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CAS No. : | 2067-33-6 | MDL No. : | MFCD00004414 |
Formula : | C5H9BrO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WNXNUPJZWYOKMW-UHFFFAOYSA-N |
M.W : | 181.03 | Pubchem ID : | 16368 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.8 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 35.79 |
TPSA : | 37.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.45 cm/s |
Log Po/w (iLOGP) : | 1.36 |
Log Po/w (XLOGP3) : | 1.35 |
Log Po/w (WLOGP) : | 1.64 |
Log Po/w (MLOGP) : | 1.45 |
Log Po/w (SILICOS-IT) : | 1.2 |
Consensus Log Po/w : | 1.4 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.55 |
Solubility : | 5.12 mg/ml ; 0.0283 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.74 |
Solubility : | 3.33 mg/ml ; 0.0184 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.72 |
Solubility : | 3.42 mg/ml ; 0.0189 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.12 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | 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 |
---|---|---|
99% | at 110℃; Flow reactor | General procedure: Lauric acid (1a) (2.01 g, 10.0 mmol) was dissolved in methanol (10 mL) and then placed in a syringe, which wasthen attached to a syringe pump. The methanol solution was fedinto a stainless steel column (inner volume: 0.53 mL, 4.0 mm i.d. © 50 mm) filled in HO-SAS (334 mg) with a flow rate of0.177 mL.min-1. The column was immersed into an oil bath(110°C). A back-pressure regulator (75 psi) was connected.The reaction mixture was collected from the outlet. The reaction mixture eluted during the first 10 min was discarded. Thereaction mixture was collected during 3 min and added n-decane as an internal standard for GC analysis. The followingportion was collected for a 30 min period in a glass flask, andsolvent was evaporated. The crude mixture was purified byflash column chromatography on SiO2 (hexane/ethyl acetate =5/1) to give 3a (1.13 g, 99percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | for 48 h; Inert atmosphere; Reflux | General procedure: A mixture of ω-bromocarboxylic acid (1 equiv) and triphenylphosphine (1 equiv) in 300 mL of toluene was refluxed for 48 h under argon. The mixture was allowed to cool at room temperature and concentrated in vacuum. The residue was crystallized from various solvents to give the corresponding phosphonium salt. |
50% | at 80℃; for 48 h; | 5-bromopentanoic acid (5.01 g, 0.03 mol) and triphenylphosphine (2.62 g, 0.01 mol) were added to a 100 mL flask, 50 mL of acetonitrile was added and the mixture was heated to 80 ° C for 48 hours. After the reaction was completed, the solvent was spin dried. The reaction system was introduced into cyclohexane to collect precipitated oily precipitate and vacuum-dried product in a yield of 50percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 0.5 h; Stage #2: at 0 - 20℃; for 0.25 h; |
28-1 A 28-2A To a solution of 28-1A (5 g, 27.62 mmol) in DCM, added oxalyl chloride (5.2 g, 41.436 mmol) and catalytic amount of DMF at 0 °C and stirred at RT for 30 min, then added i-BuOH (8.2 g, 110.49 mmol) at 0 °C and stirred at RT for 15 min. The reaction mixture completely distilled off, then added water (100 mL) and extracted with EtOAc (100 mL). The organic layer washed with water (50 mL), NaHC03 solution (50 mL) and dried over Na2S04, and the organic phase was concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (3percent EtOAc in hexanes) to afford 28-2A (5 g, 21.18 mmol, 77percent yield) as a colorless oily liquid. |
62.6% | Stage #1: With dmap; dicyclohexyl-carbodiimide In dichloromethane for 0.5 h; Cooling with ice Stage #2: at 20℃; |
5-bromo-pentanoic acid (5g, 27.62mmol) in dry DCM solution to this while stirring with ice cold N,N'-dimethylaminopyridine (1.68g, 13.75mmol) and DCC (6.83g, 33.15mmol) was added successively. After half an hour was added to tert-butanol (15.8ml, 165.75mmol) in the reaction mixture. The resulting solution was stirred overnight at room temperature. Was then diluted with DCM and washed with successive water and brine. The organic layer was dried and the solvent was evaporated. Using hexane-ethyl acetate to 1percent solution of the residue was purified by chromatography to give the pure tert-butyl 5-bromopentanoate 4.1g (62.6percent yield) of a pale yellow liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.4 g | for 120 h; | Diisopropylcarbodiimide (25.2 g; 0.2 mol), tert-butyl alcohol (14.8 g; 0.2 mol) and CuCl (0.5 g) was stirred overnight at rt. 5-Bromovaleric acid (10.0 g; 55.7 mmol) was dissolved in 150 mL of dichloromethane, and the crude tert-butyl isourea generated in situ was added in 15 equal portions (approximately 3 mL of each) over the period of 5 days. Any increase in the temperature of the reaction mixture above 30 °C led to a rapid decomposition of the alkylating agent. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography on silica gel using a linear gradient of diethyl ether in petroleum ether. Yield: 7.4 g (56percent). Colorless liquid, Rf = 0.81 (S8). 1H NMR (600 MHz, CDCl3): δ = 3.42 (t, J = 6.7 Hz, 2H), 2.25 (t, J = 7.4 Hz, 2H), 1.88 (m, 2H), 1.74 (m, 2H), 1.45 (s, 9H, t-Bu). 13C NMR (150.9 MHz, CDCl3): δ = 172.47 (-CO-O), 80.28, 34.47, 33.14, 31.95, 28.04 (3C), 23.60. IR (film) νmax (cm-1): 1729 vs (C=O); 2978 m, 2934 m, 1367 s (CH3). 1156 vs (C-O). HRMS (ESI) calc for C9H17O2BrNa [M + Na]+ 259.03041, found: 259.03037. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With acetyl chloride for 5h; Reflux; | |
99% | With hydroxy-substituted sulfonic acid-functionalized silica (HO-SAS) at 110℃; Flow reactor; | Typical Procedure for Flow Esterification (Table1,Entry 6) General procedure: Lauric acid (1a) (2.01 g, 10.0 mmol) was dissolved in methanol (10 mL) and then placed in a syringe, which wasthen attached to a syringe pump. The methanol solution was fedinto a stainless steel column (inner volume: 0.53 mL, 4.0 mm i.d. 50 mm) filled in HO-SAS (334 mg) with a flow rate of0.177 mL.min-1. The column was immersed into an oil bath(110°C). A back-pressure regulator (75 psi) was connected.The reaction mixture was collected from the outlet. The reaction mixture eluted during the first 10 min was discarded. Thereaction mixture was collected during 3 min and added n-decane as an internal standard for GC analysis. The followingportion was collected for a 30 min period in a glass flask, andsolvent was evaporated. The crude mixture was purified byflash column chromatography on SiO2 (hexane/ethyl acetate =5/1) to give 3a (1.13 g, 99%). |
99% | With acetyl chloride for 5h; Reflux; |
90% | With p-toluenesulfonic acid monohydrate In methanol for 0.75h; Reflux; | |
87% | With chloro-trimethyl-silane | |
82% | With sulfuric acid Heating; | |
82% | With acetyl chloride at 70℃; for 24h; | |
72% | With toluene-4-sulfonic acid for 1h; Reflux; | S2.4.1 Methyl 5-bromovalerate (25) A solution of 5-bromovaleric acid (24; 10 mmol) and p-toluenesulfonic acid (6 mmol) in MeOH was refluxed for 1 h. The solvent was then removed under reduced pressure, and the residue was dissolved in EtOAc and washed with saturated aqueous solutions of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give methyl 5-bromovalerate (25). MS m/z: 195.10, 197.10 [M+H] + Yield: 72% 1H NMR (400 MHz, DMSO) δ 3.57 (s, 3H, -OCH3), 3.51 (t, J = 6.6 Hz, 2H, -CH2Br), 2.33 (t, J = 7.4 Hz, 2H, -CH2CO-), 1.85-1.75 (m, 2H, -CH2-CH2-CH2-), 1.68 - 1.57 (m, 2H, -CH2-CH2-CH2-). |
With sulfuric acid | ||
With sulfuric acid | ||
for 16h; Ambient temperature; | ||
With sulfuric acid Heating; | ||
With SOCl2 or oxalyl chloride at 20℃; | ||
With thionyl chloride at 20℃; for 2h; | Representative procedure for 10a-e General procedure: SOCl2 (15.0 mmol) was added dropwise into a solution of bromo carboxylic acid (10.0 mmol) in methanol (30 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated to give the crude product, which was used directly for the next step. | |
With thionyl chloride at 20℃; for 3h; | ||
With sulfuric acid | ||
With toluene-4-sulfonic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sodium hydroxide In ethanol at 40℃; for 48h; | |
52% | Stage #1: 5-bromopentanoic acid; phenylmethanethiol With sodium hydroxide In ethanol for 44h; Heating; Stage #2: With sodium hydroxide In ethanol at 25℃; for 0.5h; Further stages.; | |
52% | Stage #1: 5-bromopentanoic acid; phenylmethanethiol With sodium hydroxide In ethanol; water for 44h; Heating / reflux; Stage #2: With sodium hydroxide; potassium hexacyanoferrate(III) In ethanol; water at 25℃; for 0.5h; Stage #3: With hydrogenchloride In water for 0.166667h; | A solution of α-mercapto toluene (9.3 g, 75 mmol) and 5-bromovaleric acid (4.5 g, 24.8 mmol) in 30 mL of absolute EtOH was treated with a 4 N aqueous solution of NaOH (30 mL) and was warmed at reflux for 44 h. The mixture was concentrated, treated with 15 mL of aqueous 4 N NaOH and 50 mL of aqueous 1 N K3FeCN6. After stirring for 30 min at 25 °C, the mixture was extracted with Et2O. The aqueous solution was treated with aqueous 6 N HCl and stirred for 10 min. The precipitate was collected by filtration, washed with H2O and dried. The solid was recrystallized in hexane to give S57 as white crystals (1.72 g, 7.7 mmol). The mother liquor and washings were concentrated and column chromatography (SiO2, 4.5 x 10 cm, 10-25% EtOAc-hexanes gradient) afforded additional amounts of S57 (1.17 g, 5.2 mmol, 52% combined yields) as a pale yellow solid: 1H NMR (CDCl3, 400 MHz) δ 7.32-7.30 (m, 4H), 7.26-7.23 (m, IH), 3.71 (s, 2H), 2.43 (t, 2H, J= 7.3 Hz), 2.34 (t, 2H, J= 7.3 Hz), 1.74-1.57 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 179.8, 138.4, 128.8 (2C), 128.4 (2C), 126.9, 36.2, 33.5, 30.7, 28.4, 23.7. |
With sodium hydroxide In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In acetonitrile at 80℃; for 24h; | |
92% | In acetonitrile for 24h; Heating; | |
88% | In toluene for 48h; Inert atmosphere; Reflux; | 3.2.4. General procedure for the synthesis of phosphonium salts (5) General procedure: A mixture of ω-bromocarboxylic acid (1 equiv) and triphenylphosphine (1 equiv) in 300 mL of toluene was refluxed for 48 h under argon. The mixture was allowed to cool at room temperature and concentrated in vacuum. The residue was crystallized from various solvents to give the corresponding phosphonium salt. |
65% | In 5,5-dimethyl-1,3-cyclohexadiene for 2h; Reflux; | 4.4.1. (E)-6-(4-Methoxyphenyl)hex-5-enoic acid (16) In a 250 mL flask equipped with a refrigerant containing 10.0 g of 5-bromovaleric acid 15 (1 eq, 55.2 mmol), 16.0 g of triphenylphosphine (1.1 eq., 61.0 mmol) and 150 mL of xylene were added. The mixture was heated at reflux for 2 h with stirring. After cooling them ixture to room temperature, the white precipitate formed was filtered on sintered glass and washed with acetone. After drying,15.92 g of (4-carboxybutyl)triphenylphosphonium bromide were recovered as a white solid with 65% yield. |
56% | In acetonitrile for 24h; Heating; | |
50% | In acetonitrile at 80℃; | |
50% | In acetonitrile at 80℃; for 48h; | 37 Example 37 A quaternary phosphonium salt of the following formula was prepared 5-bromopentanoic acid (5.01 g, 0.03 mol) and triphenylphosphine (2.62 g, 0.01 mol) were added to a 100 mL flask, 50 mL of acetonitrile was added and the mixture was heated to 80 ° C for 48 hours. After the reaction was completed, the solvent was spin dried. The reaction system was introduced into cyclohexane to collect precipitated oily precipitate and vacuum-dried product in a yield of 50%. |
In acetonitrile for 18h; Heating; | ||
In acetonitrile Heating; | ||
at 80℃; for 12h; | ||
In acetonitrile Reflux; | ||
7.42 kg | In toluene for 6h; Reflux; Large scale; | |
In acetonitrile Reflux; | ||
In toluene for 24h; Reflux; | Synthesis of phosphonium-based ionic liquids General procedure: A typical procedure for the preparation of [Ph3PC2H4NH2]Br (1c) is as follows: A solution of triphenylphosphine (5 mmol) and 2-bromoethylamine hydrobromide (5 mmol) in 20 mL toluene was heated and subject to reflux for 24 h. After cooling, the resulted crude solid was filtered out, and stirred in 10 mL triethylamine for 4 h. Afterward, the triethylamine was removed, and the as obtained solid was washed three times with ethyl acetate, then dried at 60 °C under vacuum for 12 h to give product 1c in the form of a pale yellow solid. | |
In acetonitrile for 36h; Schlenk technique; Inert atmosphere; Reflux; | ||
In acetonitrile for 36h; Schlenk technique; Reflux; Inert atmosphere; | ||
In toluene for 0.25h; Reflux; | α-1 Preparation of upper side chain: 300g of 5-bromovaleric acid and 420g of triphenylphosphine were added into a 3000ml three-necked flask and 3000ml of tolueneHeat to reflux with stirring for 15 minutes, cool and filter. The filtrate was concentrated to remove toluene. Then add 2000ml of tetrahydrofuran, heated to reflux with stirring, cooled and filtered. The resulting white solid was evacuated in vacuo to yield the upper side chain of the product of reaction al, Mp: 202-206. | |
In acetonitrile for 15h; Reflux; | 4 4.1.3. Synthesis of compounds 1c-f General procedure: To a round-bottom flask was added 5a (5.0 mmol), P(Ph)3 (20.0 mmol) and dry MeCN (10.0 mL). The mixture was stirred vigorously and heated to reflux. After the refluxing was ceased (15 h), the solution was concentrated. The residue was rinsed consecutively with benzene (3 x 10 mL), hexanes (10 mL), and ether (2 x 10 mL). The crystalline white solid was dried to give 6a (1.8 g, 87%) [26] 6b-d were prepared according to the procedure described as 6a. | |
In acetonitrile for 24h; Reflux; | 1.4 4. The modification steps of triphenylphosphine are as follows: 5-Bromopentanoic acid (3.1 g, 17.1 mmol) and triphenylphosphine (PPh3, 4.24 g, 16.1 mmol) were added to 40 mL of acetonitrile and heated to reflux for 24 h. The crude product precipitated by freezing filtration, After washing with ethyl acetate for 3 times, a white powder product, PPh3Br-(CH2)4-COOH (abbreviated as TPP), was obtained. | |
at 85℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dicyclohexyl-carbodiimide In dichloromethane at 20℃; | 1.1 Step l : Synthesis of 4-nitrophenyl 5-bromopentanoate To a solution of 5 -bromo valeric acid (5g, 27.6 mmol) and DCC (5.7g, 27.6 mmol) in DCM (200 ml), p-nitrophenol (4,23g, 30.4 mmol) was added portionwise. The mixture was stirred overnight at RT, then precipitate was filtered off and the solvent was removed under reduced pressure. The crude was purified by flash chromatography (EtOAc in cyclohexane from 5% to 50%) affording 7.1 g of desired compound (Yield: 85 %) MS: m/z = 303 [M+H]+ TLC: (Cy/ EtOAc 9: 1) Rf = 0.40 |
70% | With dicyclohexyl-carbodiimide In ethyl acetate at 20℃; for 15h; | |
53.4% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 8.5h; | 1.1 Example 1:; Preparation of compound V potassium salt (2-(hidroxy)-5-[(5- nitrooxy)pentanoyl]oxy} benzene sulfonic acid potassium salt) none First step - Preparation of intermediate compound 1 A mixture of 4-nitrophenol (25 g), 5-bromo valeric acid (32.5 g), A-(dimethylamino)pyridine (DMAP, 3.5 g) in methylene dichloride (228 ml) was cooled to O 0C, and then EDCHCl (N-(3-Dimethylaminopropyl)-Nf- ethylcarbodiimide hydrochloride, 39.38 g) was added in portionwise. The mixture was stirred for 30 minutes at 0 0C. The temperature was slowly raised to rt and then it was stirred for an additional period of 8 hours. TLC showed completion of the reaction (3:7, EtOAc/Hexane). On completion of the reaction, it was charged 750 ml of water and the organic layer was separated. The organic layer was washed with 1 N NaOH (110 ml) to remove the traces of nitrophenol and then it was washed with brine (200 ml), dried over anhydrous sodium sulphate, filtered and concentrated to yield compound 1 as a solid. Yield: 29 g (53.4%).M.P: 53-55 0C, 1U NMR (CDCl3, 400 MHz): δl.91 -2.02 (4H, m), 2.66 (2H, t, J = 7.1 Hz), 3.48 (2H, t, 7.1 Hz), 7.27 (2H, d, J = 9.2 Hz), 8.27 (2H, d, J = 9.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With hydrogenchloride In 1,4-dioxane at 20 - 22℃; for 45h; | |
88.5% | In toluene for 1.5h; Heating; | |
87% | With sulfuric acid |
84% | With sulfuric acid for 6h; Reflux; | |
With sulfuric acid Reflux; | ||
With toluene-4-sulfonic acid at 70 - 80℃; | ||
With sulfuric acid for 3h; Reflux; | 4.4 Preparation of cyclic ylides General procedure: Preparation of ylides 35-37 was carried out in four steps following the reported procedure.82 The appropriate ω-bromocarboxylic acid (0.1mol) was converted to the ethyl ester by boiling in ethanol (100cm3) in the presence of H2SO4 (0.1cm3) for 3h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dimethylsulfide borane complex In tetrahydrofuran at 45℃; for 1h; Cooling with ice; | 3.1.2. General Procedure for the Synthesis of Alcohols 4-6 General procedure: To an ice-cold solution of acid 1-3 (20 mmol) in THF (30 mL), a borane dimethylsulphide complex (2.7 mL, 28 mmol) was added dropwise. The solution was warmedat room temperature and stirred for 1 h at 45 C. Then, the reaction was cooled at 0 C,quenched with MeOH (60 mL) and concentrated under reduced pressure. The residuewas dissolved in EtOAc, washed with brine, dried over Na2SO4 and concentrated invacuo to obtain the projected alcohols 4-6, which were used in the next step withoutfurther purification. |
96% | With dimethylsulfide borane complex | |
With lithium aluminium tetrahydride; sulfuric acid In tetrahydrofuran for 0.25h; T < 2 deg C; Yield given; |
With dimethylsulfide; borane | ||
63 % Spectr. | With diphenylsilane; triphenylphosphine In tetrahydrofuran at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride | 5-bromopentanoyl chloride (11): 5-bromopentanoyl chloride (11): Degassed solution of 5-bromopentanoic acid (1 eq., 2.85 g, 15.7 mmol) and SOCl2 (1 eq., 1.87 g, 1.14 mL, 15.7 mmol) in dichloromethane DCM (50 mL) was refluxed for 3h. Obtained reaction mass was evaporated under reduced pressure to give 11 (3.11 g, 100%) as a yellowish oil. The crude product was used in the next step without purification. |
99.9% | With thionyl chloride at 80℃; for 5h; | 1.1.7. 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide (k1) General procedure: To a round bottom flask were added 5-bromopentanoic acid (i1, 2.00g, 11.05 mmol) and SOCl2 (3.94g, 33.15 mmol). The mixture was heated with stirring at 80°C for 5 h. After completion of the reaction, the mixture was cooled to room temperature, evaporated under reduced pressure to give intermediate j1 as yellow liquid (2.19g, 99.9% yield). To a solution of intermediate j1 (2.19g, 11.04 mmol) in anhydrous THF (20 mL) was added Pomalidomide (1.51g, 5.53 mmol), the mixture was heated with stirring at 72 for 8 h. After completion of the reaction, the reaction was evaporated under reduced pressure to remove THF. The crude product was mixture with diethyl ether (10 mL) and filtrated, precipitate was washed with diethyl ether and dried under vacuum to give intermediate k1 as gray solid (1.63g, 67.6% yield). |
99.9% | With thionyl chloride at 80℃; for 5h; | 1.1.7. 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide (k1) General procedure: To a round bottom flask were added 5-bromopentanoic acid (i1, 2.00g, 11.05 mmol) and SOCl2 (3.94g, 33.15 mmol). The mixture was heated with stirring at 80°C for 5 h. After completion of the reaction, the mixture was cooled to room temperature, evaporated under reduced pressure to give intermediate j1 as yellow liquid (2.19g, 99.9% yield). To a solution of intermediate j1 (2.19g, 11.04 mmol) in anhydrous THF (20 mL) was added Pomalidomide (1.51g, 5.53 mmol), the mixture was heated with stirring at 72 for 8 h. After completion of the reaction, the reaction was evaporated under reduced pressure to remove THF. The crude product was mixture with diethyl ether (10 mL) and filtrated, precipitate was washed with diethyl ether and dried under vacuum to give intermediate k1 as gray solid (1.63g, 67.6% yield). |
98% | With oxalyl dichloride In benzene at 20 - 50℃; Inert atmosphere; | |
97% | With oxalyl dichloride In benzene at 50℃; for 3h; | |
78% | With thionyl chloride | |
60% | With thionyl chloride In chloroform for 12h; Heating; | |
With oxalyl dichloride Ambient temperature; | ||
With thionyl chloride for 4h; Heating; | ||
With thionyl chloride 1.) room temperature, 45 min, 2.) 45 deg C, 2 h; | ||
With thionyl chloride for 1h; Heating; | ||
With thionyl chloride | ||
With oxalyl dichloride In benzene for 2h; Ambient temperature; | ||
With oxalyl dichloride In dichloromethane at 0 - 20℃; | ||
With oxalyl dichloride at 20℃; for 1.5h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 16h; | ||
With oxalyl dichloride at 40℃; for 1.5h; | ||
With oxalyl dichloride In dichloromethane at 0 - 20℃; for 2.5h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at -5 - 20℃; | ||
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h; | 5 SOCl2 (1.45 mL, 19.9 mmol) and a few drops of dry DMF were added to a solution of 5-bromopentanoic acid (3.0 g, 16.6 mmol; J. Am. Chem. Soc. 1947, 69, 2466) in dry CH2Cl2 (20 mL) , stirred under N2 at r.t and the stirring was continued for 1 h . The solution of the acyl chloride so obtained was slowly added to a solution of salycilic aldehyde (1.60 mL, 13.3 mmol) and dry Py (2.00 mL, 24.9 mmol) in dry CH2Cl2 (30 mL) , stirred at 0 0C under N2. The reaction was allowed to reach r.t. and it was completed after 2 h. The mixture was washed twice with HCl 2M (30 mL) . The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE/EtOAc 90/10 v/v) to give the title compound as pale yellow oil (2.66 g) . Yield 57 %.TLC: Rf = 0.56 PE/EtOAc 80/20 v/v1H-NMR (CDCl3) δ 1.91-2.05 (4H, m) , 2.70 (2H, t, J = 6.8 Hz), 3.48 (2H, t, J = 6.3 Hz), 7.18 (IH, d, Arom ), 7.40 (IH, t, Arom ), 7.64 (IH, t, Arom ), 7.88 (IH, d, Arom ), 10.1 (IH, s) . 13C-NMR (CDCl3) δ 23.2, 31.9, 32.9, 33.1, 123.5, 126.5, 128.2, 131.7, 135.3, 151.3, 171.4, 188.8. MS (CI) m/z 285/287 (M+l)+. | |
With 4-dimethylaminopyridine; triethylamine; 4-methylbenzene-1-sulfonyl chloride In tetrahydrofuran at 25℃; for 0.5h; | ||
With thionyl chloride at 20℃; for 1h; | ||
With thionyl chloride In dichloromethane at 20℃; for 2h; | ||
With thionyl chloride for 2h; Heating; | ||
With thionyl chloride for 3h; Reflux; | ||
With oxalyl dichloride In dichloromethane | ||
With oxalyl dichloride In dichloromethane at 20℃; for 16h; | 56 EXAMPLE 56 [0258] 1-[4-(5-Phenyl-1H-pyrazolo[3,4-b]pyridin-3-ylcarbamoyl)butyl]pyridinium bromide [0259] Oxalyl chloride (0.1 mL, 1.2 mmol) was added to a solution of 5-bromovaleric acid (86 mg, 0.48 mmol) in dichloromethane (10 mL). N,N-Dimethylformamide (1 drop) was added and the mixture was stirred at ambient temperature for 16 hours. The solvent was removed under vacuum, the residue was azeotroped with toluene (3×30 mL) and evaporated to dryness. To this crude acid chloride was added 5-phenyl-1H-pyrazolo[3,4-b]pyridin-3-ylamine (Description 2; 100 mg, 0.48 mmol), pyridine (20 mL). and 4-dimethylaminopyridine (cat). The solution was refluxed at 120° C. for 16 hours then evaporated. The residual material was purified by preparative BPLC on a C18 column, using a gradient elution with 10-90% v/v of acetonitrile (containing 0.01% v/v trifluoroacetic acid) and water (containing 0.1% v/v trifluoroacetic acid) to afford the title compound. [0260] 1H NMR δ (CD3OD): 1.84 (2H, m), 2.18 (2H, m), 2.65 (2H, t), 4.73 (2H, t), 7.42 (1H, m), 7.51 (2H, t), 7.68 (2H, d), 8.12 (2H, t), 8.60 (1H, s), 8.60 (1H, t), 8.76 (1H, d), 9.05 (2H, d). NH protons are assumed to have exchanged with the solvent. MS (APCI+ve): [M]+at m/z 372 (C22H22N5O requires [M]+at m/z 372). | |
With thionyl chloride In chloroform at 20℃; for 24h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 1h; | 5 5-Bromovaleryl Chloride To a solution of 5-bromovaleric acid (1.81 g) in methylene chloride (20 ml) was added dimethylformamide (2 drops). To the mixture was added oxalyl chloride (0.9 ml) under cooling with ice. The mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated to give the title compound (2.37 g) having the following physical data. [00977] NMR (CDCl3): δ 3.41 (t, J=6.0 Hz, 2H), 2.95 (t, J=6.8 Hz, 2H), 2.01-1.79 (m, 4H). | |
With oxalyl dichloride | ||
With thionyl chloride for 2h; Reflux; | 2.2.1. Synthesis of anthraquinone derivates General procedure: BrMAAQ (bromomethoxylamino-anthraquinone). Bromoacetic acid (10 mmol, 1.5 g) dissolved in thionyl chloride (35 mL) was refluxed for 2 h. After cooling to room temperature, thionyl chloride was removed under reduced pressure. Dry benzene (30 mL) was used to wash the residue and then removed. To this residue, a solution of AQ (5 mmol, 1.1 g) dissolved in dry benzene was added and then refluxed for 4 h. The solvent was removed under reduced pressure. BrMAAQ was then obtained after washing with 5% Na2CO3. Yield: 1.55 g, 90%. ESI-MS m/z 342.2 ([M-H]-, calcd. for C16H10BrNO3: 342.9). | |
With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 20℃; for 3.5h; Inert atmosphere; | ||
With oxalyl dichloride In benzene at 50℃; for 2h; Inert atmosphere; | ||
With oxalyl dichloride at 20℃; for 0.75h; Inert atmosphere; | General procedure for the synthesis of ?-bromo-N-(4-bromophenyl)alkanamides (10a-e) General procedure: The appropriate ω-bromoalkanoic acid (1 mmol) was suspended in oxalyl chloride (ca. 2 mL), stirred at ambient temperature for 45 min, and the excess oxalyl chloride evaporated under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL), cooled to -78 °C, and treated dropwise with a solution of 4-bromoaniline (1.1 mmol) and Et3N (1.1 mmol) in CH2Cl2 (11 mL). The mixture was warmed to ambient temperature, stirred for 1 h, and CH2Cl2 (50 mL) was added. The solution was washed with H2O (50 mL), 1 M aq. HCl (50 mL), sat. aq. Na2CO3 (50 mL), brine (50 mL), dried (MgSO4), and the solvent evaporated under reduced pressure to give crude amides 10a-10e. | |
With thionyl chloride at 75℃; Inert atmosphere; | General procedure for preparation of bromoacyl esters (8c and 8d) through acid chlorides (7c, 7d 5-bromovaleric acid (1 equiv) or 4-bromobutyric acid (1 equiv) was dissolved in thionyl chloride (4.5 equiv). The reaction mixture was then heated (75 C, oil bath) under a nitrogen atmosphere overnight. The excess thionyl chloride was removed by adding dichloromethane (25 mL) followed by rotary evaporation under aspirator vacuum. The addition of the dichloromethane and rotary evaporation was repeated (3 ) which yielded the crude acid chloride as an oil. The 5-bromobutyryl chloride 7c or the 4- bromovaleryl chloride 7d were used without further purification in the next step. Benzoin (1 equiv) was dissolved in pyridine (12 mL) followed by cooling the solution to 0 C (ice water bath). The acid chloride 7c, 7d (1 equiv) was then added dropwise to the stirred solution while cooling and stirring. The reaction flask was capped, and after 30 min, the cooling bath was removed. The reaction mixture was then stirred (4 h) at room temperature while monitoring by TLC. After the starting materials were consumed, the reaction mixture was then dissolved in dichloromethane (300 mL) and washed with 5% aqueous HCl (5 120 mL). The organic layer was then separated and dried over anhydrous sodium sulfate. Flash chromatography on silica gel (hexane/ethyl acetate, 6:1) afforded esters 8c (70%) and 8d (23%) as oils | |
With thionyl chloride In methanol at 0 - 20℃; for 20.25h; Inert atmosphere; | ||
With thionyl chloride Inert atmosphere; Reflux; | General procedure: General procedure for the preparation of acid chlorides (36a, 36b): 5 -Bromo valeric acid (1 eq) or 4-bromobutyric acid (1 eq) was dissolved in thionyl chloride (4.5 eq). The reaction mixture was then refluxed (75 °C, oil bath) under nitrogen atmosphere overnight. The excess thionyl chloride was removed by adding dichloromethane (25 mL) and removing using a rotary evaporator under aspirator vacuum. The addition of the dichloromethane and rotary evaporation was repeated (3x) which yielded the acid chloride as an oil. The 5-bromovaleryl chloride 36a or the 4-bromobutyryl chloride 36b were used without further purification in the next step. | |
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 3℃; Reflux; Inert atmosphere; | ||
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide for 2h; Reflux; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; | 8 To a solution of 5-bromovaleric acid (724 mg, 4 mmol) in dry dichloromethane (20 ml) was added oxalyl chloride (0.52 ml, 1.5 mmol), and 2-3 drops of DMF at 0 °C. Reaction mixture was stirred for 7-9 h at room temperature. After completion of the reaction checked by TLC, the solvent was evaporated under vacuum to get 5-bromopentanoyl chloride as yellow solid. Then dissolved the acid chloride in dry dichloromethane (20 ml) and was added compound 15 (1.65 g, 4 mmol) and triethylamine (1.12 ml, 8 mmol) at 0 °C. Reaction mixture was stirred for 10 h at room temperature. After completion of reaction, water (20 ml) was added and compound was extracted with dichloromethane (2 × 20 ml). The organic phase were washed with water followed by brine solution, dried over Na2SO4 and evaporated under vacuum to obtain crude compound. This was further purified by column chromatography (23% ethyl acetate-hexane) to get the compound 16a as brown solid (1.84 g, 80%); mp 115-116 °C; 1H NMR (300 MHz, CDCl3): δ 1.62-1.75 (m, 2H), 1.78-1.95 (m, 2H), 2.24-2.40 (m, 2H), 2.65-2.87 (m, 2H), 2.89-3.03 (m, 1H), 3.43 (t, 1H, J = 6.2 Hz), 3.74 (s, 3H), 3.76 (s, 3H), 3.80 (s, 3H), 3.93-4.12 (m, 1H),), 4.31-4.46 (m, 1H), 4.55-4.63 (m, 1H), 5.21-5.27 (m, 1H), 5.94 (m, 2H), 6.2 (s, 1H), 6.28 (s, 1H), 6.45-6.57 (m, 1H), 6.75 (s, 1H), MS (ESI): 576 [M+H]+. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; | ||
With thionyl chloride; N,N-dimethyl-formamide In toluene at 50℃; for 4h; | 7M Dimethylformamide (116 μΙ_, 1.5 mmol, 0.1 eq.) and thionyl chloride (1.63 ml, 22.5 mmol, 1.5 eq.) were added to a solution of 5-bromovaleric acid (2.71 g, 15 mmol, 1 eq.) in toluene (20 ml) and the reaction mixture was stirred at 50 °C for 4 h. The volatiles were removed under high vacuum, THF (130 ml) was added and the mixture was cooled to 0 °C. N,N- Diisopropylethylamine (4.2 ml, 24 mmol, 1.6 eq.) and ethylamine (2 M solution in THF, 9.0 ml, 18 mmol, 1.2 eq.) were added dropwise. The reaction mixture was stirred for 1 h at 0 °C before being quenched by the addition of saturated aq. NH4CI (100 ml). The reaction mixture was extracted with Et20 (4 x 75 ml) and the combined organic phases were washed with brine (100 ml) before being dried (MgS04), filtered, and concentrated to give the crude material. This was purified by flash chromatography, eluting with petrol/EtOAc (4:6), giving the title product 95 as a clear, colourless oil (2.75 g, 88 %). Analytical data consistent with the literature (Halazy, S. et al., WO 9612713, Pierre Fabre Medicament (1996)). max (filmVcm-1 3275 (broad), 2970, 2933, 1640, 1543, 1439, 1276, 1150, 643 *H NMR (400 MHz; CDCI3) δΗ = 1.13 (t, J = 7.2 Hz, 3H, CH3), 1.78 (m, 2H, CH2), 1.89 (m, 2H, CH2), 2.19 (t, J = 7.3 Hz, CH2CO), 3.27 (dt, J = 7.2, 5.5 Hz, 2H, NHCH2), 3.41 (t, J = 6.5 Hz, 2H, BrCH2), 5.79 (broad s, 1H, NH) 13C NMR (100 MHz; CDCI3) 5C = 15.0 (CH3), 24.4 (CH2), 32.2 (CH2Br), 33.4 (CH2), 34.4 (NHCH2), 35.7 (CH2C=0), 172.3 (C=0) m/z (CI+) 210.0 [M81BrH]+ (80%), 208.0 [M79BrH]+ (80%), 128.1 (100%), 107.1 (60%) HRMS (CI+) calcd for C7Hi581BrNO [M81BrH]+ 210.0317, found 210.0320; calcd for C7H1579BrNO [M79BrH]+ 208.0337, found 208.0341 | |
With thionyl chloride In neat (no solvent) at 20℃; | ||
With oxalyl dichloride at 20℃; for 0.75h; Inert atmosphere; | 5.2.1 5-Bromo-N-(4-bromophenyl)pentanamide (7)[1] 5-bromovaleric acid (2.0 g, 11.0mmol) was suspended in oxalyl chloride (ca. 3 mL), stirred at ambient temperature for 45 min, and the excess oxalyl chloride evaporated under reduced pressure. The residue was dissolved in CH2Cl2 (80 mL), cooled to -78 °C, and treated dropwise with a solution of 4-bromoaniline (1.9 g, 11.0mmol) and triethylamine (1.5 mL, 11.0 mL) in CH2Cl2 (20 mL). The mixture was warmed to ambient temperature, stirred for 4 h, and CH2Cl2 (80 mL) was added. The solution was washed with H2O (80 mL),hydrochloric acid (1M; 80 mL), saturated aqueous sodium hydrogencarbonate (80 mL), brine (80 mL), dried (MgSO4), filtered, and the solvent evaporated under reduced pressure to give the crude amide. Purification by flash chromatography on silica eluting with hexane-ethyl acetate (70:30) yielded amide 7 (3.41 g, 97%) as a colorless solid | |
With thionyl chloride; N,N-dimethyl-formamide In toluene at 50℃; for 4h; | ||
With oxalyl dichloride at 20℃; for 0.75h; Inert atmosphere; | General procedure 1 for the synthesis of ω-bromo-N-(4-bromophenyl)alkanamides[62] The appropriate ω-bromoalkanoic acid (1 mmol) was suspended in oxalyl chloride (ca.2 mL), stirred at ambient temperature for 45 min, and the excess oxalyl chloride evaporated under reduced pressure. The residue was dissolved in CH2Cl2(10 mL), cooled to -78 °C, and treated dropwise with a solution of 4-bromoaniline (1.1 mmol) and triethylamine (1.1 mmol) in CH2Cl2(11 mL). The mixture was warmed to ambient temperature, stirred for 4 h, and CH2Cl2(50 mL) was added. The solution was washed with H2O (50 mL), hydrochloric acid (1M; 50 mL), saturated aqueous sodium hydrogencarbonate (50 mL), brine (50 mL), dried (MgSO4), filtered, and the solvent evaporated under reduced pressure to give the crude amides. | |
With thionyl chloride; N,N-dimethyl-formamide In toluene at 50℃; for 4h; | 7.7M 7M. 5-Bromo-N-ethylpentanamide, 95 Dimethylformamide (116 μL, 1.5 mmol, 0.1 eq.) and thionyl chloride (1.63 ml, 22.5 mmol, 1.5 eq.) were added to a solution of 5-bromovaleric acid (2.71 g, 15 mmol, 1 eq.) in toluene (20 ml) and the reaction mixture was stirred at 50° C. for 4 h. The volatiles were removed under high vacuum, THF (130 ml) was added and the mixture was cooled to 0° C. N,N-Diisopropylethylamine (4.2 ml, 24 mmol, 1.6 eq.) and ethylamine (2 M solution in THF, 9.0 ml, 18 mmol, 1.2 eq.) were added dropwise. The reaction mixture was stirred for 1 h at 0° C. before being quenched by the addition of saturated aq. NH4Cl (100 ml). The reaction mixture was extracted with Et2O (4*75 ml) and the combined organic phases were washed with brine (100 ml) before being dried (MgSO4), filtered, and concentrated to give the crude material. This was purified by flash chromatography, eluting with petrol/EtOAc (4:6), giving the title product 95 as a clear, colourless oil (2.75 g, 88%). Analytical data consistent with the literature (Halazy, S. et al., WO 9612713, Pierre Fabre Medicament (1996)). νmax (film)/cm-1 3275 (broad), 2970, 2933, 1640, 1543, 1439, 1276, 1150, 643 1H NMR (400 MHz; CDCl3) δH=1.13 (t, J=7.2 Hz, 3H, CH3), 1.78 (m, 2H, CH2), 1.89 (m, 2H, CH2), 2.19 (t, J=7.3 Hz, CH2CO), 3.27 (dt, J=7.2, 5.5 Hz, 2H, NHCH2), 3.41 (t, J=6.5 Hz, 2H, BrCH2), 5.79 (broad s, 1H, NH) 13C NMR (100 MHz; CDCl3) δC=15.0 (CH3), 24.4 (CH2), 32.2 (CH2Br), 33.4 (CH2), 34.4 (NHCH2), 35.7 (CH2C=O), 172.3 (C=O) m/z (CI+) 210.0 [M81BrH]+ (80%), 208.0 [M79BrH]+ (80%), 128.1 (100%), 107.1 (60%) HRMS (CI+) calcd for C7H1581BrNO [M81BrH]+ 210.0317. found 210.0320. calcd for C7H1579BrNO [M79BrH]+ 208.0337. found 208.0341. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2.5h; | 5 2.1.5 (4,4-Difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene-8-yl)butylbromide (9c) To a solution of 5-bromovaleric acid (9a) (2 g, 12 mmol) in CH2Cl2 (60 mL) were added DMF (5 drops) and oxalyl chloride (1.4 mL, 16.8 mmol) and the mixture was stirred for 2.5 h at rt. |
|
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 4h; | 1.1. 3-(3-bromopropanamido)benzoic acid (3a) General procedure: In ice bath, 3-bromopropanoic acid (1a, 1.53 g,10 mmol) was dissolved in dichloromethane (30 ml), oxalyl chloride (1.71 ml, 20 mmol) and one drop of dimethylformamide were added. The solution was stirred for 4 h at room temperature. The solvent and excess oxalyl chloride was evaporated. Then, the produced 3-bromopropanoyl chloride was dissolved in 10 ml THF and dropped in the mixture of 3-aminobenzoic acid (2a,1.37 g, 10 mmol) and sodium bicarbonate (1.68 g, 20 mmol) in THF. After stirred for 8 h, the solvent was removed and the mixture was acidified with 1M HCl. The final product was purified by recrystallization with ethanol. Yield 66%, mp: 210-211 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.93(s, 1H), 10.23 (s, 1H), 8.24 (t, J =1.6 Hz,1H), 7.81 (dt, J = 8.0 Hz, 1.6Hz, 1H), 7.63 (dt, J = 8.0 Hz, 1.6Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H),3.74 (t, J = 6.0 Hz, 2H), 2.97 (t, J = 6.0 Hz, 2H). | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; | Step i General procedure: Acid chlorides 16-19 were prepared by combining the parent acids (10mmol) and DMF (1 drop) in dichloromethane (10mL) at 0°C and treating the mixture with oxalyl chloride (1.0mL, 11mmol) and stirring continued at room temperature for 2h then concentrating under a stream of nitrogen to afford acyl chlorides 16-19 as yellow oils and used immediately in the following step | |
With thionyl chloride In dichloromethane for 3h; Reflux; | 1 39d: 5-Bromopentanoyl chloride 39d: 5-Bromopentanoyl chloride (0335) Degassed solution of 5-bromopentanoic acid (1 eq., 2.85 g, 15.7 mmol) and SOCl2 (1 eq., 1.87 g, 1.14 mL, 15.7 mmol) in DCM (50 mL) was refluxed for 3 hours. The obtained reaction mass was evaporated under reduced pressure to give 39d (3.11 g, 100%) as a yellowish oil. The crude product was used in the next step without purification. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 4 - 25℃; | 1.4 General procedure for the preparation of compounds (2d-2o) General procedure: To a solution ofbromocarboxylicacids (0.2mol) in dichloromethane (200 mL) was addedoxalylchloride (0.4mol) at 4oC.N,N-dimethylformamide(2 mL) was then added cautiously, and the reaction was stirred for 4 h at 25oC.The solvent was removed by distillation under vacuum at 30-40oC.This concentrate was taken directly into the next stage. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Inert atmosphere; | ||
With thionyl chloride for 2h; Reflux; | ||
With oxalyl dichloride In dichloromethane at 20℃; for 4h; | 1.ED.3 Step 3: tert-Butyl 5-bromopentanoate To a solution of 5-bromovaleric acid (2.5 g, 14.0 mmol) in dichloromethane (10 mL) was added oxalyl chloride (1.15 mL, 13.2 mmol) and the reaction mixture stirred at room temperature for 4 hours. The solvent and excess oxalyl chloride were removed under vacuum. The crude acid chloride was dissolved in dichloromethane (10 mL) and cooled to 0°C. Then fert-butanol (10 mL) was added and the reaction mixture stirred at room temperature overnight. The solvent was removed, and the crude was purified by flash chromatography (SiCh: ethyl acetate/hexane 0 to 50%) to get fert-butyl 5-bromopentanoate (3.02 g, 92%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ: 3.40 (t, 2H, J = 6.6 Hz); 2.24 (t, 2H, J = 7.3 Hz); 1.90-1.81 (m, 2H); 1.75-1.69 (m, 2H); 1.43 (s, 9H). | |
With oxalyl dichloride at 20℃; for 4h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 25℃; for 3h; | ||
Stage #1: 5-bromopentanoic acid With thionyl chloride In dichloromethane at 20℃; for 0.0166667h; Stage #2: With N,N-dimethyl-formamide In dichloromethane for 2h; Reflux; | 4; 9 Synthesis of Compound 4-3 To a stirred solution of 5-bromovaleric acid (1.12 mmol, 204 mg) in CH2CI2 (1 mL) at room temperature was added a solution of thionyl chloride (3.36 mmol, 400 mg, 0.25 mL) in CH2CI2 (5 mL) in a period of 1 minute, followed by addition of DMF (ca 16 mg). The mixture was then heated to reflux for 2 hours. The reaction mixture was then concentrated in vacuo. The acid chloride was directly used for the next step. | |
With thionyl chloride for 2h; Reflux; Inert atmosphere; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; | ||
With thionyl chloride In dichloromethane for 4h; Reflux; | 1 Pomalidomide derivative 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl-pentyl)pentan Take the preparation of amide as an example, the steps are as follows:Weigh 5-bromovaleric acid (181.0mg, 1.0mmol) into a 25mL single-neck bottle,Add 5mL of dichloromethane to dissolve it,Slowly add thionyl chloride (0.5mL, excess),After refluxing for 4h, spin-dry the solvent,Add 5mL of tetrahydrofuran,Pomalidomide (136.6mg, 0.5mmol), refluxed for 17h.After TLC confirms that the reaction is complete, spin dry,Purify by silica gel column with mobile phase dichloromethane: methanol=50:1 (V/V) to obtain 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3 -Dioxyisoindol-4-yl-pentyl)pentanoamide. | |
With thionyl chloride In toluene at 100℃; for 2h; | 19 Synthesis of 5-((4-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1- yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3- dioxoisoindolin-4-yl)pentanamide B78 To a stirred solution of 5-bromopentanoic acid (300 mg, 1.66 mmol) in toluene (6 mL) was added thionyl chloride (988 mg, 8.3 mmol). The mixture was stirred at 100 °C for 2 h and then concentrated to give 5-bromopentanoyl chloride (320 mg, crude) | |
With thionyl chloride at 75℃; for 2h; Sealed tube; Inert atmosphere; | 4.2. General procedure for synthesis of 3a-d General procedure: The reaction vessel was capped and heated to 75 C for 2 h and thesolvent was removed by rotary evaporation. To the crude acidchloride was added isobutanol (10 mL), and the resulting mixturewas allowed to sit at 25 C for 12 h. The solvent was removed byrotary evaporation to provide the crude product which was sufficientlypure to carry forward. | |
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 23℃; for 0.5h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 50℃; for 4h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With toluene-4-sulfonic acid In toluene Reflux; Dean-Stark; | 8.8a Preparation of benzyl 5-bromopentanoate General procedure: Procedure B Preparation of benzyl esters using azeotropic distillation; A mixture of the carboxylic acid, benzyl alcohol, and p-toluenesulphonic acid in toluene was refluxed overnight through a Dean-Stark trap. After cooling to ambient temperature, the mixture was washed with saturated NaHC03 solution (1 x 15 mL) and saturated NaCI (1 x 15 mL). After drying (MgS04), filtration, and evaporation, the residue was vacuum dried at 50°C (bath temperature) and 0.014 mm Hg using a Kugelrohr apparatus; This compound was prepared from 5-bromopentanoic acid (1.81 g; 10.0 mmol), benzyl alcohol (1.62 g; 15.0 mmol), and p-toluenesulphonic acid (50 mg) in toluene (100 mL) using Procedure B. 2.60 g (96%) product was obtained (clear oil). The product was used in 8c without further purification. 1H NMR (200 MHz; CDCI3): δ 1.8-1.9 (4H, m, J = 7.2 Hz), 2.39 (2H, t, J = 7.2 Hz); 3.39 (2H, t, J = 6.4 Hz); 5.12 (2H, s), 7.35 (5H, s) ppm. 13C NMR (50 MHz; CDCI3): δ 23.5, 31.9, 32.9, 33.2, 66.2, 128.1 , 128.2, 128.4, 135.8, 172.7 ppm |
95% | With 4-(dimethylamino)pyridinium tosylate; diisopropyl-carbodiimide | 1 The Gd(III) chelator was synthesized using a hydrogenation labile protection scheme with benzyl 2-bromoacetate and benzyl 5-bromopentanoate as the chelating arms of the macrocycle (Figure 1). Addition of three benzyl 2-bromoacetate arms to cyclen was followed by addition of benzyl 5-bromopentanoate. Global deprotection by hydrogenation of the chelator and subsequent metallation with GdCl3 afforded molecule Gd (III) ion 6 to be conjugated to the protein polymer. |
95% | Stage #1: 5-bromopentanoic acid With 4-(dimethylamino)pyridinium tosylate; diisopropyl-carbodiimide In dichloromethane at 20℃; for 2h; Stage #2: benzyl alcohol In dichloromethane |
92% | With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; | 1 Step 1: Benzyl 5-bromopentanoateA solution of 5-bromopentanoic acid (1.00 g, 5.52 mmol) and benzyl alcohol (0.286 mL, 2.76 mmol) in methylene chloride (14 mL) was treated sequentially with Ν,Ν'- diisopropylcarbodiimide (0.523 g, 4.14 mmol) and 4-dimethylaminopyridine (43.9 mg, 0.359 mmol). The solution was allowed to stir at room temperature. A precipitate formed within 1 minute of the addition of the 4-dimethylaminopyridine. After -65 h, the reaction mixture was filtered, the solid was washed with CH2C12 and the filtrate was washed with 20 mL portions of IN HC1, sat NaHC03 and brine and dried over Na2S04. The solution was filtered and concentrated to yield a nearly colorless liquid along with a solid (DIC urea). The material was taken up in 1/1 MTBE/heptane to yield a solution with a white precipitate. The mixture was filtered and concentrated and the crude material was purified by flash chromatography (75 g silica gel; 5-10% MTBE/hept) to yield the title compound (0.69 g, 92%) as a colorless liquid. HPLC purity >95% (ret. time, 4.73 min). |
73.8% | With dicyclohexyl-carbodiimide In diethyl ether at 0 - 20℃; | |
With dmap; dicyclohexyl-carbodiimide In dichloromethane Ambient temperature; | ||
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 7h; | ||
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 12h; | ||
With dicyclohexyl-carbodiimide In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 8. Synthesis of S-5-oxo-5-(phenylamino)pentyl methanesulfonothioate; Step 1: Synthesis of 5-methanesulfonylsulfanyl- pentanoic acid; A solution of sodium methanthiosulphonate (2 g; 14.9 mmol) and 5-bromovaleric acid (1.42 mg; 7.84 mmol) in dimethylformamide (DMF, 12 ml) is heated at reflux, stirring under nitrogen for 4 hours. After evaporation to dryness of the solvent, the residue is dissolved in water (70 ml) acidified with 10 ml of a 2N KHSO4 solution and the solution is extracted with <n="27"/>ethylacetate. The organic phase is extracted with a cold solution of 2N KHSO4, then with iced water and finally dried on anhydrous sodium sulphate and evaporated to dryness . An oily yellow product is obtained that crystallizes in refrigerator and, after washing with ether, melts at 64-65 0C. |
Yield | Reaction Conditions | Operation in experiment |
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Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: 5-bromopentanoic acid With thiourea In ethanol at 80℃; for 20h; Stage #2: With sodium hydroxide at 90℃; for 16h; | |
87% | Stage #1: 5-bromopentanoic acid With thiourea In ethanol for 20h; Reflux; Stage #2: With sodium hydroxide In water at 90℃; for 16h; Inert atmosphere; Stage #3: With sulfuric acid In water Cooling with ice; Inert atmosphere; | |
82% | Stage #1: 5-bromopentanoic acid With thiourea In ethanol for 16h; Heating; Stage #2: With sodium hydroxide for 6h; Heating; |
78% | Stage #1: 5-bromopentanoic acid With thiourea In ethanol at 100℃; for 16h; Reflux; Stage #2: With sodium hydroxide at 100℃; for 6h; Reflux; | |
Multi-step reaction with 2 steps 1.1: NaOMe / toluene; methanol 1.2: 71 percent / toluene; methanol / 5 - 20 °C 2.1: 67 percent / TFA; trisopropylsilane / CH2Cl2 / 2 h / 20 °C | ||
With sodium hydroxide; thiourea In ethanol | 1 Synthesis of Maytansinoid Derivatives 5-Mercaptopentanoic acid (2d). Compound 2d was prepared by a modification of a literature method (Khim et al, 37 J. Org. Chem. 2714-2720 (1972)). To a stirred solution of 5-bromopentanoic acid (1.80 g, 0.01 mol) in absolute ethanol (25 ml) was added thiourea (0.761 g, 0.01 mol) and the reaction mixture was refluxed for 6 hours. A solution of 50% aqueous NaOH (20 ml) was then added and the mixture refluxed for an additional two hours. The mixture was then diluted with water (100 ml), acidified (aqueous HCl), and extracted with ethyl acetate (4*50 ml). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed over silica gel eluding with methylene chloride/ethyl acetate to give 0.885 g (66%) of a colorless liquid. 1 H NMR (CDCl3) δ1.3 (1H, t), 1.6 (4H, m), 2.4 (4H, m), 11.5 (1H, s). | |
With sodium hydroxide; thiourea In ethanol | 10.a Methylprednisolone,21-[5-[[2-(diisopropylamino)ethyl]thio]pentanoate]hydrochloride (a) 13.6 g of 5-bromovaleric acid is refluxed in 95% ethanol with 6 g of thiourea to form an ω-isothiouronium salt. The isothiouronium group is cleaved by adding 40 ml of 4N NaOH solution and heating under a nitrogen atmosphere. The ω-mercaptovaleric acid is isolated by extractive procedures, and 5.0 g of said acid is reacted with 7 g of diisopropylaminoethyl chloride hydrochloride in 105 ml of 1N Na2 CO3 in the presence of 0.5 g of sodium bisulfite. | |
With sodium hydroxide; thiourea In ethanol | 1 Synthesis of Thiol-Containing Maytansinoid Derivatives 5-Mercaptopentanoic acid (3d). 5-Mercaptopentanoic acid (3d) was prepared by a modification of a literature method (Khim et al, 37 J. Org. Chem. 2714-2720 (1972)). To a stirred solution of 5-bromopentanoic acid (1.80 g, 0.01 mol) in absolute ethanol (25 mL) was added thiourea (0.761 g, 0.01 mol) and the reaction mixture was refluxed for 6 hours. A solution of 50% aqueous NaOH (20 mL) was then added and the mixture refluxed for an additional two hours. The mixture was then diluted with water (100 mL), acidified (aqueous HCl), and extracted with ethyl acetate (4*50 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed over silica gel eluding with methylene chloride/ethyl acetate to give 0.885 g (66%) of a colorless liquid. 1H NMR (CDCl3) δ1.3 (1H, t), 1.6 (4H, m), 2.4 (4H, m), 11.5 (1H, s). | |
Stage #1: 5-bromopentanoic acid With thiourea In ethanol for 20h; Reflux; Stage #2: With sodium hydroxide; water at 90℃; for 16h; Stage #3: With sulfuric acid In water Cooling with ice; | ||
With thiourea In ethanol Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.5% | With sodium methylate In methanol; toluene at 0 - 20℃; for 8h; | 9 To a flame-dried roundbottom flask purged with N2 was added trityl mercaptan (347 mg, 1.26 mmol). The solid was dissolved in dry toluene (5.5 mL) and stirred with a magnetic stirbar before the addition of a 25% solution of sodium methoxide in methanol (860 μL, 3.77 mmol) via syringe. The solution was cooled to 0 0C in an ice/water bath, then a solution of 5- bromovaleric acid (250.0 mg, 1.38 mmol) in MeOH (3 mL) was added. The solution changed to a light brown color and was allowed to warm to room temp and stir for 8 hours, after which it was concentrated in vacuo, brought up in distilled H2O (30 mL) and IM aq. H2SO4 (10 mL), extracted with ethyl acetate (40 mL x 3), dried over MgSO4, filtered, and concentrated in vacuo. The resulting yellow solid was purified via silica gel chromatography (pentane-ethyl acetate-acetic acid, gradient from 69:30:1 to 64:35:1) to give 419.8 mg (88.5%) of pure 133: 1H-NMR (500 MHz, CDCl3): δ 7.48 (6H, d, J = 8.5 Hz), 7.33 (6H, t, J = 8 Hz), 7.26 (3H, 8 Hz), 2.26 (2H, t, J = 7.5 Hz)5 2.23 (2H, t, J = 7.5 Hz), 1.64 (2H, quintet, J = 7.5 Hz), 1.48 (2H, quintet, J = 7.5 Hz). |
73% | With potassium <i>tert</i>-butylate In methanol; toluene at 5 - 50℃; | |
71% | Stage #1: triphenylmethanethiol With sodium methylate In methanol; toluene Stage #2: 5-bromopentanoic acid In methanol; toluene at 5 - 20℃; |
70% | With sodium methylate In methanol; toluene at 5 - 50℃; for 2h; | |
70% | With sodium methylate In methanol; toluene at 5 - 50℃; for 2h; Inert atmosphere; | 5-(Tritylthio)pentanoic acid: To the oven dried round bottom flask, trityl mercaptan (150.8 mg, 0.545 mmol, 1.0 eq) was added under nitrogen atmosphere. The solid was dissolved in dry toluene (2 mL) with continuous stirring before the addition of a 30% (w/w) solution of sodium methoxide in methanol (220 pL, 1.2 mmol, 2.2 eq). To this mixture, a solution of bromovaleric acid (108.6 mg, 0.599 mmol, 1.1 eq) in methanol (1 mL) was slowly added at 5- 10°C. The reaction mixture temperature was raised to 50°C and then stirred for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in 10 mL of water. The resulting aqueous solution was acidified (pH approximately 5-6) with 0.1 M H2SO4 and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over Na2SC>4 and concentrated under reduced pressure. The crude product was recrystallized from EtO Ac/hexanes to afford 5-(tritylthio)pentanoic acid as a white crystalline solid (142 mg, 70%). H'-NMR (500 MHz, CDCh): d 7.43-7.37 (m, 6H), 7.31-7.22 (m, 6H), 7.21-7.15 (m, 3H), 2.19 (t, J= 2.2 Hz, 2H), 2.14 (t, 7= 2.1 Hz, 2H), 1.60-1.51 (m, 2H), 1.44-1.35 (m, 2H); C13-NMR (125 MHz, CDCh): d 179.8, 144.8, 129.6, 127.9, 126.6, 66.7, 33.5, 31.5, 28.1, 24.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: n-hexyl resorcinol With sodium hydride In N,N-dimethyl-formamide for 1h; Stage #2: 5-bromopentanoic acid In N,N-dimethyl-formamide at 60℃; for 18h; | 4 The titled compound was prepared starting from resorcinol (4.00 g, 36.3 mmol) in 230 ml_ of anhydrous DMF and NaH (0.87 g, 36.3 mmol). The mixture was left under magnetic stirring for 20 minutes at room temperature, then 1-bromohexane (5.99 g, 36.3 mmol) was added. The reaction mixture was left 72 hours at 800C then was poured in H2O (about 1 L) and extracted with AcOEt (3 x 250 ml_). The organic layer was dried on Na2SO4, filtered, the solvent evaporated and the obtained residue (6.50 g, 97 % yield) was used without further purification; 1H NMR (CDCI3, 300 MHz), δ 7.10 (brm, 1 H), 6.50 (m, 3H), 3.98 (t, 2H), 1.80 (m, 2H), 1.40 (m, 6H), 0.90 (m, 3H).Preparation of the intermediate methyl-5-f (3-hexyloxy)phenoxylpentanoate The titled compound was prepared starting from 3-hexyloxyphenol (prepared as above described), (360 mg, 1.85 mmol) in anhydrous DMF (14.4. ml_) and NaH 80% (61.5 mg, 2.03 mmol). After one hour, methyl 5-bromovalerate (361 mg, 1.85 mmol) was added, the reaction mixture was left under magnetic stirring at 60 0C for 18 hours, then H2O (100 ml_) was added and the mixture was extracted with AcOEt (3 x 30 ml_). The combined organic layers were washed with water, dried on Na2SO4 and evaporated under vacuum. The residue was purified by two chromatographies on silica gel using in the first hexane/AcOEt 97/3, in the second CH2CI2/hexane 80/20 and 85/15, to give 408 mg of an oily product (70 % yield); 1H NMR (CDCI3, 300 MHz), δ 7.10 (t, 1 H), 6.50 (m, 3H), 3.98 (m, 4H), 3.70 (s, 3H), 2.40 (brt, 2H), 1.98 (m, 6H), 1.40 (m, 6H), 0.90 (m, 3H).Preparation of the intermediate acid 5-[(3-hexyloxy)phenoxylpentanoicTo a solution of methyl 5-[3-(hexyloxy)phenoxy]pentanoate, (3.4 g, 11.02 mmol) in 216 ml_ of CH3OH, were added NaOH 2N (11.05 ml_) and H2O (59 ml_) and the reaction mixture was warmed up to 50 0C for 3 hours and then left at room temperature for other 18 hours. The solution was then evaporated under vacuum and the residue diluted with H2O and extracted with AcOEt.. The basic aqueous phase was acidified to pH 2 with HCI 2N, and extracted with AcOEt (3 x 250 ml_). The combined organic phases were washed with water, dried on Na2SO4, filtered and then evaporated under vacuum to give 2.7 g of product (yield 83%) which was used without further purification; 1H NMR (CDCI3, 300 MHz), δ 7.20 (t, 1 H), 6.50 (m, 3H), 3.98 (m, 4H), 2.50 (m, 2H), 1.85 (m, 6H), 1.40 (m, 6H), 0.95 (m, 3H).Preparation of (R)-4-trimethylammonium-3-[[4-[(3-hexyloxy)- phenoxylbutyllcarbamoyll-amino-butyrate (ST2425) To a solution of acid 5-[(3-hexyloxy)phenoxy]pentanoic, (1.3 g, 4.41 mmol) in CH2CI2 (6.5 ml_), CO2CI2 (3.4 g, 26.4 mmol) was added a 0 0C and the reaction was left at 10 0C for 2 hours under magnetic stirring. The organic solvent was then evaporated under vacuum and the residue was washed three times with anhydrous diethilic ether. The oily residue was used without further purification. NaN3 (488 mg, 7.50 mmol) was dissolved in H2O (1.7 ml_) and the solution so obtained was cooled to 8-15 0C: To this solution the acyl chloride above prepared dissolved in 1.7 ml_ of acetone was added. The reaction was left for ten minutes at this range of temperature and for an additional hour at room temperature. After this time the reaction was poured in a flask with toluene (5.5 ml_), and the solution was heated at 700C under magnetic stirring. The organic layer was evaporated under vacuum and the residue obtained was used without further purification. The obtained isocyanate was added to (R)-aminocarnitine (706 mg, 4.41 mmol) dissolved in anhydrous CH3OH (53 ml_) at 5 0C and the reaction was left for 18 hours at room temperature under magnetic stirring. The reaction mixture was then evaporated under vacuum and the residue purified by silica gel chromatography using as eluent CH3OH/CHCI3 from 7/3 to 8/2 to give 370 mgof a white solid (18.6%, yield). TLC: silica gel Rf = 0.59, eluent CHCI3:MeOH:isopropanol:CH3COOH:H2O 42:28:7:10.5:10.5,; 1H NMR (MeOHd4, 300 MHz) δ 7.10 (t, 1 H), 6.45 (m, 3H), 4.50 (brm, 1 H), 3.90 (q, 4H), 3.50 (m, 2H), 3.20 (s, 9H), 2.40 (m, 2H), 1.75 (m, 6H), 1.45 (m, 6H), , 1.20 (m, 2H), 0.90 (t, 3H); HPLC: column Symmetry-C18 (5μm) 150 x 4.6 mm, mobile phase CH3CNZNH4H2PO4 50 mM (40/60 v/v), pH as it is, room temperature, flow rate = 1.0 mL/min, detector UV 205 nm, retention time = 5.8 min; [α]20D = -15 °, (c = 0.2 % MeOH); KF = 3.2 % H2O; A.E. conforms for C24 H4i N3 O5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: NH3 / tetrahydrofuran / 15 h 2: diethyl ether 3: LiAlH4 / diethyl ether / 2 h / 0 °C 4: 58 percent / LiNH2, Fe(NO3)3 / tetrahydrofuran; NH3 / 20 h 5: H2 / PtO2 / diethyl ether |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: 5-bromopentanoic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 40℃; for 2h; Stage #2: With ammonium hydroxide In tetrahydrofuran at 20℃; for 2h; | Synthesis of 5-bromopentanamide Synthesis of 5-bromopentanamide 5-bromopentanoic acid (5g, 27.6mmol) was dissolved in methylene chloride (50mL). To the resulting solution was added N,N-dimethylformamide (DMF). The resulting mixture was cooled to 0-5°C in an ice-water bath. To the cooled mixture was slowly and dropwise added oxalyl chloride (10g, 82.8mmoL). After the completion of the dropwise addition, the mixture was stirred for 2 hours at 40°C to conduct the reaction. The reaction mixture was concentrated under a reduced pressure to produce a yellow solid. The resulting solid was dissolved in tetrahydrofuran (THF, 50mL). The resulting solution was slowly and dropwise added to ammonia-water (10mL). The resulting mixture was stirred for 2 hours at room temperature, and extracted with methylene chloride. The organic phase was dried over anhydrous sodium sulfate and concentrated to produce a white solid (4.85g, yield: 98%). |
Multi-step reaction with 2 steps 1: SOCl2 / 4 h / Heating 2: 28percent NH4OH / H2O / 0.75 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 5-(2-fluoro-3-hydroxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3-[(N-tert-butoxycarbonyl)-1(R)-1,2,3,4-tetrahydroisoquinoline]methylpyrimidine-2,4(1H,3H)-dione; 5-bromopentanoic acid With potassium carbonate In DMF (N,N-dimethyl-formamide) at 80℃; for 5h; Stage #2: With sodium hydroxide; water In methanol; DMF (N,N-dimethyl-formamide) at 80℃; for 1h; | 11.11D Step 11D: Preparation of 3-[(N-tert-butoxycarbonyl)-1(R)-1,2,3,4-tetrahydroisoquinoline]methyl-5-(2-fluoro-3-([4-hydroxycarbonyl]-1-butoxy)phenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 11-1 To compound lie (0.17 g, 0.26 mmol) in DMF (1 mL) was added methyl 5-bromovalerate (0.044 mL, 0.31 mmol) and K2CO3 (0. 18, 1.3 mmol). The mixture was heated at 80 °C and stirred vigorously for 5 hr. NAOH (0.1 g, 2.6 mmol) and MEOH/H2O (1: 1,4 mL) were then added, and heated at 80 °C for 1 hr. The reaction mixture was evaporated and partitioned between EtOAc and IN HCl (to make aq. phase pH 3). The organic layer was washed with brine, dried over NA2S04, concentrated and purified by column chromatography on silica gel with ethyl acetate/hexanes 3/1 to afford compound lid (0.15 g, 77%). MS (CI) m/z 658.0 (MH+- Boc) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.18% | With silver nitrate In acetonitrile at 70℃; for 16h; | 1.1 Step 1: To a solution of 5-bromopentanoic acid (3 g, 16.57 mmol) in MeCN (30 mL) was added AgNO3 (4.22 g, 24.86 mmol), the reaction mixture was stirred at 70°C for 16 h.Cooled to room temperature and filtered, the filtrate was evaporated under reduce pressure and the residue was purified by column chromatography to afford 5-(nitrooxy)pentanoic acid (2.6 g, 96.18% yield) as a light-yellow oil. MS: m/z =164.1(M+1, ESI+). |
89% | With silver nitrate In acetonitrile at 20℃; for 48h; | 4.4a AgNO3 (14 g, 82.8 mmol) was added to a solution of 5-bromovaleric acid (10 g, 55 mmol) in acetonitrile (70 mL). The reaction mixture was stirred at room temperature for 2 days. The residue after filtration and evaporation was chromatographed on silica gel eluting with EtOAc:Hexane (1:1) to give the title compound (8 g, 89% yield) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 10.80 (br s, 1H), 4.51 (t, J=5.9 Hz, 2H), 2.47 (t, J=6.9 Hz, 2H), 1.87-1.76 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 179.7, 72.8, 33.4, 26.2, 20.9. Mass spectrum (API-TIS) m/z 181 (MNH4+). |
77% | With silver nitrate In acetonitrile at 70℃; for 2h; Darkness; Inert atmosphere; |
65% | With silver nitrate In acetonitrile at 70℃; for 2h; Darkness; | 18; 19 Synthesis of 5-Nitrooxy-pentanoic acid 2; To a solution of 5-bromovaleric acid 1 (5.00 g, 1.0 eq) in 50.0 mL of dry acetonitrile was added silver nitrate (5.10 g, 1.1 eq). The reaction mixture was heated in the dark at 70° C. for 2 hours. The resulting mixture was filtered off through celite and the filtrate was concentrated under vacuum. The residue was dissolved into an aqueous solution of hydrochloric acid (1N) (100.0 mL), extracted with dichloromethane (2×100.0 mL), dried over magnesium sulphate and solvents were evaporated under vacuum to afford compound 2 as a colourless liquid. (2.92 g, yield=65%). |
With silver nitrate In dichloromethane; acetonitrile | 102 Synthesis of 5-nitrooxy-pentanoic Acid Synthesis of 5-nitrooxy-pentanoic Acid A mixture of 5-bromo-pentanoic acid (180 mg, 1 mmol), silver nitrate (255 mg, 1.5 mmol) in acetonitrile is stirred at 40° C. The reaction is monitored by thin layer chromatography (TLC). After completion, dichloromethane is added, and the mixture is washed with water, dried with anhydrous sodium sulfate, filtered and concentrated. The crude product is purified by column chromatography. | |
With silver nitrate In acetonitrile at 70℃; for 6h; Darkness; | 2 Preparation of compound 4b 5-bromo-pentanoic acid (500mg, 2.76mmol) was dissolved in 10mL of anhydrous acetonitrile, and then added dropwise to the reaction solution of silver nitrate (934mg, 5.52mmol) in acetonitrile. After the dropwise addition was heated to 70 ° C in the dark The reaction 6h.Completion of the reaction, the reaction solution was cooled, filtered, concentrated, and the solvent evaporated under reduced pressure.Water was added to the residue, extracted with ethyl acetate, the organic layers combined, dried over anhydrous Na2SO4Dried and concentrated to give 5- nitrooxy valeric acid as a pale yellow liquid, it was used directly in the next reaction.5- nitrooxy acid dissolved in 5mL methylene chloride at room temperature was added DIEA (0.16mL, 0.92mmol) and HBTU (350mg, 0.92 mmol), stirred at rt for 1h.The reaction was washed with water (3 × 5mL), the organic layer was retained for later use.The compound 2 (300mg, 0.77mmol) was dissolved in 5mL of dichloromethane was added 5mL of water and 375mg of sodium hydrogen carbonate.Under ice-cooling, the DBU (0.46mL, 3.08mmol), the organic layer was added to the reaction solution, under ice-cooling the reaction 2h.Liquid separation was allowed to stand, the organic layer was washed with aqueous acetic acid 10mL1% (v / v) is washed three times, dried over anhydrous Na2SO4Dried and concentrated, the mixture was separated by silica gel column (PE: EA = 2: 1 )to give compound 4a (146mg, 35.5%), as a white solid | |
With silver nitrate In acetonitrile at 75℃; Darkness; | General procedure for the synthesis of the target compounds T1-T8: General procedure: The ω-bromo-substituted alkylcarboxylic acid 1d and two molar amounts of AgNO3 were dissolved in 30mL of dry CH3CN, and the mixture was stirred under dark reaction conditions at 75°C for 8-12h. Then, the resulting mixture was filtered, dried, and evaporated to dryness to obtain 2d. Next, sitagliptin and an equivalent molar amount of EDCI were dissolved in 20mL of dry DMF, and the mixture was stirred at room temperature for 0.5h. Then, a solution of an equivalent molar amount of 2d in 5mL of dry DMF was added, followed by a catalytic amount of DMAP. The solution was stirred at room temperature for 8-10h. The resulting mixture was washed sequentially with 1M HCl, water, and brine, and the solution was then dried, filtered, and evaporated to dryness. The residue was purified by column chromatography (chloroform/methanol 20:1 v/v) to obtain the target compound T4 as a white solid. The target compounds T1-T3 were obtained by the same synthesis process. Compound T4 was dissolved in 25mL of 95% ethanol, and Pd/C was added. The solution was left stirring under hydrogen conditions at room temperature for 12-24h. The resulting mixture was then filtered and evaporated to dryness. The residue was purified by column chromatography (chloroform/methanol 20:1 v/v) to obtain the target compound T8 as a white solid. The target compounds T5-T7 were obtained by the same synthesis process. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydroxide; thionyl chloride; In ethanol; | EXAMPLE 9 N-Cyclohexyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)thiovalerohydroxamic acid (I9) STR19 The compound (IV1') which was prepared from 1.81 g (10 mmol) of 5-bromovaleric acid (IV1) and 1 ml of thionyl chloride according to the procedure shown in Example 8 was allowed to react with 1.75 g (11.5 mmol) of <strong>[25100-12-3]N-cyclohexylhydroxylamine hydrochloride</strong> to give the crude N-cyclohexyl-5-bromovalerohydroxamic acid (V2) as a pale yellow oil. Without further purification the oil was added to 20 ml of a solution of 2.83 g (10 mmol) of 2,6-di-tert-butyl-4-mercaptophenol in ethanol and then 10 ml of an aqueous solution of 1 g (25 mmol) of sodium hydroxide was added thereto and the mixture was stirred for 4 hours at room temperature. To the reaction mixture was added 50 ml of a 5% aqueous solution of hydrochloric acid under ice-cooling and the mixture was extracted with 100 ml of dichloromethane. The organic layer was washed with 100 ml of water twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crystalline residue, which was recrystallized from ether containing small amount of methanol to give 1.82 g of the aimed compound (I9) as colorless prismatic crystals in 49.6%. The physical data are shown in Table 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; In 7-bromoheptanoic acid; acetonitrile; benzene; | PREPARATION 3 (6-carboxyhexyl)triphenylphosphonium bromide. A mixture of 63.6 g. of 7-bromoheptanoic acid, 80 g. of triphenylphosphine, and 30 ml. of acetonitrile, is refluxed for 68 hr. Thereafter 200 ml. of acetonitrile is removed by distillation. After the remaining solution is cooled to room temperature, 30 ml. of benzene is added with stirring. The mixture is then allowed to stand for 12 hr. A solid separates which is collected by filtration, yielding 134.1 g. of product, melting point 185-187 C. Following the procedure of Preparation 3, but using 3-<strong>[590-92-1]bromopropionic acid</strong>, 4-bromobutanoic acid, 5-bromopentanoic acid, or 6-bromohexanoic acid, in place in 7-bromoheptanoic acid, there are prepared the corresponding (omega-carboxyalkyl) triphenylphosphonium bromides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In ISOPROPYLAMIDE at 20℃; for 24h; | 10.N To a solution of 5-bromo-valeric acid (535 mg, 2,86 mmol) in 15 ml of DMA, in a 50ml round bottom flask, was added 4-hydroxy-benzene-sulfonamide (500 mg, 2,86 mmol). EDAC (1,645 g, 8,58 mmol) was then added portion wise followed by a catalytic amount of DMAP and the resulting suspension was stirred at room temperature for 24 hours. 300 ml of ethyl acetate was added and the organic solution was extracted with water, 5% aqueous HCl and water. The organic layer was dried with anhydrous sodium sulphate and the solvent evaporated. The crude residue was purified by flash chromatography eluent methylene chloride/methanol 20/1. Compound N (640 mg) was obtained (67%). |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl acetamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In 2-methoxy-ethanol; | Step A: 1-[2-(5-Chloro-1H-indol-3-yl)ethyl]piperidin-2-one To a solution of 100 g of <strong>[942-26-7]5-chlorotryptamine hydrochloride</strong> in 1.4 litres of 2-methoxyethanol there are added 60 g of Na2CO3. The reaction mixture is stirred at reflux under nitrogen. A solution of 111.2 g of 5-bromovalerate in 200 ml of 2-methoxyethanol is added dropwise over a period of 5-6 hours and the mixture is heated at reflux for 24 hours. After cooling, the reaction mixture is filtered over Celite and the filtrates are concentrated under reduced pressure. The oil is extracted with 500 ml of CH2Cl2 and 3000 ml of water. The organic phases are washed with saturated sodium chloride solution, then dried over Na2SO4 and concentrated under reduced pressure. The solid is recrystallized from a 9/1 acetone/pentane mixture to yield 107 g of the expected product. Melting point. 155 C. Mass spectrometry (EI, m/z): 276.8 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 5-bromopentanoic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 30℃; for 2h; Stage #2: (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7H-8,9-dihydropyrano[2,3-c]-imidazo[1,2-a]pyridine With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 25℃; for 2h; | AAA 3.33 g (18. 2 mmol) 5-bromovaleric acid and 3.04 g (18.2 mmol) N, N'-carbonyldiimidazole are stirred in THF for 2h at 30°C. Subsequently 3.29 g (8.90 mmol) (7R, 8R, 9R)-2, 3-dimethyl-8-hydroxy-7- (2- methoxyethoxy)-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c] imidazo [1,2-a] pyridine and 2.77 ml (18.2 mmol) 1, 8-diazabicyclo [5.4. 0] undec-7-ene are added at 25°C and the mixture is stirred for further 2 h. The reaction is quenched by adding of saturated aqueous hydrogen carbonate solution. The mix- ture is extracted with dichloromethane three times and the combined organic layers are concentrated in vacuo. The crude product is purified by chromatography (dichloromethane/methanol : 100/3 to 13/1) to provide the title compound as a colourless solid (3.88 g/7.30 mmol/82 %) with a melting point of 134-136°C (dichloromethane/methanol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 5-bromopentanoic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -15℃; for 0.0833333h; Stage #2: pyrrolidine In tetrahydrofuran at -15 - 20℃; for 1.08333h; | 37 Referential Example 37: 5-Bromo-1-(1-pyrrolildinyl)-1-pentanone Referential Example 37: 5-Bromo-1-(1-pyrrolildinyl)-1-pentanone Under an argon atmosphere, N-methylmorpholine (606 μl, 5.52 mmol) and isobutyl chloroformate (757 μl, 5.80 mmol) were added to a tetrahydrofuran solution (35 ml) of 6-bromovaleric acid (1.00 g, 5.52 mmol) at -15°C. The resulting mixture was stirred for 5 minutes at -15°C. pyrrolidine (484 μl, 5.80 mmol) was added and the resulting mixture was stirred at -15°C for 5 minutes and then, at room temperature for 1 hour.. ice water was added and the mixture was extracted with dichloromethane.. The extract was washed with brine, dried over magnesium sulfate and then, concentrated.. The residue thus obtained was subjected to flash chromatoraphy on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=1:2 elude was concentrated, whereby the title compound (1.18 g, 5.04 mmol, 91%) was obtained as a colorless oil.1H-NMR (400 MHz, CDCl3) δ: 1.77-2.00(8H,m), 2.29(2H,t,J=7.3Hz), 3.39-3.48(6H,m). MS m/z: 234 (M++H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 5℃; for 12h; | 4.2.2. 5-Bromopentanoic acid 2-benzyloxycarbonylamino-2-[1-(hydroxy-diphenyl-methyl)-2-methyl-propylcarbamoyl]-1-methyl-ethyl esters (4a) and (4b) General procedure: A mixture of amide 3a or 3b (5.0 g, 10.2 mmol), 5-bromovaleric acid (1.84 g, 10.2 mmol), DCC (2.10 g, 10.2 mmol), and DMAP (cat.) in CH2Cl2 (30 mL) was stirred at 5 °C for 12 h. The precipitate was filtered off and washed with CH2Cl2 (3×5 mL). The combined organic extracts were evaporated, the residue was purified by column chromatography on silica gel (eluent: n-hexane/EtOAc 3/1) to afford ester 4a or 4b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 5℃; for 12h; | 4.2.2. 5-Bromopentanoic acid 2-benzyloxycarbonylamino-2-[1-(hydroxy-diphenyl-methyl)-2-methyl-propylcarbamoyl]-1-methyl-ethyl esters (4a) and (4b) General procedure: A mixture of amide 3a or 3b (5.0 g, 10.2 mmol), 5-bromovaleric acid (1.84 g, 10.2 mmol), DCC (2.10 g, 10.2 mmol), and DMAP (cat.) in CH2Cl2 (30 mL) was stirred at 5 °C for 12 h. The precipitate was filtered off and washed with CH2Cl2 (3×5 mL). The combined organic extracts were evaporated, the residue was purified by column chromatography on silica gel (eluent: n-hexane/EtOAc 3/1) to afford ester 4a or 4b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: oxalyl dichloride / benzene / 2 h / 50 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.33 h / -78 °C / Inert atmosphere 2.2: 1.75 h / -78 - 20 °C / Inert atmosphere 3.1: n-butyllithium; diisopropylamine / tetrahydrofuran; hexane / 0.58 h / -78 °C / Inert atmosphere 3.2: 4 h / -78 °C / Inert atmosphere 3.3: -78 - 20 °C / Inert atmosphere 4.1: lithium hydroxide monohydrate; water / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.3 g | In water; at 20℃; | N,N-dimethyl-5-aminopentanoic acid.Bromovaleric acid (2 g) was dissolved in aqueous solution of dimethylamine and stirred at room temperature overnight. The solvent was removed on a rotovap and the residue treated with an aqueous solution containing one equivalent of sodium bicarbonate. The solvent was removed, the residue suspended in ethanol and filtered. The solvent was removed from the filtrate and the residue suspended in methylene chloride and suspended again. After filtration, removal of the solvent from the filtrate yielded an oil (1.3 g) that slowly crystallized on storage. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With Caswell No. 744A In dimethyl sulfoxide | |
75% | Stage #1: 5-bromopentanoic acid With thionyl chloride In methanol at 0 - 20℃; for 24.5h; Inert atmosphere; Stage #2: With Caswell No. 744A In dimethyl sulfoxide at 50℃; for 24h; Inert atmosphere; Stage #3: With lithium hydroxide monohydrate In tetrahydrofuran; lithium hydroxide monohydrate at 20℃; for 4h; Inert atmosphere; | |
61% | With Caswell No. 744A In N,N-dimethyl-formamide at 70℃; for 12h; | 1 To a solution of 5-bromopentanoic acid (5.7g, 32mmol) in DMF (40m1) was added solid sodium azide (3.Og, 48mmol). The reaction mixture was heated to 700C and stirred for 12h at same temperature. Solvent was removed under high vacuum to afford a residue. The residue was diluted with dichloromethane and washed with 0.1NHC1. The aqueous phase was extracted withdichloromethane twice. The combined organic phases were washed with brine, dried over Na2504 and concentration to afford 2.75g 5-azidopentanoic acid as a yellow oil. Yield: 61% 1HNMR (400MHz, CDC13): 6 9.30(br, 1H), 3.29(t, 2H, J=6.SHz), 2.37(t, 2H, J=7.lHz), 1.66(m, 4H) ppm. |
59% | With Caswell No. 744A In N,N-dimethyl-formamide at 60℃; for 12h; Inert atmosphere; | |
48% | With Caswell No. 744A In N,N-dimethyl-formamide at 80℃; for 2h; | 4.2. Synthesis of 5-azidopentanoic acid The compound was synthetized as described [41,42]. To a stirred solution of 5-bromovaleric-acid (5 g; 27.61 mmol) in dry DMF (50 mL)was added sodium azide (2.15 g; 33.14 mmol; 1.2 eq). The mixture wasstirred for 2 h at 80 °C, and then diluted with EtOAc (50 mL). Theorganic phase was washed with brine (2 × 100 mL), water(2×100 mL), dried over sodium sulfate, filtered and concentrated. Thecrude product was purified by “manual” flash chromatography (Cyclohexane/EtOAc, 5/5) to give the compound (1.90 g; 48%). 1H NMR(CDCl3, 300 MHz) δ(ppm) 11.11 (s, 1H, COOH); 3.33 (t, J = 6.6 Hz,2H, CH2d); 2.43 (t, J = 7 Hz, 2H, CH2a); 1.85-1.55 (m, 4H, CH2b,CH2c). 13C NMR (CDCl3, 75 MHz) δppm 179.6 (COOH); 51.0 (C-d); 33.4(C-a); 28.1(C-c); 21.8 (C-b) (Supplementary Fig. 5a). |
47% | With Caswell No. 744A In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 0 - 20℃; | Procedure A. 5-azidopentanoic acid (9) 5-bromovaleric acid (2 g, 11.0 mmol) was dissolved in DMF (40 mL) and H2O (10 mL), and cooled to 0 °C. NaN3 (1.79 g, 27.5 mmol) was then added, and the reaction was stirred for 30 min. The reaction was then allowed to warm to room temperature and stirred overnight. The reaction was then acidified to pH 3, and the product was extracted into Et2O. The organic layer was then washed extensively with acidified H2O, and concentrated to give 9 (740 mg, 47%) as a clear oil. Azide was confirmed by IR absorbance band at 2100 cm-1. 1H NMR (400 MHz, CDCl3) δ 10.27 (br. s, 1H), 3.31 (t, J = 6.53 Hz, 2H), 2.40 (t, J = 7.00 Hz, 2H), 1.63 - 1.76 (m, 4H). |
45% | With Caswell No. 744A In N,N-dimethyl-formamide at 85℃; | |
41% | With Caswell No. 744A In N,N-dimethyl-formamide Heating; | |
Multi-step reaction with 3 steps 1: thionyl chloride / methanol / 20.25 h / 0 - 20 °C / Inert atmosphere 2: Caswell No. 744A / dimethyl sulfoxide / 24 h / 50 °C 3: lithium hydroxide monohydrate / tetrahydrofuran; lithium hydroxide monohydrate / 4 h / 20 °C | ||
With Caswell No. 744A In N,N-dimethyl-formamide at 85℃; | 5-Azido-O-tritylpentahydroxamate (3b) To a stirred solution of 5-bromopentanoic acid (5.00 g, 27.6 mmol) in DMF (20 mL) was added sodium azide (5.74 g, 88.4 mmol), and the reaction mixture was heated at 85 oC overnight. The reaction mixture was diluted with CH2Cl2, and was washed with 0.1 N aq. HCl. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 5-azidopentanoic acid (3.10 g, 79%) as colorless oil, which was used without further purification. | |
Multi-step reaction with 3 steps 1: sulfuric acid / Reflux 2: Caswell No. 744A; sodium iodide / N,N-dimethyl-formamide; lithium hydroxide monohydrate / 90 °C 3: potassium hydroxide / lithium hydroxide monohydrate; tetrahydrofuran / 20 °C | ||
With Caswell No. 744A In N,N-dimethyl-formamide at 85℃; for 3h; | ||
Multi-step reaction with 3 steps 1: acetyl chloride / 5 h / Reflux 2: Caswell No. 744A / dimethyl sulfoxide / 24 h / 60 °C 3: sodium hydroxide; lithium hydroxide monohydrate / methanol / 24 h | ||
With Caswell No. 744A In dimethyl sulfoxide | ||
With Caswell No. 744A In acetonitrile for 3h; Reflux; | 4 Synthesis of Azido Carboxylic Acid Succinimidyl Esters (6) Synthesis of 6a and its precursor 3-azidopropionic acid (5a) from 3-bromopropionic acid (4a), and synthesis of 6b from 4-bromobutyric acid (4b) were achieved by following the procedures of Grandjean et al. (C. Grandjean et al., J. Org. Chem., 2005, 70, 7123-7132). The synthesis of 6c generally adhered to the method of Seo et al. (T. S. Seo et al., J. Org. Chem., 2003, 68, 609-612). | |
With Caswell No. 744A In dimethyl sulfoxide at 80℃; | ||
With Caswell No. 744A In lithium hydroxide monohydrate at 20℃; for 168h; | ||
With Caswell No. 744A In N,N-dimethyl-formamide at 20℃; | ||
With Caswell No. 744A In N,N-dimethyl-formamide at 70℃; for 20h; Schlenk technique; Inert atmosphere; | ||
With Caswell No. 744A In acetonitrile Reflux; | General procedure for the synthesis of 7a, 7b1 and 7c General procedure: To a stirred solution of 3-bromopropionic (5.3g, 35mmol) in acetonitrile (30mL) was added sodium azide (4.55g, 70mmol) and slowly heated to reflux. After 8h of reaction, the mixture was filtrated and the filtrate was evaporated in vacuo to remove part of the acetonitrile. The condensation was diluted in DCM (200mL) and washed three times with water (50mL). The organic layer was dried over anhydrous sodium sulfate, filtrated and evaporated to obtain the desired compound 7a as colorless oil, yield 50%. | |
With Caswell No. 744A In N,N-dimethyl-formamide at 20℃; for 24h; | ||
With Caswell No. 744A In N,N-dimethyl-formamide at 60℃; | Synthesis of 5-azidovaleric acid 5 5-Bromovaleric acid (0.5 g, 2.5 mmol) and NaN3 (0.163 g, 2.5 mmol) were dissolved in DMF (13.75 ml), the reaction mixture was heated to 60°C and kept stirring overnight at this temperature. 0.1 M HCl was added to the reaction mixture and washed 3x with EtOAc. Combined organic phases were washed with H2O and brine, then dried over Na2SO4 and concentrated under vacuum. Crude product 5 (0.30 g) was used without further purification. Rf=0.74 (100% EtOAc); 1H NMR (400 MHz, CDCl3) δ 3.31 (t, J = 6.6 Hz, 2H, CH2), 2.40 (t, J = 7.1 Hz, 2H, CH2), 1.77 - 1.60 (mult., 4H, 2x CH2); 13C NMR (101 MHz, CDCl3) δ 179.2 (C=O), 51.2 (CH2), 33.5 (CH2), 28.3 (CH2), 22.0 (CH2). | |
With Caswell No. 744A In N,N-dimethyl-formamide at 60℃; | Synthesis of 5-azidovaleric acid 5 5-Bromovaleric acid (0.5 g, 2.5 mmol) and NaN3 (0.163 g, 2.5 mmol) were dissolved in DMF (13.75 ml), the reaction mixture was heated to 60°C and kept stirring overnight at this temperature. 0.1 M HCl was added to the reaction mixture and washed 3x with EtOAc. Combined organic phases were washed with H2O and brine, then dried over Na2SO4 and concentrated under vacuum. Crude product 5 (0.30 g) was used without further purification. Rf=0.74 (100% EtOAc); 1H NMR (400 MHz, CDCl3) δ 3.31 (t, J = 6.6 Hz, 2H, CH2), 2.40 (t, J = 7.1 Hz, 2H, CH2), 1.77 - 1.60 (mult., 4H, 2x CH2); 13C NMR (101 MHz, CDCl3) δ 179.2 (C=O), 51.2 (CH2), 33.5 (CH2), 28.3 (CH2), 22.0 (CH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With dmap; dicyclohexyl-carbodiimide In dichloromethane | |
77% | Stage #1: 5-bromopentanoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 0.5h; Stage #2: <i>tert</i>-butyl alcohol In dichloromethane at 0 - 20℃; for 0.25h; | 28.A tert-Butyl 5-bromopentanoate (28-2A). 28-1 A 28-2A To a solution of 28-1A (5 g, 27.62 mmol) in DCM, added oxalyl chloride (5.2 g, 41.436 mmol) and catalytic amount of DMF at 0 °C and stirred at RT for 30 min, then added i-BuOH (8.2 g, 110.49 mmol) at 0 °C and stirred at RT for 15 min. The reaction mixture completely distilled off, then added water (100 mL) and extracted with EtOAc (100 mL). The organic layer washed with water (50 mL), NaHC03 solution (50 mL) and dried over Na2S04, and the organic phase was concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (3% EtOAc in hexanes) to afford 28-2A (5 g, 21.18 mmol, 77% yield) as a colorless oily liquid. |
74% | With sulfuric acid In dichloromethane at 20℃; |
62.6% | Stage #1: 5-bromopentanoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane for 0.5h; Cooling with ice; Stage #2: <i>tert</i>-butyl alcohol In dichloromethane at 20℃; | 3.1.1-1 Synthesis of tert-butyl 5-bromopentanoate (9a) 5-bromo-pentanoic acid (5g, 27.62mmol) in dry DCM solution to this while stirring with ice cold N,N'-dimethylaminopyridine (1.68g, 13.75mmol) and DCC (6.83g, 33.15mmol) was added successively. After half an hour was added to tert-butanol (15.8ml, 165.75mmol) in the reaction mixture. The resulting solution was stirred overnight at room temperature. Was then diluted with DCM and washed with successive water and brine. The organic layer was dried and the solvent was evaporated. Using hexane-ethyl acetate to 1% solution of the residue was purified by chromatography to give the pure tert-butyl 5-bromopentanoate 4.1g (62.6% yield) of a pale yellow liquid. |
60% | Stage #1: 5-bromopentanoic acid; <i>tert</i>-butyl alcohol With dmap In dichloromethane at 0℃; for 0.0833333h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; | |
Stage #1: 5-bromopentanoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; Stage #2: <i>tert</i>-butyl alcohol | 21.A Step A: fert-butyl 5-bromopentanoateTo a solution of 5 -bromo valeric acid (l.Og, 5.52 mmol) in CH2CI2 (10 mL) at 0 °C was added oxalyl chloride (1.05 g, 8.29 mmol) and followed by a few drops of DMF. After stirring at rt for 2 h, the mixture concentrated and to which tert-butanol (1.64 g, 22.10 mmol) was added. After stirring at rt for 30 min, the mixture was concentrated to afford the title compound. | |
Stage #1: 5-bromopentanoic acid With trifluoroacetic anhydride In dichloromethane at 0 - 20℃; for 2h; Stage #2: <i>tert</i>-butyl alcohol In dichloromethane at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4,5-dichloroimidazole With potassium hydroxide In acetonitrile for 0.5h; Reflux; Stage #2: 5-bromopentanoic acid In acetonitrile for 5h; Reflux; Stage #3: bromoacetic acid | 4,5-dichloroimidazole (1.00g, 7.36mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828g, 14.72mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 5-bromopentanoic acid (1.33g, 7.36mmol) was added to the solution and refluxed for 5h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. 2-bromoacetic acid (2.15g, 15.46mmol) was added to the solution and refluxed for 2.5h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting white precipitate was collected and analyzed. 1H NMR (300 MHz, DMSO-d6): δ 3.11 , 3.56, 4.68, 4.91 , 5.24, 8.24, 10.06, 12.04. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4,5-dichloroimidazole With potassium hydroxide In acetonitrile for 0.5h; Reflux; Stage #2: 5-bromopentanoic acid In acetonitrile for 5h; Reflux; Stage #3: 2-bromomethylnaphthyl bromide | 4,5-dichloroimidazole (1.00g, 7.36mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828g, 14.72mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 5-bromopentanoic acid (1.33g, 7.36mmol) was added to the solution and refluxed for 5h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. An equivalent of 2-(bromomethyl)naphthalene (1.63g, 7.36mmol) was added to solution and refluxed for 2.5h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting white precipitate was collected and analyzed. 1H NMR (300 MHz, DMSO-d6): δ 1.61 , 1.80, 2.25, 3.51 , 5.76, 7.61 , 8.05, 9.74, 12.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With dmap; diisopropyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide at 20℃; for 48h; | General procedure: In a typical reaction, the Wang resin (3, 2.0 g, 1.2 mmol/g, 100-200 mesh and 1% DVB) was swollen in CH2Cl2 (20 mL). 5-Bromopentanoic acid (4, 2.15 g, 12.0 mmol) and DIC (1.51 g, 12.0 mmol) were dissolved in the minimum volume of CH2Cl2/DMF (1:1) required for complete dissolution. The activated scaffold solution was added to the resin, followed by the addition of slurry of DMAP (4 mg, 10 mol %) in CH2Cl2 (0.5 mL). The reaction vessel was shaken at room temperature for 48 h. The resin was washed with CH2Cl2 (2 × 25 mL), DMF (2 × 25 mL), MeOH (2 × 25 mL) again followed by DMF (2 × 25 mL), CH2Cl2 (3 × 25 mL), and then further dried in vacuo overnight to afford the resin-bound 5-bromopentanoic acid in good yield (2.73 g, 81%). Next, to the resin-bound 5-bromopentanoic acid (2.70 g, 3.9 mmol), swelled in DMF (10 mL), K2CO3 (2.13 g, 15.6 mmol) was added at ambient temperature, and the reaction suspension was stirred for another 30 min. Later, methyl 2-azido-4-hydroxy-5-methoxybenzoate (5, 1.73 g, 7.8 mmol) was added to the resin. The reaction suspension was stirred at 50 °C for 48 h. The solid-support was washed with water (3 × 20 mL), CH2Cl2 (2 × 20 mL), MeOH (3 × 15 mL), and then dried in vacuo to afford the resin-bound precursor 6a (3.07 g, 75%). To a suspension of this resin-bound ester in 1,4-dioxane (10 mL) was added 1 N NaOH solution (2.5 mL) and the reaction mixture was heated at 80 °C for 12 h. On cooling, the resin was filtered and rinsed with water (2 × 15 mL), water/dioxane (1:9, 2 × 15 mL), MeOH (2 × 15 mL), CH2Cl2 (2 × 15 mL), Et2O (2 × 15 mL) and dried in vacuo to afford the resin-bound acid. Next, to the resin-bound 2-azido-4-(5-ethoxy-5-oxopentyloxy)-benzoic acid (2.81 g, 2.6 mmol) swelled in CH2Cl2 (10 mL), EDCI (0.99 g, 5.2 mmol), HOBt (0.71 g, 5.2 mmol) and l-proline methyl ester (7a, 0.84 g, 6.5 mmol) were added. This reaction mixture was stirred for 12 h at room temperature, then resin was filtered and washed with H2O (3 × 10 mL), CH2Cl2 (2 × 10 mL), MeOH (3 × 10 mL) and Et2O (3 × 10 mL) to afford the resin bound methyl 5-(5-azido-4-(2-formylpyrrolidine-1-carbonyl)-2-methoxyphenoxy) pentanoate 8a in good yield (2.89 g, 71%). To a suspension of this resin (0.110 g, 1.2 mmol) in CH2Cl2 (5 mL), AlCl3 (0.79 g, 6 mmol), NaI (0.22 g, 2 mmol) and 2-(4-methoxyphenyl)ethanamine (9a, 0.35 mL, 2.4 mmol) were added at room temperature and stirred for 6 h. Aqueous 1 M potassium carbonate solution (2 mL) was added to the reaction mixture followed by excess of NaI, quenched with saturated sodium thiosulfate (Na2S2O3), and then resin was separated by simple filtration and washed with CH2Cl2 (10 mL). The removal of excess amine impurities from the final resin cleaved crude product was achieved by solid-supported liquid-liquid extraction (SLE) with a fritted vessel previously packed with ‘Varian’s Hydromatrix’. The crude compound 1a which contains excess of amine was passed through the Hydromatrix support into a collection plate below, while the amine salts were retained by the solid matrix, resulting in the effective removal of the amine impurities. This filtrate and washings were evaporated to dryness under reduced pressure. Finally, it was further purified by the preparative thin layer chromatography by using ethyl acetate:methanol (98:2) as eluent to afford the corresponding compound 1a in high purity (brown solid, 0.013 g, 56%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 2-(R,S)-4-(methylsulfanyl)butyramide hydrochloride With ammonia; sodium Stage #2: 5-bromopentanoic acid In tetrahydrofuran at 20℃; | The general procedure for the preparation of compounds 11 and 12 General procedure: A 250 mL three-necked flask was equipped with a dry ice condenser, a glass-coated magnetic bar, and a potassium hydroxide tube in the inlet, and the outlet was charged with 1 equiv. of ammonium salt 8, 9 or 10. First, the apparatus was flushed vigorously with a stream of dry ammonia. When 150 mL of gas was condensed in the flask, approximately 4.1 equiv. (3.1 equiv. for 10) of sodium was added in small portions until the dark blue color of the reaction mixture persisted for at least 20 min. The excess sodium was destroyed by adding a small amount of ammonium chloride (decolorization of the solution), and 1.1 equiv. of 5-bromovaleric acid was added to the clear solution in dry THF (10 mL). Stirring and cooling of the reaction mixture was stopped, and the ammonia was allowed to evaporate overnight. The remaining white solid was dissolved in 20 mL of water, followed by acidification with chilled 10% (aq.) TFA to pH~1. The final solution of the product was passed through a Rotalibo filter (0.22 mm) and then was subjected to preparative RP-HPLC (G2). Finally, the pure product was lyophilized from water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: 5-bromopentanoic acid; N,0-dimethylhydroxylamine In toluene at 0℃; for 0.166667h; Stage #2: With phosphorus trichloride In toluene at 20 - 60℃; for 0.5h; | N-Methoxy-N-methylbenzamide (3a);38,39 Typical Procedure General procedure: A solution of NHMe(OMe) (0.360 g, 6.0 mmol) and benzoic acid (0.244 g, 2.0 mmol) was stirred in dry toluene (10 mL) at 0 °C for 10 min. A solution of PCl3 (0.137 g, 1.0 mmol) in dry toluene (2 mL) was then added dropwise to the mixture. The mixture was warmed to r.t. slowly and then stirred at 60 °C for 0.5 h. When the reaction was complete (TLC monitoring), the mixture was cooled to r.t. The mixture was then quenched with sat. NaHCO3 soln (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (anhyd MgSO4). The solvent was removed in vacuo.The product was purified by column chromatography (silica gel, petroleum ether-EtOAc, 3:2) to give pure 3a as a colorless oil; yield: 320 mg (97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 1.5h; Reflux; | 4 2.4. Synthesis of (2S,4R)-tert-butyl 4-((5-bromopentanoyl)oxy)-2-(hydroxydiphenylmethyl) pyrrolidine-1-carboxylate (10) 2.4 Synthesis of (2S,4R)-tert-butyl 4-((5-bromopentanoyl) oxy)-2-(hydroxydiphenylmethyl) pyrrolidine-1-carboxylate (10) 5-Bromopentanoic acid (0.81 g, 4.48 mmol) was added to a solution of N,N'-dicyclohexylcarbodiimide (DCC) (0.92 g, 4.48 mmol) and 4-dimethylaminopyridine (DMAP) (0.42 g, 0.1 mmol) in CH2Cl2 (20 mL) at 0 °C and then compound 9 (1.29 g, 3.5 mmol) was added in a 10 min. The reaction mixture was stirred at 0 °C for 1 h, later DCC (0.46 g, 2.24 mmol) and 5-bromopentanoic acid (0.40 g, 2.24 mmol) were added and the reaction mixture was refluxed for 30 min, precipitate was filtered off and washed with CH2Cl2 (3 * 25 mL). Organic filtrate was washed with conc. HCl (1.65 mL), saturated aqueous NaHCO3 (2 * 15 mL), water (25 mL) and dried over Na2SO4. The solvent was evaporated by rotavapor and the product was isolated by column chromatography using a mixture of hexane/Et2O (8:2) to afford brown solid (1.78 g, 96%). Mp = 108.1 °C; = + 33.9 (c 0.8, chloroform); 1H NMR (400 MHz, CDCl3): δ = 7.42-7.23 (m, 10H), 5.03 (dd, J = 8.79, 5.86 Hz, 1H), 4.72 (brs, 1H), 3.54 (brs, 1H), 3.38 (t, J = 6.59 Hz, 2H), 3.01 (brs, 1H), 2.28-2.22 (m, 3H), 2.14-2.11 (m, 1H), 1.87-1.83 (m, 2H), 1.76-1.71 (m, 2H), 1.34 (brs, 9H) ppm; 13C NMR (100 MHz, CDCl3): δ = 172.7, 145.2, 143.2, 128.1 (2 C), 127.9 (2 C), 127.7 (2 C), 127.4 (2 C), 81.7, 73.0, 65.2, 53.5, 36.2, 33.3, 33.0, 32.0, 28.3, 23.4 ppm; IR (CH2Cl2, film): ν = 3433, 3058, 2963, 1730, 1679, 1407, 1259, 1165, 701 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 5-bromopentanoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.5h; Stage #2: (R,S)-2,2-dimethyl-1,3-dioxolane-4-methanol In dichloromethane at 20℃; for 18h; | 1 2,3-Dihydroxypropyl 5-bromopentanoate (24) DCC (5.14 g, 24.9 mmol, 1.5 equiv) and DMAP (600 mg, 4.9 mmol, 0.3 equiv) were sequentially added to a solution of 5-bromovaleric acid (3.31 g, 18.3 mmol, 1.1 equiv) in CH2Cl2 (110 mL, 0.15 M) at 0 °C and stirred for 30 min. A solution of DL-1,2-isopropylideneglycerol (17) (2.1 mL, 17 mmol, 1 equiv) in CH2Cl2 (220 mL, 0.075 M) was added to the reaction mixture, which was then stirred at rt for 18 h. The reaction mixture was filtered through celite, washed with CH2Cl2 (50 mL), and then concentrated in vacuo. The crude residue was purified by flash column chromatography on silica using 30% ethyl acetate in petroleum ether as eluent to give the ester (3.78 g, 75%) as a pale yellow oil; νmax (CDCl3/cm-1) 2987, 2939, 2886, 1739, 1213, 1256, 1085 and 648; δH (300 MHz, CDCl3) 4.36-4.28 (1H, ddt, J 4.6, 5.9 and 6.1, OCH), 4.18 (1H, dd, J 4.6 and 11.6, CHHCOO), 4.12-4.06 (2H, m, OCHHCHCHHOOC), 3.74 (1H, dd, J 6.1 and 8.4, OCHHCH), 3.42 (2H, t, J 6.4, CH2Br), 2.40 (2H, t, J 7.1, OOCCH2), 1.95-1.73 (4H, m, CH2CH2CH2Br), 1.43 (3H, s, CH3), 1.37 (3H, s, CH3); δC (75 MHz, CDCl3) 173.0, 110.0, 73.7, 66.4, 64.9, 33.2, 33.0, 32.0, 26.8, 25.5, 23.5; m/z (ES) 295.0546 (M++H, 82%, C11H20O4Br requires 295.0539). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h; | 3β-Hydroxylup-20(29)-en-28-yl 5-bromopentanoate(2c). A mixture of 0.88 g (2.0 mmol) of betulin,0.38 g (2.1 mmol) of 5-bromopentanoic acid, 0.43 g(2.1 mmol) of DCC, and 0.04 g of DMAP in 12 mL ofmethylene chloride was stirred for 24 h at room temperature(TLC). The precipitate was filtered off, thefiltrate was evaporated, and the residue was purified bycolumn chromatography on silica gel (CHCl3-EtOH,100 : 1). Yield 1.0 g (85%), mp 112-115°C. IR spectrum,ν, cm-1: 3438, 2940, 2869, 1733 (C=O), 1628(C=C), 1454, 1389, 1250 (C-O-C), 1193, 1044, 983.1H NMR spectrum, δ, ppm (J, Hz): 0.78 s, 0.84 s,0.98 s, 0.99 s, and 1.05 s (3H each, C23H3, C24H3,C25H3, C26H3, C27H3); 1.70 s (3H, C30H3), 1.80 m (2H,CH2, 3J = 7.0), 1.92 m (2H, CH2, 3J = 6.9), 2.39 [2H,C(O)CH2, 3J = 7.3], 2.45 m (1H, 19-H, 3J = 11.0, 5.7),3.19 (1H, 3-H, 3J = 11.1, 5.0), 3.43 (2H, CH2Br, 3J =6.5), 3.87 d (1H, 28-HA, 2J = 11.0), 4.27 d (1H, 28-HX,2J = 11.0), 4.60 (1H, 29-HA), 4.70 (1H, 29-HB).13C NMR spectrum, δC, ppm (JCH, Hz): 14.78 m (C27,1J = 124.3), 15.35 m (C24, 1J = 124.5), 16.05 br.q (C26,overlapped by the C25 signal), 16.09 br.q (C25, overlappedby the C26 signal), 18.29 br.t (C6, 1J = 124.0),19.15 m (C30, 1J = 125.4), 20.81 br.t (C11, partiallyoverlapped by the C30 s i g n a l ) , 2 3 . 6 0 b r. q[OC(O)CH2CH2, 1J = 129.1], 25.23 br.t (C12, 1J =122.1), 27.09 br.t (C15, 1J = 122.5), 27.42 br.t (C2, 1J =124.2), 27.99 br.q (C23, 1J = 124.3), 29.63 m (C16),29.85 m (C21), 32.06 m (CH2CH2Br), 32.92 m[OC(O)CH2], 33.45 br.t (CH2Br, 1J = 128.0), 34.22 br.t(C22, 1J = 126.1), 34.60 br.t (C7, 1J = 128.8), 37.17 br.s(C10), 37.62 br.d (C13, overlapped by the C10 signal),38.74 br.t (C1, 1J = 26.1), 38.87 br.s (C4), 40.91 br.s(C8), 42.73 br.s (C14), 46.42 br.s (C17), 47.71 br.d (C18,partially overlapped by the C19 signal), 48.84 br.d (C19,partially overlapped by the C18 signal), 50.40 br.d (C9,1J = 122.1), 55.33 br.d (C5, 1J = 118.5), 62.80 br.t (C28,1J = 146.7), 78.98 br.d (C3, 1J = 142.0), 109.85 m (C29,1J = 154.1), 150.10 br.s (C20), 173.51 br.s (C=O).Found, %: C 68.8; H 8.9; Br 12.1. C35H56BrO3. Calculated,%: C 69.5; H 9.2; Br 13.2. |
85% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; | |
81% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; |
40% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; | |
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h; | Lup-20(29)-ene-3β,28-diyl bis(5-bromopentanoate) (3c). A mixture of 0.88 g (2.0 mmol) of betulin,0.76 g (4.2 mmol) of 5-bromopentanoic acid, 0.86 g(4.2 mmol) of DCC, and 0.08 g of DMAP in 12 mL ofmethylene chloride was stirred for 24 h at roomtemperature (TLC). The precipitate was filtered off, thefiltrate was evaporated, and the residue was purified bycolumn chromatography on silica gel (CHCl3-EtOH,100 : 1). Yield 1.0 g (70%), mp 49-50°C. IR spectrum,ν, cm-1: 3438, 2940, 2869, 1733 (C=O), 1628 (C=C),1454, 1389, 1250 (C-O-C), 1193, 1044, 983. 1H NMRspectrum, δ, ppm (J, Hz): 0.87 s, 0.88 s, 1.00 s, and1.06 s (15H, C23H3, C24H3, C25H3, C26H3, C27H3);1.71 s (3H, C30H3), 2.18 m (2H, CH2, 3J = 6.8-7.0),2.20 m (2H, CH2, 3J = 6.8-7.0), 2.21 m (2H, CH2, 3J =6.8-7.0), 2.23 m (2H, CH2, 3J = 6.8), 2.46 m (1H,19-H, 3J = 11.1, 6.1), 2.52 m [2H, OC(O)CH2, 3J =7.5], 2.55 m [2H, OC(O)CH2, 3J = 7.2], 3.48 t (2H,CH2Br, 3J = 6.5), 3.49 t (2H, CH2Br, 3J = 6.4), 3.89 d(1H, 28-HA, 2J = 11.4), 4.32 d (1H, 28-HX, 2J = 11.4),4.52 m (1H, 3-H, 3J = 11.0, 6.0), 4.62 m (1H, 29-HA),4.72 m (1H, 29-HB). Found, %: C 61.58; H 7.9;Br 18.9. C40H64Br2O4. Calculated, %: C 62.5; H 8.3;Br 20.8. |
70% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; | |
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; Cooling with ice; | 2 4.3. Synthesis of N-(2-(4-substituted phenylamino)benzo[d]oxazol-5-yl)-5-bromo-pentanamide (3a-c) General procedure: Compound 2a-c (0.31 mmol), 5-bromovaleric acid (0.051 g,0.28 mmol), and PyBOP (0.163 g, 0.31 mmol) in DMF(8 mL) wereadded to diisopropyl ethylamine (0.073 g, 0.57 mmol) in ice bathand the mixture was stirred for 16 h at room temperature. Ethylacetate 8 mL was added and the mixture was washed with 10%HCl, saturated NaHCO3 and NaCl solution. The organic layer wasdried over MgSO4 and the solvent was removed in vacuo. Columnchromatography (EtOAc/hexane = 2:1) gave compound 3a-c. |
62% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; | 2.2-D 2-D. Preparation of 5-bromo-N- (2- (phenylamino) benzo [d] oxazole 5-yl) pentanamide (D2RC) 15 mL of DMF was added to the compound D2R (0.361 g, 1.60 mmol), 5-bromovaleric acid (0.029 g, 1.60 mmol) and PyBOP (0.918 g, 1.76 mmol). Diisopropylethylamine (0.168 L, 0.96 mmol) was added thereto and reacted at room temperature for 16 hours. It was diluted with 30 mL of EtOAc and washed three times with 10% aqueous HCl solution, twice with saturated aqueous NaHCO3 solution and once with saturated aqueous NaCl solution. After drying over MgSO4, the solvent was concentrated under reduced pressure to obtain a compound D2RC (0.385 g, 62%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; Cooling with ice; | 3 4.3. Synthesis of N-(2-(4-substituted phenylamino)benzo[d]oxazol-5-yl)-5-bromo-pentanamide (3a-c) General procedure: Compound 2a-c (0.31 mmol), 5-bromovaleric acid (0.051 g,0.28 mmol), and PyBOP (0.163 g, 0.31 mmol) in DMF(8 mL) wereadded to diisopropyl ethylamine (0.073 g, 0.57 mmol) in ice bathand the mixture was stirred for 16 h at room temperature. Ethylacetate 8 mL was added and the mixture was washed with 10%HCl, saturated NaHCO3 and NaCl solution. The organic layer wasdried over MgSO4 and the solvent was removed in vacuo. Columnchromatography (EtOAc/hexane = 2:1) gave compound 3a-c. |
55% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; | 3.3-D 3-D.Synthesis of N-(2-(4-methoxyphenylamino)benzo[d]oxazol-5-yl)-5-bromopentanamide(D5RC) 8 mL of DMF was added to the compound D5R (0.067 g, 0.26 mmol), 5-bromovaleric acid (0.043 g, 0.24 mmol) and PyBOP (0.135 g, 0.26 mmol). Diisopropylethylamine (33 [mu] l, 0.19 mmol) was added thereto and reacted at room temperature for 16 hours. Diluted with 8 mL of EtOAc and washed three times with 10% aqueous HCl solution, twice with saturated aqueous NaHC03 solution and once with saturated aqueous NaCl solution. After drying over MgSO4, the solvent was concentrated under reduced pressure to obtain a compound D5RC (0.055 g, 55%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; Inert atmosphere; Darkness; | 1.2.7 A 100 ml flask equipped with a magnetic stirring bar and an inert gas inlet was charged with 60 ml DCM and 300 mg (351 μmol) paclitaxel in the absence of light. 95 mg (525 μmol) of 5-bromovaleric acid were added and the mixture was allowed to stir for 15 minutes. The flask was cooled in an ice-water bath to 0° C. 19 mg (157 μmol) DMAP and 81.5 mg (525 μol) EDC were added and the reaction mixture was allowed to warm up to room temperature. The course of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was washed twice with 100 ml of a 0.5% sodium bicarbonate solution and twice with 100 ml of 0.1 N hydrochloric acid. The organic phase was further washed with 100 ml of water followed by 100 ml of brine, dried over sodium sulfate and evaporated to dryness. The crude product was applied on silica and purified by column chromatography on silica (DCM/ethyl acetate 2:1). Yield was 0.27 g (334 mol, 75%) of a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 16h; Inert atmosphere; | 29.1; 40.1 Step 1, 005-21: Step 1, 005-21:Under an argon atmosphere, to a round-bottom flask charged with DLen(γ)-MeOH (005-12, 262 mg, 0.5 mmol), 5-bromovaleric acid (181 mg, 1.0 mmol) and 4-(dimethylamino)pyridine (30 mg) in dichloromethane (10 mL) was added dicyclohexylcarbodiimide (227 mg). After the mixture is stirred for 16 hr at ambient temperature, the solvent was evaporated and the residue was taken in hexanes. The white precipitate was discarded by filtration. The filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (230-400 mesh, 50 mL) eluted with acetate in hexanes (0-2%). Fractions containing the pure product were combined and concentrated. This gave 290 mg (0.42 mmol, 84%) of 005-21 as slightly yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: 5-bromopentanoic acid; (3Z,13Z)-7-[(3Z)-hex-3-en-1-yl]-10-[(3Z)-non-3-en-1-yl]nonadeca-3,13-dien-9-ol With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 30℃; for 18h; Stage #2: 2-(N,N-dimethylamino)ethanol In dichloromethane at 80℃; for 5h; Sealed tube; | 3 Synthesis of (3Z,13Z)-7-[(3Z)-hex-3-en-1-yl]-10-[(3Z)-non-3-en-1-yl]nonadeca-3,13-dien-9-yl 5-(dimethylamino)pentanoate The (3Z, 13Z) -7 - ((Z) - 3-en-1-yl) -10 - ((Z) - nonane-3-en-1-yl) nonadeca-3,13 diene-9-ol (110,700mg, 1.44 mmol) in CH2Cl2The (10 mL) washed with a solution of 5-bromo-pentanoic acid (390mg, 2.16 mmol), EDC (413mg, 2.2 mmol) and DMAP (10mg) and stirred (30 , 18H).The solution was washed with CH2Cl2And diluted with saturated NaHCO3And brine, dried (MgSO4), Filtered and concentrated.The crude material was dissolved in ethanol dimethylamine (10mL as 2M solution) was placed in a sealed container and heated (80 , 5H).Once the solution was concentrated and the crude material through chromatography (EtOAc) to afford a pale yellow oil 111 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | 5-bromopentanoic acid (1.09g, 6.03mmol) with stirring to a cold solution of dry DCM in an ice Here the HOBt (0.74g, 4.82mmol) and EDCI (1.15g, 6.02mmol) were added sequentially. After half an hour the N(epsilon)-Z-lysine methyl ester hydrochloride (2g, 6.04mmol) was dissolved in dry DCM was added to the reaction mixture. Then DIPEA was added dropwise until the reaction mixture becomes slightly basic. The reaction mixture was stirred at room temperature overnight. Then diluted with chloroform and washed successively with 0.5N HCl, water and brine. The organic layer was dried and the solvent was evaporated. Using a chloroform solution of 1% methanol to give the residue was purified by chromatography to give the water to a white solid pure N(epsilon)-Z-Lysine(-OMe)C5-Br 1.83g (66% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.9% | With sulfuric acid; sodium bromide In water at 90 - 95℃; for 8h; | 8.3; 8.4 3) brominationThe filtrate was rotary evaporated to B no liquid was distilled off, followed by addition of sodium bromide and 0.4mol water 70ml, 0.4mol solution of sulfuric acid, 90 ~ 95 the reaction time 8h, the C to obtain a solution;4) Isolation and PurificationSolution C was added to 100ml toluene extraction, the toluene layer was washed with water to remove impurities and washed twice, each 20ml, toluene was recovered under reduced pressure, to give 16.1 g of 5-bromo valeric acid, the GC purity of 98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With toluene-4-sulfonic acid In toluene at 125℃; for 4h; | Allyl Protection; General Procedure 1 (GP1) General procedure: A 250 mL round bottom flask was charged with a magnetic stirring bar, bromoalkanoic acid 4 (1.0 equiv), allyl alcohol 12 (10 equiv), pTsOH*H2O (0.1 equiv), and toluene (4 mL/mmol bromoalkanoic acid,0.25 M). The resulting reaction mixture was stirred at 125 °C for 4 h. After cooling to r.t., the reaction mixture was diluted with EtOAc and washed with aq 0.1 M NaOH, H2O, and brine. The combined organic layers were concentrated under reduced pressure. Purification of the crude residue by flash column chromatography afforded the desired analytically pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; Inert atmosphere; | 1.1.3 General Procedures for Preparation ofBoc-Protected Bromide (7a-d) General procedure: Bromoacid (0.42 mmol, 1.0 equiv.) was dissolved in dry CH2Cl2(15 mL).EDC (322 mg, 1.68 mmol, 4.0 equiv.) and compound3(153 mg, 0.42 mmol, 1.0 equiv.) were added into this solution. The reaction mixture was stirred at room temperature under nitrogen for 12 hr, then washed withbrine(2×30 mL) and dried over MgSO4. After solvent evaporation, the crude product was purified on a silica gel column, eluting withEtOAc/CH2Cl2(1/20) to give the product7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1 (Synthesis of 131-2) (0671) In a dry three-necked flask, compound 131-1 (18.00 g, 99.43 mmol, 1.0 eq.) was dissolved in thionyl chloride (59.15 g, 497.15 mmol, 5.0 eq.), and the mixture was warmed to 80° C., stirred for 1 hour, and then cooled to 50° C. Br2 (31.78 g, 198.8 mmol, 2.0 eq.) was added into the reaction mixture, at 50° C. was stirred the mixture for 40 hours. The reaction mixture was cooled to 30° C., and anhydrous methanol (40 mL) was carefully added, then the mixture was heated up 50° C. and continued stirring for 1 hour. The reaction mixture was cooled to 25° C., and concentrated under reduced pressure. The residue was dissolved with EtOAc, and washed with saturated sodium sulfite. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 20 g crude product as yellow oil. The crude product was directly used in the next reaction. (0672) 1H NMR (400 MHz, CDCl3) delta: 4.28 (q, J=6.0 Hz, 2H), 3.80 (s, 3H), 3.43 (t, J=6.0 Hz, 2H), 1.95-2.26 (m, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.166667h; | 1-[5-{N-(5-Bromopentanoyl)aminomethyl}-2-nitrophenyl]ethanol (5). To a solution of 4 (727 mg, 3.71 mmol) in DMF (20 mL) containing HBTU (2.12 g, 5.57 mmol), HOBt (54 mg, 0.4 mmol) and DIPEA (2 mL, 11.13 mmol) was added 5-bromovaleric acid (1.02 g, 5.57 mmol), and the whole mixture was stirred for 10 min at room temperature. The reaction was quenched by addition of ice, and the solvent was removed in vacuo. The residue was partitioned with AcOEt and H2O, and the organic layer was washed with saturated aqueous NaHCO3, followed by brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by a silica gel column, eluted with hexane/AcOEt (1/2-0/1), to give 5 (1.21 g, quant) as a pale yellow oil: ESI-LRMS m/z 359 (MH+); ESI-HRMS calcd for C14H20BrN2O4 359.0606, found 359.0592; 1H NMR (CDCl3) δ 7.90 (1 H, d, J = 8.5 Hz), 7.73 (1 H, d, J = 1.7 Hz), 7.31 (1 H, dd, J = 1.7 and 8.5 Hz), 5.97 (1 H, br s), 5.44 (1 H, q, J = 6.2 Hz), 4.52 (2 H, d, J = 6.2 Hz), 3.42 (2 H, t, J = 6.2 Hz), 2.29 (2 H, t, J = 7.5 Hz), 1.96-1.80 (4 H, m), 1.55 (3 H, d, J = 6.2); 13C NMR (CDCl3,) δ 172.80, 146.50, 144.79, 141.94, 126.79, 126.34, 124.87, 65.46, 42.93, 35.38, 33.19, 32.05, 24.54, 24.15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; | Terminal Bromoalkyl Carboxylic Acid N-Hydroxyphthalimide Esters (NHP Ester); General Procedure 1 (GP1) General procedure: To a solution of NHPI (N-hydroxyphthalimide, 1.1 equiv), terminal bromoalkyl carboxylic acid (1.0 equiv), and DMAP (4-dimethylaminopyridine, 10 mol%) in DCM (0.2 M) was added DCC (dicyclohexylcarbodiimide, 1.1 equiv). The resulting mixture was stirred at r.t. and monitored by TLC technique. After the alkyl carboxylic acid was consumed, the mixture was filtered through a pad of silica gel, and the filtrate was collected and concentrated under reduced pressure. Then MeOH was added and cooled at -20 °C overnight; the precipitated solid was collected by filtration and identified as pure product |
75% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; Inert atmosphere; Schlenk technique; | |
With dmap; diisopropyl-carbodiimide In dichloromethane |
With dmap; diisopropyl-carbodiimide In dichloromethane | ||
With dmap; dicyclohexyl-carbodiimide at 20℃; | ||
With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; | Typical procedure for the preparation of NHPI esters General procedure: A 100 mL round-bottom flask was charged with 4-phenylbutanoic acid (1.64 g,10 mmol), N-hydroxyphthalimide (1.63 g, 10 mmol) and 4-dimethylaminopyridine(122 mg, 1.0 mmol). Dichloromethane (50 mL) was added and the mixture was stirred vigorously. N,N’-Diisopropylcarbodiimide (1.39 g, 11 mmol) was then added dropwise via syringe and the mixture was allowed to stir at room temperature until the carboxylic acid or the N-hydroxyphthalimide was fully consumed (monitored byTLC). The resulting mixture was filtered over Celite and rinsed with additional CH2Cl2 (10 mL × 3). The solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel with hexane/ethylacetate (20:1, v:v) as the eluent to give the pure product 1,3-dioxoisoindolin-2-yl 4-phenylbutanoate (1a) as a white solid. Yield: 2.72 g (88% yield). | |
With dmap; dicyclohexyl-carbodiimide In ethyl acetate at 20℃; Inert atmosphere; | (b) General procedure for synthesis of alkyl NHP esters [2] General procedure: To a 100 mL round bottom flask equipped with magnetic stir bar, N-Hydroxyphthalimide (1.63g,10.0 mmol), 4-dimethylaminopyridine (61mg, 0.5 mmol), N, N’-dicyclohexylcarbodiimide (2.06 g,12 mmol), carboxylic acid (12 mmol) was added and dissolved in ethyl acetate (40 mL). The mixtu rewas stirred for 30-180 minutes at room temperature. After completing the reaction, the solid wasseparated via vacuum filtration and the filtrate was washed by brine (10 ml) for three times. Theorganic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Thecrude product was purified by chromatography on a silica gel column (0 to 20% ethyl acetate/petroleum ether). | |
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 6h; Inert atmosphere; Sealed tube; | ||
With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: (2R)-(-)-2-phenyl-2-(piperidin-1-yl)ethanol With methanesulfonyl chloride; triethylamine In chloroform at 0 - 5℃; for 0.5h; Stage #2: 5-bromopentanoic acid With triethylamine In chloroform at 5 - 20℃; for 16h; enantiospecific reaction; | (S)-1-Phenyl-2-(piperidin-1-yl)ethyl 5-bromopentanoate (3b) General procedure: To a stirred solution of compound 1 (0.5 g, 2.43 mmol) in CHCl3 (10 mL) at 0 oC in presence oftriethylamine (1.01 mL, 7.30 mmol). Then, methanesulfonyl chloride (0.22 mL, 2.92 mmol) was addeddropwise at a rate to keep the reaction temperature bellow 5 oC. After 30 min, the reaction was monitoredby TLC (CH2Cl2/MeOH, 95:5), indicating the reactants were consumed. Triethylamine (0.50 mL, 3.65mmol) was added. Finally, the corresponding carboxylic acid (1.2 equiv.) was added and the reactionmixture was allowed to warm to room temperature for 16 h. After completion of the reaction as indicatedby TLC, the crude product was purified by column chromatography (CH2Cl2/MeOH, 97:3) provided thecorresponding product 3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 5-bromopentanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane for 0.5h; Stage #2: 3-indolylacetic acid amidoxime In dichloromethane at 20℃; for 2h; | 3.1.6. Synthesis of Carboxamidine 13 General procedure: To a solution of carboxylic acid (0.8 mmol, 1.0 equiv) in CH2Cl2 (5 mL), DIPEA (1.0 mmol,1.3 equiv) and HATU (0.8 mmol, 1.0 equiv) were added, and the reaction mixture was stirred for 30 min, after which compound 7 (0.8 mmol, 1.0 equiv) in CH2Cl2 (2 mL) was added and stirred for 2 h. The mixture was filtered, the residue was washed with CH2Cl2, and then the solution was combined and concentrated. The residue was subjected to silica gel chromatography with petroleum ether/EtOAc (2:1) to give 13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; Inert atmosphere; | 4.8 4.8. 2-(Azulen-6-yl)ethyl 5-bromopentanoate (AzulE 5-bromovalerate), 1g 5-Bromovaleric acid (70 mg, 0.39 mmol, 1.0 eq.), 6-(2-hydroxyethyl)azulene (74 mg, 0.43 mmol, 1.1 eq.), DCC (100 mg, 0.48 mmol, 1.3 eq.) and DMAP (9 mg, 0.07 mmol, 0.2 eq.) were dissolved in dry DCM (10 mL) and stirred overnight at room temperature under an atmosphere of N2. The reaction mixture was then diluted with DCM and washed with brine followed by water. The solvent was removed under reduced pressure. Chromatographic purification (dichloromethane) yielded the protected carboxylic acid 1g as an indigo oil (104 mg, 0.31 mmol, 80%). λmax: 570 nm. IR (ATR): nmax 3080, 2955, 1729, 1579, 1395, 1168, 836, 751 cm1. 1HNMR (500 MHz, CDCl3) d 8.28 (d, J = 10.0 Hz, 2H, H-4,8), 7.86 (t, J = 3.5 Hz, 1H, H-2), 7.37 (d, J = 3.5 Hz, 2H, H-1,3), 7.10 (d, J = 10.0 Hz, 2H, H-5,7), 4.40 (t, J = 7.0 Hz, 2H, H-10), 3.33 (t, J = 6.5 Hz, 2H, H-15), 3.13 (d, J = 7.0 Hz, 2H, H-9), 2.32 (t, J = 7.0 Hz, 2H, H-12), 1.85-1.78 (m, 2H, H-14), 1.77-1.69 (m, 2H, H-13). 13C NMR (126 MHz, CDCl3) d 173.0 (C, C-11), 147.9 (C, C-6), 139.1 (C, C-3a, 8a), 136.5 (CH, C-2),135.8 (CH, C-4,8), 124.1 (CH, C-5,7), 118.3 (CH, C-1,3), 65.2 (CH2, C-10), 41.1 (CH2, C-9), 33.2 (CH2, C-12), 33.0 (CH2, C-15), 31.9 (CH2, C-14), 23.4 (CH2, C-13). HRMS: m/z C17H20O2Br [MH] Calculated 335.0641, found 335.06501. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; | 4.2.1 General procedure for preparation of compound 1 and 2 General procedure: A solution of glycyrrhetinic acid (470mg, 1mmol) in DCM (20mL) was stirred. EDCI (482mg, 2.5mmol), DMAP (49mg, 0.4mmol) and 5-bromovaleric acid (750mg, 4mmol) or 7-bromoheptanoic acid (836mg, 4mmol) were added successively, and the mixture was stirred at 25°C until the reaction was complete based on TLC detection. The solvent was removed under diminished pressure, and the residue was purified by column chromatography using 10:1:0.1 petroleum ether/ethyl acetate/formic acid to obtain the target product of compound 1 (518.2mg, 82%) and 2 (514.8mg, 78%) as a white powder. (0017) 45 18β-3-O-(5′-Bromovaleryl)-11-oxo-olean-12-en-30-oic acid (1). 1H NMR (300MHz, CDCl3) δ 5.71 (s, 1H), 4.53 (dd, J=11.3, 4.8Hz, 1H), 3.42 (t, J=6.5Hz, 2H), 2.80 (d, J=13.5Hz, 1H), 2.36 (d, J=7.1Hz, 2H), 2.33 (s, 1H), 2.19 (d, J=9.6Hz, 1H), 2.07 - 1.92 (m, 4H), 1.88 - 1.67 (m, 6H), 1.65 - 1.40 (m, 8H), 1.37 (s, 3H, CH3), 1.26 (s, 2H), 1.23 (s, 3H, CH3), 1.15 (d, J=10.7Hz, 6H, 2×CH3), 1.03 (d, J=13.0Hz, 2H), 0.88 (s, 6H, 2×CH3), 0.84 (s, 3H, CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 19h; | 9 Intermediate 3 in the scheme above was prepared as follows. DMAP (0.7 mg, 5.8 tmol) and EDC•HC1 (3.3 mg, 17.4 tmol) were added to a solution of phenol 2 (3.2 mg, 5.8 tmol) and 5-bromovaleric acid (2.1 mg, 11.6 tmol) in CH2C12 (0.6 mL) and the mixture stirred at rt for 19 hours. The reaction was concentrated under a stream of N2 gas to give the crude product. Purification by silica gel chromatography (4% to 5% ethyl acetate/hexanes) gave bromovalerate ester 3 (3.1 mg, 76%) as a colorless oil. ‘HNIVIR (401 IVIFIz, CDC13) 7.76-7.56 (m, 4H), 7.46- 7.30 (m, 6H), 6.28 (d, J 1.5 Hz, 1H), 6.05 (s, 1H), 5.24 (m, 1H), 4.61 (s, 2H), 4.22 (m, 1H), 3.46 (t, J 6.5 Hz, 2H), 2.76 (m, 1H), 2.60-2.14 (m, 4H), 2.13 - 1.94 (m, 6H), 1.93 - 1.71 (m, 4H), 1.67 (s, 3H), 1.62 (s, 3H), 1.32- 1.24 (m, 2H), 1.07 (s, 9H), 1.12- 1.01 (m, 2H), 0.97-0.83 (m, 2H), 0.73 (t, J 7.3 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; | 18 Methyl (E)-6-(4-((5-bromopentanoyl)oxy)-6-methoxy-7-methyl-3-oxo-1 ,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate (7) DMAP (10.9 mg, 0.0897 mmol) and EDC•HC1 (43.0 mg, 0.224 mmol) were added to a solution of 5-bromovaleric acid (24.4 mg, 0.13 5 mmol) and methyl ester 2 (30.0 mg, 0.0897 mmol) in CH2C12 (2 mL) and the mixture stirred at RT for 30 minutes. The reaction was diluted with CH2C12 (5 mL), silica gel was added, and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (35% ethyl acetate/hexanes) gave 5-bromovalerate ester 7(38.1 mg, 85%) as a colorless solid; ‘HNIVIR (401 IVIHz, CDC13) 5.13 (s, 2H), 5.08 (m, 1H),3.77 (s, 3H), 3.61 (s, 3H), 3.47 (t, J 6.4 Hz, 2H), 3.33 (d, J= 6.6 Hz, 2H), 2.71 (t, J= 7.0 Hz, 2H), 2.40 - 2.33 (m, 2H), 2.32 -2.25 (m, 2H), 2.21 (s, 3H), 2.07 - 1.88 (m, 4H), 1.76 (d, J= 0.7 Hz, 3H). ‘3C NIVIR (101 IVIHz, CDC13) 173.7 (C), 171.2 (C), 168.4 (C), 162.8 (C), 146.3 (C), 146.0 (C), 134.7 (C), 129.3 (C), 123.1 (C), 122.4 (CH), 113.6 (C), 68.5 (CH2), 61.3 (CH3), 51.6 (CH3), 34.5 (CH2), 33.4 (CH2), 32.82 (CH2), 32.81 (CH2), 31.9 (CH2), 23.7 (CH2), 23.2 (CH2), 16.4 (CH3), 11.9 (CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; dicyclohexyl-carbodiimide at 25℃; for 3h; | Synthesis of compound 2 Diosgenin (10.0 g, 24.1 mmol) was dissolved in dichloromethane (300 mL), and EDC · HCl (18.4 g, 96.3 mmol) was sequentially added.4-dimethylaminopyridine (1.20g, 9.82mmol), 5-bromovaleric acid (17.5g, 96.7mmol), reaction at 25 ° C for 3h,The TLC test was complete. The reaction solution was washed with 2N hydrochloric acid (3 × 100mL), saturated sodium bicarbonate (3 × 100mL), and water (3 × 100mL) in this order.The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from ethanol to obtain white solid 2 (12.1 g, 87%). |
81% | With 4-dimethylaminopyridine; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride In dichloromethane at 25℃; for 3h; | |
79% | With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 25℃; for 3h; | Synthesis of compound 3 Diosgenin (10.0 g, 24.1 mmol) was dissolved in dichloromethane (300 mL). Successively add EDC · HCl (18.4g, 96.3mmol), 4-dimethylaminopyridine (1.20 g, 9.82 mmol), 5-bromopentanoic acid (17.5 g, 96.7 mmol). Reaction at 25 for 3h. TLC detected the reaction to be complete. The reaction solution was sequentially washed with 2N hydrochloric acid (3 × 100 mL), saturated sodium bicarbonate (3 × 100 mL), and water (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from ethanol to give white solid 3 (11.0 g, 79%). |
79% | With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 25℃; for 3h; | 1.2.1 Synthesis of compound 2.6 To a stirred mixture of diosgenin (10.0 g, 24.1 mmol) in dichloromethane (300 mL), EDCHCl (18.4 g, 96.3 mmol), DMAP (1.20 g, 9.82 mmol) and 5-bromovaleric acid (17.5 g, 96.7 mmol) were added successively. The mixture was stirred at 25 °C until the reaction was completed based on TLC detection. Then the reaction mixture was washed successively with 2 N HCl (3 × 100 mL), aqueous saturated solution of NaHCO3 (3 × 100 mL) and H2O (3 × 100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was recrystallized from ethanol to furnish compound 2.6 as a white solid (11.0 g, 79%). m.p. 108-109 °C. [α]18 D -94.3 (c 0.003, CHCl3). IR (KBr) νmax 3464, 2959, 1745, 1459, 1388, 1281, 1200, 1052, 1010, 989, 903 cm-1. 1H NMR (400 MHz, CDCl3) δ 5.37 (d, J = 3.4 Hz, 1H, H-6), 4.68-4.53 (m, 1H, H-3), 4.40 (q, J = 6.8 Hz, 1H, H-16), 3.52-3.29 (m, 4H, H-26 and -CH2-Br), 2.41-2.23 (m, 4H, H-4 and -COCH2-) ppm. 13C NMR (100 MHz, CDCl3) δ 172.66, 139.75, 122.53, 109.40, 80.92, 74.04, 66.96, 62.18, 56.54, 50.04, 41.73, 40.38, 39.84, 38.24, 37.06, 36.85, 33.76, 33.22, 32.16, 32.12, 31.96, 31.51, 30.42, 28.93, 27.90, 23.71, 20.94, 19.47, 17.28, 16.42, 14.67 ppm. HR-ESI-MS m/z calcd for C32H49BrO4Na [M+Na]+ 601.2692, found 601.2690. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 5-bromopentanoic acid With dmap; dihydrogen peroxide; dicyclohexyl-carbodiimide In dichloromethane at 10℃; for 2h; Stage #2: Diphenylphosphine oxide With [2,2]bipyridinyl; copper diacetate In dichloromethane at 55℃; | 11 Example 11: Synthesis of 4-bromo-n-butyldiphenoxyphosphine oxide Using 5-bromovaleric acid and diphenylphosphine as raw materials, the reaction steps are as follows:Add 5-bromovaleric acid (181 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 18.3 mg, 0.15 mmol), and dicyclohexylcarbodiimide (DCC, 340 mg, 1.65 mmol) to the reaction flask. , Hydrogen peroxide (57 μL 1.9 mmol) and dichloromethane (5 mL), stirred at 10 ° C for 2 hours, filtered, and the solvent in the filtrate was distilled off to obtain a concentrate;To the concentrate were added copper acetate (11.9 mg, 0.06 mmol), 2,2'-bipyridine (7.8 mg, 0.05 mmol), dichloromethane (1 mL), and diphenylphosphine oxide (50.5 mg, 0.25 mmol). , 55 oC stirred reaction to the end (TLC monitoring);The crude product obtained after the reaction was separated by column chromatography (petroleum ether: acetone = 4: 1) to obtain the target product (yield 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.3% | Stage #1: tetrahydroprogesterone With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.25h; Stage #2: 5-bromopentanoic acid In dichloromethane at 20℃; for 16h; | 2.1 Synthesis of ALL-FSI5-C12a'aMe-2-TG I-5. [00803] Step 1: Compound 3 [00804] To a solution of of allopreganolone (200 mg, 0.62 mmol) in DCM (3 ml) was added EDC.HCl (300 mg, 1.57 mmol) and DMAP (38 mg, 0.31 μmmol) and stirred at rt for 15 min, then 5-bromopentanoic acid (220 mg, 1.13 mmol) was added at room temperature and stirred at rt for 16 h. The reaction was monitored by TLC, and after completion of reaction, the reaction mixture was diluted with water (10 ml) and extracted with DCM (3 x 10 ml). The combined organic layer was dried over Na2SO4, and concentrated to get crude material. The crude material was purified by column purification. The product was eluted at 4% ethyl acetate/hexane to afford 3 (270 mg, 89.30%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.11 - 5.05 (m, 1H), 3.48 (t, 2H), 2.57 (t, 1H), 2.40 (t, 2H), 2.16 (s, 3H), 2.08-2.02 (m,1H), 2.10 - 1.90 (m, 2H), 1.90 - 1.79 (m, 2H), 1.75-1.60 (m,4H),1.59-1.40(m,4H), 1.35-1.15(m,7H), 1.01(m,2H), 0.84 (s, 6H), 0.65 (s, 4H). |
89.3% | Stage #1: tetrahydroprogesterone With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.25h; Stage #2: 5-bromopentanoic acid In dichloromethane at 20℃; for 16h; | 2.1 Synthesis of ALL-FSI5-C12a'aMe-2-TG I-5. [00803] Step 1: Compound 3 [00804] To a solution of of allopreganolone (200 mg, 0.62 mmol) in DCM (3 ml) was added EDC.HCl (300 mg, 1.57 mmol) and DMAP (38 mg, 0.31 μmmol) and stirred at rt for 15 min, then 5-bromopentanoic acid (220 mg, 1.13 mmol) was added at room temperature and stirred at rt for 16 h. The reaction was monitored by TLC, and after completion of reaction, the reaction mixture was diluted with water (10 ml) and extracted with DCM (3 x 10 ml). The combined organic layer was dried over Na2SO4, and concentrated to get crude material. The crude material was purified by column purification. The product was eluted at 4% ethyl acetate/hexane to afford 3 (270 mg, 89.30%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.11 - 5.05 (m, 1H), 3.48 (t, 2H), 2.57 (t, 1H), 2.40 (t, 2H), 2.16 (s, 3H), 2.08-2.02 (m,1H), 2.10 - 1.90 (m, 2H), 1.90 - 1.79 (m, 2H), 1.75-1.60 (m,4H),1.59-1.40(m,4H), 1.35-1.15(m,7H), 1.01(m,2H), 0.84 (s, 6H), 0.65 (s, 4H). |
78% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 28h; | 4.1 Step 1: Synthesis of Intermediate 3.2 4-(Dimethylamino)pyridine (DMAP, 1.9 mg, 15.7 mmol) and EDC•HCl (7.5 mg, 39.2 mmol) were added to a solution of commercially available allopregnanolone (3.1) (5.0 mg, 15.7 mmol) and 5-bromovaleric acid (5.1 mg, 28.3 mmol) in CH2Cl2 (0.8 mL) and the mixture was stirred at room temperature for 25 hours. Additional amounts of DMAP (1.0 mg, 7.8 mmol), EDC•HCl (5.0 mg, 26.1 mmol) and 5- bromovaleric acid (5.1 mg, 28.3 mmol) were added and the solution was stirred at room temperature for an additional three hours. The reaction was then diluted with CH2Cl2 (5 mL), silica gel was added, and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (15% ethyl acetate/hexanes) gave bromovalerate ester 3.2 (5.9 mg, 78%) as a colorless oil 1H NMR (401 MHz CDCl3) d 503 (m 1H) 343 (t J = 66 Hz 2H) 252 (t J = 8.9 Hz, 1H), 2.35 (t, J = 7.2 Hz, 2H), 2.15 (m, 1H), 2.11 (s, 3H), 2.01 (dt, J = 11.9, 3.2 Hz, 1H), 1.96- 1.87 (m, 2H), 1.84- 1.76 (m, 2H), 1.76- 1.32 (m, 12H), 1.30- 1.12 (m, 6H), 0.94 (m, 1H), 0.80 (m, 1H), 0.79 (s, 3H), 0.61 (s, 3H); 13C NMR (101 MHz, CDCl3) d 172.7 (C), 70.3 (CH), 64.0 (CH), 56.9 (CH), 54.3 (CH), 44.4 (C), 40.3 (CH), 39.2 (CH2), 36.0 (C), 35.6 (CH), 34.0 (CH2), 33.3 (CH2), 33.1 (CH2), 33.0 (CH2), 32.2 (CH2), 32.0 (CH2), 31.7 (CH3), 28.4 (CH2), 26.3 (CH2), 24.5 (CH2), 23.9 (CH2), 22.9 (CH2), 21.0 (CH2), 13.6 (CH3), 11.5 (CH3); ESI- HRMS: calcd. for C26H4279BrO3 [M + H+] 481.2312; found 481.2320. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.6% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 1h; | 1 To a solution of 4-methoxybenzyl alcohol (3.0 g, 21.73 mmol) and 5-bromopentanoic acid (7.8 g, 43.47 mmol) in DCM (30 mL) at room temperature was added DMAP (5.3 g, 43.47 mmol) followed by DCC (8.0 g, 43.47 mmol), and then the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a celite bed, and washed with DCM (200 mL). The filtrate was concentrated concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography, with the compound eluting at 10% ethyl acetate/hexane, to afford Int-158 (3.3 g, 50.6%) as a viscous oil. 1H NMR (400 MHz, CDCl3) d 7.38- 7.30 (m, 2H), 6.98- 6.89 (m, 2H), 5.10 (s, 2H), 3.86 (s, 3H), 3.44 (t, J = 6.5 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 1.99- 1.87 (m, 2H), 1.83 (dddd, J = 12.5, 9.5, 6.1, 3.4 Hz, 2H). |
50.6% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 1h; | 1 FSI5-C12a'aMe-acid-2-TG (Int-160): To a solution of 4-methoxybenzyl alcohol (3.0 g, 21.73 mmol) and 5-bromopentanoic acid (7.8 g, 43.47 mmol) in DCM (30 mL) at room temperature was added DMAP (5.3 g, 43.47 mmol) followed by DCC (8.0 g, 43.47 mmol), and then the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a celite bed, and washed with DCM (200 mL). The filtrate was concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography, with the compound eluting at 10% ethyl acetate/hexane, to afford Int-158 (3.3 g, 50.6%) as a viscous oil. 1H NMR (400 MHz, CDCl3) d 7.38- 7.30 (m, 2H), 6.98- 6.89 (m, 2H), 5.10 (s, 2H), 3.86 (s, 3H), 3.44 (t, J = 6.5 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 1.99- 1.87 (m, 2H), 1.83 (dddd, J = 12.5, 9.5, 6.1, 3.4 Hz, 2H). |
50.6% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 1h; | 1 To a solution of 4-methoxybenzyl alcohol (3.0 g, 21.73 mmol) and 5-bromopentanoic acid (7.8 g, 43.47 mmol) in DCM (30 mL) at room temperature was added DMAP (5.3 g, 43.47 mmol) followed by DCC (8.0 g, 43.47 mmol), and then the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a celite bed, and washed with DCM (200 mL). The filtrate was concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography, with the compound eluting at 10% ethyl acetate/hexane, to afford lnt-158 (3.3 g, 50.6%) as a viscous oil. NMR (400 MHz, CDC13) d 7.38 - 7.30 (m, 2H), 6.98 - 6.89 (m, 2H), 5.10 (s, 2H), 3.86 (s, 3H), 3.44 (t, J= 6.5 Hz, 2H), 2.41 (t, J= 7.2 Hz, 2H), 1.99 - 1.87 (m, 2H), 1.83 (dddd, J= 12.5, 9.5, 6.1, 3.4 Hz, 2H). |
50.6% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 1h; | [00655] To a solution of 4-methoxybenzyl alcohol (3.0 g, 21.73 mmol) and 5-bromopentanoic acid (7.8 g, 43.47 mmol) in DCM (30 mL) at room temperature was added DMAP (5.3 g, 43.47 mmol) followed by DCC (8.0 g, 43.47 mmol), and then the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a celite bed, and washed with DCM (200 mL). The filtrate was concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography, with the compound eluting at 10% ethyl acetate/hexane, to afford Int-158 (3.3 g, 50.6%) as a viscous oil. NMR (400 MHz, CDCh) d 7.38 - 7.30 (m, 2H), 6.98 - 6.89 (m, 2H), 5.10 (s, 2H), 3.86 (s, 3H), 3.44 (t, J= 6.5 Hz, 2H), 2.41 (t, J= 7.2 Hz, 2H), 1.99 - 1.87 (m, 2H), 1.83 (dddd, J= 12.5, 9.5, 6.1, 3.4 Hz, 2H). |
50.6% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 1h; | 1 FSI5-C12α'αMe-acid-2-TG (Int-160): [00606] To a solution of 4-methoxybenzyl alcohol (3.0 g, 21.73 mmol) and 5-bromopentanoic acid (7.8 g, 43.47 mmol) in DCM (30 mL) at room temperature was added DMAP (5.3 g, 43.47 mmol) followed by DCC (8.0 g, 43.47 mmol), and then the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a celite bed, and washed with DCM (200 mL). The filtrate was concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography, with the compound eluting at 10% ethyl acetate/hexane, to afford Int-158 (3.3 g, 50.6%) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.30 (m, 2H), 6.98 - 6.89 (m, 2H), 5.10 (s, 2H), 3.86 (s, 3H), 3.44 (t, J = 6.5 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 1.99 - 1.87 (m, 2H), 1.83 (dddd, J = 12.5, 9.5, 6.1, 3.4 Hz, 2H). |
50.6% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 1h; | 1 FSI5-C12α'αMe-acid-2-TG (Int-160): [00606] To a solution of 4-methoxybenzyl alcohol (3.0 g, 21.73 mmol) and 5-bromopentanoic acid (7.8 g, 43.47 mmol) in DCM (30 mL) at room temperature was added DMAP (5.3 g, 43.47 mmol) followed by DCC (8.0 g, 43.47 mmol), and then the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a celite bed, and washed with DCM (200 mL). The filtrate was concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography, with the compound eluting at 10% ethyl acetate/hexane, to afford Int-158 (3.3 g, 50.6%) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.30 (m, 2H), 6.98 - 6.89 (m, 2H), 5.10 (s, 2H), 3.86 (s, 3H), 3.44 (t, J = 6.5 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 1.99 - 1.87 (m, 2H), 1.83 (dddd, J = 12.5, 9.5, 6.1, 3.4 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With boron trifluoride diethyl etherate In chlorobenzene at 80℃; | 2.3.1. General method for the synthesis of the precursor ketones General procedure: A mixture of the appropriate carboxylic acid (5.44 mmol) and resorcinol (1.36 mmol) in C6H5Cl (0.6 mL) was treated with BF3.Et2O (5.44 mmol). The reaction was stirred at 80 °C until complete consumption of resorcinol was assessed by TLC. The reaction mixture was treated with brine (10 mL) and the products were extracted with EtOAc (3 × 10 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. The residues were purified by column chromatography, eluting with mixtures of hexanes and EtOAc |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With pyridine; trichlorophosphate In dichloromethane at -10℃; for 2h; | 5.1 The first step: (S)-2-{4-[(methoxycarbonyl)amino]benzamide}-3-[4-(2-oxopiperidin-1-yl)phenyl]-propionic acid Methyl ester (6a)Synthesis (S)-2-{4-[(Methoxycarbonyl)amino]benzamide}-3-(4-aminophenyl)-propionic acid methyl ester (5c) (1.50g, 4.04mmol) and 5 -Bromo-valeric acid (731 mg, 4.04 mmol) was dissolved in 40 mL of dichloromethane, pyridine (959 mg, 12.12 mmol) was added dropwise with stirring at room temperature, POCl3 (990 mg, 6.46 mmol) was added dropwise with cooling at -10°C, and stirring was continued for 2 h, The reaction was quenched by adding water (10 mL), extracted with dichloromethane (40 mL×2), the organic phases were combined, and the organic phases were washed with water (30 mL) and saturated brine (30 mL), respectively, and dried over anhydrous sodium sulfate. Filtration, concentration under reduced pressure, and separation by column chromatography gave the title compound (S)-2-{4-[(methoxycarbonyl)amino]benzamide}-3-[4-(2-oxopiperidine- 1-yl)phenyl]-propionic acid methyl ester (6a) (1.48 g, yield 81%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.1% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 5h; | 1.1.29. (2S,4R)-1-((S)-2-(5-bromopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (s1) General procedure: To a solution of VHL-L (1.00g, 2.32 mmol) and intermediate i1 (0.50g, 2.76 mmol) in DCM (15 mL) were added HATU (1.06g, 2.79 mmol) and DIEA (0.90g, 6.96 mmol). The suspension was stirred at room temperature for 5 h. After completion of the reaction, the organic phase was washed with H2O (10 mL×3) and saturated brine (10 mL). Then dried over Na2SO4 overnight, and evaporated under vacuum. The crude product was purified by silica gel column chromatography (DCM: MeOH = 40:1) to give intermediate s1 as white solid (0.91 g, 66.1% yield). 1H NMR (300MHz, DMSO-d6) δ (ppm): 8.99 (s, 1H), 8.58 (t, J = 6.30 Hz, 1H), 7.92 (d, J = 9.27 Hz, 1H), 7.37-7.44 (m, 4H), 4.35-4.57 (m, 4H), 4.21 (dd, J = 15.93, 5.46 Hz, 1H), 3.62-3.70 (m, 2H), 3.53 (t, J = 6.57 Hz, 2H), 2.45 (s, 3H), 2.26-2.35 (m, 1H), 2.12-2.21 (m, 1H), 2.00-2.07 (m, 1H), 1.86-1.94 (m, 1H), 1.73-1.82 (m, 2H), 1.57-1.68 (m, 2H), 0.94 (s, 9H). MS (ESI): m/z calcd for C27H37BrN4O4S: 593.2 [M+H]+; found: 593.2. |
66.1% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 5h; | 1.1.29. (2S,4R)-1-((S)-2-(5-bromopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (s1) General procedure: To a solution of VHL-L (1.00g, 2.32 mmol) and intermediate i1 (0.50g, 2.76 mmol) in DCM (15 mL) were added HATU (1.06g, 2.79 mmol) and DIEA (0.90g, 6.96 mmol). The suspension was stirred at room temperature for 5 h. After completion of the reaction, the organic phase was washed with H2O (10 mL×3) and saturated brine (10 mL). Then dried over Na2SO4 overnight, and evaporated under vacuum. The crude product was purified by silica gel column chromatography (DCM: MeOH = 40:1) to give intermediate s1 as white solid (0.91 g, 66.1% yield). 1H NMR (300MHz, DMSO-d6) δ (ppm): 8.99 (s, 1H), 8.58 (t, J = 6.30 Hz, 1H), 7.92 (d, J = 9.27 Hz, 1H), 7.37-7.44 (m, 4H), 4.35-4.57 (m, 4H), 4.21 (dd, J = 15.93, 5.46 Hz, 1H), 3.62-3.70 (m, 2H), 3.53 (t, J = 6.57 Hz, 2H), 2.45 (s, 3H), 2.26-2.35 (m, 1H), 2.12-2.21 (m, 1H), 2.00-2.07 (m, 1H), 1.86-1.94 (m, 1H), 1.73-1.82 (m, 2H), 1.57-1.68 (m, 2H), 0.94 (s, 9H). MS (ESI): m/z calcd for C27H37BrN4O4S: 593.2 [M+H]+; found: 593.2. |
110 mg | With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In dichloromethane at 20℃; for 1h; | 21 Take (2S, 4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl Base) pyrrolidine-2-carboxamide (S40) 88mg, 5-bromopentanoic acid (S41) 40mg,Dissolve in 5mL of anhydrous dichloromethane, add HATU 75mg, DIPEA 0.1mL to an ice water bath, react at this temperature for 1h, and dilute the reaction solution with 45mL ethyl acetate.Wash three times with water, dry with anhydrous sodium sulfate, and column chromatography (dichloromethane/methanol=15/1) to obtain(2S,4R)-1-((S)-2-(5-Bromoheptanamide)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(S42)110mg |
110 mg | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane for 1h; Cooling with ice; | 1-21 Take (2S, 4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (S40) 88mg,5-Bromopentanoic acid (S41) 40mg, dissolved in 5mL of anhydrous dichloromethane, add HATU 75mg, DIPEA 0.1mL to an ice-water bath, and react at this temperature for 1h,The reaction solution was diluted with 45 mL ethyl acetate, washed three times with water, and dried over anhydrous sodium sulfate.Column chromatography (dichloromethane/methanol=15/1) to obtain (2S, 4R)-1-((S)-2-(5-bromoheptanamide)-3,3-Dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (S42) 110mg |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25 - 40℃; | 4.1.1. Procedure for the synthesis of intermediates 1a-d, 2a-d and 3a-d General procedure: AD-1/AD-2/PD (2 mmol) was first dissolved in DCM (30 mL). EDC(3 mmol), DMAP (0.08 mmol) and ω-bromoalkanoic acid (2-2.3 mmol)were added successively. The mixture was stirred at 25-40 °C until thereaction was complete according to TLC detection (petroleum ether/acetone 7:4). The mixture was poured into ice-cold water slowly, andthen ethyl acetate was used to extract (40 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The crudeproduct was purified via column chromatography with silica gel(300-400 mesh, petroleum ether/acetone 30:1) to afford 1a-d, 2a-dand 3a-d. The spectral data are given below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25 - 40℃; | 4.1.1. Procedure for the synthesis of intermediates 1a-d, 2a-d and 3a-d General procedure: AD-1/AD-2/PD (2 mmol) was first dissolved in DCM (30 mL). EDC(3 mmol), DMAP (0.08 mmol) and ω-bromoalkanoic acid (2-2.3 mmol)were added successively. The mixture was stirred at 25-40 °C until thereaction was complete according to TLC detection (petroleum ether/acetone 7:4). The mixture was poured into ice-cold water slowly, andthen ethyl acetate was used to extract (40 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The crudeproduct was purified via column chromatography with silica gel(300-400 mesh, petroleum ether/acetone 30:1) to afford 1a-d, 2a-dand 3a-d. The spectral data are given below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With boron trifluoride dihydrate for 0.333333h; Microwave irradiation; | 2.2. Synthesis of acylhydroquinones and acylchlorohydroquinones General procedure: The synthetic methodology for obtaining acylhydroquinones hasbeen already reported [29,30] and was used to synthesize the compounds13-27 (Table 1). Briefly, acylhydroquinones 13-27 were obtainedusing microwave irradiation at 90 C, at a fixed power of 150 Was follows. To a 10 mL CEM microwave (CEM Discovery SP Labmate, NC,USA) process vial equipped with a magnetic bar, a mixture of oneequivalent of hydroquinone was added (1) or dimethyl hydroquinone(2), 1.5 equivalent of the corresponding carboxylic acid (3-11), and 4mL of boron trifluoride dihydrate (Sigma-Aldrich, DA, Germany). Themixture was irradiated under microwave for 20 min. After that, themixture was extracted with ethyl acetate (Panreac Quimica, BCN,Spain), washed with water, and dried with anhydrous sodium sulfate(Sigma-Aldrich, DA, Germany), then it was filtered and concentratedunder vacuum. Afterward, the corresponding acylhydroquinone waspurified by flash chromatography with hexane/ethyl acetate (PanreacQuimica, BCN, Spain) 4:1 as eluent. In this manner, the acylhydroquinones13-27 were obtained. As shown in Table 1, compounds28-38 were obtained by chlorination, with hydrogen chloride (obtainedby reaction of concentrated sulfuric acid with sodium chloride) [31] ofthe corresponding quinones obtained by oxidation of the hydroquinones12-15, 17-22, and 24, with Ag2O (obtained by adding concentratedsodium hydroxide to a silver nitrate solution) [32] in dichloromethane(Merck, DA, Germany) [29], these compounds were also purified byflash chromatography with hexane/ethyl acetate 4:1 as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.3% | Stage #1: 5-bromopentanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione In N,N-dimethyl-formamide for 6h; | 10.1 Example 10 Preparation of Compound 10 S1, compound 2b (4-bromovaleric acid, 1.81 g, 10.0 mmol) and N,N-diisopropylethylamine (DIEA,2.58g, 20.0mmol) was dissolved in N,N-dimethylformamide (DMF, 20mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetrazolium was added. Methyl urea hexafluorophosphate (HATU, 5.70 g, 15.0 mmol) was stirred at room temperature for 10 min, then compound 5a (5-lenalidomide, 2.59 g, 10.0 mmol) was added, and the reaction was incubated for 6 hours, and the reaction was monitored by TLC After the reaction was completed, purified water (200 mL) was added, a solid was precipitated, filtered, the filter cake was washed with water, and the filter cake was dried to obtain 3.6 g of intermediate 10c with a yield of 85.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.5% | With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 5h; | 4.1 Preparation of Example 4 Compound 4 S1, compound 3a (lenalidomide, 2.59 g, 10.0 mmol) and compound 2b (4-bromovaleric acid,1.81 g, 10.0 mmol) was dissolved in N,N-dimethylformamide (DMF, 10 mL), potassium carbonate (2.76 g, 20.0 mmol) was added, the temperature was raised to 50 °C for 5 hours, and the reaction was monitored by TLC. The temperature was lowered to room temperature, purified water (100 mL) was added, a solid was precipitated, filtered, the filter cake was washed with water, and the filter cake was dried to obtain 3.19 g of intermediate 4c with a yield of 88.85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.97% | With triphenylphosphine In toluene at 110℃; for 12h; Inert atmosphere; | 2.13.1 Step 1: Synthesis of (4-carboxybutyl)triphenylphosphonium bromide (aa32-2) To a solution of 5-bromopentanoic acid (10 g, 55.24 mmol,6.76 mL, 1 eq.) in toluene (100 mL) was added PPh3 (15.94 g,60.76 mmol, 1 .1 eq.). The mixture was stirred at 110 °C for 12 h under N2. The reaction progress was monitored by LCMS. Upon completion, the reaction mixture was cooled to 0 °C, then filtered and washed with toluene (10 mL *3), the filter cake was collected and dried under reduced pressure. Compound aa32-2 (16.4 g, 36.99 mmol,66.97% yield) was obtained as a white solid. LCMS (ESI): RT = 1 .076 min, mass calcd. for C22H22O2P+, 349.14 [M+H]+, found 349.2 [M+H]+. LCMS conditions: 1.5 ML/4L TFA in water (solvent A) and 0.75 ML/4L TFA in acetonitrile (solvent B), using the elution gradient 10%-80% (solvent B) over 1.35 minutes and holding at 80% for 0.9 minutes at a flow rate of 0.8 ml/min; Column: Xtimate C18 2.1 * 30 mm, 3 mm; Wavelength: LIV 220 nm & 254 nm Column temperature: 50 °C; 1H NMR (400 MHz, CD3CI) 5 7.91 -7.66 (m, 15H), 3.31 - 3.22 (m, 2H), 2.55 (t, J = 6.3 Hz, 2H), 1 .86-1 .82 (m, 4H) ppm. |
66.97% | With triphenylphosphine In toluene at 110℃; for 12h; Inert atmosphere; | 2.13.1 Step 1: Synthesis of (4-carboxybutyl)triphenylphosphonium bromide (aa32-2) To a solution of 5-bromopentanoic acid (10 g, 55.24 mmol,6.76 mL, 1 eq.) in toluene (100 mL) was added PPh3 (15.94 g,60.76 mmol, 1 .1 eq.). The mixture was stirred at 110 °C for 12 h under N2. The reaction progress was monitored by LCMS. Upon completion, the reaction mixture was cooled to 0 °C, then filtered and washed with toluene (10 mL *3), the filter cake was collected and dried under reduced pressure. Compound aa32-2 (16.4 g, 36.99 mmol,66.97% yield) was obtained as a white solid. LCMS (ESI): RT = 1 .076 min, mass calcd. for C22H22O2P+, 349.14 [M+H]+, found 349.2 [M+H]+. LCMS conditions: 1.5 ML/4L TFA in water (solvent A) and 0.75 ML/4L TFA in acetonitrile (solvent B), using the elution gradient 10%-80% (solvent B) over 1.35 minutes and holding at 80% for 0.9 minutes at a flow rate of 0.8 ml/min; Column: Xtimate C18 2.1 * 30 mm, 3 mm; Wavelength: LIV 220 nm & 254 nm Column temperature: 50 °C; 1H NMR (400 MHz, CD3CI) 5 7.91 -7.66 (m, 15H), 3.31 - 3.22 (m, 2H), 2.55 (t, J = 6.3 Hz, 2H), 1 .86-1 .82 (m, 4H) ppm. |
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H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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