2-(3-氯丙基)-1,3-二噁戊环

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a flame dried flask fitted with a nitrogen inlet, magnetic stirrer, and oil bath was dissolved the 2-(3-chloropropyl)-1,3-dioxolane (25.4 g, 169 mmol) in 70 ml of dimethylsulfoxide. Sodium cyanide (9.1 g, 186 mmol) in 100 ml of dimethylsulfoxide was added and the mixture was heated to 80° C. for 18 hours. The reaction was cooled to room temperature then poured onto ice water and stirred for 1 hour. The mixture was extracted thoroughly with diethyl ether, testing the aqueous after each extraction by TLC for the presence of product. The ether was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a colorless oil. The oil was purified by silica gel chromatography (50/50 ethyl acetate/hexane) to give 19.2 g of product. (80.7%). In a flame dried flask fitted with a nitrogen inlet, magnetic stirrer, and oil bath The reaction was cooled to room temperature then poured onto ice water The mixture was extracted thoroughly with diethyl ether aqueous after each extraction by TLC for the presence of product The ether was washed with brine dried over sodium sulfate concentrated in vacuo to give a colorless oil The oil was purified by silica gel chromatography (50/50 ethyl acetate/hexane)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2-(3-chloro-propyl)-[1,3]-dioxolane (5.7 g; 0.038 mol), THF (50 ml) and aqueous acid chloride (1/1) was stirred at room temperature for 24 hours. O-phenyl-hydroxylamine hydrochloride (5 g; 0.034 mol) was then added and the resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under vacuum. Then the product was extracted with methylene chloride. The organic extract was dried (Mg SO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent hexane/ethyl acetate (95/5), the desired compound was obtained. the resulting mixture was stirred at room temperature for 48 hours The reaction mixture was concentrated under vacuum Then the product was extracted with methylene chloride The organic extract was dried (Mg SO4) evaporated under vacuum After purification by Flash Chromatography on silica gel using as eluent hexane/ethyl acetate (95/5)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared from 4-((3-(((tert-butoxycarbonyl)amino)-(phenyl)methyl)phenoxy)methyl)benzoic acid and 2-(3-chloropropyl)-1,3-dioxolane according to the method of Chiral Example 5 Step 1.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared in two steps. Boc-Phe-OH was reacted with 2-(3-chloropropyl)-1,3-dioxolane according to Example 10 Step 1, and the subsequent product reacted with hydrogen chloride in dioxan according to Example 79 Step 5.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared as described in Example 54 Step 1 with -(3-(((tert-Butoxycarbonyl)amino)(phenyl)methyl)phenoxy)acetic acid and 2-(5-bromopentyl)-1,3-dioxolane 4-((3-(azido(phenyl)methyl)phenoxy)methyl)benzoic acid and 2-(3-chloropropyl)-1,3-dioxolane respectively.

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 3-chloropropyl-1,3-dioxolane (0.2 g, 1.35 mmol) in dimethyl formamide (14 mL), was added 4-((3-(azido(phenyl)methyl)phenoxy)-methyl)benzoic acid (Example 51 Step 3) (0.5 g, 1.39 mmol) and potassium carbonate (0.38 g, 2.78 mmol). The reaction was allowed to stir at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (×3). The organic extracts were washed with brine, dried (sodium sulphate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford the title compound (0.63 g, 96%). The reaction mixture was cooled to room temperature extracted with ethyl acetate (×3) The organic extracts were washed with brine dried (sodium sulphate) filtered concentrated under reduced pressure The crude material was purified by silica gel chromatography eluting with 0-100% ethyl acetate in iso-hexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 21.8 g of sodium hydride (80 percent strength suspension in mineral oil) is introduced into 1.5 l of dry dimethylformamide, and 90 g of methyl 1-hydroxypyrazole-4-carboxylate are added a little at a time to the stirred mixture. When the evolution of hydrogen is complete, stirring is continued for 30 minutes, after which 95.5 g of 2-(3-chloropropyl)-1,3-dioxolane are added dropwise and the mixture is kept at 120° C. for 10 hours. Thereafter, the dimethylformamide is distilled off under reduced pressure, the residue is taken up in methyl tertbutyl ether, and the solution is washed with water, boiled and evaporated down to give 151 g of a slightly colored oil which crystallizes completely. M.p. 40°-42° C. NMR (CDCl3): 7.82 s [1]; 7.70 s [1]; 4.50 t [1]; 4.39 t [2]; 3.85-3.95 m [4]; 3.80 s [3]; 1.75-1.95 m [4]. are added a little at a time to the stirred mixture the mixture is kept at 120° C. for 10 hours Thereafter, the dimethylformamide is distilled off under reduced pressure the solution is washed with water evaporated down to give 151 g of a slightly colored oil which crystallizes completely

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of Compound B of Example 23 (410 mg, 1 mmol) dissolved in CH2Cl2 (10 mL) was added 2(chloropropyl)-1,3-dioxolane(0.53 mL, 4 mmol) followed by trifluoroacetic acid (10 mL) and triethylsilane (0.64 mL, 4 mmol). Stirring was continued for 1 hr and the solvent was removed under vacuum. The residue was neutralized with saturated aqueous Na2CO3, diluted with CH2Cl2, washed with brine and evaporated to a yellow solid (500 mg). the solvent was removed under vacuum diluted with CH2Cl2 washed with brine evaporated to a yellow solid (500 mg)

反应条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 4-(5-fluoro-2-pyrimidinyl)piperazine (7.29 g, 40.0 mmol), 2-(3-chloropropyl)-1,3-dioxolane (6.62 g, 5.8 mL, 44.0 mmol) and triethylamine (12.5 mL, 90.0 mmol) in 2-butanone (250 mL) was heated to reflux and treated dropwise (1h) with a solution of NaI (3.0 g, 20.0 mmol) in 2-butanone (70 mL). The reaction mixture was refluxed for 12 h then treated dropwise (1 h) with a solution of NaI (3.0 g, 20.0 mmol) in 2-butanone (70 mL) and refluxed for another 12 h. After cooling at 23° C., the solvent was evaporated in vacuo leaving a residue which was solubilized in EtoAC (400 mL). The organic solution was washed with aqueous NaOH solution (20 mL, 2N); the aqueous phase was extracted with EtoAC (2×50 mL). The organic extracts were combined, dried (MgSO4) and concentrated to dryness. The solution was chromatographed on a silica gel column (4.5×15 cm) using a mixture of 20% MeCN in EtoAc. Appropriate fractions were concentrated in vacuo leaving a pale yellow syrup which crystallized on standing, 10.5 g, mp 54°-55° C. (89%). Recrystallization from EtoAC-pet.ether mixture (1;14) gave an analytical sample, mp 55°-56° C.; 1HNMR (CDCl 3, 200 MHz) δ: 1.5-1.9 (m, 4H), 2.3-2.7 (m, 6H), 3.6-4.1 (m, 8H), 4.8-5.0 (m, 1H), 8.16 (s, 2H); IR (KBr) ν: 1610, 1555, 1489 cm-1 ; UV (EtOH) λ: 244 (ε 17239), 332 (ε 1948); was heated to reflux The reaction mixture was refluxed for 12 h refluxed for another 12 h the solvent was evaporated in vacuo leaving a residue which The organic solution was washed with aqueous NaOH solution (20 mL, 2N) the aqueous phase was extracted with EtoAC (2×50 mL) dried (MgSO4) concentrated to dryness The solution was chromatographed on a silica gel column (4.5×15 cm) a mixture of 20% MeCN in EtoAc Appropriate fractions were concentrated in vacuo leaving a pale yellow syrup which crystallized Recrystallization from EtoAC-pet ether mixture (1;14) gave an analytical sample, mp 55°-56° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 2.5M hexane solution of butyl lithium (180 ml) was added to an ice-cooled solution of phenylacetic acid (20 g), hexamethylphosphoramide (25.6 ml) and tetrahydrofuran (260 ml). The reaction mixture was stirred to room temperature, then cooled back to 0° C. A solution of 2-(3-chloropropyl)-1,3-dioxolane in THF (20 ml) was added dropwise and the mixture was stirred to room temperature overnight. The reaction was cooled back down to 0° C. then butyl lithium (60 ml of a 2.5M hexane solution) was added dropwise followed by picolyl chloride (0.147 mol) in THF (40 ml). The ice-bath was removed and the reaction was stirred at room temperature for 3 days. The reaction mixture was quenched with half-saturated aqueous NH4Cl. Ethyl acetate and chloroform were added to dissolve the solids. The aqueous layer was neutralized with 1N HCl and extracted with chloroform. The combined organic layers were dried (MgSO4) and concentrated to give a solid which was washed with ether to give the subtitle compound (28.1 g). cooled back to 0° C the mixture was stirred to room temperature overnight The reaction was cooled back down to 0° C. The ice-bath was removed the reaction was stirred at room temperature for 3 days The reaction mixture was quenched with half-saturated aqueous NH4Cl Ethyl acetate and chloroform were added to dissolve the solids extracted with chloroform The combined organic layers were dried (MgSO4) concentrated to give a solid which was washed with ether

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2-(3-chloropropyl)-1,3-dioxolane (15.88 g; 0.1054 moles), sodium cyanide (6.46 g; 0.132 moles) and sodium iodide (1.57 g; 0.0105 moles) in DMF (100 mL) was heated at 80° C., with magnetic stirring, under a nitrogen atmosphere for 15 hours. The mixture was allowed to cool, added to water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined extracts were washed with water (200 mL) and saturated aqueous sodium chloride solution (100 mL) and then dried over sodium sulfate. Filtration and evaporation of solvent gave a crude yellow oil which was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (5:2). Removal of solvent under vacuum gave the product 4-(1,3-dioxolan-2-yl)-butanenitrile (11.28 g; 76%) as a colorless oil. 1H NMR (CDCl3) δ 4.89-4.91 (1H, m), 3.92-4.01 (2H, m), 3.82-3.90 (2H, m), 2.40-2.46 (2H, m), 1.77-1.85 (4H, m). to cool extracted with ethyl acetate (3×200 mL) The combined extracts were washed with water (200 mL) and saturated aqueous sodium chloride solution (100 mL) dried over sodium sulfate Filtration and evaporation of solvent gave a crude yellow oil which was purified by chromatography on silica gel eluting with hexane/ethyl acetate (5:2) Removal of solvent under vacuum

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 2.75 g (7 mmol) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester (prepared as in Example 1, part D) in 10 mL of anhydrous DMF was added to a suspension of 0.36 g (9.1 mmol) of a NaH (60% dispersion in mineral oil) in 5 mL of anhydrous DMF under an inert atmosphere. After stirring for 30 minutes at room temperature, a solution of 1.1 mL (8.4 mmol) of 2-(3-chloro-propyl)-[1,3]dioxolane in 3 mL of DMF was added. The crude mixture was stirred at room temperature for 16 hours and the solvent was removed under reduced pressure. The residue obtained was dissolved with 150 mL of ethanol and 6 mL of a 2N NaOH aqueous solution were added. After 12 h at room temperature, the solvent was removed under reduced pressure. The crude mixture was dissolved with 50 mL of water and neutralised with a 2N HCl aqueous solution. The crude mixture was purified by flash chromatography over silica gel affording 0.83 g (29% of yield) of the expected product. the solvent was removed under reduced pressure The residue obtained were added After 12 h at room temperature the solvent was removed under reduced pressure The crude mixture was dissolved with 50 mL of water and neutralised with a 2N HCl aqueous solution The crude mixture was purified by flash chromatography over silica gel affording 0.83 g (29% of yield) of the expected product