* 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.
Reference:
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1988, vol. 37, # 7, p. 1514[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1988, # 7, p. 1696
11
[ 67-56-1 ]
[ 123-99-9 ]
[ 1732-10-1 ]
[ 2104-19-0 ]
Reference:
[1] Arkiv foer Kemi, 1949, vol. 26 A, # 19, p. 10
[2] Journal of the American Chemical Society, 1982, vol. 104, # 14, p. 3990 - 3997
12
[ 67-56-1 ]
[ 123-99-9 ]
[ 1732-10-1 ]
[ 2104-19-0 ]
Reference:
[1] Green Chemistry, 2016, vol. 18, # 21, p. 5764 - 5768
[2] Helvetica Chimica Acta, 1926, vol. 9, p. 265
13
[ 123-99-9 ]
[ 623-42-7 ]
[ 2104-19-0 ]
Reference:
[1] Synthesis, 1998, # 12, p. 1793 - 1802
With oxalyl dichloride; In benzene; for 2h;Reflux;
Monomethyl azelate (500 mg, 2.4 mmol) was added dropwise via syringe to a solution of oxalyl chloride (300 mg, 3.5 mmol, 1.5 equiv) in benzene (3 mL). The reaction mixture was stirred for 30 min at room temperature and then refluxed for 2 h, after which time no acid starting material was detected by IR. Upon completion, the solvent was evaporated under reduced pressure and the residue purified by vacuum distillation to give 5c (491 mg, 90%). IR (film, cm-1) 2943, 2861, 1811, 1733, 1462, 1434, 1251, 1205. 1H NMR (400 MHz, CDCl3) delta 3.66 (s, 3H), delta 2.87 (m, 2H), 2.30 (m, 2H), 1.65 (m, 2H), 1.60 (m, 2H), 1.35 (6H).
With oxalyl dichloride; N,N-dimethyl-formamide; In toluene; at 0 - 20℃; for 3.08333h;
Azelaic acid monomethyl ester (14.8 g, 73.2 mmol) was dissolved in toluene (74 mL), DMF (57 muL, 0.732 mmol) was added, cooled with ice under a nitrogen atmosphere, and oxalyl dichloride (19.1 mL, 220 mmol) was added dropwise over 5 minutes. After completion of the dropwise addition, an ice cooler was removed, followed by stirring for 3 hours at room temperature. Toluene and oxalyl dichloride were distilled off with an evaporator, and subsequently toluene (74 mL) was added again to distill off the solvent. The whole amount of the crude product 1 was used directly for the next reaction.
With thionyl chloride; In benzene; for 3h;Reflux;
General procedure: A solution of monomethyl alkanoic acid (n = 3-7) (1.2 eq) and thionyl chloride (1.4 eq) in benzene (5 mL) was refluxed for 3 h. Subsequently, the majority of the SOCl2 and benzene were removed by distillation. The mixture was cooled down to room temperature and dried under a vacuum to give a crude chlorocarbonyl-alkanoic acid methyl ester. A solution of chlorocarbonyl-alkanonic acid methyl ester in dichloromethane (5 mL) was added to a round flask containing 14 (1 eq) by cannula, and subsequently added pyridine (3.5 eq). The resulting solution was stirred at room temperature overnight, and quenched by adding water. The solution was extracted with ethyl acetate, dried (MgSO4), and evaporated to give a residue which was purified by column chromatography (Al2O3), eluting by ethyl acetate /hexane (1:15) to provide 15-19.
With oxalyl dichloride; N,N-dimethyl-formamide; In toluene; at 60℃; for 2.16667h;Inert atmosphere;
Step B-1 Under a nitrogen atmosphere, monomethyl azelate (6.70 g, 33.1 mmol), commercially available from Tokyo Chemical Industry Co., Ltd., was dissolved in toluene (60 mL), N,N-dimethylformamide (DMF, 25.6 muL, 0.331 mmol) was added thereto, and the solution was warmed to 60 C. While maintaining the temperature at 60 C, a solution of oxalyl chloride (2.94 mL, 34.8 mmol) in toluene (7.0 mL) was added dropwise over 10 minutes. After completion of the dropwise addition, the mixture was stirred at 60 C for 2.0 hours. Toluene and oxalyl chloride were distilled off under reduced pressure, and subsequently tetrahydrofuran (THF, 67 mL) was added to distill off the solvent. Under a nitrogen atmosphere, this crude product was dissolved in THF (50mL), tris(2,4-pentadionato) iron (III) (Fe(acac)3, 0.585 g, 0.166 mmol) was added thereto, and the solution was cooled to -40 C. Subsequently, a dilution of n-heptyl magnesium bromide (1 M solution in THF, 36.4 mL, 36.4 mmol) with THF (30mL) was added dropwise over 1 hour. After completion of the dropwise addition, the mixture was stirred at -40 C for 1.5 hours. To the reaction solution was added 0.5 M aqueous hydrochloric acid solution (40 mL) to stop the reaction, and the solution was extracted with ethyl acetate. The aqueous layer was washed with ethyl acetate, and the organic layers were combined, washed sequentially with water, a saturated sodium bicarbonate aqueous solution, and a saturated brine and dried over anhydrous sodium sulfate. After the organic layer was filtered and the solvent was distilled off, the resulting residue was purified with SP1 (Si02 cartridge, 10% ethyl acetate / n-hexane, Rf = 0.2) to obtain methyl 9-oxo-hexadecanoate (No. 4984860; 7.33 g, 78% yield).
With 1,2,3-Benzotriazole; thionyl chloride; In dichloromethane; at 20℃; for 1h;
Step 2; 8-{2-[((lR,2S)-l-tert-Butoxycarbonylamino-2-vinyl-cyclopropanecarbonyl)-sulfamoyl]- phenylcarbamoyl}-octanoic acid methyl ester; To a solution of 2.65 g (13 mmol) Monomethyl azelate in 20 mL DCM is added at rt a solution of 1.87 g (16 mmol) Benzotriazole and 1.87 g (16 mmol) Thionylchloride in 10 mL DCM. The suspension is stirred for 1 h, filtered, washed with 20 mL DCM and the solvent is removed in vacuo. The residue is dissolved in 10 mL DCM and added at 0C to a solution of 2.0 g (5.2 mmol) [(lR,2S)-l-(2-Amino-benzenesulfonylaminocarbonyl)-2-vinyl- cyclopropylj-carbamic acid tert-butyl ester, 5.1 g (50 mmol) NEt3 and 100 mg DMAP in 50 mL DCM. After stirring for 15 h at rt the reaction is quenched by addition of aq. bicarbonate, extracted with DCM, dried with Na2SO4, filtered and the solvent is removed in vacuo. The residue is purified by FC on silica (eluent: CH2Cl2/Me0H 98:2 -> 95:5) to give the title compound as a red oil.HPLC (method A) tR = 5.19 min TLC, Rf (CH2Cl2/MeOH 9:1) = 0.46 MS (method D): 566 [M+]
With oxalyl dichloride; In hexane;
The 9-keto-12,13-trans-epoxy-(10E)-methyl-octadecenoate (9K-12,13E-LA methyl ester) was prepared following similar procedures as published by Sayre et. al. in J. Org. Chem.2007, 72, 9471-9480, with the modification of installing the epoxide on the dienone produced by the Wittig reaction instead of on the en-al (prior to the Wittig reaction) as published by Sayre. The hydroxy compound was produced as in Example 3: 9-hydroxy-12,13-trans-epoxy-(10E)-octadecenoic acid (9H-12,13E-LA): 1H NMR (400 MHz, CDCl3) delta 5.91 (dd, J=6.22, 15.55 Hz, 1H), 5.41 (dd, J=7.87, 15.55 Hz, 1H), 4.12 (quin, J=5.95 Hz, 1H), 3.04-3.16 (m, 1H), 2.82 (dt, J=1.92, 5.54 Hz, 1H), 2.33 (t, J=7.50 Hz, 2H), 1.49-1.64 (m, 5H), 1.27-1.47 (m, 11H), 1.09-1.27 (m, 3H), 0.79-0.93 (m, 3H).
Azelaic acid (100 g, 0.532 mole) was dissolved in Methanol (100 mL) and then H2SO4 was added into reacted vessel. Reacted at reflux temperature for 3 hours. After reaction, Methanol was removed by evaporation. The crude mixture was extracted with Ethyl acetate/H2O and then evaporated to obtain di-methyl azelate. Di-methyl azelate (100 g, 0.462 mole) was dissolved in Methanol (100 mL), and then Ba(OH)2.8H2O (58.5 g, 0.185 mole) was poured into vessel. The mixture was reacted at 45 C. overnight. After reaction, Ba-salt was washed with Methanol and then acidified by HCl to get mono-methyl azelate.Then, Mono-methyl azelate (10 g, 0.0495 mole) and N-Hydroxysuccinimide (6.26 g, 0.0544 mole) were dissolved in THF. A solution of Dicyclohexylcarbodiimide (12.24 g, 0.0592 mole) and THF was poured into the reacted vessel. Reacted at room temperature overnight, the DCU was removed by filter. Dimethylaminopropylamine (5.5 g, 0.0544 mole) was added into and reacted for overnight. Removed the solvent and extracted with Ethyl acetate/H2O. After evaporation, 8-(3-Dimethylamino-propylcarbamoyl)-octanoic acid methyl ester was obtain. 8-(3-Dimethylamino-propylcarbamoyl)-octanoic acid methyl ester was dissolved in Methanol and added NaOH/Methanol (1 N, 50 ml). The mixture was stirred at room temperature for 36 hours and concentrated under vacuum. The residue was acidified with HCl/Ethyl acetate (1 N 55 ml). The crude was purified by column chromatography Ethyl acetate/Methanol to obtain [8-(3-Dimethylamino-propylcarbamoyl)-octanoic acid.hydrochloride].
Azelaic acid (100g, 0.532mole) was dissolved in Methanol(100mL) and then H2SO4 was added into reacted vessel. Reacted at reflux temperature for 3hours. After reaction, Methanol was removed by evaporation. The crude mixture was extracted with Ethyl acetate /H2O and then evaporated to obtain di-methyl azelate. Di-methyl azelate (100g, 0.462mole) was dissolved in Methanol (100mL), and then Ba(OH)2.8H2O (58.5g, 0.185mole) was poured into vessel. The mixture was reacted at 45C overnight. After reaction, Ba-salt was washed with Methanol and then acidified by HCl to get mono-methyl azelate. Then, Mono-methyl azelate (10g, 0.0495mole) and N-Hydroxysuccinimide (6.26g, 0.0544mole) were dissolved in THF. A solution of Dicyclohexylcarbodiimide (12.24g, 0.0592mole) and THF was poured into the reacted vessel. Reacted at room temperature overnight, the DCU was removed by filter. Dimethylaminopropylamine (5.5g, 0.0544mole) was added into and reacted for overnight. Removed the solvent and extracted with Ethyl acetate/H2O. After evaporation, 8-(3-Dimethylamino-propylcarbamoyl)-octanoic acid methyl ester was obtain. 8-(3-Dimethylamino-propylcarbamoyl)-octanoic acid methyl ester was dissolved in Methanol and added NaOH/Methanol (1N, 50ml). The mixture was stirred at room temperature for 3?6 hours and concentrated under vacuum. The residue was acidified with HCl/ Ethyl acetate (1N 55ml). The crude was purified by column chromatography Ethyl acetate / Methanol to obtain [8-(3-Dimethylamino-propylcarbamoyl)-octanoic acid . hydrochloride].
EXAMPLE 1; Step a); The following substances were fed continuously to a CSTR with a working capacity of 80 1, equipped with stirrer and with an adequate temperature regulation system:methyl oleate (technical purity approximately 85%; flow rate 10 kg/h);an aqueous solution of hydrogen peroxide at 60%> (flow rate 2.3 kg/h);- tungstic acid (H2W04) (flow rate 48 g/h).The reaction was conducted at a constant temperature of 62C under vacuum (absolute pressure of 0.10-0.20* 105 Pa) to evaporate the water fed together with the hydrogen peroxide; the evaporated gas was collected and condensed (approximately 1 kg/h of water).FIG. 3 shows the hydrogen peroxide over-all concentration during step a).As can be seen in Fig. 3, the over-all hydrogen peroxide concentration in the reactor was constant at about 1.5 g/kg.The intermediate product containing vicinal diols was continuously discharged from the reactor and fed to step b) by means of a gear pump, adjusted to maintain a constant level in the reactor, with a flow rate of approximately 11.4 kg.; Step b; Step b) was performed in a jet loop reactor with a working capacity of 80 1 equipped with a 3 m3/h recirculation pump and heat exchanger. The intermediate product of step a) was continuously fed with a flow rate of 11.4 kg/h together with:cobalt acetate (Co(CH3COOH)2»4H20, dissolved at 1.5% in an aqueous current(approximately 2 kg/h);- pressurized air (20* 105 Pa; flow rate 12 to 15 kg/h).The air flow rate was adjusted to maintain a constant 02 content (approximately 10%) at the reactor outlet.The reaction was conducted at 60C, keeping constant the reaction volume to 50 1. The reaction time was about 3.5h.The reaction mixture of step b) was continuously discharged from the jet loop reactor and fed to a decanter to separate the oily phase from the aqueous phase. Approximately 13 kg/h of oily product was obtained.; Step (c); The separated oily phase was dried and degassed, and then transferred to a distillation column which allowed fractioning of the monocarboxylic acids, to separate the pelargonic acid from the lighter monocarboxylic acids. The main component of the lighter monocarboxylic acids fraction (byproducts of the oxidative cleavage reaction) was octanoic acid.Approximately 3.8 kg/h of vapor phase containing monocarboxylic acids (raw pelargonic acid), of which 3.5 kg/h are pelargonic acid with a titer of over 99%, was obtained. The 3.8 kg/h current of raw pelargonic acid contained approximately 3.3% of octanoic acid.An organic current of approximately 9 kg/h, containing as major component mono-methyl azelate, together with methyl palmitate, methyl stearate and esters of methyl dihydroxy stearate, was extracted from the bottom of the distillation column.Said organic current was then continuously fed to an emulsifier together with 18 kg/h of water. The emulsion was hydro lyzed by feeding it to three consecutive columns filled with acid ion exchange resin and heated at the temperature of 100C. The total reaction time was 6 h.Each column was provided with a fractionating column on the top, to separate 1.1 kg/h of methanol from water. Approximately 8.5 kg/h of carboxylic acids were obtained from the bottom of the column, of which about 4.3 kg was azelaic acid.
Example 1Comparative ExampleOzonolysis and Oxidation without Addition of Acid20 g of a 0.182 molal solution of methyl oleate (95% pure) in a solvent mixture of propionic acid and water (15 equivalents based on moles of double bond) were initially charged in a two-neck flask with gas inlet tube and reflux condenser. The feed gas, consisting of 5% by volume of oxygen in carbon dioxide was passed through an ozone generator at a flow rate of 40 ml/min. The ozone generator was set to maximum power. The ozone-containing gas mixture was passed into the reaction mixture with stirring. The offgas stream was passed by means of gas wash bottles into a 5% aqueous potassium iodide solution. After 60 minutes, the substrate was converted, and the gas introduction was then stopped. According to GC analysis, the reaction mixture had a content of 39.5 wt % of 9-nonanal and 38.2 wt % of methyl 9-oxononanoate.After adding hydrogen peroxide (0.454 g of a 30% aqueous solution), the reaction mixture was then heated to 100 C. in an oil bath. After 120 minutes, nonanal and methyl 9-oxononanoate were converted completely to the respective carboxyl compounds. GC analysis: 41.05% pelargonic acid, 39.65% monomethyl azelate (FID signal, figure in area percent, uncorrected).
With borane-THF; In tetrahydrofuran; at -20 - 20℃; for 4h;
[0418] To prepare 4, a solution of nonanedioic acid monomethyl ester (3) (923 mg, 4.6 mmol) in dry THF (3 ml) at -20C was treated with 1 M BH3 in THF (4.6 ml, 4.6 mmol) over 10 minutes. After stirring at room temperature for 4 hours, the reaction was quenched with 0.77 M aqueous K2C03 solution (10 ml) at 0C. The product was extracted with diethyl ether (3 x 20 ml), washed with saturated aqueous NaCl solution, dried over Na2S04, and concentrated in vacuum to afford methyl 9- hydroxynonanoate (4) (Kai K. et al, Tetrahedron 64:6760-69 (2008), which is hereby incorporated by reference in its entirety) (850 mg, 99% yield) as a colorless oil, which was used directly without any further purification. 1H NMR (400 MHz, chloroform-<ii): delta 1.27-1.37 (8H, m), 1.50-1.66 (4H, m), 2.29 (2H, t, J = 7.5 Hz), 3.62 (2H, t, J 3.66 (3H, s). See Figure 75 C.
55%
With dimethylsulfide borane complex; In tetrahydrofuran; at -20 - 20℃; for 0.333333h;
Preparation of 9-Hydroxy-nonanoic acid methylester 4-BTo a solution of nonanedioic acid monomethyl ester (4.80 g,20 mmol) in THF (20 mE) at -20 C. was added a solution ofborane-dimethylsulfide in THF (2.0 M, 10 mE) over 10 mm.The resulting mixture was stirred for an additional 10 mm,and then allowed to stir at room temperature overnight. Aqueous K2C03 solution was added, and the product was extractedwith ethyl ether (3x). The crude product was purified by flashcolunm chromatography (hexane/EtOAc:2/1) to yield 9-hy-droxy-nonanoic acid methyl ester 4-B (2.0 g, 55%).iH NMR (CDC13) oe 4.86 (bs, 1H, OH), 3.67 (s, 3H), 3.63(t, J=7.4 Hz, 2H), 2.29 (t, J=7.4 Hz, 2H), 1.68-1.48 (m, 4H),1.40-1.24 (m, 8H).
With potassium carbonate; In tetrahydrofuran; diethyl ether; water;
EXAMPLE 41 4-Hydroxy-3-[10-(4-chlorophenyl)-1-oxodecyl]-2(5H)-furanone To a solution of 165 mL (165 mmol) of a 1.0M solution of boranetetrahydrofuran complex in tetrahydrofuran in 200 mL of dry diethyl ether at 0 C. is added dropwise 25.0 g (123 mmol) of <strong>[2104-19-0]azelaic acid monomethyl ester</strong>, added at such a rate as to prevent excessive release of gas and exothermicity. The solution is allowed to warm to room temperature overnight and is worked up by slowly adding water until gas evolution ceases. Then solid potassium carbonate is added and the organic layer is separated. The aqueous layer is extracted three times with diethyl ether. The combined extracts are washed with brine, dried over Na2 SO4, filtered, and concentrated in vacuo to give 8-carbomethoxyoctan-1-ol as a colorless oil.
With thionyl chloride;
[Reference Example 8-1] Synthesis of methyl 9-hydroxynonanoate (65). To commercially available <strong>[2104-19-0]azelaic acid monomethyl ester</strong> (2.02 g, 10 mmol) was added thionyl chloride (2.0 ml), and the mixture was refluxed for 5 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, and excess thionyl chloride was evaporated to give a residue containing acid chloride 64 . This residue was dissolved in ether (10 ml) and added dropwise into a suspension of sodium borohydride-alumina complex (5.0 g) in ether (15 ml). After stirring for 12 hours at room temperature, the reaction mixture was filtered and was washed with ether. The filtrate was concentrated and resulting residue was purified by column chromatography over silica gel to give objective Compound 65 (1.59 g, Yield: 90%) as colorless oil. [see, Synthesis, 1978 : 891]. 1H-NMR (270MHz, CDCl3): delta = 3.67 (3H, s, CO2Me), 3.62 (2H, t, J=6.6 Hz, CH 2OH), 2.31 (2H, t, J=7.4 Hz, CH 2CO), 2.22 (1H, br.s, OH), 1.70-1.50 (4H, m, CH2x 2), and 1.31 (8H, m).
With hydrogenchloride; In tetrahydrofuran; diethyl ether;
Step A. Methyl 9-hydroxynonanoate A solution of 9-methoxy-9-oxononanoic acid (<strong>[2104-19-0]azelaic acid monomethyl ester</strong>) (40.45 g, 200 mmol) in tetrahydrofuran (200 mL) was treated via syringe with borane-methyl sulfide complex, 10.0 M (20 mL, 200 mmol) and warmed to 40 C. The reaction was stirred for one hour at ambient temperature. The excess borane reagent was destroyed with excess methanol and the solvent evaporated in vacuo to a residue. The residue was dissolved in diethyl ether and extracted sequentially with 2N hydrochloric acid and water. The organic phase was dried over anhydrous sodium sulfate, filtered through a short pad of silica gel, and the solvent evaporated in vacuo to yield the title compound (33.88 g, 180 mmol) as a viscous oil, which was used without further purification. 1H NMR (DMSO-d6, 300 MHz) delta 4.32 (t, J=5.2 Hz, 1H), 3.58 (s, 3H), 3.37 (td, J=6.7, 5.2 Hz, 2H), 2.48 (t, J=7.4 Hz, 2H), 1.58 (p, J=7.1 Hz, 2H), 1.40 (p, J=7.1 Hz, 2H), 1.26 (broad s, 8H)
Preparation of 9-{2-[((lR,2S)-l-[(2S,4R)-4-(7-Methoxy-2-phenyl-quinolin-4-yloxy)- pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarbonyl)-sulfamoyl]- phenylaminoj-nonanoic acid; Step l; 9-Hydroxy-nonanoic acid methyl ester; To an ice-cold solution of 10.0 g (45 mmol) Mono-methyl azelate in 250 mL THF is added 90 mL (90 mmol) BH3*THF-Komplex (IM in THF), the ice-bath is removed and stirring is continued at rt for 90 min. The reaction is quenched by careful addition of Methanol, the main solvent is evaporated, the residue is diluted with water and extracted with EtOAc. The combined organic phase is dried with Na2SO4, filtered, and the solvent is removed in vacuo to give the title compound as a colorless oil, which is used without further purification. MS (method D): 206 [M+H2O]
With potassium hydroxide In methanol at 45℃; electrolysis: anode: platinum foil; current source: galvanostat; current density 220 mA cm-2; current consumption: 1.4 F mol-1; cell voltage 20 V; Yield given;
80%
With potassium hydroxide In methanol at 45℃; electrolysis: anode: platinum foil; current source: galvanostat; current density 220 mA cm-2; current consumption: 1.4 F mol-1; cell voltage 20 V; Yields of byproduct given;
D Synthesis of 8-Methoxycarbonyloctanol
Example D Synthesis of 8-Methoxycarbonyloctanol The synthetic scheme employed in this example is illustrated below: STR5 An 8 L jacketed reactor and cooling machine is assembled and the temperature of the cooling, machine is set at -10° C. The reactor is then purged with nitrogen and equipped with a mechanical stirrer. To this reactor is added 1000 g, of methyl hydrogen azelate (4.94 moles, 1 equivalent) and 4 L of DCM. The mixture is stirred while maintaining a nitrogen purge. When the reaction solution reaches about -10° C., 544 mL of borane dimethylsulfide complex (5.44 moles, 1.1 equivalents) is added dropwise to the reaction solution over about 2 hours. The reactor is vented through a moisture trap. Upon complete addition, the temperature of the reaction solution is allowed to rise to about 15° C. and the reaction is stirred at this temperature overnight. The following day, 83 mL of ethanol is added dropwise to the reaction solution over 20 minutes and then 600 mL of water is added dropwise over 60 minutes while venting the reactor in a fume hood. After addition, the mixture is stirred for 30 minutes. The precipitated B(OH)3 is filtered and the solids washed with DCM. The filtrate is slowly added to 10 L of water and then the resulting mixture stirred for at least 15 minutes. The organic layer is drained and washed for a second time with 10 L of water, then with 1*10 L of 6% sodium bicarbonate solution and then with 2*10 L of water. The organic layer is then dried over anhydrous sodium sulfate (1000 g) and stripped to provide for the title compound.
With thionyl chloride; triethylamine;AlCl3; In dichloromethane;
EXAMPLE 1 9-keto-10-undecenoic acid, methyl ester (III) A solution of <strong>[2104-19-0]azelaic acid monomethyl ester</strong> (II) (21 g; 0.1 mole) and thionylchloride (15.4g; 0.13 mole) in methylene chloride (190 ml) is refluxed for 18 hours. The thus obtained solution is added dropwise at 0 C. into a suspension of AlCl3 (28.1 g; 0.21 mole) in methylene chloride (38 ml). After 10 minutes, ethylene (6 g; 0.21 mole) is bubbled into the solution for about 1 hour. It is poured into water/ice. the product is extracted with methylene chloride (3*20 ml). The organic extracts are washed with 5% NaHCO3 solution (30 ml) and then with water (2*30 ml) and dried with Na2 SO4. Triethylamine (16.6 g; 0.11 mole) is added to this solution, under stirring, and the mixture is refluxed for 2 hours. The mixture is poured into water and acidified with concentrated hydrochloric acid to pH 3.5, under stirring, and the phases are then separated. The organic phase is washed with water (30 ml) and dried to obain a yellow/orange oil, a sample of which is purified by silica gel chromatography (yield=100%). I.R. (film): 1740, 1705, 1685, 1620 cm-1 1 H-Nmr (delta, CDCl3): 1.0÷2.0 (m, 10H, CH2) 2.2÷2.8 (m, 4H, CH2 --C=) 3.8 (s, 3H, OCH3) 5.8÷6.2(m, 1H, =CH--C=O) 6.4÷6.6(m, 2H, CH2 =C)
With sodium tetrahydroborate; water; In 1,4-dioxane; at 25℃;
To a solution of 9-methoxy-9-oxononanoic acid (1) (2.0 g, 9.89 mmol, 1.0 eq) in dioxane/water (v/v, 25mL/25 mL) was added NaBH4 (2.6 g, 70.27 mmol, 7.0 eq) in portions. The reaction mixture was stirred at 25 C for one night. Then the mixture was quenched by IN aqueous solution of hydrochloric acid at 0 C and extracted with dichloromethane (3 x 30 mL). The organic layers were dried over anhydrous Na2SC>4 and concentrated to give 9-hydroxynonanoic acid (2) (2.0 g, 99%) which was used directly to next step without purification. [0133] Step 2 -hydroxynonanoate reflux, 5 h, 46%
Stage #1: Methyl oleate With dihydrogen peroxide In water at 62℃;
Stage #2: With water; oxygen at 60 - 62℃; for 6h;
1.a; 4.b
EXAMPLE 1; Step a); The following substances were fed continuously to a CSTR with a working capacity of 80 1, equipped with stirrer and with an adequate temperature regulation system:methyl oleate (technical purity approximately 85%; flow rate 10 kg/h);an aqueous solution of hydrogen peroxide at 60%> (flow rate 2.3 kg/h);- tungstic acid (H2W04) (flow rate 48 g/h).The reaction was conducted at a constant temperature of 62°C under vacuum (absolute pressure of 0.10-0.20* 105 Pa) to evaporate the water fed together with the hydrogen peroxide; the evaporated gas was collected and condensed (approximately 1 kg/h of water).FIG. 3 shows the hydrogen peroxide over-all concentration during step a).As can be seen in Fig. 3, the over-all hydrogen peroxide concentration in the reactor was constant at about 1.5 g/kg.The intermediate product containing vicinal diols was continuously discharged from the reactor and fed to step b) by means of a gear pump, adjusted to maintain a constant level in the reactor, with a flow rate of approximately 11.4 kg.; Step b; Step b) was performed in a jet loop reactor with a working capacity of 80 1 equipped with a 3 m3/h recirculation pump and heat exchanger. The intermediate product of step a) was continuously fed with a flow rate of 11.4 kg/h together with:cobalt acetate (Co(CH3COOH)2»4H20, dissolved at 1.5% in an aqueous current(approximately 2 kg/h);- pressurized air (20* 105 Pa; flow rate 12 to 15 kg/h).The air flow rate was adjusted to maintain a constant 02 content (approximately 10%) at the reactor outlet.The reaction was conducted at 60°C, keeping constant the reaction volume to 50 1. The reaction time was about 3.5h.The reaction mixture of step b) was continuously discharged from the jet loop reactor and fed to a decanter to separate the oily phase from the aqueous phase. Approximately 13 kg/h of oily product was obtained.; Example 4 Comparative; Step b) performed batchwise vs continuous56 kg of the oily phase (intermediate product formed at the end of the reaction step (a) of Example 2 Comparative) were transferred to a jet loop reactor. 14 kg of aqueous solution of 1%) cobalt acetate were added (0.4 % by moles with respect to the diol produced in step (a)). The reactor was then brought to 60-62 °C and to a pressure of 22* 105 Pa with air to perform step (b). Air was continuously fluxed to provide a sufficient supply of oxygen.The batch reaction lasted 6 h.At the end of step (b) hot separation of the aqueous phase from the organic phase was performed.The separated organic phase was dried and degassed, and then transferred to a distillation column which allowed fractioning of the monocarboxylic acids, to separate the pelargonic acid from the lighter monocarboxylic acids (by-products of the oxidative cleavage reaction). Approximately 16.8 kg of monocarboxylic acids (raw pelargonic acid), of which 14.4 kg was pelargonic acid with a titer of over 99% and approximately 1.5 kg was octanoic acid, were obtained. The distillation residue contained approximately 19 kg of monomethyl azelate. The corresponding yield for the oxidative cleavage reaction (step b)) was of about 66 % with respect to the moles theoretically obtainable.The conversion achieved after 3.5 h reaction of step b) in the continuous process according to Example 1 was higher than the final yield reached after 6 h reaction in the batch process (Example 4 Comparative), as can be seen in Table 1 :The selectivity of the oxidative cleavage reaction in the in the continuous process according to Example 1 was also higher than in the batch process, as can be seen in Table 2, showing that the by-product/product ratio was lower.
Stage #1: Methyl oleate With ozone In water; propionic acid for 1h;
Stage #2: With dihydrogen peroxide In water; propionic acid at 100℃; for 1.25h;
2
Example 2Ozonolysis and Oxidation with Addition of Acid20 g of a 0.182 molal solution of methyl oleate (95% pure) in a solvent mixture of propionic acid and water (15 equivalents based on moles of double bond) were initially charged in a two-neck flask with gas inlet tube and reflux condenser. The feed gas, consisting of 5% by volume of oxygen in carbon dioxide was passed through an ozone generator at a flow rate of 40 ml/min. The ozone generator was set to maximum power. The ozone-containing gas mixture was passed into the reaction mixture with stirring. The offgas stream was passed by means of gas wash bottles into a 5% aqueous potassium iodide solution. After 60 minutes, the substrate was converted, and the gas introduction was then stopped. According to GC analysis, the reaction mixture has a content of 39.5% of 9-nonanal and 38.2% of methyl 9-oxononanoate.After adding hydrogen peroxide (0.454 g of a 30% aqueous solution) and sulphuric acid (0.019 g, 95%) the reaction mixture was then heated to 100° C. in an oil bath. After 75 minutes, nonanal and methyl 9-oxononanoate were converted completely to the respective carboxyl compounds. GC analysis: 40.22% pelargonic acid, 38.50% azelaic acid derivative (21.90% monomethyl azelate+16.6% azelaic acid) (FID signal, figure in area percent, uncorrected).
Methyl hydrogen azelate (479 mg, 2.3 mmol), BOP (1 .14 g, 2.6 mmol), anhydrous triethylamine (512 [it, 3.6 mmol) and anhydrous DCM (40 mL) were placed in an oven-dried three neck flask under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes. 1-(4- (Trifluoromethyl)phenyl)piperazine (600 mg, 2.6 mmol) was added and the reaction mixture stirred under nitrogen and monitored by TLC. After 16 hours, the DCM was removed under reduced pressure and the resulting oil was acidified using a 0.1 M HCI. The aqueous mixture was extracted with DCM (20 mL, followed by 4 x 10 mL) and the organic layer washed with a saturated sodium bicarbonate solution (3 x 20 mL) and brine (3 x 20 mL). The organic layer was dried over magnesium sulphate and the solvent removed in vacuo. The residue was purified using flash chromatography (3:2, EtOAc et. Ether) to obtain the desired product as an off white solid in a 98% yield. H NMR (300 MHz, CDCI3) ? 7.41 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 3.73-3.69 (m, 2H), 3.58 (overlapping -OCH3 and piperazine -CH2 signal, m, 5H), 3.23-3.19 (m, 4H), 2.28 (t, J = 7.8 Hz, 2H), 2.21 (t, J = 7.8 Hz, 2H), 1.58-1.56 (m, 4H), 1.30-1.26 (m, 6H). 3C NMR (75 MHz, CDCI3) 174.2, 171 .7, 152.9, 126.4 (q, J = 3.75 Hz), 120.6 (q, J = 33 Hz), 1 19.2 (q, J = 271.5 Hz), 1 14.9, 51.4, 48.4, 48.1 , 45.1 , 41.1 , 34.0, 33.2, 29.2, 29.0, 28.9, 25.1 , 24.8. MS (+ESI) calcd for C2i H29 F3 N2 03 m/z: [M + H]+, 415.2203; found 415.219 [Diff(ppm) = -3.14].
methyl 9-((3-α-acetoxy-24-norurs-12-en-4-yl)amino)-9-oxononanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 0 - 20℃; for 16.5h;
General procedure: To a cooled (0 C) solution of the 3 (586 mg, 1.25 mmol) and Glutaric acid monomethyl ester (241 mg, 0.20ml, 1.65 mmol) in THF (20 mL) were added 1-hydroxybenzotriazole (HOBT, 162 mg, 1.25 mmol), Et3N (310 mg, 0.42 mL, 3.05 mmol), and 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI, 317 mg, 1.65 mmol). The mixture was stirred at 0 C for 0.5 h and then was allowed to warm to room temperature and was stirred for 16 h. The solvent was removed in vacuum. Then reaction mixture was diluted with ethyl acetate and washed with water, 5% HCl, saturated aqueous NaHCO3 solution, H2O, and brine. The organic layer was dried with Na2SO4 and the solvent was removed in vacuum, and the residue was purified by column chromatography to give 5a in 93% yield.
methyl 9-((3-α-acetoxy-11-oxo-24-norurs-12-en-4-yl)amino)-9-oxononanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 0 - 20℃; for 16.5h;
General procedure: To a cooled (0 C) solution of the 3 (586 mg, 1.25 mmol) and Glutaric acid monomethyl ester (241 mg, 0.20ml, 1.65 mmol) in THF (20 mL) were added 1-hydroxybenzotriazole (HOBT, 162 mg, 1.25 mmol), Et3N (310 mg, 0.42 mL, 3.05 mmol), and 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI, 317 mg, 1.65 mmol). The mixture was stirred at 0 C for 0.5 h and then was allowed to warm to room temperature and was stirred for 16 h. The solvent was removed in vacuum. Then reaction mixture was diluted with ethyl acetate and washed with water, 5% HCl, saturated aqueous NaHCO3 solution, H2O, and brine. The organic layer was dried with Na2SO4 and the solvent was removed in vacuum, and the residue was purified by column chromatography to give 5a in 93% yield.
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h;
General procedure: HBTU (1.82g, 3.59mmol), DIPEA (0.84mL, 4.80mmol) and monomethyl suberate (0.93mL, 5.28mmol) were added to a solution of 34 (1.0g, 4.80mmol) in DMF (10mL) and the mixture was stirred for 12hat rt. Then the reaction was quenched with H2O and extracted using EtOAc, dried over MgSO4 and passed through a filter column to give corresponding ester which was dissolved in the minimum amount of dioxane. H2O with pH adjusted to 3 using 3N HCl was added and the reaction mixture was stirred at reflux overnight to yield the corresponding free amine. The reaction was basified and extracted using EtOAc, then dried, concentrated and passed through a filter column to give the free amine. To a solution of this free amine (1.0g, 3.59mmol) in DMF (10mL) was added HBTU (1.36g, 3.59mmol), DIPEA (0.66mL, 3.59mmol) and 1,4-dibenzyloxy-5-isopropyl benzoic acid (0.76g, 4.31mmol) and the solution was stirred for 12hat 80C. The reaction mixture was quenched with H2O and extracted with EtOAc (25mL×3). The combined organic layer was collected, dried over anhydrous MgSO4 and concentrated under reduced pressure to give a light yellow residue, which was purified by silica gel chromatography (EtOAc:n-hexane=1: 1) to give 42 as a colorless liquid in 65% yield (overall from 34)
methyl 9-((3-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)propyl)amino)-9-oxononanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 5h;
General procedure: A mixture of compound 19 (350 mg, 1.22 mmol), EDCHCl(467 mg, 2.4 mmol), HOBt (250 mg, 1.85 mmol), DIPEA (0.46 mL,3 mmol) in DMF (3 mL) and 4-methoxy-4-oxobutanoic acid(230 mg, 1.7 mmol) was stirred at rt for 5 h. The reaction mixturewas quenched with H2O and extracted with EtOAc (50 mL x 3). Thecombined organic layer was dried over anhydrous MgSO4,concentrated under reduced pressure and purified by silica gelchromatography (EtOAc:Hexane 1:1) to give 20 in 84% yield.
methyl 9-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl) amino)-9-oxononanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 5h;
General procedure: A mixture of 22 (0.3 g, 0.609 mmol), EDC.HCl (0.232 g,1.21 mmol), HOBt (0.123 g, 737 mg, 0.914 mmol), 4-methoxy-4-oxobutanoic acid (0.96 g, 0.727 mmol) and DIPEA (0.265 mL,1.52 mmol) in DMF (5 mL) was stirred at rt for 5 h. After being stirred for a further 5 h, the reaction mixture was quenched withH2O and extracted with EtOAc (50 mL x 3). The combined organiclayer was dried over anhydrous MgSO4, concentrated underreduced pressure and purified by silica gel chromatography (hexane:EtOAc 4 : 1) to give 25 in 80% yield;