16.2 Hz, J2=5.0 Hz, 1H); 6.51 (d, J=16.3 Hz, 1H); 7.05˜7.09 (m, 2H); 7.63˜7.66 (m, 2H); HRMS (ESI) calculated: C30H42FN3O6S; [M+1H]+=592.28, determined: 592.3.
With potassium carbonate In dimethyl sulfoxide at 70 - 80℃;
A solution of 4- (4-fluorophenyl) -5- (methyl diphenylpropionylphosphonium) -6-isopropyl-2 - [(N-Methyl-N-methanesulfonamido)] - pyrimidine (Compound I), 180.0 g of (4R-cis) -6-aldehyde-2,2-dimethyl- (Compound II) 74.5 g, 125 g of potassium carbonate and 1000 g of DMSO, and the mixture was heated to 70 to 80C by stirring. The reaction was carried out until the compound (I) was completely consumed. After the reaction was completed, the filtrate was filtered and the filtrate was added with 1000 g of water, Times. Control the water bath temperature T ≤ 60 , concentrated toluene to dry to dry, crude add 900g of methanol, temperature dissolve, slow cooling crystallization, filtration, frozen methanol leaching. Control the temperature T = 40 ~ 50 dry. The dry product compound (III) was 124.3 g. Quality yield69.1percent, molar yield 82.3percent. Purity (HPLC) 99.6percent, stereoselectivity E / Z = 99.8: 0.2.
Reference：
[1] Patent: CN106674281, 2017, A, . Location in patent: Paragraph 0049; 0050
24
[ 124752-23-4 ]
[ 289042-12-2 ]
Yield
Reaction Conditions
Operation in experiment
77.8%
With cesium fluoride In N,N-dimethyl-formamide at 20 - 120℃; for 3 h;
In a 250 ml three-necked flask, a thermometer, a pH meter and a constant pressure dropping funnel and a magnetic stirrer were attached.In a reaction flask, 10 g of compound II, 100 ml of DMF and 6.5 g of tert-butyl (4R-cis) -6-aldehyde-2,2-dimethyl-1,3-dioxan-4-acetate g of cesium fluoride 0.4 g and stirred for 1 hour. Then heated to 120 , incubated for 2 hours, cooled down, poured into ice water 200ml, extracted with toluene 150ml * 2, concentrated under reduced pressure, dissolved in 100ml of methanol, cooled to room temperature, incubated for 6 hours crystallization, filtration The product (4R, 6S, E) -2- {6- [2- [4- (4- fluorophenyl) -6- isopropyl- 2- (N- methylsulfonyl) amino) 5-yl] vinyl] -2,2-dimethyl-1,3-dioxan-4-yl} acetate 11.0 g Yield 77.8percent.
With potassium carbonate In dimethyl sulfoxide at 70 - 80℃;
A solution of 4- (4-fluorophenyl) -5- (diphenylpropanoylphosphonium bromide) -6-isopropyl-2 - [(N-methyl-N-methanesulfonamido)] - pyrimidine(Compound I) 180.0 g,(4R-cis) -6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (Compound II), 125 g of potassium carbonate and 1000 g of DMSO were stirred and stirred to 70 ~ 80 , insulation reaction Until the compound (I) consumption is complete, after the end of the reaction, cooling filter, the filtrate by adding water 1000g, toluene extraction twice. Control water Bath temperature T ≤ 60 ° C, concentrated toluene to dry to dry crude product, the crude product by adding 900g of methanol, dissolved in temperature, slow cooling crystallization, Filter, frozen methanol leaching. Control the temperature T = 40 ~ 50 dry. The dry product compound (III) was 128.0 g. The yield was 71.1percent The molar yield was 83.0percent. Purity (HPLC) 99.7percent, stereoselectivity E / Z = 99.7: 0.3.
Reference：
[1] Patent: CN106674281, 2017, A, . Location in patent: Paragraph 0042; 0043
26
[ 1221497-92-2 ]
[ 124752-23-4 ]
[ 289042-12-2 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.333333 h; Inert atmosphere Stage #2: at -35 - 0℃; for 21 h;
Example 3: tert-Butyl (E)-(6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-yl] vinyl] (4R, 65) -2,2-dimethyl [1,3] dioxane-4-yl) acetate [Show Image] To a solution of dimethyl [4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl] phosphonate (1.0 g, 2.25 mmol) produced in Example 1 dissolved in anhydrous tetrahydrofuran (20 ml), a 1.9 M tetrahydrofuran solution of sodium hexamethyldisilazide (1.4 ml, 2.58 mmol) was added dropwise at -78°C under nitrogen stream for 5 minutes. After the mixture was aged at -78°C for 15 minutes, a solution of tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate (0.7 g, 2.69 mmol) dissolved in anhydrous tetrahydrofuran (7 ml) was added thereto dropwise for 10 minutes. The device for dropwise addition was washed with anhydrous tetrahydrofuran (2 ml), and the wash fluid was added to the reaction mixture dropwise. The temperature of the reaction mixture was raised to -35°C for 3 hours, and the reaction was carried out at the same temperature for 15 hours. The temperature was raised to 0°C for 2 hour, and the mixture was aged for 1 hour. The reaction was terminated by adding a saturated ammonium chloride aqueous solution (20 ml) to the reaction mixture, and then the mixture was extracted with toluene (50 ml). The organic layer was washed distilled water (10 ml) two times and saturated brine (10 ml) two times. The quantity of the content amount of tert-butyl (E)-(6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidine-5-yl]vinyl](4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl)acetate in the organic layer was determined with high-performance liquid chromatography; as a result, the title compound (1.2 g, yield: 95percent) was contained.
With sodium methylate In tetrahydrofuran at -15 - 10℃;
Alternate Method for Tert-Butyl [(4R,6S)-6-{(E)-2-[4-(4-Fluorophenyl)-2-[Methyl(Methylsulfonyl)Amino]-6-(Propan-2-Y1)Pyrimidin-5-Yl]Ethenyl}-2,2-Dimethyl-1,3-Dioxan-4-Yl]Acetate Sodium methoxide (12.8 g) was added in lots to a pre cooled mixture of N-[4-(4-fluorophenyl)-5-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl]methyl}-6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethanesulfonamide (100 g) and tert-butyl 3,5-dideoxy-2,4-O-(1-methylethylidene)-L-erythro-hexuronate (60 g) in tertrahydrofuran (500 mL) at -15° C. to 10° C. After the completion of the reaction, the mixture was quenched with saturated aqueous solution of ammonium chloride. To the resultant mixture, dichloromethane (500 mL) was added and the pH of the mixture was adjusted to 5.0 to 7.0 using dilute hydrochloric acid (2N). The organic layer was washed with aqueous solution of sodium bicarbonate (5percent; 200 mL). The organic layer was separated and concentrated under vacuum at 40° C. to 45° C. to give residue. Methanol (1000 mL) was added to the resulting residue and stirred at 20° C. to 25° C. for 2 hours. The product was filtered, washed with methanol (100 mL) and dried at 40° C. to 45° C. for 4 hours to 5 hours. Dry weight: 60 g
(4R-cis)-6-(hydroxymethyl)-2,2-dimethyl- 1 ,3 -dioxane-4-acetic acid, 1 , 1 -dimethyl ethyl ester (10.0 g ,0.0385 mol) mol) was dissolved in dimethyl sulfoxide (15.0 g , 0.192 mol) and dichloromethane (100 ml) followed by cooling at 0 to -5 0C. The reaction mass was cooled for 15 min at 0 to -5 0C followed by addition of Diisopropylethyl amine( 17.42 g ,0.1347 mol) at 0 to -5 0C and continued stirring for 15 min at 0 to -5 0C. In another flask, charged pyridine-sulfur trioxide complex (12.25 g, 0.077 mol), pyridine (6.09 g, 0.077 mol) and dimethyl sulfoxide (15.0 g, 0.192 mol) at room temperature followed by stirring for 10 min. Resulting suspension was added to the above alcohol solution in dichloromethane at 0 to -5 0C and continued stirring for 1 hr at 0 to -5 0C. After the completion of reaction, water (50.0 ml) was added and stirred for 10 min. This was followed by layer separation. Aqueous layer was extracted with dichloromethane (2 x 20 ml).Dichloromethane layer was washed with water ( 3 x 100.0 ml ) followed by drying over sodium sulfate and distilled dichloromethane under vacuum at 40 to 45.0 C.Degased mass for 1 hr at 40 to 45.0 0C under reduced pressure to obtain tertiary butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl] acetate, compound of formula II (9.22 g, 93.0%).
86%
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; acetonitrile; at 0 - 25℃; for 5.5h;Molecular sieve;
(6-Formyl-2, 2-dimethyl- [1, 3] dioxan-4-yl)-acetic acid tert-butyl ester To a solution of (6-hydroxymethyl-2. 2-dimethyl-11, 3] dioxan-4-yl)-acetic acid tert- butyl ester (30.0 g, 115 mmol) at 0 C in DCM: MeCN (10: 1,225 mL) was added 4 A molecular sieves (55 g), 4-methylmorpholine N-oxide (20. 3 g, 172.9 mmol) and tetrapropylammonium perruthenate (0.41 g, 1. 15 mmol). The reaction was warmed from 0 C to 25 C over 0.5 hr and then stirred at that temperature for 5 hrs. Once complete, as determined by TLC, the reaction mixture was filtered through celite and the filtrate was concentrated to a brown oil that was purified by silica gel chromatography (20-70 % EtOAc/Hexane) to provide (6-formyl-2, 2-dimethyl- [1, 3] dioxan-4-yl)-acetic acid tert-butyl ester (25.5 g, 86%): H-NMR (CDCI3) 09. 54 (s, 1 H), 4.30-4. 26 (m, 2 H), 2.45-2. 39 (m, 1 H), 2.33-2. 27 (m, 1 H), 1.81-1. 77 (m, 1 H), 1.46-1. 41 (m, 16 H), 1.28-1. 20 (m, 1 H).
85.9%
With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hypochlorite; sodium hydrogencarbonate; potassium bromide; In dichloromethane; at -15 - 0℃;pH 10;
(2) step (1) to obtain compound II of the methylene chloride solution, adding 0.15g (0.99mmol) TEMPO, 2.36g (0.0198mol) potassium bromide and 16.6g (0.198mol) sodium bicarbonate, stirring and mixing after cooling to -15 C, dropping pre-adjusting the pH to 10 sodium hypochlorite solution (175.9g (0.238mol) sodium hypochlorite solution (content 10.9%) in terms of mass percentage concentration is 5% sulfuric acid adjusted to pH 10), control reaction solution temperaturethe <0 C.drop finishes, 0 C stirring for reaction, GC tracking of the reaction, the response finishes (compound III less than0.2%)adding quality percentage concentration is 10% aqueous solution of sodium thiosulfate 156.5g stirring quenching reaction, the resulting organic phase after transferring, to 300g × 2 washing, to obtain light yellow clear solution, adding 50g drying by anhydrous sodium sulfate, filter, to 20g dichloromethane wash the filter cake, the spin vaporization (40 C, -0.09 MPa) unless the solvent to obtain strawcoloured solid 46.0g, yield 90.1%, GC purity 98.7%, crude I is compound;
83%
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; potassium bromide; In dichloromethane; water; at -15 - 5℃; for 1h;Large scale;
0.02 g of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy free radical), 0.96 g of potassium bromide, 18.6 g of sodium hydrogencarbonate and 50 ml of methylene chloride were placed in a 500 ml flask, Stirred at ~ 5 C.After dissolving 11.64 g (44.71 mmol) of t-butyl 2 - [(4R, 6S) -6-hydroxymethyl-2,2-dimethyl- 1,3-dioxane- 4-yl] acetate in 50 ml of methylene chloride , Added to the above reaction. After cooling the reaction product to -15 C. or lower, 36.6 ml (53.65 mmol, 1.2 equivalent) of a 10.9% (w / w) sodium hypochlorite aqueous solution was added dropwise at once. After the dropwise addition, stirring was carried out at 0 C. for 1 hour, the reaction progress degree was checked by gas chromatography (GC), the reaction product was filtered under reduced pressure, 10% sodium thiosulfate solution (10 w / w% sodium thiosulfate solution) 100 ml was added and the organic layer was separated. 100 ml of a saturated sodium chloride solution was added to the organic layer, and the organic layer was further separated. After adding 150 ml of water to the organic layer and stirring for 10 minutes, the stagnant organic layer was separated, dried over anhydrous magnesium sulfate, filtered, methylene chloride as an organic solvent was distilled under reduced pressure at 40 C. and 3 cmHg for 10 minutes To obtain a concentrated residue 1 as an oil phase (step A).The concentrated residue 1 was adjusted to a pressure of 3 cmHg in a vacuum vacuum dryer and dried for 30 minutes at 80 C. without separately adjusting the humidity to obtain the title compound as pale brown crystals (Step B) . (The XRD graph of the product is shown in Figure 1 and its value is as shown in Figure 2. The DSC value of the product is shown in Figure 3.) Yield of product 83% (8.2kg)
65%
With sodium hydrogencarbonate;
The reaction vessel was charged with t-butyl 2 - ((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan- 6.7 L), & lt; / RTI & gt;The mixture was cooled to -15 [deg.] C and sodium bicarbonate (NaHCO3, 487 g, 5.8 mol) was added to the mixture.Pay attention to heat generation. Sodium bromide (NaBr, 131g, 1.3mol) is added temporarily and then sodium hypochlorite (NaOCl, 798ml, 1.42mol) is gradually added while maintaining the temperature below -10 C.PIPO-TEMPO (0.001 equivalent, 0.838 g, 0.0013 mol) is dissolved in toluene solvent (300 ml), and the solution is slowly dropped to -5 C. When the reaction was completed, Na2S2O3 (1.5 L) was added thereto, and the mixture was stirred at room temperature for 20 minutes to terminate the reaction,The organic layer is recovered by layer separation. The aqueous layer was further washed twice using a toluene solvent (1 L), and the recovered organic layer was subjected to anhydrous treatment with Na2SO4 and filtered.The obtained organic layer was concentrated under reduced pressure to obtain a solid product, which was then recrystallized with heptaneThe title compound of Formula 2 was obtained as a high purity solid (199 g, yield 65%, very pale yellow solid, GC analysis:> 98%).
54%
With sodium hypochlorite; TEMPOL; sodium hydrogencarbonate; potassium bromide; In water; ethyl acetate; at -10 - 5℃; for 1h;Inert atmosphere;
Reference Example 2: tert-Butyl 2-[(4R,6S)-6-formyl-2,2-dimeihyl-1, 3-dioxane-4-yl] acetate [Show Image] To a dispersion of tert-butyl 2-[(4R,6S)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-yl] acetate (15 g, 57.6 mmol), sodium hydrogencarbonate (13.6 g, 161.3 mmol), potassium bromide (1.37 g, 11.5 mmol) and 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine-1-oxyl free radical (248 mg, 1.44 mol) in ethyl acetate (150 ml), an aqueous solution of sodium hypochlorite (44.2 g, 16.7wt%, 70.2 mmol) was added under nitrogen stream at -10C carefully dropwise to keep the inner temperature within 5C. After the dropwise addition, the mixture was stirred at 0C for 1 hour and the aqueous layer was separated. The organic layer was further diluted with ethyl acetate (100 ml), and sequentially washed with a 5% sodium thiosulfate aqueous solution (75 ml) and water (40 ml × 2). Then, the organic layer was dried with anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained crude product was purified with silica gel column chromatography (silica gel: 200 g, developing solvent: hexane / ethyl acetate = 2 / 1 by volume) to obtain the title compound (8.0 g, yield: 54%) as white crystals. 1H-NMR (CDCl3): delta1.35(1H, q, J=12.7Hz), 1.45 (9H, s), 1.46 (3H, s), 1.49(3H, s), 1.83(1H, dt, J=2.7Hz, 12.9Hz), 2.35(1H, dd, J=5.9Hz, 15.4Hz), 2.46(1H, dd, J=7.1Hz, 15.4Hz), 4.33(1H, m), 9.58 (1H, s)
With sodium hypochlorite; sodium hydrogencarbonate; potassium bromide;4-oxo-2,2,6,6-tetramethylpiperidin-oxyl; In dichloromethane; water; at 0 - 5℃; for 1 - 2h;
2,2,6,6-tetramethyl piperidinyl oxy free radical (TEMPO) (0.2 g), potassium bromide (9.6 g) and sodium bicarbonate (90 g) were dissolved in methylene chloride (600 ml) and stirred the contents together at 0-5 C. A solution of (4R-cis)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 1,1-dimethylethyl ester of Formula III (100 g) in methylene chloride (400 ml) was added to the above solution at 0-5 C. To this solution 10% sodium hypochlorite solution (159 ml) (NaOCl) was added at 0-5 C. Again sodium bicarbonate (96 g) and followed by 10% sodium hypochlorite solution was added to the reaction mass. Reaction mass was maintained for 1-2 hours at 0-5 C. and filtered through perlite. The organic layer was separated and washed with 10% sodium thiosulfate solution (250 ml), then water (250 ml) followed by saturated sodium chloride solution (250 ml). Organic layer was distilled at below 40 C. under reduced pressure to afford the title product. Yield: 95 g.
With sodium hypochlorite;2-azatricyclo[3.3.1.13,7]dec-2-yloxidanyl; potassium bromide; In dichloromethane; at -15 - -5℃;
To the -15C to -5C pre-cooled reaction mixture of AZADO(0.002g), potassium bromide(0.22 g) and methylene chloride(30 ml) added 5 g of tert-butyl 2-((4R,6S)-6- (hydroxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate. Stirred the reaction mixture for 15 minutes at -15C to -5C. 19 ml of sodium hypochlorite solution was added to the reaction mixture at same temperature. Stirred the reaction mixture for 15 minutes. Quenched the reaction mixture with 10% aqueous sodium thiosulfate solution. 20 ml of water was added and separated the both aqueous and organic layers. Washed the organic layer with water followed by brine solution. Distilled off the solvent completely to get the title compound as a solid.Yield: 4.1 grams
Example-28Preparation of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate; To the -15 C. to -5 C. pre-cooled reaction mixture of AZADO (0.002 g), potassium bromide (0.22 g) and methylene chloride (30 ml) added 5 g of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate. Stirred the reaction mixture for 15 minutes at -15 C. to -5 C. 19 ml of sodium hypochlorite solution was added to the reaction mixture at same temperature. Stirred the reaction mixture for 15 minutes. Quenched the reaction mixture with 10% aqueous sodium thiosulfate solution. 20 ml of water was added and separated the both aqueous and organic layers. Washed the organic layer with water followed by brine solution. Distilled off the solvent completely to get the title compound as a solid.Yield: 4.1 grams
19.2 g
Preparation of Tert-Butyl 3,5-Dideoxy-2,4-O-(1-Methylethylidene)-L-Erythro-Hexuronate tert-Butyl 2,4-dideoxy-3,5-O-(1-methylethylidene)-D-erythro-hexonate (commercially available; 20 g) was added to a pre cooled (0 C. to 5 C.) mixture of 2,2,6,6-tetramethylpiperidine-1-oxyl (0.04 g), potassium bromide (1.92 g), and sodium bicarbonate (18 g) in dichloromethane (120 mL) and stirred at 0 C. to 5 C. for 15 minutes. Aqueous sodium hypochlorite (10%; 40 mL) was added slowly to the resulting mixture and stirred at 0 C. to 5 C. for 30 minutes. Sodium bicarbonate (18 g) was added to the mixture and stirred at 0 C. to 5 C. for 10 minutes, followed by the slow addition of aqueous sodium hypochlorite (10%; 40 ml) in 30 minutes at 0 C. to 5 C. The reaction mixture was stirred at 0 C. to 5 C. for 30 minutes. After completion of the reaction, the reaction mixture was filtered through hyflo bed and washed with dichloromethane (20 mL). The filtrate was washed with aqueous sodium thiosulphate (10%; 100 mL). The organic layer was separated and washed with de-ionized water (100 mL) and finally washed with aqueous solution of sodium chloride (10%; 100 mL). The organic layer was separated and concentrated under vacuum at 40 C. to give tert-butyl 3,5-dideoxy-2,4-O-(1-methylethylidene)-L-erythro-hexuronate. Dry weight: 19.2 g.
With [2,2]bipyridinyl; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; copper(l) chloride; In dichloromethane; acetonitrile; at 25 - 40℃;
A reactor was charged with 1.1 g of copper (I) chloride and 10 mL of acetonitrile. 2-2' Bipyridyl (156 mg) and TEMPO (156 mg) were added to the reactor under oxygen environment at 25C. A solution of (6-Hydroxymethyl-2,2-dimethyl-[l,3]dioxan-4-yl)- acetic acid tert-butyl ester 2.6 g in 26 mL DCM was added dropwise over a period of 10 min into it. The reaction mass was stirred at 40C and progress of reaction was monitored on GLC, which shows that 90% conversion for desired product
With potassium carbonate; In dimethyl sulfoxide; at 25 - 65℃; for 13h;Product distribution / selectivity;
34.67 grams of potassium carbonate is added to a solution of 25 grams of sulfone compound of Formula-13a prepared as per example 3 and 125 ml of dimethyl sulfoxide at 25 to 35C. Added 10.8 grams of Tertiary butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3- dioxane-4-yl] acetate compound of formula-14a. Stirred for 13 hours at 60 to 65C. Quenched the reaction mixture with chilled water slowly in 30 minutes. Extracted the reaction mixture twice with ethyl acetate. Separated and washed the organic phase with saturated sodium chloride solution. Distilled the solvent completely under reduced pressure at below 700C. hexanes added to the residue and decanted twice then dissolved the residue in toluene and isolated the title compound using hexanes as a solvent. Dried the compound at 40-450C for 6 hours . Yield : 13.5 grams. M.R : 148-155C
With caesium carbonate; In dimethyl sulfoxide; at 25 - 35℃; for 3h;Product distribution / selectivity;
8.4 grams of cesium carbonate is added to a solution of 10 grams of sulfone compound of formula-13b prepared as per example 14 and 50 ml of dimethyl sulfoxide at25 to 35C. Added 4.5 grams of Tertiary butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3- dioxane-4-yl] acetate compound of formula-14a. Stirred for 3 hours at 25 to 35C. Quenched the reaction mixture with chilled water slowly in 30 minutes. Extracted the? reaction mixture twice with ethyl acetate. Separated and washed the organic phase with <n="70"/>saturated sodium chloride solution. Distilled the solvent completely under reduced pressure at below 700C. hexanes added to the residue and decanted twice then dissolved the residue in toluene and isolated the title compound using hexanes as a solvent. Dried the compound at 40-45C for 6 hours. 5 Yield: 6.0 grams. M.R: 148-155C. Purity by HPLC > 96%
With caesium carbonate; In dimethyl sulfoxide; at 25 - 35℃; for 3h;Product distribution / selectivity;
8.4 grams of cesium carbonate is added to a solution of 10 grams of sulfone compound of Formula-13c prepared as per example 15 and 50 ml of dimethyl sulfoxide0 at 25 to 35C. Added 4.5 grams of Tertiary butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3- dioxane-4-yl] acetate compound of formula-14a. Stirred for 3 hours at 25 to 35C. Quenched the reaction mixture with chilled water slowly in 30 minutes. Extracted the reaction mixture twice with ethyl acetate. Separated and washed the organic, phase with saturated sodium chloride solution. Distilled the solvent completely under reduced5 pressure at below 7O0C. hexanes added to the residue and decanted twice then dissolved the residue in toluene and isolated the title compound using hexanes as a solvent. Dried the compound at 40-450C for 6 hours. Yield: 6.2 grams. M.R: 148-155C. Purity by HPLO 96%
With potassium carbonate; In dimethyl sulfoxide; at 70 - 75℃; for 4h;Product distribution / selectivity;
A mixture of 23.1 Kgs. compound of formula-3A and 90 liters of dimethylsulfoxide and 48 Kgs. of potassium carbonate is heated to 70-750C. Added a solution of 15 Kgs. of aldehyde compound of formula-4 in 90 liters of dimethylsulfoxide lot wise to the above reaction mixture. Stirred the reaction mixture for 4 hours at 70-750C. Added 225 liters of toluene to the above reaction mixture. Stirred the reaction mixture for 45 minutes at 25-300C. Filtered the byproduct and washed the byproduct with toluene. Added 240 liters of water followed by aqueous sodium chloride solution to the above reaction mixture. Stirred the reaction mixture for 15 minutes. Separated the organic <n="75"/>and aqueous layer. Extracted Hie aqueous layer with toluene. Washed the total organic layer with water. Purified the organic layer with silica gel. Distilled the solvent completely under reduced pressure at below 70C.
Example-1: Preparation of tert-butyl-2-(4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl- 2-(N-methylmethane sulfonamide)pyrimidin-5-yI)vinyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetate compound of formula-la:Sodium tertiary butoxide (36.8 grams) was added to a mixture of N-(4-(4-fluorophenyl)-6- isopropyl-5-( 1 -methyl- 1 H-benzo[i/]imidazol-2-ylsulfonyl)pyrimidin-2-yl)-N-methylmethane sulfonamide (185 grams) in tetrahydrofuran (400 ml) and this mixture was added to tert-butyl 2-((4R,6R)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate (100 grams) in tetrahydrofuran (200 ml) at -20 to -15C and stirred. After the completion of reaction, quenched it with sodium bicarbonate solution. The reaction mixture was stirred for 4 hours at 25-30C. The solid was filtered and washed with water. The wet solid was recrystallized from methanol to get the title compound.Yield: 165 gramsPurity by HPLC: 99.62%; 0.03% (Z isomer)
2-cyclopropyl-4-(4-fluorophenyl)-3-[(1-methyl-1H-benzo[d]imidazol-2-yl)sulfonyl]methyl}quinoline[ No CAS ]
[ 124752-23-4 ]
[ 147489-06-3 ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In dimethyl sulfoxide; at 25 - 35℃; for 3h;
5.2 grams of cesium carbonate is added to a solution of 3.5 grams of sulfone compound of Formula-13d and 20 ml of dimethyl sulfoxide at 25 to 35C. Added 1.68 grams of Tertiary butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxane-4-yl]acetate compound of Formula- 14a. Stirred for 3 hours at 25 to 350C. Quenched the reaction <n="73"/>mixture with chilled water slowly in 30 minutes. Extracted the reaction mixture twice with ethyl acetate. Separated and washed the organic phase with saturated sodium chloride solution. Distilled the solvent completely under reduced pressure at below 70C. hexanes added to the residue and decanted twice then dissolved the residue in toluene and isolated the title compound using hexanes as a solvent. Dried the compound at 40-45C for 6 hours. Yield: 1.2 grams. M.R: 115-121C.
<2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide[ No CAS ]
[ 147489-06-3 ]
Yield
Reaction Conditions
Operation in experiment
72.3%
To a solution of tert-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate (the compound of Formula 3, R=tert-butyl) (1.38 kg) in dimethyl sulfoxide (6 L) was added the compound of Formula 2 (3 kg). The reaction mixture was heated to about 35 C. under stirring. K2CO3 (1 kg) was added to the resulting clear solution, which was washed with DMSO (3 L). The reaction mixture was heated to about 70 C. and then stirred for 4 hours. After confirming with HPLC that the starting material was exhausted, the reaction was quenched. The reaction mixture was cooled to about 45 C. and then methanol (18 L) was added thereto. The reaction mixture was additionally cooled to about 5 C. and then stirred for additional 2 hours. The resulting precipitate was isolated by filtering under reduced pressure, washed with water (3 L), and then dried under reduced pressure at about 50 C. to give the titled compound (1.82 kg) as a white crystalline form (Yield: 72.3%). The HPLC analysis result of the obtained product is shown in FIG. 2.[0048]Melting point: 113 C.-116 C.[0049]HPLC % Area: 99.396 %[0050]1H-NMR (CDCl3): 0.9?1.0 (m, 2H), 1.0?1.03(m, 1H), 1.2?1.3(m, 2H), 1.3?1.38(s, 6H), 1.38?1.4(m, 1H), 1.45(s, 9H), 2.2?2.3(dd, 1H, J=0.015, J=0.038), 2.3?2.4 (m, 2H), 4.1?4.2(m, 1H), 4.3?4.4(m, 1H), 5.5?5.6(dd, 1H, J=0.015, J=0.04), 6.5(d, 1H, J=0.04), 7.0?7.3(m, 6H), 7.5(t, 1H), 7.9(d, 1H, J=0.021)
55.8%
With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 3h;Inert atmosphere;
Under the protection of nitrogen, in a 500ml round bottom flask, add 2.7g (0.0104mol) (3R,5S)-6-oxo-3,5-dihydroxy-tert-butyl 3,5, O-isopropylidenohexanoate, 46ml DMSO,5.0g (0.0081mol)triphenyl bromide 2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-ylmethyl) phosphine, 2.88g (0.0208mol) potassium carbonate, turn on the stirring and slowly warm up to 70C , incubate at 70C for 3h, then cool to room temperature, add 200ml water and 200ml toluene, stir for 30 minutes, separate the layers, extract the lower aqueous layer with 200 ml of toluene, and combine the upper toluene layers.Wash with 50ml of water once, the toluene layer was desolvated to dryness under reduced pressure, and 20ml of n-hexane was added,Stir and heat to complete dissolution, lower the temperature and crystallize, suction filter, filter solid and dry,2.60g (0.0050mol) (4R,6S)-(E)-6-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-vinyl]-2, 2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, product purity 90.5%, the pure yield was 55.8%.
With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 3h;
Example -3:Preparation of (4R, 6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyI) quinoline-3-yl)- vinyl]-2, 2-dimethyl-l, 3-dioxane-4-yl] acetic acid tertiary butyl ester compound of formula-5; Added a solution of 2.7 grams tert-butyl-2-((4R,6S)-6-formul-2,2-dimethyl-l,3- dioxan-4-yl)acetate compound of formula-4 in 46 ml of dimethylsulfoxide to a mixture of 5 grams of triphenyl[2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-ylmethyl)- phosphonium]bromide compound of formula-3 and 2.88 grams of potassium carbonate. Heated the reaction mixture to 70C. Stirred the reaction mixture for 3 hours at 70C. Quenched the reaction mixture with water. Extracted the reaction mixture with toluene. Concentrated the organic phase and isolated the title compound using hexanes. Yield: 13 gram M.R: 105 - 1160C
With potassium carbonate; In dimethyl sulfoxide; at 25℃; for 10h;
To the solution of 0.751 Kg of tert-butyl-2-((4R,6S)-6-formul-2,2-dimethyl-l ,3- dioxan-4-yl)acetate (III) in 7 L of dimethylsulphoxide was added 1 Kg of phosphonium bromide compound of formula (IV) and 0.67 Kg of potassium carbonate. The reaction mixture was stirred at 25C for 10 hours. The reaction mixture was quenched with water and extracted with toluene. The organic layer was concentrated and the title compound was isolated using isopropanol as crude solid. The crude product thus obtained was recrystallized in methanol as shown below.Purification of Olefin compound of formula IIPitavastatin Olefin compound (II) (100 g) and methanol (600 mL) were heated to 60C to 65C to obtain the clear solution and stirred for 10 mins. Activated Carbon (10 g) were added at 60C to 65C and stirred for 10 min. The reaction mixture was filtered and washed with methanol (100 mL). The filtrate was cooled to 25C and gradually to 10C followed by stirring for 2 hours at 10C. The resulting slurry was filtered and washed with chilled methanol (100 mL). The wet-cake was heated in methanol (480 mL) at 60C to 65C to obtain the clear solution. Activated Carbon (10 g) were added at 60C to 65C and stirred for 10 min. The reaction mixture was filtered and washed with methanol (100 mL). The filtrate was cooled to 25C and gradually to 10C followed by stirring for 2 hours at 10C. The resulting slurry was filtered and washed with chilled methanol (100 mL). The wet-cake was dried under vacuum for 30 minutes followed by drying in hot air oven at 50C to 55C for 12 hours to obtain crystalline olefin compound (II) characterized by X-ray powder diffraction substantially as same as shown in FIG.3 and DSC thermogram having endothermic peak at about 1 16.04C as shown in FIG.4.
With potassium carbonate; In dimethyl sulfoxide; at 25℃; for 10h;Industry scale;
To the solution of 0.751 Kg of tert-butyl-2-((4R,6S)-6-formul-2,2-dimethyl-1,3-dioxan-4-yl)acetate (III) in 7 L of dimethylsulphoxide was added 1 Kg of phosphonium bromide compound of formula (IV) and 0.67 Kg of potassium carbonate. The reaction mixture was stirred at 25 C. for 10 hours. The reaction mixture was quenched with water and extracted with toluene. The organic layer was concentrated and the title compound was isolated using isopropanol as crude solid. The crude product thus obtained was recrystallized in methanol as shown below.
With potassium carbonate; In dimethyl sulfoxide; at 25℃; for 10h;Inert atmosphere; Industry scale;
Example-1:Preparation of (4R,6S)-(E)-6-f2-(2-cvclopropyI-4-(4-flourophenyl)quinoline-3-yl)- vinyl-2,2-dimethyl-l,3-dioxane-4-yllacetic acid tertiary butyl ester compound of Formula PiTo a solution of 0.751 Kg of tert-butyl-2-((4R,6S)-6-formul-2,2-dimethyl-l,3- dioxan-4-yl)acetate (III) in 7 L of dimethylsulphoxide, was added 1 Kg of phosphonium bromide compound of Formula (IV) and 0.67 Kg of potassium carbonate. The reaction mixture was stirred at 25C for 10 hours under nitrogen atmosphere. The reaction mixture was quenched with water and extracted with toluene. The organic layer was concentrated and the compound of Formula (II) was isolated using isopropanol. The product thus obtained was recrystallized in methanol.
[4-[4-fluorophenyl-6-(1-methylethyl)-2-[N-methyl-(N-methanesulfonyl)amino]]-5-pyrimidinyl]methylphenyltriphenylphosphonium bromide[ No CAS ]
[ 124752-23-4 ]
[ 289042-12-2 ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium carbonate; In dimethyl sulfoxide; at 20 - 70℃;Inert atmosphere;
1) Preparation of the crude product containing the intermediate of formula (III)Under nitrogen atmosphere, 8.76 g of the compound of formula (II) was placed in a four-neck reaction flask at room temperature,Add 70mL dimethyl sulfoxide,Stirring completely dissolved, followed by the addition of 20g compound of formula (I) and 12.2g of anhydrous potassium carbonate powder,The solution was heated to 70 reaction, TLC detection and tracking, the reaction was completed, the solution was cooled to room temperature,To the solution was added 200mL of ethyl acetate and stirred for a few minutes, filtered,The filtrate was washed with pure water (100mL wash 3 times), saturated brine (100mL wash 2 times),The organic phase was separated, dried over anhydrous magnesium sulphate, filtered, the filtrate was concentrated to dryness under reduced pressure,17 g of crude product containing the intermediate of formula (III) was obtained.2) Purification of the crude product containing the intermediate of formula (III)Mass ratio of 1: 11 mass ratio of the solid obtained in step (1) was added 187mL of ethanol and n-hexane mixedSolution, absolute ethanol and n-hexane volume ratio of 1: 1,Heated to reflux, completely dissolved, stop heating, water bath down to room temperature,Then cooled in an ice bath to 0 ~ 10 C, filtered, the solid was dried to give a white solid 15.4g,Yield 89%, HPLC purity of 99.41%The cis-isomer content is less than 0.1%.
80%
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 2.16h;
The compound prepared in Preparation Example 2 (11 g, 16.2 mmol) and the compound prepared in Preparative Example 1 (5.01 g, 19.4 mmol) were dissolved in 30 ml of dimethylsulfoxide, and the mixture was stirred at room temperature for 10 minutes, Potassium carbonate (3.35 g, 24.3 mmol)And the mixture was stirred at 70 C for 2 hours.After completion of the reaction, the temperature was maintained, 90 ml of isopropyl alcohol was added, 60 ml of H 2 O was added, refluxed at 70 to 80 C. for 20 minutes, and then slowly cooled to form crystals.Stir at room temperature for 30 minutes and filter the precipitate under reduced pressure.(7.48 g, yield: 80%, HPLC: 99.5%, white solid)
76%
With potassium carbonate; In toluene; at 95℃; for 6h;
Adding a compound to a three-neck bottle4-(4-fluorophenyl)-5-triphenylphosphonium bromide-6-isopropyl-2-[(N-methyl-N-methylsulfonamido)]-pyrimidine 50 g,Further added 350 ml of toluene and (4R-cis)-6-[(acetoxy)methyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester 38.06 g, carbonic acid Potassium 30 grams,The temperature is raised at 95 C for 4.5 hours, and the temperature is lowered to room temperature.The potassium carbonate was filtered, and the solvent was evaporated to give a crude material.The crude product was refined with ethanol to give a product of 32.3 g.The yield was 76% and the purity was 99.2%.
75 - 76%
With potassium carbonate; In dimethyl sulfoxide; at 25 - 75℃; for 2h;
Into a 2 L 4-necked round bottom flask, DMSO (600 ml), potassium carbonate (104 g), TPPBr (170 g) of Example 1 and BFA (65 g) were added at a temperature in the range of from about 25 C. to about 35 C. under stirring. The reaction mixture was heated to a temperature in the range of from about 70 C. to about 75 C. for about 2 hours. After completion of the reaction as determined by TLC, the reaction mixture was cooled to a temperature in the range of from about 25 C. to about 35 C. Toluene (1000 ml) was added for dilution of the reaction mixture under stirring for about 30 minutes at a temperature in the range of from about 25 C. to about 35 C. The reaction mixture was filtered, and the insoluble cake was separated. The organic layer was added to water (1000 ml) under stirring at a temperature in the range of from about 25 C. to about 35 C. and maintained for about 30 minutes. The organic layer was separated and washed twice with water (2×1000 ml). The organic layer was distilled in rotavapor bath at a temperature in the range of from about 50 C. to about 70 C. under in a vacuum. After distillation, methanol (750 ml) was added to the residue at a temperature in the range of from about 55 C. to about 60 C. and maintained for about 30 minutes. The reaction mixture was brought to a temperature in the range of from about 25 C. to about 30 C. by slowly Circulating water. During this time, a product precipitated out. The precipitated mass was further cooled to a temperature of about 11 C. for about 30 minutes and then filtered. The cake was washed with prechilled methanol (100 ml at a temperature of about 10 C.). The product was dried in an oven at a temperature of about 55 at a temperature of about 10 C. until the moisture content was about 1%. The dried product appeared as an off-white crystalline solid weighing about 108 g to about 110 g. The yield was about 75% to about 76%, having a m.p. of 150-154 C. The IR (KBr) spectrum shows the absorption bands at 3100 cm-1 (C-H str), 2900 (C-H str), 1720 (-COO str), 1605 (-CC-str), 1150 (SO2str). The 1HNMR (CDCl3) TMS as internal standard shows the following signals delta 7.65 [m,2H,Ar-H], 7.09 [m,2H,Ar-H], 6.52 [dd,1H,ArCHCH], 5.47 [dd,1H,ArCHCH], 3.57, 3.50 [2×s,6H,NCH3,SO2CH3], 3.38 [hept,1H,Ar-CHMe2], 2.45-2.30 [2×dd,2H,CH2CO2 t-Bu], 1.55, 7.3 [dt,dd,2H,acetonide,CH2], 1.50, 1.40 [2×s,6H,acetonide C(CH3)2], 1.45 [s,9H,CO2C(CH3)3], 1.27 [dd,6H,ArCH(CH3)2]. The CI mass shows m/z 578 (base peak). The elemental analysis shows calculated % C 60.29; % H 6.98; % N 7.27; observed % C 60.12; % H 6.89; % N 7.17.
75%
With potassium carbonate; In dimethyl sulfoxide; at 70 - 75℃; for 2h;
600 ml of dimethyl sulfoxide, 104 grams (0.75 mole) of potassium carbonate, 170 g (0.25 mol) [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl sulfo ) amino] pyrimidin-5-yl - methyl] triphenylphosphonium bromine and 65 g (0.26mol) (4R-cis) -6- aldehyde dimethyl-1,3-dioxane ring -4- acetate mixture was stirred and heated to 70-75 degrees for two hours. 1L of toluene was added, and then cooled and filtered to remove most of the inorganic impurities and phosphorus oxide. The organic phase was washed with 1L with water and then vacuum distilled to dryness and 750 ml of methanol was added to the residue, and then heated to boiling. At 25-30 degrees crystallized product. Cooled further to 11 degrees, the product isolated to give 108 g (75% yield).
tributyl[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-ylmethyl]phosphonium bromide[ No CAS ]
[ 124752-23-4 ]
[ 289042-12-2 ]
Yield
Reaction Conditions
Operation in experiment
88 - 90%
With potassium carbonate; In dimethyl sulfoxide; at 25 - 75℃; for 5 - 7h;
In a 250 mL 4-necked round bottom flask, DMSO (150 ml), potassium carbonate (33.54 g), TBPBr (50 g) of Example 2 and BFA (20.87 g) were added at a temperature in the range of about 25 C. to about 35 C. under stirring. The reaction mixture was heated to a temperature of about 70 C. to about 75 C. for about 5 to about 7 hours. After the completion of the reaction as determined by TLC, the reaction mixture was cooled to a temperature in the range of about 25 C. to about 35 C. Toluene (250 ml) was added for dilution of the reaction mixture and stirred for about 30 minutes. The organic layer was added to water (100 ml) under stirring and maintained for 30 minutes. The organic layer was separated and washed with water (2×100 ml) in the same manner as described above. The organic layer was distilled in Rota vapor bath at temperature in the range of from about 50 C. to about 60 C. under vacuum. After distillation, EPA (100 ml) was added to the residue at a temperature of about 55 C. to about 60 C. and the mixture was maintained for about 30 minutes. The reaction mixture was brought to a temperature in the range of from about 25 C. to about 30 C. by Circulating room temperature water slowly. In this period, the product precipitates and the precipitated mass was further cooled to a temperature of about 10 C. for about 30 minutes, and then filtered. The cake was washed with prechilled (at a temperature of about 10 C.) IPA (50 ml). The product was dried in an oven at a temperature of about 55 C. until the moisture content was about 1%. The dried product appeared as an off-white crystalline solid weighing about 44 g to about 45 g. The yield was about 88% to about 90%, and having a m.p. of 150-154 C. The IR (KBr) spectrum shows the absorption bands at 3100 cm-1 (C-H str), 2900 (C-H str), 1720 (-COO str), 1605 (-CC-str), 1150 (SO2str). The 1HNMR (CDCl3) TMS as internal standard shows the following signals delta 7.65 [m,2H,Ar-H], 7.09 [m,2H,Ar-H], 6.52 [dd,1H,ArCHCH], 5.47 [dd,1H,ArCHCH], 3.57, 3.50 [2×s,6H,NCH3,SO2CH3], 3.38 [hept,1H,Ar-CHMe2], 2.45-2.30 [2×dd,2H,CH2CO2t-Bu], 1.55, 7.3 [dt,dd,2H,acetonide,CH2], 1.50, 1.40 [2×s,6H,acetonideC(CH3)2], 1.45 [s,9H,CO2C(CH3)3], 1.27 [dd,6H,ArCH(CH3)2]. The CI mass shows m/z 578 (base peak). The elemental analysis shows calculated % C 60.29; % H 6.98; % N 7.26; observed % C 60.17; % H 6.93; % N 7.21.
With dimethyl sulfoxide; triethylamine; In dichloromethane;
EXAMPLE 6 t-Butyl (3R,5S)-6-oxo-3,5-O-isopropylidene-3,5-dihydroxyhexanoate (formula XII) 0.43 g (5.50 mmol) of dimethyl sulfoxide was added dropwise, at -78 C., to a solution of 0.235 ml (2.75 mmol) of oxalyl chloride in 10 ml of dichloromethane, and the mixture was stirred at the same temperature for 5 min. Then 0.65 g (2.5 mmol) of the compound from Example 5 was added dropwise. After stirring for 5 minutes, 1.70 ml of triethylamine were added, and the reaction mixture was raised to room temperature in 2 h. For working-up, the mixture was poured onto water and extracted by shaking 3* with 50 ml of ether each time. The combined organic extracts were dried over MgSO4 and evaporated. Volatile constituents were removed from the remaining oil under high vacuum and it was immediately reacted further. Rf (cyclohexane/ethyl acetate=1:1): 0.24.
A mixture of DPPO (19.17 g) and THF (227 ml) were warmed briefly to 40 C. until a clear solution had formed then inerted by the sequential application of vacuum and nitrogen (5 cycles). The mixture was immersed in an acetone/CO2 bath cooling the contents to -75 C. Sodium bis(trimethylsilyl)amide (37.4 ml of 1.0 M solution in THF) was added to the reaction mixture over 10 minutes from a pressure equalising dropping funnel maintaining the temperature below -74 C and forming a red solution of the anion. THF (10 ml) was rinsed through the dropping funnel into the mixture and the mixture stirred a further 1 hour at -76 C forming a red suspension. BFA (80 ml of 13.5% w/w toluene solution) was added in portions to the suspension over 20 minutes from a pressure equalising dropping funnel maintaining the temperature below -73 C. Toluene (20 ml) was rinised through the dropping funnel into the mixture and the mixture stirred a further 15 minutes at -76 C. The chilling bath was lowered and the suspension allowed to warm to 10 C over 1.5 hours. Glacial acetic acid (3.21 g) in water (15 g) was added in one portion raising the temperature to 18 C and dissolving all solids and the mixture was stirred a further 5 minutes. The mixture was concentrated by distillation at atmospheric pressure (jacket 110 C) to a temperature of 94 C collecting a total of 274 ml distillates. The concentrated mixture was cooled to 40 C, water (40 ml) was added and the mixture stirred for 5 minutes then allowed to settle for 15 minutes. The lower aqueous phase was discarded. Sodium hydrogen carbonate (2.99 g) in water (40 ml) was added and the mixture stirred for 5 minutes then allowed to settle for 15 minutes. The lower aqueous phase was discarded. Water (30 ml) was added and the mixture stirred for 5 minutes then allowed to settle for 15 minutes. The lower aqueous phase was discarded. The organic phase was transferred to a distillation apparatus with toluene (20 ml) and concentrated by distillation at atmospheric pressure (jacket 125-130 C) to a temperature of 116 C collecting 85 ml distillates. Vacuum was applied (400-500 mbar) and a further 16.5 ml distillates collected to a temperature of 111 C. The vacuum was released and the concentrated mixture allowed to cool to 80 C. Warm MeOH (140 ml, 50 C) was added with rapid stirring and the batch allowed to self-cool to 20 C over 30 minutes during which time a solid was deposited. The suspension was further cooled to 2 C for 30 minutes then the solid was collected by filtration on a sinter and pulled as dry as possible. The solid was washed with cold MeOH (60 ml, 2C.) and again pulled as dry as possible then transferred to a vacuum oven and dried overnight (50 C, 200 mbar); giving BEM (14.01 g, 67.7%). 1H NMR (CDCl3, 270 MHz) 7.65 [m, 2H, ArH], 7.09 [m, 2H, ArH], 6.52 [dd, 1H, ArCH=CH], 5.47 [dd, 1H, ArCH=CH], 3.57, 3.50 [2 x s, 6H, NCH3, SO2CH3], 3.38 [hept., 1H, ArCHMe2], 2.45, 2.30 [2x dd, 2H, CH2CO2tBu], 1.55, 1.13 [dt, dd, 2H, acetonide CH2], 1.50, 1.40 [2x s, 6H, acetonide C(CH3)2], 1.45 [s, 9H, CO2C(CH3)3], 1.27 [dd 6H, ArCH(CH3)2]
61%
Sodium bis (trimethylsilyl) amide (1 M in tetrahydrofuran, 23 mi) is added dropwise, AT-74C, to a suspension of the compound of formula (38) (12 g, 22.3 MMOL) in tetrahydrofuran (130 M .). STIRRING is carried out at-74C for 1 hour and then a solution of the compound of formula (40) (6.9 g, 26.8 MMOI) in toluene (28 ML) is added dropwise. Stirring is then carried out AT-74C for 1 hour, then warming to 10C over the course of 1 hour and stirring for a further 1 hour at that temperature. A mixture of acetic acid (2 ml) and water (8.4 ML) is added, at 10C, to the resulting yellow suspension and stirring is carried out at room temperature for 5 minutes. The tetrahydrofuran is then distilled off, and, at 40C, 45 ml of water are added to the reaction mixture and vigorous stirring is carried out for 5 minutes. The aqueous phase is separated off and a solution of sodium hydrogen carbonate (2.27 G) in water (45 ml) is added to the organic phase. Vigorous stirring is again carried out for 5 minutes and then the aqueous phase is removed again. The organic phase is diluted with 250 ML of toluene, washed successively with water and saturated sodium chloride solution and dried (using NA2SO4). The salt mixture is filtered off and the filtrate is concentrated by evaporation. The concentrated residue is then purified by column chromatography on silica gel (hexane: ethyl acetate 8: 1). 2.59 G (61 %) of the desired product (39) can be obtained in the form of colourless crystals. 'H NMR (300 MHz, CDCI3) : 0.91-1. 08 (m, 1H) ; 1.20 (d, J = 6. 7 HZ, 6H); 1. 24 (S, 3H); 1. 38 (S, 9H); 1.41 (S, 3H); 1.41-1. 56 (m, 1 H) ; 2.21 (dd, J = 15. 2, 7. 9, 1 H) ; 2. 35 (dd, J = 15. 0, 5. 0 HZ, 1H) ; 3. 27-3. 37 (m, 1H) ; 3. 43 (S, 3H); 3.52 (S, 3H); 4.17-4. 24 (m, 1H) ; 4. 47-4. 53 (m, 1H) ; 5.43 (dd, J = 16.4, 5.5 Hz, 1H) ; 6.55 (dd, J = 16.1, 0.8 Hz, 1H) ; 7.24 (dd, J = 8.8, 8.8 HZ, 2H); 7.65 (dd, J = 8.8, 5.6 Hz, 2H). 13C NMR (75 MHz, CDCI3) : 18.7, 20.6, 20.7, 27.0, 29.0, 30.9, 32.0, 35.0, 41.3, 41.4, 64.8, 68.1, 79.6, 97.7, 113.7 (JCF = 21.7 Hz), 120.0, 122.0, 131. 0 (JCF = 8.4 Hz), 133.2 (JCF = 3.2 Hz), 136.3, 156.0, 162.0 (JCF = 249 Hz), 162.2, 168.8, 173.6.
30 g
40.0 g of compound (DPPO) and 500 ml of THF were added to a 1000 ml four-necked flask.Stir and dissolve, and replace with nitrogen three times.Under nitrogen protection, the internal temperature was lowered to -75.0 C, and 79.0 ml of 1.0 M NaHMDS/THF solution was slowly added dropwise.Control the internal temperature -80.0 C ~ -75.0 C, after the completion of the addition of the reaction, 2.0 h,After the end of the heat preservation reaction, the internal temperature is controlled from -80.0 C to -75.0 C.The compound (D7) THF solution (D7: 23.1 g, THF: 20 ml) was added dropwise, and the reaction was kept for 1.0 h after the dropwise addition;The sample was controlled until the residual of the compound (DPPO) in the reaction solution was ?1.0%, and the reaction was completed. Rise to room temperature,The reaction was quenched by adding 100 ml of a saturated ammonium chloride solution. After quenching, the material was subjected to distillation under reduced pressure at an external temperature of 50.0 C.Vacuum degree ? -0.09MPa, after evaporation to dryness, add 400.0g of toluene to dissolve,It was washed with water, concentrated, and crystallized from 400.0 g of methanol to give compound (R1) 30.0 g.
With potassium tert-butylate; In tetrahydrofuran; at -30 - 20℃;Product distribution / selectivity;
3 g (6.3 mmol) of 3-[[(benzothiazol-2-yl)sulfonyl]methyl]-2-cyclopropyl-4- (4-fluorophenyl)quinoline obtained in Example 3 and 2.1 g (8.2 mmol) of tert-butyl (3R,5S)-6-oxo-3,5-O-isopropylidene-3,5-dihydroxyhexanoate were dissolved in 63 mL of tetrahydrofuran and then cooled to -30 0C. To the resulting mixture was added 1.2 g (10.7 mmol) of potassium tert-bupsilontoxide dropwise followed by stirring for 30 minutes. After the reaction temperature was increased to room temperature, the reaction mixture was stirred for an hour, and then 20 mL of sat. ammonium chloride was added thereto. The resulting mixture was distilled under a reduced pressure to remove tetrahydrofuran, and extracted twice with 30 mL of ethyl acetate. The organic layer was separated, washed with 20 mL of water, dried over anhydrous sodium sulfate, and distilled under a reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 10/1) to obtain 2.83 g of the title compound as a foam (yield: 86 %.)1H-NMR (CDCl3, ppm) delta 7.94 (d, IH), 7.58 (dd, IH)5 7.36-7.14 (m, 6H), 6.56 (dd, IH)5 5.57 (dd, IH)5 4.38-4.32 (m, IH), 4.30-4.24 (m, IH), 2.54 (dd5 IH), 2.44 (m, IH)5 2.34 (dd, IH)5 1.46 (s, 12H), 1.41-1.35 (m, 4H), 1.37 (s, 3H), 1.32-1.26 (m, 2H), 1.04 (dd, 2H).
Example 3: tert-Butyl (E)-(6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-yl] vinyl] (4R, 65) -2,2-dimethyl [1,3] dioxane-4-yl) acetate [Show Image] To a solution of dimethyl [4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl] phosphonate (1.0 g, 2.25 mmol) produced in Example 1 dissolved in anhydrous tetrahydrofuran (20 ml), a 1.9 M tetrahydrofuran solution of sodium hexamethyldisilazide (1.4 ml, 2.58 mmol) was added dropwise at -78C under nitrogen stream for 5 minutes. After the mixture was aged at -78C for 15 minutes, a solution of tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate (0.7 g, 2.69 mmol) dissolved in anhydrous tetrahydrofuran (7 ml) was added thereto dropwise for 10 minutes. The device for dropwise addition was washed with anhydrous tetrahydrofuran (2 ml), and the wash fluid was added to the reaction mixture dropwise. The temperature of the reaction mixture was raised to -35C for 3 hours, and the reaction was carried out at the same temperature for 15 hours. The temperature was raised to 0C for 2 hour, and the mixture was aged for 1 hour. The reaction was terminated by adding a saturated ammonium chloride aqueous solution (20 ml) to the reaction mixture, and then the mixture was extracted with toluene (50 ml). The organic layer was washed distilled water (10 ml) two times and saturated brine (10 ml) two times. The quantity of the content amount of tert-butyl (E)-(6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidine-5-yl]vinyl](4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl)acetate in the organic layer was determined with high-performance liquid chromatography; as a result, the title compound (1.2 g, yield: 95%) was contained.
With potassium carbonate In N,N-dimethyl-formamide at 20 - 80℃;
1.IV
{2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}methyltriphenylphosphonium- bromide (50 gm) as obtained in step-Ill was dissolved in dimethylformamide (750 ml) and stirred for 15 minutes to obtain a solution. To the solution was added potassium carbonate (22.3 gm) and then added a solution of tert-butyl-2-(4R,6S)-6-formyl-2,2- dimethyl-l,3-dioxan-4-yl)acetate (25.1 gm) in dimethylformamide (50 ml) slowly at room temperature. The reaction mixture was heated to 80°C and stirred for 5 hours. The reaction mass was then cooled to room temperature and then added toluene (300 ml) and water (300 ml). Then the layers were separated and the aqueous layer was extracted with toluene. The combined organic layers were dried with sodium sulfate and then concentrated to obtain a residual mass. To the residual mass was added n-hexane (220 ml) and stirred for 1 hour. The reaction mass was filtered to remove unwanted solid and then concentrated the n-hexane layer to obtain a residual solid. To the residual solid obtained was added 30% aqueous acetonitrile (500 ml) and then cooled to 0°C. The reaction mass was maintained for 3 hours 30 minutes and filtered. The solid obtained was dried to give 32 gm of tert-butyl-(3R, 5S, 6Z)-7-{2-cyclopropyl-4-(4- fluorophenyl)quinoline-3-yl}-3,5-isopropylidenedioxy-6-heptenoate.
Stage #1: <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide With triphenylphosphine In dimethyl sulfoxide at 50℃; for 3h;
Stage #2: 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester With 1,8-diazabicyclo[5.4.0]undec-7-ene In dimethyl sulfoxide at 25 - 30℃; for 5h;
1; 6; 9 Example 1
In a 3L reaction flask, add 100.00g (280.71mmol) of the parent nucleus bromide and 700ml (7v) of dimethyl sulfoxide, stir and heat to 50°C, add 87.40g (1.18eq, 333.21mmol) of triphenylphosphorus, keep the reaction for 3h After cooling to about 25°C, add 100.00g (1.35eq, 378.95mmol) side chain aldehyde and 128.25g (3.00eq, 842.13mmol) DBU, stir at 30°C for 5h, add water after the reaction to quench the reaction, add toluene for extraction, organic The phase was concentrated and crystallized with isopropanol to obtain 118.4 g of pitavastatin calcium intermediate with a yield of 81%.
N-(5-((diphenylphosphoryl)methyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide[ No CAS ]
[ 124752-23-4 ]
[ 289042-12-2 ]
Yield
Reaction Conditions
Operation in experiment
COMPARATIVE EXAMPLE 1Preparation of rosuvastatin hemicalcium salt from N-(5-((diphenylphosphoryl)methyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (DPPO) described in WO 00/49014N-(5-((diphenylphosphoryl)methyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (20 g) was dissolved in tetrahydrofuran (240 ml) at 40 C., and then inactivated by repeated applications of vacuum and argon five times. This solution was cooled to -78 C. under an argon atmosphere, and sodium bis(trimethylsilyl)amide (39 ml of a 1.0M solution in tetrahydrofuran) was added thereto over 10 minutes. The dropping funnel was rinsed with tetrahydrofuran (10 ml), followed by stirring for 1 hour, and t-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate (84.5 ml of a ca. 13.5% w/w toluene solution) was added portionwise thereto over 20 minutes. The dropping funnel was rinsed with toluene (20 ml), and the mixture was stirred for another 15 minutes at -78 C. and then stirred while warming to 10 C. over about 1.5 hours. To the reaction liquid was added a 20% acetic acid aqueous solution (15 ml), followed by stirring for 10 minutes.The mixture was concentrated by distillation under atmospheric pressure (jacket 110 C.) at 93 C. to thereby collect the total distillate (270 ml). The concentrated mixture was cooled to 40 C., and water (40 ml) was added thereto. Then, the mixture was further stirred for 5 minutes and allowed to precipitate for 15 minutes. The lower aqueous phase was discarded, a 7% (w/w) sodium bicarbonate aqueous solution (40 ml) was added, and the mixture was stirred for 5 minutes, followed by precipitation for 15 minutes. The lower aqueous phase was discarded, water (30 ml) was added, and the mixture was further stirred for 5 minutes and allowed to precipitate for 15 minutes. The aqueous phase was discarded.The organic phase was charged to distillation equipment containing toluene (20 ml), and distilled under atmospheric pressure (jacket 125 to 130 C.) at 116 C. to collect 86 ml of a distillate. Following a vacuum treatment, 17 ml of a distillate was additionally collected at a temperature of 111 C. Vacuum was released, and the concentrated mixture was cooled to 80 C. Warmed MeOH (140 ml, 50 C.) was added thereto under high-speed stirring, followed by cooling to 20 C. for 30 minutes. The resulting suspension was further cooled to 2 C. for 30 minutes, and the solid was collected by filtration, washed with cold MeOH (60 ml, 2 C.), collected in a dried state, and dried in a vacuum oven overnight (50 C., 200 mbar) to obtain BEM (14.61 g) as a desired compound. A mixture of BEM (5.0 g) and acetonitrile (35 ml) was stirred at 40 C. under an inert atmosphere. To the resulting solution was added 0.02M hydrochloric acid (9.5 ml) over 30 minutes, and the temperature was maintained at 35 to 42 C. The mixture was stirred at 40 C. for 3 hours and then cooled to 25 C. A 1.0M sodium hydroxide solution (9.5 ml) was added with stirring thereto at 25 C. and the mixture was stirred for another 1 hour at 25 C. Sodium chloride (4.7 g) was added and the mixture was cooled to -5 C. over 1 hour. A solution of 1M hydrochloric acid (9.5 ml) and sodium chloride (2.4 g) was added thereto at -5 C. to achieve a pH of 3.4 to 4.0, and the mixture was stirred at the same temperature for 5 minutes. The mixture was allowed to precipitate at -5 C. for 10 minutes to obtain two layers. The lower layer was separated and discarded. Acetonitrile (65 ml) at -5 C. was added to the remaining solution, and the mixture was filtered through a filter. A 40% methylamine solution (1.1 ml) in water was added at -5 C., and the mixture was warmed to 30 C. over 40 minutes. This temperature was maintained for 90 minutes. Thereafter, the mixture was cooled to 0 C. for 40 minutes, and this temperature was maintained for 90 minutes. The resulting solid was collected by filtration, and washed with acetonitrile (2×12 ml). This solid was dried at 35 C. under vacuum (3.5 g). 2M aqueous sodium hydroxide (5.44 ml) was added to a stirred mixture of a methylamine salt (6.0 g) in deaerated water (30 ml) at 20 C., and the mixture was stirred for 1 hour. The mixture was filtered, and concentrated under reduced pressure at 40 C. until 24 ml of a distillate was collected. Water (24 ml) was added thereto, and the mixture was concentrated again under reduced pressure at 40 C. until 24 ml of a distillate was collected. Water (30 ml) was added thereto, and a solution of calcium chloride dihydrate (1.03 g) in water (6 ml) was added dropwise at 20 C. The mixture was stirred for 45 minutes, and the resulting solid was filtered. The solid was washed with water (36 ml) and dried under vacuum at 40 C. to give a (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid hemicalcium salt (5.27 g, 48%).
With sodium methylate; In tetrahydrofuran; at -15 - 10℃;
Alternate Method for Tert-Butyl [(4R,6S)-6-{(E)-2-[4-(4-Fluorophenyl)-2-[Methyl(Methylsulfonyl)Amino]-6-(Propan-2-Y1)Pyrimidin-5-Yl]Ethenyl}-2,2-Dimethyl-1,3-Dioxan-4-Yl]Acetate Sodium methoxide (12.8 g) was added in lots to a pre cooled mixture of N-[4-(4-fluorophenyl)-5-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl]methyl}-6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethanesulfonamide (100 g) and tert-butyl 3,5-dideoxy-2,4-O-(1-methylethylidene)-L-erythro-hexuronate (60 g) in tertrahydrofuran (500 mL) at -15 C. to 10 C. After the completion of the reaction, the mixture was quenched with saturated aqueous solution of ammonium chloride. To the resultant mixture, dichloromethane (500 mL) was added and the pH of the mixture was adjusted to 5.0 to 7.0 using dilute hydrochloric acid (2N). The organic layer was washed with aqueous solution of sodium bicarbonate (5%; 200 mL). The organic layer was separated and concentrated under vacuum at 40 C. to 45 C. to give residue. Methanol (1000 mL) was added to the resulting residue and stirred at 20 C. to 25 C. for 2 hours. The product was filtered, washed with methanol (100 mL) and dried at 40 C. to 45 C. for 4 hours to 5 hours. Dry weight: 60 g
In a 500 mL three-necked flask, 10 g of D-5, 100 mL of methanol and 4.0 g of potassium carbonate were successively added, and the mixture was stirred for 3 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure at 35 to 45 C.The resulting syrup was dissolved in 150 mL of dichloromethane, and 3.0 g of sodium hydrogencarbonate, 0.5 g of potassium bromide and 0.4 g of TEMPO were sequentially added.After the mixture was stirred and cooled to -5 to 5 C, 50.0 g of an 8% sodium hypochlorite solution was added dropwise.After the completion of the dropwise addition, the mixture was stirred at -5 to 5 C for 1 hour.The reaction was monitored by TLC, and the reaction was quenched by the addition of 0.7 g of sodium thiosulfate and 10.0 g of water.The layers were static and the aqueous layer was stripped with 100 mL of dichloromethane.The organic layers were combined and the organic layer was washed with 2×200 mL water.The washed organic layer was dried under reduced pressure at 35 to 45 C to give a pale red solid 8.2 g of D-7, yield 96.1%.
[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl(methyl)amino)pyrimidin-5-yl-methyl]triphenylphosphonium triflate[ No CAS ]
[ 124752-23-4 ]
[ 289042-12-2 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In tetrahydrofuran; at -15 - 0℃;
Procedure analogous to that employed in Example 10 was carried out using different bases, solvents and reaction temperatures and is summarized in the following table:
N-(5-((4,4'-methylphenylphosphoryl)-methyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide[ No CAS ]
[ 124752-23-4 ]
[ 289042-12-2 ]
Yield
Reaction Conditions
Operation in experiment
82%
(1) Preparation of tert-butyl 6-[(1E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methane sulfonyl)amino]-5-pyrimidinyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-acetate (compound III) To a 5 L four-necked flask, 2 L (8 mL/g) of tetrahydrofuran and 250 g (1 mol) of N-(5-((4,4'-tolylphosphono)-methyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methyl methane sulfonamide (compound I) were sequentially added, and stirred to clearness. The mixture was cooled down to -70?-65 C., followed by adding 486.2 mL (1.1 mol, calculated from virtually titrated content) of sodium hexamethyldisilazide. The system was kept at -70?-65 C. for 2 hours, followed by adding dropwise a solution of 132.4 g (1.1 mol) of tert-butyl (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetate in 500 mL of tetrahydrofuran (2 mL/g). After the addition was completed, the system was stirred at the same temperature for 2 hours, followed by warming up to about 10 C. and reacting until compound I was completely consumed. The reaction system was then quenched with 1 L (4 mL/g) of purified water. The liquid was separated. The aqueous phase was extracted twice with 1.25 L (5 mL/g) of n-heptane. The organic phase was combined, washed with 750 mL (3 mL/g) of saturated brine, and concentrated to dryness. To the concentrated system was added 500 mL (2 mL/g) of methanol, leading to crystallization to give compound III with a purity of about 98%, a stereo-selectivity of E/Z=99.8:0.2, and a yield of 82%. 1H NMR (400 MHz, CDCl3) delta: 0.88 (t, J=7.4 Hz, 3H); 1.09?1.25 (m, 7H); 1.39?1.52 (m, 13H); 1.77 (q, J=7.3 Hz, 2H); 2.30 (dd, J1=15.1 Hz, J2=5.9 Hz, 1H); 2.45 (dd, J1=15.3 Hz, J2=7.0 Hz, 1H); 3.35?3.39 (m, 1H); 3.51 (s, 3H); 3.56 (s, 3H); 4.28 (br, 1H); 4.41?4.43 (br, 1H); 5.46 (dd, J1=16.2 Hz, J2=5.0 Hz, 1H); 6.51 (d, J=16.3 Hz, 1H); 7.05?7.09 (m, 2H); 7.63?7.66 (m, 2H); HRMS (ESI) calculated: C30H42FN3O6S; [M+1H]+=592.28, determined: 592.3.
With lithium chloride; In tetrahydrofuran; at 0 - 35℃; for 5.66667h;Inert atmosphere;
35 g of compound 2, 210 ml of anhydrous THF, and 0.07 g of lithium chloride were placed in a reaction flask, nitrogen-protected, stirring was started, the temperature was lowered to 0-5 C, and 3.7 g of NaH (60%) was added.24 g of compound 3 ((4R-CIS)-6-formaldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester) was dissolved in 70 ml of anhydrous THF and added dropwise to the above reaction. In the liquid, add 40 minutes.The reaction was kept at 0-5 C for 1-2 hours, and the temperature was raised to 30-35 C for 5 hours.After TLC detection, the reaction was cooled to 0-5 C, and acetic acid was slowly added dropwise to pH = 7-7.5, and 70 ml of water was added. Static, liquid separation, collecting the upper organic phase. The organic phase is washed 1-2 times with water, dried over anhydrous sodium sulfate, and filtered to remove the desiccant.Distillation of THF under reduced pressure afforded 42 g of a yellow oil.The crude product yield was 95.8%. Add 95ml of isopropanol to the above crude product, start stirring, warm up to 75 C to dissolve, heat off for 30 minutes, start to cool down, cool down to 5 C for 3 hours, keep warm for 1 hour, suction filtration, filter cake with a small amount of ice isopropyl Alcohol wash, yield cake, dry,Obtained 39 g of compound B as a white solid.HPLC = 99.3% (E configuration), total yield 89%.
71%
With n-butyllithium; In tetrahydrofuran; at -80 - -10℃; for 1h;Inert atmosphere;
To a solution of 200 ml of tetrahydrofuran, 30 g of compound III was added dropwise to prepare the reaction liquid III-I. To a solution of tetrahydrofuran in 200 ml of tetrahydrofuran was added dropwise compound 1515 g to give the reaction solution III-II. 1000ml four-necked flask was added 200 ml THF (tetrahydrofuran), cooled to -10 C, under the protection of nitrogen by adding n-butyl lithium 30ml, stirring down to -70 ~ -80 C, dropping reaction liquid III-I, stirring at least 1 hour after the addition of reaction liquid III-II, continue to stir, to TLC detection reaction is complete, adding saturated sodium bicarbonate solution to terminate the reaction. adding the ethyl acetate to the reaction mixture, adding the residue to the mixture, removing the organic layer by adding anhydrous sodium sulfate, filtering and filtering the filtrate under reduced pressure to obtain the compound V 27.4g, melting point: 44-46 C , The yield was 71%.
With potassium carbonate; In dimethyl sulfoxide; at 70 - 80℃;
A solution of 4- (4-fluorophenyl) -5- (diphenylpropanoylphosphonium bromide) -6-isopropyl-2 - [(N-methyl-N-methanesulfonamido)] - pyrimidine(Compound I) 180.0 g,(4R-cis) -6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (Compound II), 125 g of potassium carbonate and 1000 g of DMSO were stirred and stirred to 70 ~ 80 , insulation reaction Until the compound (I) consumption is complete, after the end of the reaction, cooling filter, the filtrate by adding water 1000g, toluene extraction twice. Control water Bath temperature T ? 60 C, concentrated toluene to dry to dry crude product, the crude product by adding 900g of methanol, dissolved in temperature, slow cooling crystallization, Filter, frozen methanol leaching. Control the temperature T = 40 ~ 50 dry. The dry product compound (III) was 128.0 g. The yield was 71.1% The molar yield was 83.0%. Purity (HPLC) 99.7%, stereoselectivity E / Z = 99.7: 0.3.
With potassium carbonate; In dimethyl sulfoxide; at 70 - 80℃;
A solution of 4- (4-fluorophenyl) -5- (methyl diphenylpropionylphosphonium) -6-isopropyl-2 - [(N-Methyl-N-methanesulfonamido)] - pyrimidine (Compound I), 180.0 g of (4R-cis) -6-aldehyde-2,2-dimethyl- (Compound II) 74.5 g, 125 g of potassium carbonate and 1000 g of DMSO, and the mixture was heated to 70 to 80C by stirring. The reaction was carried out until the compound (I) was completely consumed. After the reaction was completed, the filtrate was filtered and the filtrate was added with 1000 g of water, Times. Control the water bath temperature T ? 60 , concentrated toluene to dry to dry, crude add 900g of methanol, temperature dissolve, slow cooling crystallization, filtration, frozen methanol leaching. Control the temperature T = 40 ~ 50 dry. The dry product compound (III) was 124.3 g. Quality yield69.1%, molar yield 82.3%. Purity (HPLC) 99.6%, stereoselectivity E / Z = 99.8: 0.2.
With cesium fluoride; In N,N-dimethyl-formamide; at 20 - 120℃; for 3h;
In a 250 ml three-necked flask, a thermometer, a pH meter and a constant pressure dropping funnel and a magnetic stirrer were attached.In a reaction flask, 10 g of compound II, 100 ml of DMF and 6.5 g of tert-butyl (4R-cis) -6-aldehyde-2,2-dimethyl-1,3-dioxan-4-acetate g of cesium fluoride 0.4 g and stirred for 1 hour. Then heated to 120 , incubated for 2 hours, cooled down, poured into ice water 200ml, extracted with toluene 150ml * 2, concentrated under reduced pressure, dissolved in 100ml of methanol, cooled to room temperature, incubated for 6 hours crystallization, filtration The product (4R, 6S, E) -2- {6- [2- [4- (4- fluorophenyl) -6- isopropyl- 2- (N- methylsulfonyl) amino) 5-yl] vinyl] -2,2-dimethyl-1,3-dioxan-4-yl} acetate 11.0 g Yield 77.8%.
[4-[4-fluorophenyl-6-(1-methylethyl)-2-[N-methyl-(N-methanesulfonyl)amino]]-5-pyrimidinyl]methylphenyltriphenylphosphonium bromide[ No CAS ]
[ 124752-23-4 ]
[ 289042-12-2 ]
tert-butyl 6-[(1Z)-2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In dimethyl sulfoxide; at 75℃; for 2h;
To a 1000 mL four-necked flask was added 250 mL of DMSO19g D7 ((4R-cis) -6-Formaldehyde-2,2-DimethylYl-1,3-dioxane-4-acetate),Z8.2 ([4- (4-fluorophenyl) -6- isopropyl-2- (N -methyl- N -methanesulfonamido) -5-pyrimidinyl] triphenylphosphonium bromide) 45g,20.8 g of potassium carbonate was added,Heating, 75 insulation 2h,After Z8.2 reaction is complete,Cool to 20 , add 200ml of toluene,Stirred and filtered, the organic layer was added 200ml of water,Stir for 10min.The layers were separated and the aqueous layer was extracted with 100 mL of toluene. The organic phases were combined, washed twice with 200 mL * 2 water and the organic layer was evaporated to dryness.Methanol recrystallization E configuration (trans) products,HPLC purity 99% (see Figure 1).The mother liquor was spin-dried after adding 500ml of cyclohexane, warming to clear, cooling, solid precipitation (triphenylphosphine oxide),Cooling to 10 , heat 2h,Filtered by suction and rinsed with 50 ml of cyclohexane.The mother liquor was depressurized to dryness at 45 C, 300ml of methanol was added, dissolved and the mixture was evaporated to about 100ml under reduced pressure. The mixture was stirred and slowly cooled down to precipitate a solid.Cooling to 10 , heat 2h, suction filtration,Rinse with 20ml of methanol, the cake was dried at 50 ,Z configuration (cis) purity of 97% (HPLC spectrum shown in Figure 1, 1H-NMR spectrum shown in Figure 2).
((2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)methyl)triphenylphosphoniumchloride[ No CAS ]
[ 124752-23-4 ]
[ 147489-06-3 ]
Yield
Reaction Conditions
Operation in experiment
80.2%
With potassium carbonate; In dimethyl sulfoxide; at 30 - 50℃; for 3h;Large scale;
20.0 kg of [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] methyltriphenylphosphonium chloride (Formula 3 ') obtained in Step 1,10.8 kg of 2 - [(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4- yl] acetic acid tert-butyl (formula 2 '176.0 kg of dimethylsulfoxide was charged.At an internal temperature of 30 C.,5.8 kg of potassium carbonate was added.After addition of potassium carbonate, the reaction was carried out at an internal temperature of 50 C. for 3 hours.As a result of HPLC analysis, the ratio of E / Z was 95/5, and the E form predominantly formed.139.2 kg of toluene,200.0 kg of water was added and stirred.After separation, the organic layer was washed with 60.0 kg of water and the aqueous layer was separated.36.0 kg of silica gel was added and stirred, followed by filtration. The silica gel was washed with 52.2 kg of toluene, and the washing solution and the filtrate were combined and concentrated.The concentrate was heated and dissolved in 90.0 kg of acetonitrile, and then 25.8 kg of water was added.The solution was cooled to 10 C. to precipitate crystals.The crystals were filtered, washed with a mixture of acetonitrile and water, and then dried to obtain 14.5 kg (yield 80.2%) as white crystals, and as a result of HPLC analysis of the white crystals, the ratio of E / Z was 99/1 ) Of the title compound.
With potassium carbonate; In tetrahydrofuran; at 0 - 30℃; for 16.5h;
Operation step: adding K2CO3 (12.4 g, 90 mmol) to the organozinc reagent (III),The mixture was stirred at 0 to 10 C; the compound (IV) (7.8 g, 30 mmol) was dissolved in tetrahydrofuran (15 ml), stirred and dissolved, and then added to the above organozinc reagent (III).It is dripped in about 0.5h.Raise the reaction to 25-30 C and stir the reaction for 16 h.The endpoint of the reaction was followed by HPLC.After the reaction is over,The temperature was controlled at 10-20 C, 130 ml of distilled water was added dropwise, and the reaction was quenched by stirring for 1 h. After suction filtration, the filter cake was washed three times with distilled water (25 ml × 3) and anhydrous methanol (20 ml × 3). The filter cake was dried under vacuum at 50 C for 4 h to give compound (1) as a white solid (13.9 g, 27 mmol).Operation steps: the compound (I) is placed in a 250 ml three-necked flask, 83 ml of anhydrous methanol is added, and heated to reflux for 5 min. The filtrate is slowly cooled to 35-45 C and stirred for 1 h, and the temperature is further lowered to 10 C, and the mixture is kept under stirring for 2 h. After suction filtration, the filter cake was washed three times with cold methanol (25 ml x 3).The filter cake was dried under vacuum at 50 C for 4 h to give the purified compound (I) as a white solid (10.4 g, 20 mmol).The yield was 66.7%.
With lithium carbonate; sodium hydride; In tetrahydrofuran; at 0 - 35℃; for 4.83333h;Inert atmosphere;
50 g of compound 1, 300 ml of anhydrous THF, and 0.16 g of lithium carbonate were placed in a reaction flask, protected with nitrogen, and stirred.The temperature was lowered to 0-5 C, and 4.6 g of NaH (60%) was added.30 g of compound 3 ((4R-CIS)-6-formaldehyde-2,2 dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester) was dissolved in 80 ml of anhydrous T HF,It was added dropwise to the above reaction solution, and the addition was completed in 50 minutes.The reaction was kept at 0-5 C for 1-2 hours, and the temperature was raised to 30-35 C for 4 hours.TLC detection, after the reaction is completed, the temperature is lowered to 0-5 C,Acetic acid was slowly added dropwise to pH = 7-7.5, and 100 ml of water was added.Static, liquid separation, collecting the upper organic phase. The organic phase is washed 1-2 times with water, dried over anhydrous sodium sulfate, and filtered to remove the desiccant.The THF was distilled off under reduced pressure to give 56.6 g of a yellow oil.The crude product yield was 92.6%. Add 125 ml of isopropanol to the above crude product, start stirring, warm up to 70 C until the solution is cleared, and then start to cool down after 30 minutes of heat preservation, and cool down to 5 C through 3 hours.Incubate for 1 hour, suction filtration, filter cake with a small amount of ice isopropanol, yield cake, dry,Obtained 53.2 g of Compound A as a white solid.HP LC = 99.2% (E configuration) with a total yield of 87.3%.
With sodium hexamethyldisilazane; In tetrahydrofuran; toluene; at -76℃; for 0.25h;Inert atmosphere;
Compound II (25 g) was added to a reaction flask, which was dissolved in THF (290 ml). Protect with nitrogen and cool the mixture. To the reaction mixture was added a solution of sodium bis(trimethylsilyl)amide in THF (50 ml, 1.0 M), and the mixture was stirred at -76 C. A toluene solution (100 ml, 13.5% W/W) of the compound III obtained in Example 1 was added to the mixture in portions.Stirring was continued for 15 min at -76 C.The cooling was removed and the mixture was warmed to 10 C. Aqueous glacial acetic acid solution was added, the temperature was raised to 18 C and the mixture was stirred. The mixture was concentrated by atmospheric distillation, and the distillate was collected. The concentrated mixture was cooled, water and an aqueous sodium hydrogencarbonate solution were added repeatedly, and the mixture was stirred, and then allowed to stand and the lower aqueous phase was discarded. The organic phase was transferred to a distillation apparatus with toluene, concentrated, and the distillate was collected and cooled. Warm methanol (175 ml, 50 C) was added with rapid stirring, and then cooled, during which time solids were deposited, solids were collected and dried, washed with cold methanol (75 ml, 2 C) and then dried, vacuum drying oven It was dried overnight to give Compound I (18.8 g) in a yield of 70%.
The compound I' (10 g) was added to the reaction flask, which was dissolved in methanol/dichloromethane (50 ml/50 ml), and continuously passed through O3 at 25 C.After 5 hours, the thin layer was monitored, and the compound I' had no residue, and the ozone was stopped.Add 3eq of thiourea aqueous solution and stir well until the ozonide intermediate disappears.Adjust the pH of the system to about 7, separate the organic layer and the water layer, and the waterThe layer was extracted with a small amount of DCM (dichloromethane). The methylene chloride extract and the organic layer were evaporated to dryness and crystallised from methanol/water to give compound IV (5 g), purity 99.2%, yield 82.2%. The mother liquor was distilled under reduced pressure to give Compound III, purity 99%.
With sodium hydride; In tetrahydrofuran; at -30℃; for 12h;Green chemistry;
Mix material B, tetrahydrofuran, (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, and cool to -30 C, 4 parts of sodium hydride was added in 4 parts, the reaction was incubated for 12h, and the temperature was raised to room temperature. The reaction was quenched with saturated aqueous ammonium chloride. The organic phase was extracted with ethyl acetate. Recrystallization of propanol gave a pitavastatin calcium intermediate in which the molar ratio of substance B to sodium hydride was 1:4.7, substance B and (4R-Cis)-6-formyl-2,2-dimethyl-1 The molar ratio of 3-dicyclohexa-4-acetic acid tert-butyl ester was 1:3.6, and the weight volume (g/ml) ratio of substance B to tetrahydrofuran was 1:10.
30.0 g of the compound (R1) and 500 ml of THF were added to a 1000 ml four-necked flask, stirred and dissolved, and replaced with nitrogen three times.Under the protection of nitrogen, the internal temperature is lowered to -75.0 C, and the internal temperature is controlled to -60.0 C to -75.0 C.63 ml of a 1.66 M n-BuLi n-hexane solution was slowly added dropwise, and the reaction was kept for 2.0 h after the completion of the dropwise addition.After the end of the heat preservation reaction, it is raised to an internal temperature of 0 C, the internal temperature is controlled from -5 C to 0 C, and the compound (D7) is added dropwise.THF solution (D7: 26.9 g, THF: 27 ml), after the completion of the addition, the reaction was incubated for 1.0 h;After the reaction was completed, the temperature was raised to room temperature, and the reaction was quenched by adding 70 ml of a saturated ammonium chloride solution, and after quenching,Extracted with 600 ml of Cl 2 CH 2 , washed with water, evaporated to dryness, and the crude R-1 was passed through a column (Cl2CH2:CH3OH=20:1).22.4 g of the impurity RC was isolated (yield 52%).
tert-butyl 2-[(4R,6S)-6-{2-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-1-hydroxyethyl}-2,2-dimethyl-1,3-dioxan-4-yl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Add 200 ml of tetrahydrofuran to a 3 liter three-necked flask.Then add 23 g of active zinc powder, 0.5 g of iodine,Replace with nitrogen three times, and heat to 50 to 60 C with stirring for 30 minutes until the color of iodine disappears; 121 g of 3- (bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) -3-quin Porphyrin is dissolved in 450 ml of tetrahydrofuran and then added dropwise to the reaction flask.Control the drop acceleration to make the reaction temperature between 50 and 60 C.After the dropwise addition, the reaction was incubated for 2 hours.The temperature of the reaction system is reduced to 10 to 20 C.A solution of 88 g of tert-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate in tetrahydrofuran (250 ml) was added dropwise. The reaction flask is controlled at a temperature of 10 to 20 C. After the addition, stir for 2 hours, and then lower the temperature to 0 to 5 C.65 g of p-toluenesulfonyl chloride tetrahydrofuran (200 ml) solution was added dropwise, and the temperature was maintained at 0 to 5 C. After the addition, stirring was continued for 1 hour, and then 52 g of 1,8-diazabicycloundec-7 was added dropwise. -Ene, hold for 3 hours after the addition is complete; add 800 grams of ice water to quench the reaction, stir for 30 minutes, concentrate the reaction mixture under reduced pressure, remove most of the tetrahydrofuran, reduce the temperature to 0 to 5 C, filter to obtain a pale yellow solid, wash with two Times,The obtained solid was put into a 1 liter reaction flask,Add 500 ml of methanol and heat to dissolve the solid.Slowly lower the temperature to 0 to 5 C and keep it for 5 hours.145 grams of white solid powder was obtained after suction filtration and drying,Yield: 82.0%, chemical purity: 99.1%,The Z configuration was 0.14%, and the chiral purity was 99.7%.
Stage #1: <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide With triphenylphosphine In dimethyl sulfoxide at 55℃; for 4h;
Stage #2: 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester With anhydrous sodium carbonate In dimethyl sulfoxide at 30℃; for 5h;
1-5; 7-8; 10 Comparative Example
1 In a 1L reaction flask, add 20.00g (56.14mmol) of the parent nucleus bromide and 140ml of dimethyl sulfoxide, stir and heat to 55°C, add 18.40g (70.50mmol) of triphenylphosphorus, and then add 21.75g (1.5g) after the reaction is maintained for 4h. eq, 84.20mmol) side chain aldehyde and 14.87g (2.5eq, 140.33mmol) sodium carbonate, stirred at 30°C for 5h, after the reaction was completed, water was added to quench the reaction, toluene was added for extraction, the organic phase was concentrated and crystallized with isopropanol to obtain 15.10g pitavastatin calcium intermediate, yield 52%.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
