Methyl (3R)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-oxo-6-(triphenylphosphoranylidene)hexanoate

(1) Into a three-necked flask, 9.26 g (0.026 mol) of triphenylmethylphosphonium bromide was added36gTHF, stirring, cooling to -10 ~ 0 , Add potassium tert-butoxide, plus warming, stirring, clarification;Clarified and cooled to below -60 , 5.3 g (0.012 mol) of J5 was added dropwise10g THF solution, incubated with stirring, -60 below 5percent sodium bicarbonate solution was added dropwise, stirring, delamination, The aqueous layer was extracted with ethyl acetate, the combined organic phases were washed with saturated sodium bicarbonate solution and the layers were separated.(2) and then washed with saturated salt water, points to the water layer, The organic phase is dried over anhydrous magnesium sulphate, filtered off with suction, the filter cake is washed with ethyl acetate, The solvent was evaporated under reduced pressure to give a dark red oil;After silica gel column chromatography of 200-300 mesh, the chromatography liquid was concentrated to dryness, J6 crude(3) Crystallization with petroleum ether to give J6, the filtrate was recovered, A total of J6 4.85g, a yield of 78percent, purity ≥ 99percent ee value ≥ 99percent;A solution of triphenylmethylphosphonium bromide (60.2 g)Tetrahydrofuran 400ml, stirring and stirring.Cooling to -40 ~ -50 , Under nitrogen protection, the concentration of:2.0mol / LTert-butyl lithium solution 85 ml. Drop Bi, insulation reaction 3 to 4 hours.The reaction solution was allowed to stand.25.0 g of the compound II obtained in was dissolved in 100 ml of tetrahydrofuran and then added dropwise to the above reaction solution, Temperature control to -30 ~ -40 stirring cooling 2 to 3 hours.Reaction completed temperature control 0 ~ -10 drop 1N hydrochloric acid, adjust the PH = 6 ~ 7, add methyl tert-butyl ether 300ml extractFloor. The organic layer was added dropwise 83.0 g of 15percent KHSO4 solution, and the layers were extracted.Water layer by adding potassium carbonate solution adjusted to pH = 8 ~ 9, adding methyl tert-butyl ether 300ml extraction layer. Organic phase separatelyWashed with saturated sodium bicarbonate solution and saturated brine. And then added magnesium sulfate for 2 hours, filtered to remove the desiccantThe solution was distilled under reduced pressure to give a yellow oil.A yellow oil was obtained which was dissolved in 50 ml of methyl tert-butyl ether, and the mixture was stirred at 0 to 10 ° C with 100 ml of n-hexaneMixed with crystals, filtered, and dried in vacuo to give 14.9 g of white crystals. The yield was 36.4percent and the HPLC purity was 99.6percent.20.5 g of a compound represented by formula V-1 (GC: 70.0percent), 26.0 g of triphenylphosphine, 18.2 g of potassium carbonate and 61.5 mL of DMF are added to the 500 mL reaction flask, and the system reacts at the temperature of 20 - 30°C. In the middle control of GC, 100 mL of water is added to the system for dissolution of solid after complete reaction of the compound represented by formula V-1, extraction is carried out by three times with 100 mL x 3 of methyl tert-butyl ether, organic phases are filtered after being dried with anhydrous sodium sulfate, and then concentrated at the temperature of 30 - 35°C and under the vacuum degree of 250 - 350 Pa to obtain an oily substance, i.e., the compound represented by formula I-1, 50 g of ethyl acetate/petroleum ether (2: 1) is added for crystallization, 7.9 g of a compound represented by formula I-1 is obtained after filtering and drying, its purity detected by HPLC (high-performance liquid chromatography) is 96.5percent, its ee value is 99.7percent, and its yield is 30.6percent. 1 H NMR (300 MHz, CDCl3): δ7.46 - 7.70 (m, 15 H), δ4.54 - 4.59 (m, 1 H), δ3.67 (s, 3 H), δ2.73 - 2.77 (m, 1H), δ2.59 - 2.63 (m, 1 H), δ2.45 - 2.55 (m, 2 H), δ0.83 (s, 9 H), δ0.03 - 0.06 (m, 6 H). MS: m/z = 535.5[M+H]+To 160 g of a 30percent solution of sodium acetylene in tetrahydrofuran was added 275 g of Salen Co (III) (OAc)Dropping 92. 0 grams of epichlorohydrin burning, The reaction was carried out for 12 hours, Concentrated to recover tetrahydrofuran, Ethyl acetate (200 ml)Washed with 100 ml of saturated aqueous sodium chloride solution, Layered, The ethyl acetate was concentrated to recover 98.0 g of (2R) -1-chloro-2-hydroxy-4-pentyne (I) 118.0 g of (2R) -1-chloro-2-hydroxy-4-pentyne (I) was added dropwise to 245 g of a 20percent aqueous sodium cyanide solution, 30 ° C reaction for 4 hours, After completion of the reaction, Ethyl acetate (500 ml)Washed with 100 ml of saturated aqueous sodium chloride solution, Layered, Concentrated to recover ethyl acetate(2R) -methyl-2-98.0 g. 109.0 g of (2R) -1 -methylidene-2-yl-4-pentyne (II) was added dropwise to 1000 ml of methanol, By hydrogen chloride gas, Gas chromatography followed the reaction end point, 0 ° C reaction for 10 hours, After completion of the reaction, And concentrated to recover methanol to obtain 135.0 g of methyl (3R) -hydroxy-5-octynoate (III). (3R) -hydroxy-5-octynoic acid methyl ester (III) was added to 1000 ml of methylene chloride, 150 g of t-butyldimethylsilyl chloride was reacted at room temperature for 3 hours, After completion of the reaction, Concentrated recovery in the system(R) -3 - [(tert-butyldimethylsilyl) oxy] -5-octynoate (IV)247. 8 g. Was added dropwise to 1280 g of aqueous sodium hypochlorite solution having an available chlorine content of 10percent(R) -3 - [(tert-butyldimethylsilyl) oxy] -5-octynoic acid methyl ester (IV)After the reaction, 1000 ml of ethyl acetate was added to the reaction solution, Concentrated to recover ethyl acetate, (R) - (+) - 3- (tert-butyldimethylsilyloxy) -5-oxo-hexanoic acid methyl ester (V)300 g. In 1000 ml of 2-methyltetrahydrofuran(R) - (+) - 3- (tert-butyldimethylsilyloxy) -5-oxo-hexanoic acid methyl ester 340. 0G and triphenylphosphine 262. 0 g, 60 ° C for 10 hours, After completion of the reaction, 2-methyltetrahydrofuran was concentrated to recover 2-To give 448.8 g of methyl (3R) -tert-butyldimethylsilyloxy-5-oxo-6-triphenylphosphinohexanoic acid methyl ester (VI)Using high performance liquid chromatographyThe value is 99.7percent.30 g of a compound represented by formula V-5 (GC: 75.0percent), 26.9 g of triphenylphosphine, 18.6 g of potassium carbonate and 75 mL of methylene chloride are added to the 500 mL reaction flask, and the system reacts at the temperature of -10 - 10°C. In the middle control of GC, 150 mL of water is added to the system for dissolution of solid after complete reaction of the compound represented by formula V-5, extraction is carried out by three times with 150 mL*3 of methyl tert-butyl ether, organic phases are filtered after being dried with anhydrous sodium sulfate, and then concentrated at the temperature of 30 - 35°C and under the vacuum degree of 250 - 350 Pa to obtain an oily substance, i.e., the compound represented by formula I-1, 50 g of ethyl acetate/petroleum ether (2: 1) is added for crystallization, 9.0 g of a compound represented by formula I-1 is obtained after filtering and drying, it purity detected by HPLC (high-performance liquid chromatography) is 98.2percent, its ee value is 97.9percent, and its yield is 25.4percent. 1 H NMR (300 MHz, CDCl3): δ7.46 - 7.70 (m, 15 H), δ4.54 - 4.59 (m, 1 H), δ3.67 (s, 3 H), δ2.73 - 2.77 (m, 1H), δ2.59 - 2.63 (m, 1 H), δ2.45 - 2.55 (m, 2 H), δ0.83 (s, 9 H), δ0.03 - 0.06 (m, 6 H). MS: m/z = 535.5[M+H]+20.6 g of a compound represented by formula V-6 (GC: 72.7percent), 15.7 g of triphenylphosphine, 10.4 g of potassium carbonate and 50 mL of methylene chloride are added to the 500 mL reaction flask, and the system reacts at the temperature of 10 - 27°C. In the middle control of GC, 100 mL of water is added to the system for dissolution of solid after complete reaction of the compound represented by formula V-6, extraction is carried out by three times with 100 mL*3 of methyl tert-butyl ether, organic phases are filtered after being dried with anhydrous sodium sulfate, and then concentrated at the temperature of 30 - 35°C and under the vacuum degree of 250 - 350 Pa to obtain an oily substance, i.e., the compound represented by formula I-1, 60 g of ethyl acetate/petroleum ether (2: 1) is added for crystallization, 5.0 g of a compound represented by formula I-1 is obtained after filtering and drying, its purity detected by HPLC (high -performance liquid chromatography) is 97.4percent, its ee value is 96.8percent, and its yield is 23.7percent. 1H NMR (300 MHz, CDCl3): δ7.46 - 7.70 (m, 15 H), δ4.54 - 4.59 (m, 1 H), δ3.67 (s, 3 H), δ2.73 - 2.77 (m, 1H), δ2.59 - 2.63 (m, 1 H), δ2.45 - 2.55 (m, 2 H), δ0.83 (s, 9 H), δ0.03 - 0.06 (m, 6 H). MS: m/z = 535.5[M+H]+

Molecular Weight:534.7
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:12
Exact Mass:534.23552325
Monoisotopic Mass:534.23552325
Topological Polar Surface Area:52.6
Heavy Atom Count:37
Complexity:744
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes