* 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.
A reaction mixture containing (+)-pinanediol (6.9 g) and 2-methylpropylboronic acid (4.4 g) and diethylether (49.3 ml) was stirred for 23 hours at laboratory temperature, than dried over Na2SO4 (16.5 g). The sulfate was filtered off and washed with diethylether (69.4 ml), and the resulting solution was concentrated. The product was obtained as colorless oil (9.9 g, purity 100 percent (GC), yield 97.2 percent). MS (m/z): 236, 221, 195, 167, 140, 134, 83, 67, 55, 43; 1H- NMR (DMSO-d6): δ= 4.27 (IH, dd, J=2.1 Hz, 8.7 Hz); 2.30 (IH, m); 2.18 (IH, m); 1.96 (IH, t, J=5.4 Hz); 1.86 (IH, m); 1.79 (IH, sx, J-6.8 Hz); 1.69 (IH, m); 1.30 (3H, s); 1.25 (3H, s); 1.02 (IH, d, J=I 0.6 Hz); 0.9 (3H, d, J-6.6 Hz); 0.81 (3H, s); 0.69 (2H, m)).
Reference：
[1] Patent: WO2009/4350, 2009, A1, . Location in patent: Page/Page column 9
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 4, p. 1018 - 1029
2
[ 84110-40-7 ]
[ 18680-27-8 ]
[ 84110-34-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 40℃; for 8 h;
The (+) – Pinanediol (17.0g,0.10mol) with 2-methylpropylBoric acid(11.2g,0.11mol) sequentially added into 200ml of Ethylene ether then themixture was heated to 40 ° C, stirred for 8 hours; after Completion of thereaction, the mixture was dried using anhydrous magnesium sulfate; filtrated;The filtrate was concentrated under reduced pressure to dryness; With 200mLisopropyl ether beating of the reaction for two hours; again filteredthen filtrate was concentrated under reduced pressure to dryness to obtainformula 3 compound 22.4g (0.095mol, Molar yield 95percent).
94%
at 20℃; for 24 h;
A mixture of (+) -pinanediol (23.9 g, 0.140 mol) and 2- methylpropylboronic acid (15 g, 0.147 mol) in diethyl ether (300 ml) was stirred at room temperature for 24h. The mixture was dried over anhydrous sodium sulfate and purified by column chromatography (Silica gel 230-400 mesh), eluting with hexane: ethyl acetate 90: 10 mixture. The product was obtained as a clear oil (32.6 g, 94percent yield). 1H NMR (DMSO-d6) : 4. 28 (1H, dd, J=8.8 Hz, 2.0) ; 2.30 (1H, M) ; 2.18 (1H, M) ; 1.96 (1H, t, J=5.3) ; 1.86 (1H, M) ; 1.78 (1H, set, J=6.8) ; 1.68 (1H, M) ; 1.30 (3H, s); 1.25 (3H, s); 1.01 (1H, d); 0.9 (6H, d, J=6.6) ; 0.81 (3H, s); 0.69 (2H, M).
94%
at 20℃; for 24 h;
A mixture of (+)-pinanediol (23.9 g, 0.140 mol) and 2-methylpropylboronic acid (15 g, 0.147 mol) in diethyl ether (300 ml) was stirred at room temperature for 24 h. The mixture was dried over anhydrous sodium sulfate and purified by column chromatography (Silica gel 230-400 mesh), eluding with hexane:ethyl acetate 90:10 mixture. The product was obtained as a clear oil (32.6 g, 94percent yield). 1H NMR (DMSO-d6): 4.28 (1H, dd, J=8.8 Hz, 2.0); 2.30 (1H, m); 2.18 (1H, m); 1.96 (1H, t, J=5.3); 1.86 (1H, m); 1.78 (1H, set, J=6.8); 1.68 (1H, m); 1.30 (3H, s); 1.25 (3H, s); 1.01 (1H, d); 0.9 (6H, d, J=6.6); 0.81 (3H, s); 0.69 (2H, m).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 12, p. 3220 - 3224
[2] Patent: CN103421033, 2016, B, . Location in patent: Paragraph 0047-0050
[3] Tetrahedron, 2007, vol. 63, # 28, p. 6577 - 6586
[4] Patent: WO2005/21558, 2005, A2, . Location in patent: Page/Page column 52
[5] Patent: US2006/189806, 2006, A1, . Location in patent: Page/Page column 29
[6] Journal of Medicinal Chemistry, 2008, vol. 51, # 4, p. 1068 - 1072
[7] Journal of Organic Chemistry, 2010, vol. 75, # 2, p. 468 - 471
[8] Chemistry Letters, 2009, vol. 38, # 7, p. 750 - 751
[9] Organometallics, [10] Organometallics, 1983, vol. 2, p. 236 - 241
[11] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 21, p. 3199 - 3202
[12] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 5-6, p. 402 - 406
[13] Patent: WO2009/36281, 2009, A2, . Location in patent: Page/Page column 33
[14] Chemistry Letters, 2009, vol. 38, # 7, p. 750 - 751
[15] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 8, p. 1958 - 1962
3
[ 926-62-5 ]
[ 819816-59-6 ]
[ 84110-34-9 ]
Yield
Reaction Conditions
Operation in experiment
62%
Stage #1: at -78 - 20℃; Stage #2: With sulfuric acid In tetrahydrofuran; diethyl ether; di-isopropyl ether; water at 20℃; for 0.166667 h;
A 2M solution of isobutyl magnesium bromide in diethyl ether (131.5 ml, 0.263 mol) was added dropwise, in 1 hour, to a solution of 2- (1-METHYLETHOXY)- (3aS, 4S, 6S, 7aR) -hexahydro-3a, 5,5-trimethyl-4, 6-methano-1, 3, 2-benzodioxaborole obtained in Step 1 (62.6 g, 0.263 mol), in anhydrous tetrahydrofuran (330 ml) while stirring AT-78°C, under nitrogen. The mixture was then allowed to warm to room temperature, then transferred in a mixture OF 2N sulfuric acid (150 ml) and diisopropyl ether (250 ml). After stirring for 10 minutes, a saturated solution OF NACI was added (100 ml) and the layers were separated. The organic phase was washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel) eluting with 5percent diethyl ether in hexane. The product was obtained as a clear oil (38.45 g, 62percent yield).
62%
Stage #1: With sulfuric acid In tetrahydrofuran; diethyl ether at -78 - 20℃; Stage #2: With sulfuric acid In tetrahydrofuran; diethyl ether; di-isopropyl ether; water at 20℃; for 0.166667 h;
A 2M solution of isobutyl magnesium bromide in diethyl ether (131.5 ml, 0.263 mol) was added dropwise, in 1 hour, to a solution of 2-(1-methylethoxy)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole obtained in Step 1 (62.6 g, 0.263 mol), in anhydrous tetrahydrofuran (330 ml) while stirring at -78° C., under nitrogen. The mixture was then allowed to warm to room temperature, then transferred in a mixture of 2N sulfuric acid (150 ml) and diisopropyl ether (250 ml). After stirring for 10 minutes, a saturated solution of NaCl was added (100 ml) and the layers were separated. The organic phase was washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel) eluding with 5percent diethyl ether in hexane. The product was obtained as a clear oil (38.45 g, 62percent yield).
The (+) - Pinanediol (17.0g,0.10mol) with 2-methylpropylBoric acid(11.2g,0.11mol) sequentially added into 200ml of Ethylene ether then themixture was heated to 40 C, stirred for 8 hours; after Completion of thereaction, the mixture was dried using anhydrous magnesium sulfate; filtrated;The filtrate was concentrated under reduced pressure to dryness; With 200mLisopropyl ether beating of the reaction for two hours; again filteredthen filtrate was concentrated under reduced pressure to dryness to obtainformula 3 compound 22.4g (0.095mol, Molar yield 95%).
94%
In diethyl ether; at 20℃; for 24h;
A mixture of (+) -pinanediol (23.9 g, 0.140 mol) and 2- methylpropylboronic acid (15 g, 0.147 mol) in diethyl ether (300 ml) was stirred at room temperature for 24h. The mixture was dried over anhydrous sodium sulfate and purified by column chromatography (Silica gel 230-400 mesh), eluting with hexane: ethyl acetate 90: 10 mixture. The product was obtained as a clear oil (32.6 g, 94% yield). 1H NMR (DMSO-d6) : 4. 28 (1H, dd, J=8.8 Hz, 2.0) ; 2.30 (1H, M) ; 2.18 (1H, M) ; 1.96 (1H, t, J=5.3) ; 1.86 (1H, M) ; 1.78 (1H, set, J=6.8) ; 1.68 (1H, M) ; 1.30 (3H, s); 1.25 (3H, s); 1.01 (1H, d); 0.9 (6H, d, J=6.6) ; 0.81 (3H, s); 0.69 (2H, M).
General procedure: At -78, anhydrous dichloromethane (71.70 mmol ) was added in 120 mL of anhydrous THF under nitrogen atmosphere. Then n-butyl lithium (46.09 mmol) was added dropwise to the solution, and after 20 min,5a-5c(25.61 mmol) was added dropwise. The reaction was allowed to perform for another 20 min. Then the anhydrous zinc chloride in THF (58.90 mmol) was added slowly and the reaction mixture was allowed to warm to room temperature. After completion of reaction as determined by TLC analysis, the mixture was quenched with saturated ammonium chloride (40 mL) at -20. The organic layer was separated and the aqueous layer was extracted with ether (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to obtain crude product. Flash chromatography over silica gel (EtOAC:petroleum 1:40)produced6a-6c, yields 92%-97%.
4-(2-amino-3-carboxy-propionylamino)-4-[2-methyl-1-(2-methyl-1-{2-[3-methyl-1-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-pyrrolidin-1-yl}-propylcarbamoyl)-propylcarbamoyl]-butyric acid[ No CAS ]
With zinc(II) chloride; lithium diisopropyl amide; In tetrahydrofuran; diethyl ether; hexane; at -78 - -70℃; for 3.5h;
A solution of lithium diisopropylamide was prepared by addition of 10.0 M butyl lithium solution in hexane (25.4 ml, 0.254 mol) to a solution of diisopropylamine (35.7 ml, 0.254 mol) in dry tetrahydrofuran (60 ml), AT-50 C, and allowing the temperature to rise TO-30 C. This solution was transferred via canula into a solution of 2- (2-METHYLPROPYL)- (3AS, 4S, 6S, 7aR) -hexahydro-3a, 5,5-trimethyl-4, 6- METHAN-1, 3,2-benzodioxaborole of Step 1 (50 g, 0.212 mol) and CH2CI2 (50 ml, 0.848 mol) in dry tetrahydrofuran (700 ml), while keeping the temperature BELOW-70C. A 1.0 M solution of dry zinc chloride in diethyl ether (339 ml, 0. 339 mol) was then added over a 30 minutes period while keeping the internal temperature BELOW-70C. The reaction mixture was stirred AT-78C for 3 hours, then allowed to warm to room temperature. After removal of the solvents by rotary evaporation the residue was partitioned between petroleum ether (1000 ml) and a 10% aqueous solution of ammonium chloride (800 ml). The aqueous layer was further extracted with petroleum ether (300 ml). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The product was obtained as a brown oil (59.0 g, 98% yield) containing about 9% MOL/MOL of starting material (TH-NMR), and was used in the subsequent step without further purification. 'H NMR (DMSO-d6): 4.43 (1H, dd, J=8. 8,1. 8); 3.59 (1H, IN) ; 2.33 (1H, M) ; 2.21 (1H, M) ; 2.01 (1H, M) ; 1.88 (1H, M) ; 1.84-1. 55 (5H, M) ; 1. 34 (3H, s); 1.26 (3H, s); 1.09 (1H, , J=10. 1); 0.9 (3H, d, J=6.8) ; 0.87 (3H, d, J=6.4) ; 0. 82 (3H, s).
98.9%
The compound 8 (1.1 g, 4.66 mmol) was added to a reaction flask, and dissolved by adding 6.5 mL of anhydrous tetrahydrofuran and 1.54 mL of anhydrous dichloromethane. The temperature was lowered to -78 C under nitrogen, and a 2 M solution of lithium diisopropylamide (LDA, 4.66 mL, 9.32 mmol) was slowly added dropwise. After the addition, the reaction was stirred for 2 hours. A 1 M solution of zinc chloride in tetrahydrofuran (8.16 mL, 8.16 mmol) was slowly added dropwise. After the addition, the reaction was reacted at the low temperature for 2 hours. After TLC detected the reaction was completed, a small amount of 10% dilute sulfuric acid was added to quench the reaction, and the organic phase was separated. The aqueous phase was extracted with n-hexane, and the organic phases were combined, washed with brine, and concentrated. The residue was purified by silica gel column chromatography and dried in vacuo to give a product (1.31 g, yield: 98.9%). LC-MS (APCI): m/z =285.5 (M+1)+.
97.0%
Under an inert atmosphere of argon, 6.0 g (S)-pinanediol-2-methylpropane-l- boronate was charged to jacketed flask (250 ml) together with 36.0 ml THF and 9 ml dichloromethane. The mixture was cooled to -65C. A 1.5 M LDA solution in THF (22.08 ml) was added to the mixture over a period of 5 minutes and the mixture stirred for additional 20 minutes at -650C. A 0.5M ZnCl2 solution in THF (135.0 ml ) was added drop wise to the reaction over a period of 18 minutes. The reaction mixture was warmed up to -45 C and stirred at this temperature for 30 minutes. The mixture was further warmed to 10C over a period of 90 minutes. 10% H2SO4 (33.0 ml) was added and mixture warmed up to 250C. tert-Buthylmethyl ether (36.0 ml) was added and mixture was transferred to separatory funnel. The jacketed (250 <n="11"/>ml) flask was washed with 20.0 ml of water and layers were separated. The organic layer was extracted with 90.0 ml H2O; 90.0 ml H2O + 0.5ml 10% H2SO4 , 90.0 ml H2O + 1.5ml 10% H2SO4; 90.0 ml +1.5ml 10% H2SO4; 90.0 ml 10% NaCl. The organic layer was poured to 250 ml flask and dried over Na2SO4 (57.56 g) and stored in fridge over night. The next day the Na2SO4 was filtered off and washed with 2 x 50.0 ml tetrahydrofuran and residue evaporated to dryness (50C, pmm= 6 mbar ). The product was isolated as oil (7.7 g, 97.0 % yield) with purity 91.7 % (GC) and content of starting material 4.9 %. MS (m/z): 284, 283, 269, 248, 214, 199, 173, 158, 145, 134, 118, 117, 83, 67, 55, 43)
With lithium diisopropyl amide;zinc(II) chloride; In tetrahydrofuran; diethyl ether; hexane; at -78 - 20℃; for 3.5h;
A solution of lithium diisopropylamide was prepared by addition of 10.0 M butyl lithium solution in hexane (25.4 ml, 0.254 mol) to a solution of diisopropylamine (35.7 ml, 0.254 mol) in dry tetrahydrofuran (60 ml), at -50 C., and allowing the temperature to rise to -30 C. This solution was transferred via canula into a solution of <strong>[84110-34-9]2-(2-methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole</strong> of Step 1 (50 g, 0.212 mol) and CH2Cl2 (50 ml, 0.848 mol) in dry tetrahydrofuran (700 ml), while keeping the temperature below -70 C. A 1.0 M solution of dry zinc chloride in diethyl ether (339 ml, 0.339 mol) was then added over a 30 minutes period while keeping the internal temperature below -70 C. The reaction mixture was stirred at -78 C. for 3 hours, then allowed to warm to room temperature. After removal of the solvents by rotary evaporation the residue was partitioned between petroleum ether (1000 ml) and a 10% aqueous solution of ammonium chloride (800 ml). The aqueous layer was further extracted with petroleum ether (300 ml). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The product was obtained as a brown oil (59.0 g, 98% yield) containing about 9% mol/mol of starting material (1H-NMR), and was used in the subsequent step without further purification. 1H NMR (DMSO-d6): 4.43 (1H, dd, J=8.8, 1.8); 3.59 (1H, m); 2.33 (1H, m); 2.21 (1H, m); 2.01 (1H, m); 1.88 (1H, m); 1.84-1.55 (5H, m); 1.34 (3H, s); 1.26 (3H, s); 1.09 (1H, J=10.1); 0.9 (3H, d, J=6.8); 0.87 (3H, d, J=6.4); 0.82 (3H, s).
Step-b) Preparation of 2-((1 S)-1 -Chloro-3-methylbutyl)-(3aS,4S,6S,7aR)- <n="35"/>hexahydro-3a,5,5- trimethyl-4,6-nnethano-1 ,3,2-benzodioxaborol (Formula III):; I. preparing a mixture of zinc chloride with tetrahydrofuranII. preparing LDA mixtureIII. preparing a solution of compound of formula-llin a solvent mixture comprising dichloromethane and water miscible ether solventIV. adding solution of step Il into the solution of step III followed by maintaining the solution at a temperature of about -40 to -700CV. adding the mixture of step I into the product of step IV followed by maintaining the reaction mass at a temperature of about -40 to -700CVI. raising the reaction temperature up to about 10C to ambient temperatureVII. adding the aqueous acid solution VIII. separating the organic layer containing the compound of formula-Ill, and isolating the product.I. Preparing a mixture of zinc chloride with tetrahydrofuranCharged ZnCI2 (115 g) to tetrahydrofuran (805 ml) into a 1st Round bottom flask (R. B. flask) under nitrogen atmosphere at 25 to35Cand the temperature of the resulting mixture was raised to 35 to 400C, maintained for 3-4 hours to give ZnCI2 solution.II. Preparing LDA mixtureCharged diisopropyl amine (86 ml) to tetrahydrofuran (345 ml) into a 2nd R. B. flask under nitrogen atmosphere and resultant mixture was cooled to -7 to -150C, charged n-hexyl lithium to the above mixture and maintained for 30-40 minutes to give LDA mixture.III. Preparing a solution of compound of formula-ll <n="36"/>Compound of Formula Il (115.O g) was charged to a dichloromethane (161 ml) and tetrahydrofuran (690 ml) into a 3rd R. B. flask under nitrogen atmosphere at 25 to35C and the mixture was cooled to -55 to -600C.IV. Adding solution of step Il into the solution of step III Charged LDA mixture from the 2nd R. B. flask to the reaction mixture at -55 to -600C and maintained for 30 minutes. The temperature was raised to -500C.V. Adding the mixture of step I into the product of step IVCharged ZnCI2 solution from the 1st R. B. flask at -45 to -500C and maintained for I hour. Vl. Raising the reaction temperature up to about 100CThe reaction mixture was warmed to 100C. VII. Adding the aqueous acid solutionCharged 10% H2SO4, stirred for 10-15 minutes and the organic layer was separated. VIII. Separating the Organic layer containing the compound of formula-Ill, and isolating the product.The organic layer separated under step VII was subjected to next step, however, the aqueous layer was discarded.Washed the organic layer with brine solution under stirring, till the aqueous layer reached to a pH around 6-7.The organic layer was concentrated to isolate the compound of formula-Ill, under reduced pressure.
A 2M solution of isobutyl magnesium bromide in diethyl ether (131.5 ml, 0.263 mol) was added dropwise, in 1 hour, to a solution of 2- (1-METHYLETHOXY)- (3aS, 4S, 6S, 7aR) -hexahydro-3a, 5,5-trimethyl-4, 6-methano-1, 3, 2-benzodioxaborole obtained in Step 1 (62.6 g, 0.263 mol), in anhydrous tetrahydrofuran (330 ml) while stirring AT-78C, under nitrogen. The mixture was then allowed to warm to room temperature, then transferred in a mixture OF 2N sulfuric acid (150 ml) and diisopropyl ether (250 ml). After stirring for 10 minutes, a saturated solution OF NACI was added (100 ml) and the layers were separated. The organic phase was washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel) eluting with 5% diethyl ether in hexane. The product was obtained as a clear oil (38.45 g, 62% yield).
62%
A 2M solution of isobutyl magnesium bromide in diethyl ether (131.5 ml, 0.263 mol) was added dropwise, in 1 hour, to a solution of 2-(1-methylethoxy)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole obtained in Step 1 (62.6 g, 0.263 mol), in anhydrous tetrahydrofuran (330 ml) while stirring at -78 C., under nitrogen. The mixture was then allowed to warm to room temperature, then transferred in a mixture of 2N sulfuric acid (150 ml) and diisopropyl ether (250 ml). After stirring for 10 minutes, a saturated solution of NaCl was added (100 ml) and the layers were separated. The organic phase was washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel) eluding with 5% diethyl ether in hexane. The product was obtained as a clear oil (38.45 g, 62% yield).
In a separate round bottomed flask, (3aS,4S,6S,7aR)-3a,5,5-trimethyl-2-(2- methylpropyl)hexahydro-4,6-methano-l,3,2-benzodioxaborole (1 kg) and tetrahydrofuran (5 L) were added together at 20C. Dichloromethane (1 L) was added to the mixture and the mixture was cooled to -70C. Lithium diisopropylamide solution was added slowly to the mixture at -60C to -70C. The mixture was stirred for 0.5 hours at -65C to -70C. Zinc chloride solution was added slowly to the mixture at -60C to -70C. The reaction mixture was stirred for 1.5 hours at -60C to -70C. The temperature of mixture was raised to 10C in 2 hours to 3 hours and reaction progress was monitored by gas chromatography. Sulfuric acid (0.6 L) was added to the mixture at 10C to 15C and solvent was recovered under vacuum at 45 C. Hexanes (4 L) and water (4 L) were added slowly at 20C to the mixture and mixture was stirred for 0.5 hours at 20C. Organic and aqueous layers were separated and aqueous layer was washed with hexanes (2 L).Combined organic layer was washed with water (3 x 3 L), concentrated under vacuum at 35C to obtain the title compound.Yield: 1.068 kg
tert-butyl [1-({3-methyl-1-[(3aS,4S,6S)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-1-oxo-3-phenylpropan-2-yl]carbamate[ No CAS ]
N-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}-Nα-(pyrazin-2-ylcarbonyl)-L-phenylalaninamide[ No CAS ]
(3aS,4S,6S,7aR)-2-(1-chloro-3-methylbutyl)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.068 kg
With zinc(II) chloride; lithium diisopropyl amide; In tetrahydrofuran; hexane; at -70 - 10℃;Large scale;
Example 1 Preparation of (3 as,4s,6s,7ar)-2-(1-Chloro-3-Methylbutyl)-3a,5,5-Trimethylhexahydro-4,6-Methano-1,3,2-Benzodioxaborole Diisopropylamine (0.57 kg) and tetrahydrofuran (1.0 L) were added together and the mixture was cooled to -30 C. 2.5 M solution of butyl lithium in hexane (2.2 L) was added dropwise to the cooled mixture, and the temperature was maintained at -20 C. to -30 C. The mixture was stirred for 0.5 hours at -20 C. to -30 C. and a clear solution of lithium diisopropyl amide was obtained. In a separate round bottomed flask, zinc chloride (1.3 kg) and tetrahydrofuran (6 L) were added together at 20 C. The mixture was stirred at 20 C. for 0.5 hours and a clear solution of zinc chloride was obtained.In a separate round bottomed flask, <strong>[84110-34-9](3aS,4S,6S,7aR)-3a,5,5-trimethyl-2-(2-methylpropyl)hexahydro-4,6-methano-1,3,2-benzodioxaborole</strong> (1 kg) and tetrahydrofuran (5 L) were added together at 20 C. Dichloromethane (1 L) was added to the mixture and the mixture was cooled to -70 C. Lithium diisopropylamide solution was added slowly to the mixture at -60 C. to -70 C. The mixture was stirred for 0.5 hours at -65 C. to -70 C. Zinc chloride solution was added slowly to the mixture at -60 C. to -70 C. The reaction mixture was stirred for 1.5 hours at -60 C. to -70 C. The temperature of mixture was raised to 10 C. in 2 hours to 3 hours and reaction progress was monitored by gas chromatography. Sulfuric acid (0.6 L) was added to the mixture at 10 C. to 15 C. and solvent was recovered under vacuum at 45 C. Hexanes (4 L) and water (4 L) were added slowly at 20 C. to the mixture and mixture was stirred for 0.5 hours at 20 C. Organic and aqueous layers were separated and aqueous layer was washed with hexanes (2 L). Combined organic layer was washed with water (3*3 L), concentrated under vacuum at 35 C. to obtain the title compound. Yield: 1.068 kg
In tert-butyl methyl ether; toluene; at -65 - -55℃; for 1.5h;Inert atmosphere;
Under an argon atmosphere, the compound of formula 3 37.8g (0.16mol) was added to the reactionflask, and then toluene was added 200mL Dichloromethane and 27.2g (0.32mol),the mixture was cooled to -60 C, temperature at -65 ~ -55 C under theprepared diisopropyl Amino lithium was added dropwise to the above mixture,about 1 hour after drop, drip completed, additional toluene 100mL, temperature-65 ~ -55 C The reaction was stirred for 0.5 hours, the reaction was warmedto -50 C, was added dropwise a solution of ZnCl 2 THF, for about one hour after dropping,Bi drops, temperature at -45 ~ -40 C with stirring for 1 to 2 hours, supplemented plus toluene100mL, then warmed to 10 C, temperature control Below 25 C in 10% sulfuricacid was added dropwise 250g, dropping was completed, the organic layer wasseparated, washed with saturated brine once, dried over anhydrous magnesiumDried, filtered, and the filtrate was concentrated under reduced pressure todryness to give an oily compound 1-1 42.6g (0.15mol, total molar yield 93.6%).
In toluene; at -65 - -55℃; for 1.5h;Inert atmosphere;
Under an argonatmosphere, the compound of formula 3 35.4g (0.15mol) was added to the reactionflask, and then toluene was added 200mL And dibromomethane 51g (0.60mol), themixture was cooled to -60 C, temperature at -65 ~ -55 C under the prepared lithiumdiisopropylethylamide was added dropwise to the above mixture, about 1 hourafter drop, drip completed, additional toluene 100mL, temperature -65 ~ -55 CThe reaction was stirred for 0.5 hours, the reaction was warmed to -50 C, wasadded dropwise a solution of FeCl3 tetrahydrofuran, for about one hour after dropping, drops Bi,temperature at -45 ~ -40 C with stirring for 2 to 3 hours, adding supplementedtoluene 100mL, then warmed to 10 C, the temperature 25 C below 10% sulfuricacid was added dropwise 500g, dropping was completed, the organic layer wasseparated, washed twice with saturated brine, dried over anhydrous magnesiumDry, filtered, and the filtrate was concentrated under reduced pressure todryness to give an oily compound 1-2 44.6g (0.135mol, total molar yield 90.3%).
(S)-1-chloro-1-d-3-methylbutylboronic acid-(+)-pinanediol ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
The compound 8 (1.1 g, 4.66 mmol) was added to a reaction flask, and dissolved by adding 6.5 mL of anhydrous tetrahydrofuran (THF) and 1.54 mL of deuterated dichloromethane. The temperature was lowered to -78 C under nitrogen protection, and a 2 M solution of LDA (4.66 mL, 9.32 mmol) was slowly added dropwise. After the addition, the reaction was stirred for 2 h. A 1 M solution of zinc chloride in tetrahydrofuran (8.16 mL, 8.16 mmol) was slowly added dropwise. After the addition, the reaction was continued for 2 hours at the low temperature. After TLC detected the reaction was completed, a small amount of 10% dilute sulfuric acid was added to quench the reaction, and the organic phase was separated. The aqueous phase was extracted with n-hexane, and the organic phases were combined, washed with brine, and concentrated. The residue was purified by silica gel column chromatography and dried in vacuo to give a product (1.29 g, yield: 97.0%). LC-MS (APCI): m/z =286.2 (M+1)+.
2,5-dichloro-N-[2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-meth ylene-1,3,2-benzodioxaborolan-2-yl]butyl} amino)-2-oxa-1,1-d2-ethyl]benzamide[ No CAS ]
2,5-dichloro-N-[2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-meth ylene-1,3,2-benzodioxaborolan-2-yl]-1-d-butyl} amino)-2-oxaethyl]benzamide[ No CAS ]
2,5-dichloro-N-[2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-meth ylene-1,3,2-benzodioxaborolan-2-yl]-1-d1-butyl}amino)-2-oxa-1,1-d2-ethyl]benzylamide[ No CAS ]
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
