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CAS No. : | 183133-94-0 | MDL No. : | MFCD23100710 |
Formula : | C31H40O10 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MGJMLMORVVDLIU-VHLOTGQHSA-N |
M.W : | 572.64 | Pubchem ID : | 9916108 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium bromide; sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil; at -20 - 20℃; for 2h;Inert atmosphere;Product distribution / selectivity; | A solution of sodium hydride (60%, 3 eq, 0.22 g) and CsBr (0.5 eq, 0.20 g) in co-solvent THF/DMF (2/1, 6 mL) was cooled to -20 C. under nitrogen and stirred for 20 min. 10-DAB (1 eq, 1 g)/Me2SO4 (10 eq, 1.74 mL) in THF/DMF (2/1, 6 mL) was added into the NaH/CsBr reaction mixture slowly. The reaction mixture was allowed to warm up to room temperature gradually and stirred for 2 hours until the reaction was completed. The reaction was quenched with 10% AcOH/THF, and extracted with CH2Cl2 and water. After partition, the organic layer was extracted with saturated NaHCO3(aq). The organic layer was concentrated and purified by recrystallization (CH2Cl2/Hexane) to provide C1 as a white solid (yield 50%, 0.37 g, LC purity 90%). 1H NMR (400 MHz, D6-DMSO) delta 8.01 (d, J=7.2 Hz, 2H), 7.66 (t, J=7.4 Hz, 1H), 7.56 (t, J=7.6 Hz, 2H), 5.37 (d, J=7.2 Hz, 1H), 5.31 (d, J=4.0 Hz, 1H), 4.97 (d, J=8.4 Hz, 1H), 4.74 (s, 1H), 4.72-4.61 (m, 1H), 4.40 (s, 1H), 4.03 (dd, J=8.2, 13.4 Hz, 2H), 3.81 (dd, J=6.6, 10.6 Hz, 1H), 3.75 (d, J=7.2 Hz, 1H), 3.29 (s, 3H), 3.21 (s, 3H), 2.74-2.62 (m, 1H), 2.20 (s, 3H), 2.17 (d, J=8.4 Hz, 2H), 1.97 (s, 3H), 1.58-1.41 (m, 4H), 0.93 (s, 6H); 13C NMR (100 MHz, D6-DMSO) delta 205.5, 169.7, 165.2, 144.1, 133.3, 132.8, 130.2, 129.5, 128.7, 83.3, 82.8, 80.5, 80.1, 76.9, 75.3, 74.4, 66.2, 56.7, 56.5, 56.1, 47.1, 42.5, 31.8, 26.9, 22.4, 20.5, 15.2, 10.1. | |
With sodium hydride; In tetrahydrofuran; mineral oil; at 45℃;Product distribution / selectivity; | Preparation of 7, 10-dimethoxy-lO-DAB[00152] 10-DAB (100 g, 0.184 mol) was suspended in THF (500 ml) with dimethyl sulfate (57.9 g, 0.46 mol) was added. Sodium hydride (60%> dispersion in oil, 22.8 g, 0.57 mol) was added portionwise. The suspension was heated to 45C while stirring. After the reaction was complete (HPLC monitoring), the mixture was cooled to 10C, and HC1 (500ml of 2% sol.) was added into the cooled mixture, forming an off-white suspension. The suspension was cooled to below 10C and vacuum filtered through a filter funnel. The white product was washed with water (2x 175 ml) and THF (2x 100 ml) and dried in a vacuum oven at 45C to give 63.54 g (0.111 mol, 60 %) of a white product (HPLC purity 87 %). Recrystallization from hot DMF improved the purity to above 96 % (50.41 g). | |
With caesium bromide; sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; at -20 - 20℃; for 2.33333h;Inert atmosphere; | A solution of sodium hydride (60%, 3 eq, 0.22 g)/CsBr (0.5 eq, 0.20 g) was dissolved inco-solvent THF/DMF (211, 6 mL), cooled down to -20C under nitrogen, and stirred for 20minutes. Natural taxoid 10-deacetylbaccatin III (10-DAB) was obtained from Yung Shin Pharm.Ind. Co. LTD. (Taichung, Taiwan) or SM Herbal (India). 10-DAB (1 eq, 1 g)/Me2S04 (10 eq,1.74 mL) in THF/DMF (211, 6 mL) was added into the sodium hydride reaction mixture slowly.The reaction mixture was allowed to warm up to room temperature gradually. The reactionmixture was stirred for 2 hours until the reaction was completed. The mixture was quenched with10 % AcOH/THF, and extracted with CH2Cb and water. After partition, the organic layerextracted with saturated NaHC03(aq} It was concentrated and purification by recrystallization(CH2Cb/Hexane) to yielded C1 as white solid (yield: 50%, 0.37 g, LC purity: 90%). 1H NMR (400 MHz, D6-DMSO) b 8.01 (d, J= 7.2 Hz, 2H), 7.66 (t, J= 7.4 Hz, 1H), 7.56 (t, J= 7.6 Hz,2H), 5.37 (d, J= 7.2 Hz, 1H), 5.31 (d, J= 4.0 Hz, 1H), 4.97 (d, J= 8.4 Hz, 1H), 4.74 (s, 1H),4.72-4.61 (m, 1H), 4.40 (s, 1H), 4.03 (dd, J = 8.2, 13.4 Hz, 2H), 3.81 (dd, J = 6.6, 10.6 Hz, 1H),3.75 (d, J = 7.2 Hz, 1H), 3.29 (s, 3H), 3.21 (s, 3H), 2.74-2.62 (m, 1H), 2.20 (s, 3H), 2.17 (d, J =8.4 Hz, 2H), 1.97 (s, 3H), 1.58-1.41 (m, 4H), 0.93 (s, 6H); 13C NMR (100 MHz, D6-DMSO) b205.5, 169.7, 165.2, 144.1, 133.3, 132.8, 130.2, 129.5, 128.7, 83.3, 82.8, 80.5, 80.1, 76.9, 75.3,74.4, 66.2, 56.7, 56.5, 56.1, 47.1, 42.5, 31.8, 26.9, 22.4, 20.5, 15.2, 10.1. |
With caesium bromide; sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; at -20 - 20℃; for 2h;Inert atmosphere; | A solution of sodium hydride (60%, 3 eq, 0.22 g)/CsBr (0.5 eq, 0.20 g) was dissolved in co-solvent THF/DMF (2/1, 6 mL), cooled down to -20C under nitrogen, and stirred for 20 minutes. Natural taxoid 10-deacetylbaccatin III (10-DAB) was obtained from Yung Shin Pharm. Ind. Co. LTD. (Taichung, Taiwan) or SM Herbal (India). 10-DAB (1 eq, 1 g)/Me2S04 (10 eq, 1.74 mL) in THF/DMF (2/1, 6 mL) was added into the sodium hydride reaction mixture slowly. The reaction mixture was allowed to warm up to room temperature gradually. The reaction mixture was stirred for 2 hours until the reaction was completed. The mixture was quenched with 10 % AcOH/THF, and extracted with CH2C12 and water. After partition, the organic layer extracted with saturated NaHC03(aq). It was concentrated and purification by recrystallization (CH2C12/Hexane) to yielded CI as white solid (yield : 50 %, 0.37 g, LC purity: 90%). 1H NMR (400 MHz, D6-DMSO) delta 8.01 (d, J= 7.2 Hz, 2H), 7.66 (t, J= 7.4 Hz, 1H), 7.56 (t, J= 7.6 Hz, 2H), 5.37 (d, J = 7.2 Hz, 1H), 5.31 (d, J= 4.0 Hz, 1H), 4.97 (d, J= 8.4 Hz, 1H), 4.74 (s, 1H), 4.72-4.61 (m, 1H), 4.40 (s, 1H), 4.03 (dd, J= 8.2, 13.4 Hz, 2H), 3.81 (dd, J= 6.6, 10.6 Hz, 1H), 3.75 (d, J= 7.2 Hz, 1H), 3.29 (s, 3H), 3.21 (s, 3H), 2.74-2.62 (m, 1H), 2.20 (s, 3H), 2.17 (d, J = 8.4 Hz, 2H), 1.97 (s, 3H), 1.58-1.41 (m, 4H), 0.93 (s, 6H); 13C NMR (100 MHz, D6-DMSO) delta 205.5, 169.7, 165.2, 144.1, 133.3, 132.8, 130.2, 129.5, 128.7, 83.3, 82.8, 80.5, 80.1, 76.9, 75.3, 74.4, 66.2, 56.7, 56.5, 56.1, 47.1, 42.5, 31.8, 26.9, 22.4, 20.5, 15.2, 10.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With lithium hexamethyldisilazane; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 1.58333h;Inert atmosphere; | Preparation of Cabazitaxel via triethylsilyl-Cabazitaxel[00155] A solution of LHMDS (1 M/THF, ethylbenzene, 7 ml, 7 mmol) was added dropwise over 5 min to a stirred suspension of 7, 10-dimethoxy- 10-DAB (11.45 g, 20 mmol) and triethylsilyl ("TES")-beta lactam (11.3 g, 30 mmol) in DMF (26 ml) and THF (34 ml) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was then partitioned between MTBE (200 ml) and 5 % aqueous citric acid (104 ml). The organic layer was separated and extracted with water (3x100 ml). The organic layer was then evaporated to a small volume under reduced pressure at 50C. Fresh MTBE (50 ml) was added to the concentrate and the mixture was evaporated again. The addition of MTBE and its evaporation was repeated two more times to remove residual water. MTBE (10 ml) was added to the resulting syrup so that the overall estimated volume of MTBE was 30 ml and the mixture was heated to 60C. Hot n- heptane (60C, 60 ml) was added, and the mixture was stirred at 60C for 5 min and then allowed to cool to 15-20C. The cooled mixture was stirred at 15-20C for 2 h. The product was then filtered off, washed with a mixture of MTBE/heptane 1 :2 (2x), and dried to give TES-Cabazitaxel (15.4 g, 80%). A solution of p-toluenesulfonic acid (114 mg, 0.6 mmol) in MeOH (2 ml) was added to a solution of TES-Cabazitaxel (1.90 g, 2 mmol) in THF (4 ml) and MeOH (4 ml) at 0-5C. The reaction mixture was stirred at 0-5C for 1 h. The reaction was then neutralized by adding a solution of TEA/toluene (1 M, 0.63 ml). The mixture was then warmed to room temperature. Toluene (5 ml) was added and the mixture was stirred under vacuum for 1 h. Another portion of toluene (5 ml) was added and the stirring under vacuum was continued, first at room temperature and after 30 min at 30C. The mixture was then allowed to cool to room temperature over 1 h and stirred at room temperature for an additional 30 min. The product was filtered off, washed with toluene (2x) and dried to give Cabazitaxel (1.65 g, 90%). |
45% | With iron(III) chloride; sodium hydride; In tetrahydrofuran; mineral oil; at -15 - 20℃; for 2.5h;Inert atmosphere;Product distribution / selectivity; | A solution of sodium hydride (60%, 8 eq, 112 mg) in 2 mL THF was cooled to -5 C. under nitrogen. 7,10-di-methoxy-10-DAB (1 eq, 200 mg) in 2 mL THF was added dropwise to the NaH solution. The reaction mixture was added a mixture of (3R,4S)-tert-butyl 2-oxy-4-phenyl-3-(triethylsilyloxy)azetidine-1-carboxylate (beta-lactam, 2.5 eq, 329 mg) and FeCl3 (0.5 eq, 28.4 mg) in 2 mL THF. The reaction mixture was stirred for 2.5 hours at -1520 C. until the reaction was completed. The reaction was quenched with 10% AcOH/THF, and extracted with ethylacetate and water. The organic layer was dried by rotavapor to obtain crude C2 (yields 45%, LC purity 95%). |
With sodium hydride; lithium bromide; In tetrahydrofuran; at -15 - 20℃; for 2h;Inert atmosphere; | A solution of sodium hydride (60 %, 8 eq, 112 mg) was dissolved in 2 mL THF and cooled down to -15C under nitrogen. And then 7,10-di-methoxy-10-DAB CI (1 eq, 200 mg) dissolved in 2 mL THF was added into the sodium hydride mixture. And then was added the mixture of (3R,4S)-tert-butyl-2-oxy-4-phenyl-3-(triethylsilyloxy)azetidine-l-carboxylate (2.5 eq, 329 mg) and LiBr (0.5 eq, 15 mg) in 2 mL THF slowly. The reaction mixture was stirred 2 hours at -15~20C until the reaction was complete. The mixture was quenched with 10 % AcOH/THF, and extracted with ethylacetate and water. The organic layer was dried by rotavapor to obtain the crude C2 (LC purity: 58%); 1H NMR (400 MHz, CDC13) delta 8.10 (d, J= 7.2 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.47 (t, J= 7.6 Hz, 2H), 7.37 (t, J= 7.4 Hz, 2H), 7.32-7.27 (m, 3H), 6.29 (t, J= 8.6 Hz, 1H), 5.65 (d, J= 7.2 Hz, 1H), 5.49 (d, J= 9.6 Hz, 1H), 5.27 (d, J= 10.0 Hz, 1H), 5.00 (d, J = 7.6 Hz, 1H), 4.80 (s, 1H), 4.55 (s, 1H), 4.25 (dd, J= 8.4, 52.0 Hz, 2H), 3.94-3.83 (m, 2H), 3.45 (s, 3H), 3.30 (s, 3H), 2.76-2.65 (m, 1H), 2.53 (s, 3H), 2.41-2.14 (m, 2H), 1.95 (s, 3H), 1.85-1.74 (m, 2H), 1.72 (s, 3H), 1.68 (s, 1H), 1.33 (s, 9H), 1.24 (s, 3H), 1.20 (s, 3H), 0.78 (t, J= 7.8 Hz, 9H), 0.49-0.28 (m, 6H); 13C NMR (100 MHz, CDC13) delta 204.9, 171.7, 170.0, 166.9, 155.2, 139.4, 138.9, 135.0, 133.5, 130.1, 129.2, 128.6, 128.5, 127.7, 126.4, 84.1, 82.4, 81.5, 80.6, 79.8, 78.9, 76.4, 75.2, 74.8, 71.6, 57.2, 57.0, 56.7, 47.2, 43.3, 35.2, 31.9, 28.1, 26.6, 22.9, 21.2, 14.3, 10.3, 6.5, 4.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | 10-DAB (10 mmol) was added to 150 mL of tetrahydrofuran to prepare a solution, protected by N2, placed in a low temperature reactor, and cooled to -75 C; n-BuLi (35 mmol) was slowly dropped into the aforementioned solution, stirred, and the solution temperature was kept Above -70 ; After the dropwise addition is completed, slowly raise the solution temperature to -35 and stir for one hour; add methyl iodide (40mmol) to the reaction solution and continue stirring for one hour; after the reaction is complete, add 30mL of saturated ammonium chloride , 10 mL of water and 100 mL of ethyl acetate, extract and separate the liquid, take the organic phase and concentrate in vacuo to obtain the crude compound of formula (III); add the obtained crude compound of formula (III) to 20 mL of ethyl acetate and 100 mL of petroleum ether In a mixed solvent, heat to 70 C. and stir for one hour, suction filter while hot, and dry the filter cake to obtain the pure product. The structure of the product is as shown in formula (a), which is 7,10-dimethoxy-10-DAB. Yield: 52%. The 1H NMR diagram of the product is shown in FIG. 1, and the 13 C NMR diagram thereof is shown in FIG. 2. | |
With potassium hydride; In tetrahydrofuran; at -20 - 20℃; for 8h; | EXAMPLE 3; Preparation of Cabazitaxel-2'-0-Glycinate; Synthesis of 7p,10p-Dimethoxy-10-Deacetylbaccatin III; A suspension of 10-deacetylbaccatin III (Sigma- Aldrich; 4.4 g) intetrahydrofuran (50 ml) and a solution of methyl iodide (20.5 g,) in tetrahydrofuran (20 ml) was simultaneously added dropwise to a suspension of potassium hydride (10.0 g), in tetrahydrofuran (30 ml) at -20 C. Next the reaction mixture was stirred for eight hours at room temperature. Then, the reaction mixture was added to water (200 ml) and the resulting mixture was stored overnight at 4 C. Diisopropyl ether (200 ml) was added and the solid precipitate was filtered off. The crude product was purified by silica gel chromatography giving 1.55 g of the desired 7p,10p-dimethoxy-10-deacetylbaccatin III having 98% purity as determined by HPLC analysis. | |
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 25℃; for 7.5h; | Reference Exampie-: Preparation of 7,10 diaikyiated -10 DAB- Hi 7,10 di-methoxy -10 DAB-lli used in the process of the present invention may be prepared according to the process disclosed in US5962707, wherein as per exampe- 10, the process involves the use of Sodium hydride as base in the reaction of methyl iodide with 10-DAB-lil in Tetrahydrofuran (THF) solvent. The reaction is carried out between 0-25C for about 7.5 hrs and subsequently pouring in diisopropyi ether (DIPE) to provide 7,10-dimethoxy-lO-deacetybaccatin with the recovery yield of more than 60%. Also, 7, 10 di-methyfation of 10 DAB -Ml using methyi iodide and base in the defined stoichiometry and conditions can be practiced similar to as disclosed in CN1022S5947A. The process involves the reaction of 10 -DAB-III (20 mmo) with methyi iodide in the presence of KH {30% solution) as base (60 mmo) and THF solvent at temperature ranging between -30 to -60 *C to get the product in nearly 60 % yield. |
With caesium bromide; sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; at -20 - 20℃; for 2.33333h;Inert atmosphere; | A solution of sodium hydride (60%, 3 eq, 0.22 g)/CsBr (0.5 eq, 0.20 g) was dissolved inco-solvent THF/DMF (211, 6 mL), cooled down to -20C under nitrogen and was stirred for 20minutes. 10-DAB (1 eq, 1 g)/Mel (10 eq, 1.2 mL) in THF/DMF (211, 6 mL) was added into thesodium hydride reaction mixture slowly. The reaction mixture was allowed to warm up to roomtemperature gradually. The reaction mixture was stirred for 2 hours until the reaction wascompleted. The mixture was quenched with 10 % AcOH/THF, and extracted with CH2Cb andwater. After partition, the organic layer extracted with saturated NaHC03(aq} It was concentratedand purification by recrystallization (CH2Cb/Hexane) to yielded C1 as white solid (LC purity:52%) | |
10 g | With sodium hydride; In N,N-dimethyl-formamide; for 1.5h; | Dimethylformamide (100 ml) was added to 4alpha-acetoxy-2alpha-benzyloxy-5beta,20-epoxy-1beta,7beta,10beta,13alpha-tetrahydroxy-9-oxo-11-taxene (20 gm) at room temperature and cooled to -10 to 0 C. Sodium hydride (3.7 gm) was added to the reaction mass and methyl iodide (60 ml) was then added. The reaction mass was stirred for 1 hour and 30 minuted at -10 to 0 C and ethyl acetate (100 ml) was added to the reaction mass. The layers were separated and aqueous layer was extracted with ethyl acetate. Combined organic layers were dried with sodium sulfate and then concentrated to obtain 10 gm of 7beta,10beta-dimethoxy-10-deacetoxybaccatin III. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; dicyclohexyl-carbodiimide; In ethyl acetate; at 20℃;Molecular sieve; Inert atmosphere; | Synthesis of Cabazitaxel-2'-0-Glycinate; Dicyclohexylcarbodiimide (0.80 g) and then 4-(N,N-dimethylamino)pyridine(0.12 g) were added to a suspension of 7p,10p-dimethoxy-10-deacetylbaccatin III (1.35 g), beta-lactam shown above (1.55 g), and powdered 4 A molecular sieves (0.35 g) in 15 ml of ethyl acetate. The mixture was stirred overnight at room temperature under an argon atmosphere, and was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel chromatography giving the corresponding Cabazitaxel-2'-0-N-CBZ-glycinate in the form of a white solid (1.05 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium hexamethyldisilazane; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 1.08333h;Inert atmosphere;Product distribution / selectivity; | Preparation of Cabazitaxel via ethoxyethyl-Cabazitaxel[00154] A solution of lithium bis(trimethylsilyl)amide ("LHMDS" , 1 M/THF, ethylbenzene, 7 ml, 7 mmol) was added dropwise over 5 min to a stirred suspension of 7, 10-dimethoxy- 10-DAB (11.45 g, 20 mmol) and ethoxyethyl ("EE")-beta lactam (8.72 g, 26 mmol) in DMF (30 ml) and THF (30 ml) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 h. Acetic acid (4 M solution in water, 3.5 ml, 14 mmol) was added and the reaction was stirred for 5min. The reaction mixture was then partitioned between MTBE (200 ml) and water (150 ml). The organic layer was separated, extracted with water (3x100 ml) and filtered through MgSC^. n-BuOH (50 ml) was added to the MTBE filtrate and the mixture was concentrated under reduced pressure at 30C. p-Toluene sulfonic acid (571 mg, 3 mmol) and n-BuOH (130 ml) were added to the concentrate, and the mixture was stirred at 50C for 1 h. The reaction mixture was cooled to room temperature, seeded with n-BuOH solvate of Cabazitaxel and stirred overnight. The product was filtered off, washed with n-BuOH and hexane and dried to give Cabazitaxel (11.8 g, 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With water;Raney nickel; In methanol; at 23℃; | Preparation of 7,10-dimethoxy-10-DAB (compound 5)[00168] Raney Nickel (slurry in water, 20 g) was added to a solution of 7, 10-methylthio- methyl-10-DAB (4) (665 mg, 1 mmol) in methanol (30 ml) and the mixture was stirred at 23 C overnight. The methanol was evaporated under reduced pressure. THF (50 ml) was added and the mixture was stirred for 20 min and filtered through Celite, and then the filtrate was concentrated to small volume. The product was precipitated by adding methanol, and precipitate was then filtered, washed with methanol and dried (350 mg, 61 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With hydrazine hydrate; In N,N-dimethyl-formamide; at 23℃; for 18h;Inert atmosphere; | Preparation of 7,10-dimethoxy-10-DAB (compound 5)[00169] Hydrazine hydrate (0.97 ml, 20 mmol) was added to a stirred mixture of 13- acetyl-7,10-dimethoxy-10-DAB (6) (1.23 g, 2 mmol) in DMF (3.3 ml) under nitrogen, and the resulting reaction mixture was stirred at 23C for 18 h. The reaction mixture was then partitioned between EtOAc and water. The organic phase was extracted with water (2x), and concentrated under reduced pressure and the product was precipitated by adding methanol. The precipitated product was filtered, washed with methanol and dried (607 mg, 53 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With potassium hydride; In tetrahydrofuran; at 0 - 20℃; | Example 4Preparation of 7,10-dimethyl-10-DAB[0046]A suspension of 10-deacetyl-10-methyl baccatin III (20 g) in a solution of MeI in THF was added dropwise to a prewashed suspension of potassium hydride in THF at 0 C. The mixture was allowed to warm to room temperature, and after stirring the reaction mixture was poured into a mixture of diisopropyl ether and water. The mixture was filtered through a sintered funnel to provide 7,10-dimethyl-10-DAB, which was dried under vacuum at 50 C. (61% yield).[0047]1H NMR (400 Hz, MHz, DMSO) delta 8.02 (d, J=7.2 Hz, 2H), 7.68-7.65 (m, 1H), 7.57 (t, J=8 Hz, 2H), 5.39 (d, J=6.8 Hz, 1H), 5.31 (d, J=4.4 Hz, 1H), 4.98 (d, J=9.2 Hz, 1H) 4.75 (s, 1H), 4.66-4.65 (m, 1H), 4.40 (s, 1H), 4.06-4.01 (m, 2H), 3.83-3.79 (m, 1H), 3.75 (d, J=7.2 Hz, 1H), 3.30 (s, 3H), 3.22 (s, 3H), 2.69-2.65 (m, 1H), 2.21 (s, 3H), 2.20-2.17 (m, 2H), 1.98 (s, 3H), 1.52 (s, 3H), 1.52-1.46 (m, 1H), 0.91 (s, 6H). |
58.8% | With sodium hydride; In N,N-dimethyl acetamide; at -15 - -5℃; for 1h; | The solution of 325 g of 4alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-10beta-methoxy-9-oxo-1beta,13alpha,7beta-trihydroxy-11-taxene in 1.95 litre is cooled at -10 to -15C. 734.5g of methyl iodide and 23.3 g of sodium hydride were charged to the reaction mixture. Reaction mixture is stirred for one hour at -5 to -15C. 17.17 g of sodium hydride is charged to the reaction mixture and reaction mixture is stirred for 4-5 h at the same temperature. To this solution 104.8 ml of acetic acid is added slowly and stirred for 30 min. to this reaction mixture 3.25 litre of purified water is added and reaction mixture is stirred for 4 h at 20-30C. The reaction mass is filtered and wet cake is washed with purified water (1.625x2) and methanol (325x2). The wet cake is treated with 4.06 litre of methanol (325x2) and solid material is filtered and again washed with methanol. The obtained solid material is dried under vacuum at 40-50C for 4-6 hrs to get 4alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-1beta,13alpha-dihydroxy-7beta,10beta-dimethoxy-9-oxo-11-taxene. Yield = 58.8 % Chromatographic Purity: 97.13 % |
58.8% | With sodium hydride; In N,N-dimethyl acetamide; at -15 - -10℃; | Example 8 Synthesis of 4alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-1beta,13alpha-dihydroxy-70,100-dimethoxy-9-oxo-11-taxene [0104] The solution of 325 g of 4alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-10beta-methoxy-9-oxo-1beta,13alpha,7beta-trihydroxy-11-taxene in 1.95 litre is cooled at -10 to -15 C. 734.5 g of methyl iodide and 23.3 g of sodium hydride were charged to the reaction mixture. Reaction mixture is stirred for one hour at -5 to -15 C. 17.17 g of sodium hydride is charged to the reaction mixture and reaction mixture is stirred for 4-5 h at the same temperature. To this solution 104.8 ml of acetic acid is added slowly and stirred for 30 min. to this reaction mixture 3.25 litre of purified water is added and reaction mixture is stirred for 4 h at 20-30 C. The reaction mass is filtered and wet cake is washed with purified water (1.625×2) and methanol (325×2). The wet cake is treated with 4.06 litre of methanol (325×2) and solid material is filtered and again washed with methanol. The obtained solid material is dried under vacuum at 40-50 C. for 4-6 hrs to get 4alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-1beta,13alpha-dihydroxy-7beta,10beta-dimethoxy-9-oxo-11-taxene. [0105] Yield=58.8% [0106] Chromatographic Purity: 97.13% |
A first reaction mixture of 1 0f3-methoxy- 1 0-deacetoxy baccatin-IlI (5 g), methyl iodide (50 ml), and dimethyl formamide (20 ml) was stirred for 30 mm at 20-30 C and cooled to 0-5 C. To this mixture, 0.86 g of sodium hydride ( 60% in liquid paraffin oil w/w) was added and the mixture was stirred. In another flask, a second reaction mixture of water (80 ml) and ammonium chloride (24 g) was prepared, to which ethyl acetate (500ml) was added. The first reaction mixture was added to the second reaction mixture and the combined mixture was stirred. The aqueous and organic layers were separated and water (80 ml) was added to the organic layer. Layers were separated and the organic layer was washed with brine solution (prepared by using 24 g Sodium chloride dissolved in 80 ml water) and concentrated under vacuum. Methanol (20 ml) was then added to theconcentrated mass, and the mixture was stirred, producing a solid. The solid was filtered, washed with methanol, and dried to yield 7f3, 10f3-dimethoxy-10-deacetyl baccatin-Ill (Formula-IV). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 2h; | Preparation of XVa? from XIVa [0175] XVa? was prepared according to FIG. 27. To a THF (2 mL) solution of XVa (200 mg, 0.35 mmol), DMAP (9 mg, 0.67 mmol) and VIa (280 mg, 0.70 mmol) was added dicyclohexylcarbodiimide (181 mg, 0.88 mmol). The solution was stirred for 2 hours at room temperature. 1 M HCl (1 mL) was added and the product mixture was filtered and extracted with EtOAc (5 mL). The extract was washed with NaHCO3 (1 mL) and then water (1 mL) and the organic layer was evaporated under vacuum to provide an oil that was purified by column chromatography eluting with EtOAc/n-heptane (1.5:1) to furnish XVa? (303 mg, 91%) as a white solid. |
With dmap; dicyclohexyl-carbodiimide; In tetrahydrofuran; | Example 5 Preparation of 4-alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-1beta-hydroxy-7beta,10beta-dimethoxy-9-oxo-11-taxen-13alpha-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate 7,10-dimethyl-10-DAB (200 mg), 4-dimethylaminopyridine (4-DMAP), and (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylic acid (280 mg) were dissolved in THF. Dicyclohexylcarbodiimide was then added to the mixture. After the reaction was completed, the reaction mixture was quenched with HCl. The reaction mixture was filtered with filter paper and washed with EtOAc. The filtrate was washed with NaHCO3 followed by water. The organic layer was reduced under vacuum to provide an oil that was purified by column chromatography with EtOAc/n-heptane to furnish 4-alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-1beta-hydroxy-7beta,10beta-dimethoxy-9-oxo-11-taxen-13alpha-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate as a white amorphous solid. | |
With dmap; dicyclohexyl-carbodiimide; In toluene; at 20 - 30℃; | (2R, 4S, 5R)-3 -tert-butoxycabonyl -2-(4-methoxy phenyl)-4-phenyl- 1-3 -oxazolodine-5- carboxylic acid (6.1 g) was added to a mixture of 7f3, 10f3-dimethoxy-10-deacetyl baccatin-TTT (4 g), toluene (200 ml), dimethylaminopyridine (0.925 g), and N,N?dicyclohexylcarbodiimide (3.93 g) and stirred at a temperature of 20-30 C. A hydrochloric acid solution (35% of 1.2 ml of aqueous hydrochloride acid in 20 ml ofethyl acetate) was added to this mixture and reaction mass was filtered through a Hyflo bed. A sodium bicarbonate solution (2.4 g sodium bicarbonate dissolved in 40 ml of water) was added to the filtrate and the organic and aqueous layers were separated. A sodium bicarbonate solution (2.4 g sodium bicarbonate dissolved in 40 ml of water) was again added to the organic layer and again, the layers were separated. Water (40 ml) wasthen added to the organic layer, and again, the layers were separated. The organic layer was washed with brine solution (Prepared by using 12 g Sodium chloride dissolved in 40 ml Water) and dried. Activated carbon (0.4 g) was added to the filtered solution and the mixture was stirred. The solution was filtered through a Hyflo bed with toluene to remove the carbon. The filtrate was concentrated under vacuum, after which a mixture of ethyl acetate (40 ml) and heptanes (200 ml) was added, producing a solid. The solid wasfiltered, washed with heptanes, and dried to yield 4cL-acetoxy-2cL-benzoyloxy-5f3, 20- epoxy-i f3-hydroxy, 7f3, 10f3-dimethoxy-9-oxo-i i-taxene-i3cL-yl (2R, 4S, 5R)-3-tert- butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl- 1, 3 -oxazolidine-5-carboxylate (FormulaW). |
With dmap; dicyclohexyl-carbodiimide; In ethyl acetate; at 20℃; for 3h; | 137 g of oxazolidine acid derivative of Chemical Formula 8 was dissolved in 2 L of EA, and 227 g of DCC and 23 g of DMAP were added thereto. To the resulting solution 69 g of the obtained intermediate of Chemical Formula 6 was added and agitated at room temperature for about 3 hours. After reaction was completed, insoluble materials were removed by filtration, and the organic phase was concentrated under reduced pressure. The concentrated solution was dissolved in 0.1 L of DCM, and 1 L of hexane was added thereto to form a precipitate. After completion of hexane addition, the reaction mixture was additionally agitated for 30 minutes, filtrated and dried under reduced pressure in a 40C oven to obtain 78 g of the intermediate of Chemical Formula 7 as a white solid (purity: 88%, yield: 84%, cumulative yield from 10-deacetylbaccatin III is 38%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.5% | 190 g of 4alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-1beta,13alpha-dihydroxy-7beta,10beta-dimethoxy-9-oxo-11-taxene is dissolved in 3.8 1 of tetrahydrofuran and stirred for 30 min at 20-30C. Charged 20.24 g of 4-(N,N-dimethylamino)pyridine (DMAP) and 198.8 g of (2R,4S,5S)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l ,3- oxazolidine-5-carboxylic acid to the reaction mix and stirred at 20-30C for 30 min. To this reaction mixture 83.7 g of diisopropylcarbodiimide is added andreaction mixture is stirred for 4-5 hour. The solid is filtered and washed with tetrahydrofuran (425x2). The filtrate is charged in 5.13 L of water and reaction mass is stirred for 3-4 hours at 20- 30C. The solid is filtered and washed with water (425x2). The solid is again washed with 570 ml methanol and suck dried for 2 h. The solid is again treated with 1.33 litre methanol by heating to reflux for 2 hours. The solution is cooled to room temperature and solid is filtered. The solid is washed with 570 ml of methanol and suck dried for 1 hour. The material is dried under vacuum for 4-6 h at 40-50C to get 260 g of 4alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-113,13alpha-dihydroxy-7beta,10beta-dimethoxy-9-oxo-11-taxen-13alpha-yl (2R,4S,5S)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate. Yield: 82.5 % Chromatographic Purity: 98.84 % |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.3% | With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 0 - 5℃;Inert atmosphere; | 19.8 ml of THF is added to the 4.3 g of 4alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-1beta-hydroxy-7beta,10beta-dimethoxy-9-oxo-13beta-triethylsilyloxy-11-taxene. After the stirring at 0-5C under nitrogen, 9.4 ml of tetrabutyl ammonium fluoride (TBAF) is added to the reaction mixture and stirred for 4-5 hrs at 0-5C. Reaction mixture is concentrated under vacuum at below 25C to nearly the half volume. Reaction mixture is diluted by adding a solution of 0.1 ml acetic acid in 50 ml water. The slurry is filtered and solid material is washed with 30 ml DM water. The filtrate is extracted by using 50 ml ethyl acetate. Organic layer is concentrated to dryness and refluxed with 100 ml ethyl acetate. The slurry is filtered and solid material is dried under vacuum at 40-45C to get 1.05 g 4alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-1beta,13alpha-dihydroxy-7beta,10beta-dimethoxy-9-oxo-11-taxene. Yield: 29.3 % |
29.3% | With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 0 - 5℃;Inert atmosphere; | Example 13 Synthesis of 4alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-1beta,13alpha-dihydroxy-7beta,10beta-dimethoxy-9-oxo-11-taxen [0125] THF is added to the 4.3 g of 4alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-1beta-hydroxy-7beta,10beta-dimethoxy-9-oxo-13beta-triethylsilyloxy)-11-taxene. After the stirring at 0-5 C. under nitrogen, 9.4 ml of tetrabutyl ammonium fluoride (TBAF) is added to the reaction mixture and stirred for 4-5 hrs at 0-5 C. Reaction mixture is concentrated under vacuum at below 25 C. to nearly the half volume. Reaction mixture is diluted by adding a solution of 0.1 ml acetic acid in 50 ml water. The slurry is filtered and solid material is washed with 30 ml DM water. The filtrate is extracted by using 50 ml ethyl acetate. Organic layer is concentrated to dryness and refluxed with 100 ml ethyl acetate. The slurry is filtered and solid material is dried under vacuum at 40-45 C. to get 1.05 g 4alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-1beta,13alpha-dihydroxy-7beta,10beta-dimethoxy-9-oxo-11-taxen. [0127] Yield: 29.3% |
6 g | With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃; for 3h; | The crude product (10 g) obtained in the previous step was directly dissolved in tetrahydrofuran (40 ml), and tetrabutyl fluoride (3.6g) was added. The reaction was complete at room temperature for 3 hours. The reaction was complete with TLC. The tetrahydrofuran was removed by distillation under reduced pressure. Water (20 ml) and dichloromethane (10 ml) were added and stirred at room temperature overnight. The white solid was collected by filtration, and the white solid was suspended in tetrahydrofuran (10 ml) and refluxed for 2 h at room temperature overnight. The white solid was collected by filtration, dried in vacuo to give 6 g of solid, two steps in yield: 70%, purity: 96%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.6 g | With dmap; dicyclohexyl-carbodiimide; In ethyl acetate; at 20℃; for 24h;Molecular sieve; | STEP-A: Coupling of 7,10-Dimethoxy lO-DAB-tll (a) with 3-(tert-butoxycarbonyt)-2- (4-methoxyphenyl)-4-phehyloxazpjidine-5-carboxylic acid (b) 7,10-methoxy-lO-deacetylbaccatin (7,10-dimethpxy-lQ-OAB-IIJ) (2.5 g), 3-(tert- butoxycarbonyl)-2-(4-methoxyphenyi)-4-phenyioxazolidine-5-carboxylic acid (2.8 g, 1.6 moi) and ethyl acetate (25 mL) were charged in a single neck RB flask at room temperature (20-25C) under stirring. The reaction mixture was brought to 20 C. To the reaction mixture, Dicyclohexyl carbodiimide (DCC) (1,62 g, 1.8 moi), 4,4- Dimethyl aminopyridine (D AP) (210 mg, 0.4 moi) and a small quantity of molecular sieves 4A were added under stirring conditions. The temperature of 20 "C was maintained for 24 hours. Progress of the reaction is monitored by Thin Layer Chromatography (TLC). On completion of the reaction, reaction mixture is filtered to obtain solid material. Ethyl acetate was recovered from the solid material at below 40 C under vacuum. This material was further purified by column chromatography over silica ge (230-400 mesh). Column was packed in dichloromethane; hexane and run up to dichloromethane. When no product was observed on TLC then column was euted with ethyl acetate: hexane to get the coupled product (c). Yield: 1.6 g, Purity: 98.14% Mass Spectrum: {M+l] = 954.7 and [M+NH4+] = 971.9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With hydrogen; In N,N-dimethyl-formamide; at 20℃; under 2584.17 Torr; for 15h; | Preparation of 7,10-di-O-methyl-10-DAB (XVa) from XIVa [0167] XVa was prepared according to FIG. 20. A DMF (3 mL) solution of 7,10-di-O-1,3-benzodithiolan-2-yl-10-DAB (XIVa, 100 mg, 0.12 mmol) was hydrogenolysed in the presence of a suspension of Raney Nickel (approximately 2.1 g) under an atmosphere of 3.4 atm of hydrogen gas at ambient temperature for 15 hours. The mixture was filtered through a pad of diatomaceous earth and washed with EtOAc and this was evaporated to give an oil. The mixture dissolved in EtOAc, was washed three times with water and was evaporated to provide an oil that after purification by column chromatography (eluting with 1:1 n-heptane/EtOAc) provided XVa (27 mg, 42%). Rf=0.28 (EtOAc/n-heptane (2/1, v/v). m.p. 249-251 C.; IR (KBr) cm-1; IR (KBr) 3553, 3435, 2945, 2893, 2827, 1705 cm-1; [alpha]21D=-59 (c=0.5; methanol); 1H NMR (400 MHz, DMSO) delta 8.02 (d, J=7.2 Hz, 2H), 7.68-7.65 (m, 1H), 7.57 (t, J=8 Hz, 2H), 5.39 (d, J=6.8 Hz, 1H), 5.31 (d, J=4.4 Hz, 1H), 4.98 (d, J=9.2 Hz, 1H) 4.75 (s, 1H), 4.66-4.65 (m, 1H), 4.40 (s, 1H), 4.06-4.01 (m, 2H), 3.83-3.79 (m, 1H), 3.75 (d, J=7.2 Hz, 1H), 3.30 (s, 3H), 3.22 (s, 3H), 2.69-2.65 (m, 1H), 2.21 (s, 3H), 2.20-2.17 (m, 2H), 1.98 (s, 3H), 1.52 (s, 3H), 1.52-1.46 (m, 1H), 0.91 (s, 6H); 13C NMR (100 MHz, DMSO) delta 205.9, 170.1, 165.7, 144.5, 133.7, 133.3, 130.7, 130.0, 129.1, 83.8, 83.3, 20.9, 80.6, 77.3, 75.8, 74.9, 66.6, 57.1, 56.9, 56.5, 47.5, 42.9, 40.6, 32.3, 27.4, 22.8, 21.0, 15.6, 10.5; HRMS calculated for C31H40O10 was 572.2621, and found 572.2581. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen; In N,N-dimethyl-formamide; at 50℃; under 8274.59 Torr; for 23h; | Preparation of 7,10-di-O-methyl-10-DAB (XVa) from XIVb [0168] XVa was prepared according to FIG. 21. A DMF (48 mL) solution of XIVb (4.8 g, 6.4 mmol) was hydrogenolysed in the presence of a suspension of Raney Nickel (approximately 75 g) under an atmosphere of hydrogen gas at 160 psi at 50 C. for 23 h. After the reaction was complete as determined by HPLC analysis, the product mixture was filtered through a pad of diatomaceous earth and washed with EtOAc (250 mL). HPLC analysis indicated a 49% purity (area %) of XVa and HPLC assay indicated a 43% yield of XVa (based on XIVb). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen; In N,N-dimethyl-formamide; at 20℃; under 2584.17 Torr; for 15h; | Preparation of 7,10-di-O-methyl-10-DAB (XVa) from XVIa [0181] XVa was prepared according to FIG. 33. A solution of XVIa (22 mg, 0.03 mmol) in DMF (1 mL) was hydrogenolysed in the presence of a suspension of Raney Nickel (approximately 700 mg) at ambient temperature for 15 hours under an atmosphere of hydrogen gas (3.4 atm pressure). The mixture was filtered through a pad of diatomaceous earth and washed with EtOAc 30 mL) and the filtrate was evaporated under vacuum to provide a solid. The solid was triturated with EtOAc 10 mL) and filtered to provide XVa. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen; In N,N-dimethyl-formamide; at 20℃; under 2584.17 Torr; for 15h; | Preparation of 7,10-di-O-methyl-10-DAB (XVa) from XIVc [0169] XVa was prepared according to FIG. 22. A DMF (1 mL) solution of XIVc (10 mg, 0.01 mmol) was hydrogenolysed in the presence of a suspension of Raney Nickel (approximately 0.5 g) under an atmosphere of hydrogen gas at 3.4 atm at ambient temperature for 15 hours. The mixture was filtered through a pad of diatomaceous earth and washed with EtOAc and this was evaporated to give an oil that after purification by column chromatography (eluting with 1:1 n-heptane/EtOAc) provided XVa. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | To a solution of compound 8 (0.52 g, 0.96 mmol) in THF (6 mL) was added 1.0 M LiHMDS (3.82 mL, 3.82 mmol) at -72 C dropwise. The reaction mixture was stirred at -72 C for 40 min. Subsequently, a solution of TfOMe (0.33 mL, 2.87 mmol) in THF (2 mL) was added at -72 C dropwise over 5 min. The reaction was stirred at -72 C for 4 h. The resulting mixture was poured into sat. NH4Cl solution (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (n-hexane/EtOAc = 1:1) gave B-01 (0.48 g, 0.84 mmol, 87%) as a white solid. | |
55% | 10-DAB (10 mmol) was added to 150 mL of tetrahydrofuran to prepare a solution, protected by N2, placed in a low-temperature reactor, and cooled to -78 C; n-BuLi (35 mmol) was slowly dropped into the aforementioned solution, stirred, and the solution temperature was kept Higher than -70 ; After the dropwise addition is completed, slowly raise the temperature of the solution to -35 and stir for one hour; add methyl trifluoromethanesulfonate (40mmol) to the reaction solution and continue stirring for one hour; add 30mL after the reaction is completed A saturated ammonium chloride solution, 10 mL of water, and 100 mL of ethyl acetate were extracted and separated. The organic phase was taken and concentrated in vacuo to obtain the crude compound of formula (III). The crude compound of formula (III) was added to 20 mL of ethyl acetate. In a mixed solvent of ester and 100 mL petroleum ether, heat to 70 C and stir for one hour, suction filter while hot, and dry the filter cake to obtain a pure product. The structure of the product is as shown in formula (a), which is 7,10-dimethoxy -10-DAB, 55% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; toluene-4-sulfonic acid; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;Inert atmosphere; | General procedure: A solution of 4 equiv 7a in dry CH2Cl2, was added with 1 equiv baccatin derivative, 2 equiv DCC, 0.5 equiv DMAP and 0.2 equiv PTSA, at room temperature with stirring overnight. The reaction was evaporated under reduced pressure. Chromatography of the crude mixture (n-hexane/EtOAc = 2:1) afforded 16 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With manganese(IV) oxide; In acetone; at 20℃; for 4h; | The compound 2 (1 eq.) was dissolved in acetone solution, into which 10 equivalents of manganese dioxide was added at room temperature to react for 4 hours. By post-treatment of purification by column chromatography, the compound 3 was given in a yield of 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; toluene-4-sulfonic acid; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;Inert atmosphere; | General procedure: A solution of 4 equiv 7a in dry CH2Cl2, was added with 1 equiv baccatin derivative, 2 equiv DCC, 0.5 equiv DMAP and 0.2 equiv PTSA, at room temperature with stirring overnight. The reaction was evaporated under reduced pressure. Chromatography of the crude mixture (n-hexane/EtOAc = 2:1) afforded 16 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With iron(III) chloride; sodium hydride; In tetrahydrofuran; at -15 - 20℃; for 2.5h;Inert atmosphere; | A solution of sodium hydride ( 60 %, 8 eq, 112 mg) was dissolved in 2 mL THF and cooleddown to -15C under nitrogen. And then 7,10-di-methoxy-10-DAB (1 eq, 200 mg) dissolved in 2mL THF was added into the sodium hydride mixture, And then was added the mixture of(3R,4S)-tert-butyl-2-oxy-4-phenyl-3-(triethylsilyloxy)azetidine-1-carboxylate (2.5 eq, 329 mg)and FeCh (0.5 eq, 28 mg) in 2 mL THF slowly. The reaction mixture was stirred for 2.5 hours at-15~20C until the reaction was completed. The mixture was quenched with 10% AcOH/THF,and extracted with ethylacetate and water. The organic layer was dried by rotavapor to obtain thecrude C2 (Yield: 45%, LC purity: 95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium bromide; sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; at -20 - 20℃; for 2.33333h;Inert atmosphere; | A solution of sodium hydride (60%, 3 eq, 0.22 g)/CsBr (0.5 eq, 0.20 g) was dissolved inco-solvent THF/DMF (211, 6 mL), cooled down to -20C under nitrogen and was stirred for 20 minutes. 10-DAB (1 eq, 1 g)/MePhS03Me (10 eq, 2.77 mL) in THF/DMF (211, 6 mL) wasadded into the sodium hydride reaction mixture slowly. The reaction mixture was allowed towarm up to room temperature gradually. The reaction mixture was stirred for 2 hours until thereaction was completed. The mixture was quenched with 10 % AcOH/THF, and extracted withCH2Clz and water. After partition, the organic layer extracted with saturated NaHC03(aq} It wasconcentrated and purification by recrystallization (CH2Clz/Hexane) to yielded C1 as white solid(LC purity: 40%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium bromide; sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; at -20 - 20℃; for 2.33333h;Inert atmosphere; | A solution of sodium hydride (60%, 3 eq, 0.22 g)/CsBr (0.5 eq, 0.20 g) was dissolved inco-solvent THF/DMF (211, 6 mL), cooled down to -20C under nitrogen and was stirred for 20minutes. 10-DAB (1 eq, 1 g)/CF3S03Me (10 eq, 2.08 mL) in THF/DMF (211, 6 mL) was addedinto the sodium hydride reaction mixture slowly. The reaction mixture was allowed to warm upto room temperature gradually. The reaction mixture was stirred for 2 hours until the reactionwas completed. The mixture was quenched with 10 % AcOH/THF, and extracted with CH2Clzand water. After partition, the organic layer extracted with saturated NaHC03(aq)· It wasconcentrated and purification by recrystallization (CH2Clz/Hexane) to yielded C1 as white solid(LC purity: 46%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.5% | With dmap; diisopropyl-carbodiimide; In tetrahydrofuran; at 20 - 30℃; | Example 15 Synthesis of 4alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-1beta,13alpha-dihydroxy-7beta,10beta-dimethoxy-9-oxo-11-taxen-13alpha-yl-(2R,4S,5S)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate [0131] 190 g of 4alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-1beta,13alpha-dihydroxy-7beta,10beta-dimethoxy-9-oxo-11-taxene is dissolved in 3.8 l of tetrahydrofuran and stirred for 30 min at 20-30 C. Charged 20.24 g of 4-(N,N-dimethylamino)pyridine (DMAP) and 198.8 g of (2R,4S,5S)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylic acid to the reaction mix and stirred at 20-30 C. for 30 min. To this reaction mixture 83.7 g of diisopropylcarbodiimide is added and reaction mixture is stirred for 4-5 hour. The solid is filtered and washed with tetrahydrofuran (425×2). The filtrate is charged in 5.13 L of water and reaction mass is stirred for 3-4 hours at 20-30 C. The solid is filtered and washed with water (425×2). The solid is again washed with 570 ml methanol and suck dried for 2 h. The solid is again treated with 1.33 litre methanol by heating to reflux for 2 hours. The solution is cooled to room temperature and solid is filtered. The solid is washed with 570 ml of methanol and suck dried for 1 hour. The material is dried under vacuum for 4-6 h at 40-50 C. to get 260 g of 4alpha-acetoxy-2alpha-benzoyloxy-5beta,20-epoxy-1beta,13alpha-dihydroxy-7beta,10beta-dimethoxy-9-oxo-11-taxen-13alpha-yl-(2R,4S,5S)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate. [0132] Yield: 82.5% [0133] Chromatographic Purity: 98.84% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28 g | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 60℃; for 5h; | 7beta,10beta-Dimethoxy-10-deacetoxybaccatin III (22 gm), methylene chloride (660 ml), (4S,5R)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyloxazoline-5-carboxylic acid (22gm) and 4-(diemthylamino)pyridine (7 gm) were added at room temperature uner stirring. To the reaction mixture was added N,N-dicyclohexylcarbodiimide (14gm) and heated to 60 C. The reaction mass was stirred for 5 hours at 60 C and methylene chloride (200 ml) was added to the reaction mass. The layers were separated and the aqueous layers was extracted with methylene chloride. Combined organic layers were dried with sodium sulfate to obtain a wet solid. To the wet solid was added hexane (500 ml) and methanol (5 ml) at room temperature. The contents were stirred for 14 hours at room temperature and filtered. The solid obtained was dried to obtain 28 gm of 5-((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-acetoxy-12-(benzoyloxy)-11-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]-benzo[1,2-b]oxet-9-yl)-3-(tert-butyl)(4S,5R)-2,2-dimethyl-4-phenyloxazolidine-3,5-dicarboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at -30℃; for 1h; | 83 g of the obtained intermediate of Chemical Formula 5 was dissolved in 400 ml of DMF, the resulting solution was cooled to -30C, and 35 ml of Me2SO4 was added thereto. Then, 14 g of NaH (60% dispersion in mineral oil) was slowly added thereto, and the resulting mixture was agitated for about 1 hour. The reaction completion was confirmed by HPLC, and 4 L of 5% NH4Cl aqueous solution was slowly added to form a precipitate. The obtained precipitate was filtrated, washed with excess distilled water and dried under reduced pressure in a 40C oven to obtain 69 g of the intermediate of Chemical Formula 6 as a white solid (purity: 73%, yield: 79%, cumulative yield from 10-deacetylbaccatin III is 45%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 20℃; for 3h;Inert atmosphere; | The compound 1 (1 eq.) was dissolved in anhydrous tetrahydroffiran to react with methyl magnesium bromide (2.5 eq.) for 3 hours at room temperature under the protection of nitrogen. After post-treatment, the crude compound 2 was obtained afier dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.12 g | With sodium hydride; In N,N-dimethyl-formamide; at 20 - 25℃; for 5h; | To a 250 ml three-necked flask was added 114 g of methyl iodide, 5 g of compound III, and 50 mL of DMF was stirred uniformly. Add 0.9g of NaH in batches, the system turbidity, release a lot of gas; T = 20 ~ 25 insulation reaction 5h. T = 23 incubation reaction, adding 5ml water quenching reaction. Add ethyl acetate 50ml × 3, saturated salt 50ml × 3, anhydrous sodium sulfate drying. Filtered and distilled to dryness to give a yellow oil which was isolated on silica gel to give 1.12 g of a white solid, compound II. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
365 g | With lithium hexamethyldisilazane; In tetrahydrofuran; at -60 - 5℃; | 50L of the reactor were added 20L of anhydrous THF, 400g of compound IV, 400g of compound III, stirring evenly, the system cooled to an internal temperature of -55 ~ -60 . A 1-fold solution of LHMDS / THF was added dropwise thereto. Drop Bi, temperature to 0 ~ 5 insulation reaction. Reaction completed, add 1.2L water quenching reaction, adding 21L ethyl acetate extraction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated at 35 to 40 C under reduced pressure to dry 800 g of the crude product of Compound I. The crude of compound I was 800 gThe residue was purified by column chromatography, eluting with n-heptane / isopropyl acetate = 1/1 (about 4 L) and then with n-heptane / isopropyl acetate = 1/2 to collect enriched compound I High purity components (about 12L). The eluent from compound I was concentrated to dryness at 35 to 40 C. To give 510 g of a white solid. Recrystallization was carried out with 3.5 volumes of isopropyl acetate / 20 volumes of n-heptane. The compound I was purely 365g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium hexamethyldisilazane; In tetrahydrofuran; at 0 - 10℃; for 6h;Inert atmosphere; | Under nitrogen protection, 100 g (174.6 mmol) of Formula II was addedAnd 120 g (357 mmol) of the compound were dissolved in 100 ml of anhydrous tetrahydrofuran,The ice bath was cooled to C and 174 mL (174 mmol) of LiHMDS was added dropwise,The reaction temperature is less than 10 C reaction 6h, after the end of the reaction, adding 200mL water quenching reaction, followed by adding 200ml tetrahydrofuran and 0.2N hydrochloric acid 50mL, the control temperature of 25 C reaction 6h, after the end of the reaction, adding 600mL ethyl acetate and saturated chlorine Sodium chloride solution 300mL, extraction layer, collecting organic layer, saturated sodium chloride solution 300mL washed three times, purified water 300mL washing once, anhydrous magnesium sulfate drying 2h, vacuum distillation to the crude carbapamide, HPLC detection purity greater than 90.0 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 12h; | A total of 43.5 g (7.5 mmol) 5 2 · 86 g (5 mmol), DCC 2 · 06 g (10 mmol) and DMAP 0.3 g (2.5 mmol) was dissolved in 60 mL of CH2C12, Reaction at room temperature for about 12 h, TLC (petroleum ether: AcOEt = 7: 3) monitoring The reaction is complete. Filter insoluble matter, the filtrate followed by dilute HC1, Saturated NaHC03 solution, H20, saturated brine washing, Dried over anhydrous MgS04 and the solvent was removed under reduced pressure to give coupling product 6 as a white solid. Not purified directly for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
162g | With dmap; caesium bromide; sodium hydride; In tetrahydrofuran; at -30℃; for 2h; | (2) 7,10-methoxy 10-DAB selectivity with (3R,4S)-1 tert-butoxycarbonyl-3-(2-ethoxyethoxy)-4phenylpropionactamThe esterification condensation reaction is carried out under the action of a condensation reagent to obtain the cabazitaxel precursor N-1. 105 g of 7,10 methoxy 10-DAB is dissolved in 500 mL of tetrahydrofuran, stirred and dissolved, and then added to the side chain at 3 C (3R, 4S)-1 tert-butoxycarbonyl-3-(2-ethoxyethoxy)-4phenylpropanactam 52g, dissolved and added anti-degradation agent 52g bromide, sodium hydride 9g and DMAP 0.9g, mixed After the reaction was completed for 2 hours, the reaction was completed by TLC, and then acetic acid-tetrahydrofuran solution (containing a volume of 10% acetic acid in tetrahydrofuran) was added to inactivate the bubbles until the bubbles were no longer released, and the reaction solution was poured into 3000 mL of ice water for 2 hours, minus The mixture was filtered under vacuum to obtain a light yellow solid cabazitaxel precursor N-1 162 g, with a detected content of 74.5%, and a weight yield of 134.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.6% | With dmap; caesium bromide; sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; at -30℃; for 3h; | Add 100 g of 10-DAB to a dry three-necked flask, dissolve in 50 mL of DMF and 150 mL of tetrahydrofuran, stir magnetically, wait for complete dissolution, add 50 g of cesium bromide, and cool to -30 C under ice bath conditions, and add sequentially. 10 g of sodium hydride and 1 g of DMAP were kept under low temperature conditions, 50 mL of dimethyl carbonate was added dropwise, and the reaction was carried out for 3 hours after mixing. After the TLC test showed that the reaction was completed, the reaction solution was added to a solution of 20% by mass aqueous sodium hydrogencarbonate solution in 2000 mL. After 2 hours, the kaba intermediate intermediate 7,10 methoxy 10-DAB crystal was obtained by vacuum distillation; the crystal was washed successively with ethyl acetate for several times, and dried to obtain 105 g of white crystals, and the detected content was 85.3%, and the reaction yield was obtained. It is 89.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Add the formula 7,10-dimethoxy-10-DAB (10 mmol), (4S, 5R) -3- (2-furylformyl) -2- (4-methoxyphenyl) -4-phenyl -5-oxazoline carboxylic acid (23 mmol) and dimethylaminopyridine (5 mmol) were added to 10 mL of toluene to prepare a mixed solution, heated to 70 C, and stirred for 15 minutes; N, N'-dicyclohexylcarbodiimide (30mmol) was added to the aforementioned mixed solution and stirred for one hour; filtered, the filtrate was taken, and purified by flash column chromatography to obtain the compound represented by the formula (V); 20 mL of the obtained compound represented by the formula (V) was added to 5% hydrogen chloride The solution was stirred at room temperature for 16 hours, and the obtained crude product was subjected to column chromatography (using methanol: dichloromethane = 1:20 to 1:30 as eluent) to obtain a pure product. The product structural formula is shown in formula (b). , Is 3- [N- (2-furylformyl)]-phenylisoserine-<strong>[183133-94-0]7,10-dimethoxy-10-deacetylbaccatin III</strong> ester, the yield is 56%. The 1H NMR diagram of the product is shown in FIG. 5, and the 13 C NMR diagram thereof is shown in FIG. 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | The formula 7,10-dimethoxy-10-DAB (10 mmol), (4S, 5R) -3- (2-thienyl) -2- (4-methoxyphenyl) -4-phenyl -5-oxazoline carboxylic acid (23 mmol) and dimethylaminopyridine (5 mmol) were added to 10 mL of toluene to prepare a mixed solution, heated to 70 C, and stirred for 15 minutes; N, N'-dicyclohexylcarbodiimide (30mmol) was added to the aforementioned mixed solution and stirred for one hour; filtered, the filtrate was taken, and purified by flash column chromatography to obtain the compound represented by the formula (V); 20 mL of the obtained compound represented by the formula (V) was added to 5% hydrogen chloride The solution was stirred at room temperature for 16 hours, and the obtained crude product was subjected to column chromatography (using methanol: dichloromethane = 1:20 to 1:30 as eluent) to obtain a pure product. The product structural formula is shown in formula (b) , 3- [N- (2-thienyl)]-phenylisoserine-<strong>[183133-94-0]7,10-dimethoxy-10-deacetylbaccatin III</strong> ester, yield 56%. The 1H NMR diagram of the product is shown in FIG. 7, and the 13 C NMR diagram thereof is shown in FIG. 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | The formula 7,10-dimethoxy-10-DAB (10 mmol), (4S, 5R) -3- (4-dimethylaminobenzoyl) -2- (4-methoxyphenyl) -4 -Phenyl-5-oxazolinecarboxylic acid (23 mmol) and dimethylaminopyridine (5 mmol) were added to 10 mL of toluene to prepare a mixed solution, heated to 70 C, and stirred for 15 minutes; N, N'-dicyclohexyl carbon Diimine (30 mmol) was added to the aforementioned mixed solution and stirred for one hour; filtered, the filtrate was taken, and purified by flash column chromatography to obtain a compound represented by formula (V); and the obtained compound represented by formula (V) was added to 20 mL 5% In a solution of hydrogen chloride in ethanol, stirred at room temperature for 16 hours, the obtained crude product was subjected to column chromatography (using methanol: dichloromethane = 1: 20 to 1:30 as an eluent) to obtain a pure product. ) Shows 3- (N-p-dimethylaminobenzoyl) -phenylisoserine-<strong>[183133-94-0]7,10-dimethoxy-10-deacetylbaccatin III</strong> ester with a yield of 56%. A 1H NMR diagram of the product is shown in FIG. 3, and a 13C NMR diagram thereof is shown in FIG. 4. |
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