* 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.
With potassium <i>tert</i>-butylate In tetrahydrofuran at -60 - 0℃;
(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;
Reference：
[1] Patent: CN107011378, 2017, A, . Location in patent: Paragraph 0018; 0045-0048
2
[ 1343494-42-7 ]
[ 1779-49-3 ]
[ 147118-35-2 ]
Yield
Reaction Conditions
Operation in experiment
36.4%
Stage #1: With tert.-butyl lithium In tetrahydrofuran at -50 - -40℃; Inert atmosphere Stage #2: at -40 - -30℃;
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 Example 1 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.
Reference：
[1] Patent: CN106749032, 2017, A, . Location in patent: Paragraph 0063; 0064; 0065; 0066; 0067; 0068; 0069-0083
3
[ 1337981-51-7 ]
[ 603-35-0 ]
[ 147118-35-2 ]
Yield
Reaction Conditions
Operation in experiment
7.9 g
With potassium carbonate In N,N-dimethyl-formamide at 20 - 30℃;
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]+
448.8 g
at 60℃; for 10 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.
Reference：
[1] Patent: US2012/310000, 2012, A1, . Location in patent: Page/Page column 5
[2] Patent: EP2557084, 2013, A1, . Location in patent: Paragraph 0056; 0057; 0058; 0059
[3] Patent: CN105399770, 2016, A, . Location in patent: Paragraph 0010-0012
4
[ 1339958-06-3 ]
[ 603-35-0 ]
[ 147118-35-2 ]
Yield
Reaction Conditions
Operation in experiment
9 g
With potassium carbonate In dichloromethane at -10 - 10℃;
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]+
With potassium carbonate In dichloromethane at 10 - 27℃;
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]+
To a mixture of 4- (4-fluoro-phenyl)-5-formyl-1-isopropyl-3-phenyl-lH-pyrrole-2- carboxylic acid phenylamide prepared from step H (726 mg, 1.70 mmol) in toluene (20 mL) at room temperature under a nitrogen atmosphere was added wittig reagent [3- (tert- butyl-dimethyl-silanyloxy)-5-oxo-6- (triphenyl-phosphanylidene)-hexanoic acid methyl ester] (1.38 g, 2.58 mmol). The mixture was heated at reflux for 40 h and then concentrated in vacuo to give a residue, which was purified by chromatography (2%-15% ethyl acetate in hexanes) to give 0.75 g (65%) of the desired product as a yellow foam: mp 62-64 C ; MS (APCI+) : m/z 683.2 (MH+) ; Anal. Calcd for C4oH47F, N205Si, : C, 70.35 ; H, 6.94 ; N, 4.10. Found: C, 70.32 ; H, 7.07 ; N, 4.00.
1-ethyl-4-(4-fluorophenyl)-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid phenylamide[ No CAS ]
[ 147118-35-2 ]
(R)-3-(tert-butyldimethylsilanyloxy)-7-[1-ethyl-3-(4-fluorophenyl)-4-methyl-5-phenylcarbamoyl-1H-pyrrol-2-yl]-5-oxohept-6-enoic acid methyl ester[ No CAS ]
1-ethyl-4-(4-fluorophenyl)-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid 4-methoxybenzylamide[ No CAS ]
[ 147118-35-2 ]
(R)-3-(tert-butyldimethylsilanyloxy)-7-[1-ethyl-3-(4-fluorophenyl)-5-(methoxybenzylcarbamoyl)-4-methyl-1H-pyrrol-2-yl]-5-oxohept-6-enoic acid methyl ester[ No CAS ]
(3R)-7-[3,4-Bis-(4-fluoro-phenyl)-l-isopropyl-5-(4-sulfamoyl-phenylcarbamoyl)-lH-pyrrol-2-yl]-3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-hept-6-enoic acid methyl ester To a mixture of 3, 4-bis- (4-fluoro-phenyl)-5-formyl-1-isopropyl-lH-pyrrole-2- carboxylic acid (4-sulfamoyl-phenyl)-amide prepared from step F (0.53 g, 1.01 mmol) in toluene (20 mL) at room temperature under a nitrogen atmosphere was added wittig reagent [3- (tert-butyl-dimethyl-silanyloxy)-5-oxo-6- (triphenyl- phosphanylidene)-hexanoic acid methyl ester] (0.81 g, 1.5 mmol). The mixture was heated at reflux for 40 h and then concentrated in vacuo to give a residue, which was purified by chromatography (10%-50% ethyl acetate in hexanes) to give 0.52 g (66%) of the desired product as an yellow foam: mp 108-110 C ; MS (APCI+) : m/z 780.4 (MH+) ; Anal. Calcd for C40H4, F2N307SsSil : C, 61.60 ; H, 6.07 ; N, 5.39. Found: C, 61.42 ; H, 6.01 ; N, 5.46.
(3R)-3-(tert-Butyl-dimethyl-silanyloxy)-7-[1-ethyl-3-(4-fluoro-phenyl)-4-isopropyl- 5-phenylcarbamoyl-lH-pyrrol-2-yl]-5-oxo-hept-6-enoic acid methyl ester A solution of 1-ethyl-4-(4-fluoro-phenyl)-5-formyl-3-isopropyl-1H-pyrrole-2- carboxylic acid phenylamide (0.74 g, 1.96 mmol) prepared in step G and the Wittig reagent [3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6-(triphenyl-phosphanylidene)- hexanoic acid methyl ester] (2.1 g, 3.9 mmol) in 30 ml of toluene was stirred at reflux for 70 hr. The solvent was evaporated, and the residue was purified by chromatography (20% ethyl acetate in hexane) to give 0.64 g (52%) of the desired product as an orange solid: mp 143-145 C ; MS (APCI+) : niz 635 (MH+) ; Anal. Calcd for C36ES47FlN2o5Sil : C, 68.11 ; H, 7.46 ; N, 4.41. Found : C, 68.03 ; H, 7.46 ; N, 4.23.
(3R)-7- [3, 4-Bis (4-fluorophenyl)-1-isopropyl-S- (piperidine-1-carbonyl)-lH-pyrrol-2- yl]-3- (tert-butyl-dimethyl-silanyloxy)-5-oxo-hept-6-enoic acid methyl ester To a mixture of (3R) -3, 4-Bis (4-fluorophenyl)-1-isopropyl-5- (piperidine-1-carbonyl)- lH-pyrrole-2-carbaldehyde (0.78 g, 1.5 mmol) in Toluene (30mL) at room temperature under a nitrogen atmosphere was added wittig reagent [3- (tert-butyl- dimethyl-silanyloxy)-5-oxo-6- (triphenyl-phosphanylidene)-hexanoic acid methyl ester] (1.2 g, 2.2 mmol). The mixture was heated at reflux for 64 h and then concentrated in vacuo to give a residue, which-was purified by chromatography (5 to 50% EtOAc in Hexane) to give 0.68 g of a mixture of starting material and desired product. Used as is.
(5R)-5-[5-(tert-butyldimethylsilanyloxy)-6-methoxycarbonyl-3-oxohex-1-enyl]-3,4-bis-(4-fluorophenyl)-1-isopropyl-1H-pyrrole-2-carboxylic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
In toluene; at 20℃; for 24h;Heating / reflux;
(SR)-5- [S- (tert-Butyl-dimethyl-silanyloxy)-6-methoxycarbonyl-3-oxo-hex-1-enyl]- 3, 4-bis- (4-fluoro-phenyl)-1-isopropyl-1H-pyrrole-2-carboxylic acid benzyl ester To a mixture of 3, 4-bis- (4-fluoro-phenyl)-5-formyl-1-isopropyl-lH-pyrrole-2- carboxylic acid benzyl ester prepared from step A (0.98 g, 2.14 mmol) in toluene (10 mL) at room temperature under a nitrogen atmosphere was added wittig reagent [3- (tert-butyl-dimethyl-silanyloxy)-5-oxo-6- (triphenyl-phosphanylidene)-hexanoic acid methyl ester] (1.7 g, 3.21 mmol). The mixture was heated at reflux for 24 h and then concentrated in vacuo to give a residue, which was purified by chromatography (12% ethyl acetate in hexanes) to give 1.3 g (85%) of the desired product as a yellow syrup: MS (APCI+) : m/z 716.3 (MH+) ; Anal. Calcd for C4, H47F2Nl06Si, : C, 68.79 ; H, 6.62 ; N, 1.96. Found: C, 69.14 ; H, 6.47 ; N, 1.87.
To a mixture of 4- (4-fluoro-phenyl)-5-formyl-1-isopropyl-3-phenyl-lH-pyrrole-2- carboxylic acid 4-fluoro-benzylamide prepared from step A (0.50 g, 1.09 mmol) in toluene (20 mL) at room temperature under a nitrogen atmosphere was added wittig reagent [3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6-(triphenyl-phosphanylidene)- hexanoic acid methyl ester] (0.87 g, 1.64 mmol). The mixture was heated at reflux for 42 h and then concentrated in vacuo to give a residue, which was purified by chromatography (2%-20% ethyl acetate in hexanes) to give 0.5 g (64%) of the desired product as a light yellow foam: mp 62-63 C ; MS (APCI+) : m/z 715.3 (MH+) ; Anal. Calcd for C41H48F2N205Sil : C, 68.88 ; H, 6.77 ; N, 3.92. Found: C, 68.76 ; H, 6.80 ; N, 3.78.
(R)-7-[2-benzylcarbamoyl-5-(4-fluoro-phenyl)-3-isopropyl-3H-imidazol-4-yl]-3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-hept-6-enoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In toluene; for 24h;Heating / reflux;
A solution of 4-(4-Fluoro-phenyl)-5-formyl-1-isopropyl-1H-imidazole-2- carboxylic acid 4-fluoro-benzylamide (1.16 g. , 3.2 mmol) and (R)-3- (tert-Butyl- dimethyl-silanyloxy)-5-oxo-6- (triphenyl-15-phosphanylidene)-hexanoic acid methyl ester (2.5 g, 4.8 mmol) in toluene (15 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The cooled mixture was concentrated in vacuo to give a crude oil, which was purified by chromatography on silica (15 to 60% ethyl acetate in hexanes) to give the desired product as a colorless glass. Low resolution mass spectroscopy (APCI) mAz 622 [M+H] +. 1H NMR (400 MHz, CHLOROFORM-D) ppm 0.0 (d, J=3. 4 Hz, 2 H) 0.1 (m, 4H) 0.8 (m, 10 H) 1.7 (m, 8H) 2.5 (m, 2H) 2.6 (m, 2H) 3.1 (m, 1H) (d, J=3. 9 Hz, 3H) 3.7 (s, 1H) 4.6 (m 3H) 7.1 (m, 2H) 7.3 (m, 2H) 7.3 (d, J=5. 9 Hz, 4H) 7.5 (m, 1H) 7.6 (d, J=3. 4 Hz, 1H)
A solution of 5- (4-Fluoro-phenyl)-3-isopropyl-2-phenylmethanesulfonyl-3H- imidazole-4-carbaldehyde (0.318 g. , 0.82 mmol) and (R)-3- (tert-Butyl-dimethyl- silanyloxy)-5-oxo-6- (triphenyl-X-5-phosphanylidene)-hexanoic acid methyl ester (0.66 g. , 1.2 mmol) in toluene (5 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The cooled reaction mixture was concentrated ill vacuo to give an orange oil. Purification by flash chromatography (SiO2, ethyl acetate/hexanes 3: 17 to 1: 1) provided the desired product as an red-orange glass; yield: 0.347 g; Low resolution mass spectroscopy (APCI) tnlz 643 [M + H] +.
With n-butyllithium; sodium hydrogencarbonate; triethylamine; In tetrahydrofuran;
(2) To a solution of the thus obtained half ester compound in 10 ml of ether are added dropwise triethylamine and ethyl chlorocarboxylate in order under nitrogen atmosphere at -78 C. The resulting white suspension is stirred at 0 C. for 1 hour and cooled to -78 C. The resulting precipitate is filtered under nitrogen atmosphere and the filtrate is washed with 15 ml of ether. To a suspension of 1.29 g (3.6 mmol) of methyl bromide triphenylphosphonium in 5 ml of THF is added dropwise butyllithium (1.6M hexane, 2.25 ml, 3.6 mmol) under nitrogen atmosphere at -78 C. The reaction mixture is stirred at 0 C. for 1 hour and cooled to -78 C. and added dropwise to the solution of thus obtained active ester compound in ether. The reaction mixture is washed with 5 ml of THF and stirred at 0 C. for 1 hour, and 10 ml of 5% sodium hydrogencarbonate is added thereto. The reaction mixture is stirred for 5 minutes and extracted with ethyl acetate and the organic layer is separated and the remaining aqueous layer is extracted with ethyl acetate. Each organic layer is collected and washed with brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue is subjected to column chromatography of silica gel eluding with ether-ethyl acetate and crystallized from ether-hexane to give objective compound. 1 H-NMR (CDCl3)delta: 0.04 (s, 3H); 0.06 (s, 3H); 0.83 (s, 9H); 2.4-2.9 (m, 4H); 3.64 (s, 3H); 3.74 (d, 1H); 4.5-4.7 (m, 1H); 7.4-7.8 (m, 15H). IR (CHCl3): 2880, 1730, 1528, 1437, 1250, 1106, 835 cm-1.
Next, 60% sodium hydride and 1.29 g (3.6 mmol) of methyltriphenylphosphonium bromide are added to 20 ml of DMSO under nitrogen atmosphere, and stirred at 50 C. for 3 hours. To a solution of 1,5-ethoxycarbonyl methyl-3-tert-butyldimethylsilyloxypentanedioate in 10 ml of THF is added dropwise a solution of the methylene triphenylphosphorane obtained above in DMSO at -10 C. The reaction mixture is stirred for 1 hour and poured into water, and extracted with isopropyl ether. The extracted solution is dried over anhydrous sodium sulfate, concentrated; and then subjected to silica gel column chromatography (ethyl acetate) to give 740 mg of a target compound (Ia-(R)-1) in a 69% yield, which can be recrystallized from ether-hexane. 1 H-NMR (CDCl3) delta: 0.04 (s, 3H); 0.06 (s, 3H); 0.83 (s, 9H); 2.4-2.9 (m, 4H); 3.64 (s, 3H); 3.74 (d, 1H, 2 JPH =26 Hz); 4.5-4.7 (m, 1H); 7.4-7.8 (m, 15H) IR (CHCl3): 2880, 1730, 1528, 1437, 1250, 1106, 835 cm-1 [alpha]D =-6.2 (C=1.27, 22.0 C., CHCl3), mp.: 77.5-78.5 C. Rf=0.48 (CHCl3 /MeOH=9/1) Analysis (%) for C31 H39 O4 PSi Calcd.: C,69.63; H,7.35; P,5.79 Found: C,69.35; H,7.35; P,6.09
56
[ 139993-90-1 ]
[ 147118-35-2 ]
methyl 7-[4-(4-fluorophenyl)-2-isopropyl-5-methyl-1-methylsulfonylpyrrol-3-yl]-3-(tert-butyldimethylsilyl)oxy-5-oxo-6-heptenate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile;
Synthesis of Sodium (+) 7-[4-(4-fluorophenyl)-2-isopropyl-5-methyl-(1-methylsulfonyl)pyrrol-3-yl]-(3R,5S)-dihydroxy-(E)-6-heptenate STR21 To a solution of 80 mg (0.15 mmol) of the compound (Ia-(R)-1) in 0.2 ml of acetonitrile, which is obtained in Example 1, is added 73 mg (0.225 mmol) of 4-(4-fluorophenyl)-3-formyl-2-isopropyl-5-methyl-1-methylsulfonylpyrrol under a nitrogen atmosphere at room temperature, and the mixture is refluxed for 11 hours and then removing the solvent to give methyl 7-[4-(4-fluorophenyl)-2-isopropyl-5-methyl-1-methylsulfonylpyrrol-3-yl]-3-(tert-butyldimethylsilyl)oxy-5-oxo-6-heptenate (Rf=0.45, ethyl acetate/toluene=1/6).
methyl (3S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]3-[(tert-butyl-dimethylsilyl)oxy]-5-oxohept-6-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile; at 81 - 83℃; for 48h;Heating / reflux;
Example 1: Synthesis of Methyl f3S,6EV7-[3-(4-fluorophenylVl-isopropyl-lH-indol-2-vH3- |Yfert-butyl-dimethylsilyl')oxy'l-5-oxohept-6-enoateThe title compound is a compound of Formula Ic, wherein R1 is tert- butyldimethylsilyl and R3 is methyl. A mixture of 3-(4>-fluorophcnyl)-l-isopropyl indole-2-carboxyaldehyde (1.0 g) and 1- methyl-(3R)-3-[(ter^butyl-dimethylsilyl)oxy]-5-oxo-6-triphenylphosphoranylidene-hexanate (3.0 g) in acetonitrile (60 mL) was lefluxed at 81 to 83 0C for 48 hours, cooled to room temperature and concentrated under vacuum (40-100 mmHg) at 40 to 45 0C to yield a crude oil. The crude oil was suspended in cyclohexane (30 mL) and concentrated, forming a residue. The residue was suspended in cyclohexane (30 mL) and stirred for 1 hour. The solids thus obtained were filtered, washed with cyclohexane (20 mL) and the combined filtrate and washings were concentrated to yield the title compound as an oil. EPO <DP n="21"/>Yield: 1.53 g.13CNMR (delta, CDCl3): 199 .94, 172.1 1 163.1, 140.12, 131.88, 123.45, 64.58, 51.432, 25.98, 20.77, 18.52. 1HNMR (delta, CDCl3): 0.07 [(CH3)2Si, 6H, s ], 0.90 [(CELs)3C-, 9H, s ], 1.74 to 1.77 [(CH3)2C-, 6H, two singlets], 2.60 [-CH2- , 2H , m], 2.82 [-CH2-, 2H, m], 3.61 (OCH3, 3H, s ) , 4.6 [-CH(CH2) 2-, IH, m], 4.72 to 5.0 [-CH(CH3)2 , IH, m] , 6.37 to 6.47 [-CH=CH- CO-,1H, dd], 7.76 to 7.73 [-CH=CH-CO-, IH, dd], 7.58 to 7.20 [ArH, 8 H, m]. MS m/z: [M+l]+ 538.6, 421, 279. For C3iH40FNO4Si , Found: C 69.32; H 7.47; F 3.47; N 2.67; O 11.52; Si 5.55
(2); To a solution of the thus obtained half ester compound in 10 ml of ether triethylamine and then ethyl chlorocarboxylate are added dropwise under nitrogen atmosphere at -78C. The resulting white suspension is stirred at 0C for 1 hour and cooled to -78C. The resulting precipitate is filtered off under nitrogen atmosphere and the filtrate is washed with 15 mL of ether. To a suspension of 1.29 g (3.6 mmol) of methyl bromide triphenylphosphonium in 5 ml of THF butyllithium (1.6M hexane, 2.25 mL, 3.6 mmol) is added dropwise under a nitrogen atmosphere at -78C. The reaction mixture is stirred at 0C for 1 hour and cooled to -78C and added dropwise to the solution of the thus obtained active ester compound in ether. The reaction mixture is washed with 5 ml of THF and stirred at 0C for 1 hour, and 10 mL of 5 % sodium hydrogencarbonate is added thereto. The reaction mixture is stirred for 5 minutes and extracted with ethyl acetate and the organic layer is separated and the remaining aqueous layer is extracted with ethyl acetate. Each organic layer is collected and washed with brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue is subjected to column chromatography on silica gel eluting with ether-ethyl acetate and crystallized from ether-hexane to give methyl (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidenehexanate.
Example 9: Preparation of Methyl (3R)-3-(t-butyldimethylsilyloxy)-5-oxo-6- triphenyl phosphoranylidene hexanoateA solution of Hydrogen-(3R)-l -Methyl 3-[(tert-Butyldimethylsilyl)-oxy] pentanedioate (25 g), triethylamine (12.0 g) in hexane was cooled to -40 C, and to this ethylchlorocarbonate (11.0 g) was added drop wise. The reaction mass was stirred for 1-3 hr to give anhydride. In another flask a suspension of methyltriphenyl phosphonium bromide(71 g) in THF was cooled to 0C, and to this a solution of 1.6 M BuLi solution( 120 ml) in hexane was added drop wise over 60 min. The mixture was cooled to -78 C and the anhydride obtained in above was added drop wise. The resulting reaction mass was stirred for 1-3 hr. The reaction mass was poured into DM water. The reaction mass was stirred and layers were separated. Organic layer was concentrated under u/v at 40-45 C. The concentrated mass was taken into diisopropyl ether, washed the diisopropyl ether with DM water and brine solution. The organic layer was dried and concentrated to give Methyl (3R)-3-(t-butyldimethylsilyloxy)-5-oxo-6-triphenyl phosphoranylidenehexanate (55 g)
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