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Structure of 3128-07-2 * Storage: {[proInfo.prStorage]}
* 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.
Dissolve 10 g 6-oxoheptanoic acid (69.4 mmol) in 100 ml methanol. Add a few drops of concentrated sulphuric acid and stir for 1.5 h under reflux. Then concentrate by evaporation. Take up in dichloromethane and wash once with satd. sodium hydrogencarbonate solution. Separate the phases, dry the organic phase and concentrate by evaporation. 10.1 g (91.1percent of theor.) of the target compound is obtained. 1H-NMR (400 MHz, CDCl3): δ=3.67 (s, 3H), 2.44 (t, 2H), 2.32 (t, 2H), 2.13 (s, 3H), 1.67-1.55 (m, 4H).
84%
for 3 h; Reflux
A solution of 6-oxoheptanoic acid (4.0 g, 30 mmol) and concentrated H2S04 (0.1 mL) in MeOH (40.0 mL) was heated under reflux for 3 h. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with saturated aqueous NaHC03 solution (50 mL χ 2). The combined organic layers were concentrated to provide methyl 6-oxoheptanoate (4.0 g, 84percent) as a colorless oil. MS (ESI) m/z: 159.1 (M + H)+
76%
With sulfuric acid In 1,2-dichloro-ethane at 90℃;
Concentrated H2SO4 (0.2 mL) was added to a stirred solution of 6-oxoheptanoic acid (10 g, 69 mmol) in DCE/ MeOH (50 mL/20 mL). The mixture was stirred at 90° C. overnight. The solution was cooled to room temperature and concentrated. The residue was diluted with DCM (200 mL), washed with saturated NaHCO3 solution, water, brine, dried and concentrated to give methyl 6-oxoheptanoate as light yellow liquid (8.4 g) Yield 76percent (100percent purity, UV=214 nm, ESI 159 (M+H)+).
76%
With sulfuric acid In 1,2-dichloro-ethane at 90℃;
Concentrated H2SO4 (0.2 mL) was added to a stirred solution of 6-oxoheptanoic acid (10 g, 69 mmol) in DCE/MeOH (50 mL/ 20 mL). The mixture was stirred at 90 °C overnight. The solution was cooled to room temperature and concentrated. The residue was diluted with DCM (200 mL), washed with saturated NaHCCb solution, water, brine, dried and concentrated to give methyl 6-oxoheptanoate as light yellow liquid (8.4 g) Yield 76percent (100percent purity, UV = 214 nm, ESI 159 (M+H)+).
95.2 g
for 4 h; Reflux
(1) To a solution of 6-oxoheptanoic acid (99.2 g) in methanol (1 L), concentrated sulfuric acid (20 mL) was added, and the mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, and then, the solvent was distilled off under reduced pressure. Water (1 L) and ethyl acetate (600 mL) were added to the residue. The organic layer was separated and washed with a 5percent aqueous sodium bicarbonate solution (600 mL) and a saturated aqueous solution of sodium chloride (600 mL), and the solvent was distilled off under reduced pressure to obtain compound (O1) (95.2 g). TLC Rf: 0.45 (hexane/ethyl acetate=2/1)
95.2 g
for 4 h; Reflux
(1)Concentrated sulfuric acid (20 mL)was added to a methanol (1 L)solution of 6-oxopentaonic acid (99.2 g),and the mixture was heated for 4 hours under reflux. After the reaction mixture was cooled to room temperature,the solvent was distilled away under reduced pressure,and water (1 L)and ethyl acetate (600 mL)were added thereto. The organic layer was fractionated and washed with a 5percent aqueous sodium hydrogen carbonate solution (600 mL)and an aqueous saturated sodium chlorides solution (600 mL),and the solvent was distilled away under reduced pressure,thereby obtaining (01)(95.2 g). TLC Rf: 0.45 (hexane/ethyl acetate=2/1)
95.2 g
for 4 h; Reflux
(1)Concentrated sulfuric acid (20 mL) was added to a solution of 6-oxoheptanoic acid (99.2 g) in methanol (1 L)And heated under reflux for 4 hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure,Water (1 L) and ethyl acetate (600 mL) were added.The organic layer was separated,The mixture was washed with a 5percent aqueous sodium hydrogen carbonate solution (600 mL) and a saturated aqueous sodium chloride solution (600 mL), and the solvent was distilled off under reduced pressure to obtain (O1) (95.2 g).
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 7, p. 1133 - 1135
[2] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 17, p. 2463 - 2465
[3] Journal of medicinal chemistry, 2004, vol. 47, # 20, p. 4829 - 4837
[4] Patent: US2009/318475, 2009, A1, . Location in patent: Page/Page column 29
[5] Patent: WO2017/152032, 2017, A1, . Location in patent: Page/Page column 00499
[6] Patent: US2018/244648, 2018, A1, . Location in patent: Paragraph 0333; 0334
[7] Patent: WO2018/160522, 2018, A1, . Location in patent: Page/Page column 54
[8] Liebigs Annalen der Chemie, 1983, # 7, p. 1237 - 1248
[9] Journal of the Chemical Society, 1956, p. 4232,4234
[10] Journal of the American Chemical Society, 1957, vol. 79, p. 5027
[11] Justus Liebigs Annalen der Chemie, 1958, vol. 615, p. 84,90
[12] Journal of Medicinal Chemistry, 1999, vol. 42, # 14, p. 2527 - 2534
[13] Patent: WO2010/143158, 2010, A1, . Location in patent: Page/Page column 60
[14] Patent: US2012/115916, 2012, A1, . Location in patent: Page/Page column 24
[15] Patent: US2016/199520, 2016, A1, . Location in patent: Paragraph 0336; 0337
[16] Patent: US2018/8583, 2018, A1, . Location in patent: Paragraph 0447; 0448; 0449
[17] Patent: WO2018/49068, 2018, A1, . Location in patent: Paragraph 0346
[18] Patent: JP2016/183151, 2016, A, . Location in patent: Paragraph 0376-0378
2
[ 3128-07-2 ]
[ 74-88-4 ]
[ 2046-21-1 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetone at 23℃; for 0.25 h; Stage #2: for 1 h;
Methyl 6-oxoheptanoate (24) 1,8-Diazabicyclo[5.4.0]undec-7-ene (3.4 mL, 22.86 mmol) was added to a solution of 6-oxoheptanoic acid 23 (1.1 g, 7.63 mmol) in acetone (15 mL) at 23° C. After stirring for 15 min iodomethane (2.4 mL, 38.3 mmol) was added. The reaction was stirred for 1 h and then the solvent was removed in vacuo. The residue was purified by flash column chromatography (silica gel, 7:3 hex/EtOAc) to provide 1.18 g (95percent) of the methyl ester 24 (see scheme 4).
sulfuric acid; In dichloromethane; for 1.5h;Reflux;
Dissolve 10 g 6-oxoheptanoic acid (69.4 mmol) in 100 ml methanol. Add a few drops of concentrated sulphuric acid and stir for 1.5 h under reflux. Then concentrate by evaporation. Take up in dichloromethane and wash once with satd. sodium hydrogencarbonate solution. Separate the phases, dry the organic phase and concentrate by evaporation. 10.1 g (91.1percent of theor.) of the target compound is obtained. 1H-NMR (400 MHz, CDCl3): delta=3.67 (s, 3H), 2.44 (t, 2H), 2.32 (t, 2H), 2.13 (s, 3H), 1.67-1.55 (m, 4H).
84%
With sulfuric acid; for 3h;Reflux;
A solution of 6-oxoheptanoic acid (4.0 g, 30 mmol) and concentrated H2S04 (0.1 mL) in MeOH (40.0 mL) was heated under reflux for 3 h. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with saturated aqueous NaHC03 solution (50 mL chi 2). The combined organic layers were concentrated to provide methyl 6-oxoheptanoate (4.0 g, 84percent) as a colorless oil. MS (ESI) m/z: 159.1 (M + H)+
76%
With sulfuric acid; In 1,2-dichloro-ethane; at 90℃;
Concentrated H2SO4 (0.2 mL) was added to a stirred solution of 6-oxoheptanoic acid (10 g, 69 mmol) in DCE/ MeOH (50 mL/20 mL). The mixture was stirred at 90° C. overnight. The solution was cooled to room temperature and concentrated. The residue was diluted with DCM (200 mL), washed with saturated NaHCO3 solution, water, brine, dried and concentrated to give methyl 6-oxoheptanoate as light yellow liquid (8.4 g) Yield 76percent (100percent purity, UV=214 nm, ESI 159 (M+H)+).
76%
With sulfuric acid; In 1,2-dichloro-ethane; at 90℃;
Concentrated H2SO4 (0.2 mL) was added to a stirred solution of 6-oxoheptanoic acid (10 g, 69 mmol) in DCE/MeOH (50 mL/ 20 mL). The mixture was stirred at 90 °C overnight. The solution was cooled to room temperature and concentrated. The residue was diluted with DCM (200 mL), washed with saturated NaHCCb solution, water, brine, dried and concentrated to give methyl 6-oxoheptanoate as light yellow liquid (8.4 g) Yield 76percent (100percent purity, UV = 214 nm, ESI 159 (M+H)+).
sulfuric acid; In dichloromethane; for 24h;Inert atmosphere; Reflux;
6-Oxo-heptanoic acid methyl ester:; In a flame dried round-bottomed flask under inert atmosphere (N2), a solution of 5- acetylvaleric acid (7.54 g, 50.21 mmol) in a mixture of CH2CI2 (35 ml.) and MeOH (14 ml.) was treated with cone. H2SO4 (0.14 ml_, 2.51 mmol) and the reaction mixture was stirred at reflux for 24 h. The mixture was cooled to rt and sat. aq. Na2CO3 was added. The aq. layer was extracted with CH2CI2 and the combined organic layers were washed with water, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:1 --> 1 :2 hept-EA) gave the title compound as an orange oil.
sulfuric acid; In dichloromethane; for 24h;Inert atmosphere; Reflux;
6-Oxo-heptanoic acid methyl esterIn a flame dried round-bottomed flask under inert atmosphere (N2), a solution of 5-acetylvaleric acid (7.54 g, 50.21 mmol) in a mixture of CH2Cl2 (35 mL) and MeOH (14 mL) was treated with conc. H2SO4 (0.14 mL, 2.51 mmol) and the reaction mixture was stirred at reflux for 24 h. The mixture was cooled to rt and sat. aq. Na2CO3 was added. The aq. layer was extracted with CH2Cl2 and the combined organic layers were washed with water, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:1-->1:2 hept-EA) gave the title compound as an orange oil.
95.2 g
With sulfuric acid; for 4h;Reflux;
(1) To a solution of 6-oxoheptanoic acid (99.2 g) in methanol (1 L), concentrated sulfuric acid (20 mL) was added, and the mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, and then, the solvent was distilled off under reduced pressure. Water (1 L) and ethyl acetate (600 mL) were added to the residue. The organic layer was separated and washed with a 5percent aqueous sodium bicarbonate solution (600 mL) and a saturated aqueous solution of sodium chloride (600 mL), and the solvent was distilled off under reduced pressure to obtain compound (O1) (95.2 g). TLC Rf: 0.45 (hexane/ethyl acetate=2/1)
95.2 g
With sulfuric acid; for 4h;Reflux;
(1)Concentrated sulfuric acid (20 mL)was added to a methanol (1 L)solution of 6-oxopentaonic acid (99.2 g),and the mixture was heated for 4 hours under reflux. After the reaction mixture was cooled to room temperature,the solvent was distilled away under reduced pressure,and water (1 L)and ethyl acetate (600 mL)were added thereto. The organic layer was fractionated and washed with a 5percent aqueous sodium hydrogen carbonate solution (600 mL)and an aqueous saturated sodium chlorides solution (600 mL),and the solvent was distilled away under reduced pressure,thereby obtaining (01)(95.2 g). TLC Rf: 0.45 (hexane/ethyl acetate=2/1)
With hydrogenchloride; at 80℃; for 10h;
A solution of 6-oxoheptanoic acid (25 g, 173.41 mmol) in HCl/MeOH (250 mL) was stirred at 80 °C for 10 hr. LCMS showed that the product was present. The solvent was removed and the residue was dissolved in ethyl acetate (200 mL). Then the organic layer was washed with saturated NaHCO3(150 mL), brine (150 mL) then concentrated to give 19a-int; LCMS (ESI+) : m/z = 159.1 (M+H)+, RT = 0.51 min.
95.2 g
With sulfuric acid; for 4h;Reflux;
(1)Concentrated sulfuric acid (20 mL) was added to a solution of 6-oxoheptanoic acid (99.2 g) in methanol (1 L)And heated under reflux for 4 hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure,Water (1 L) and ethyl acetate (600 mL) were added.The organic layer was separated,The mixture was washed with a 5percent aqueous sodium hydrogen carbonate solution (600 mL) and a saturated aqueous sodium chloride solution (600 mL), and the solvent was distilled off under reduced pressure to obtain (O1) (95.2 g).
With dihydrogen peroxide In <i>tert</i>-butyl alcohol at 60℃; for 24h;
90%
With tris(cetylpyridinium) 12-tungstophosphate; dihydrogen peroxide In <i>tert</i>-butyl alcohol for 24h; Heating;
84%
With tert.-butylhydroperoxide In water at 90℃; for 8.2h;
83%
With manganese (VII)-oxide In tetrachloromethane; acetone at -80℃;
80%
Stage #1: 1-methylcyclohex-1-ene With ozone; acetic acid In cyclohexane
Stage #2: With sodium acetate; acetic anhydride In acetic acid
80%
With Oxone; osmium(VIII) oxide; sodium hydrogencarbonate In N,N-dimethyl-formamide; <i>tert</i>-butyl alcohol at 20℃; for 3h;
74%
With sodium periodate; RuCl3*2.9H2O In water at 20℃; for 0.25h; Sonication;
1.4%
Stage #1: 1-methylcyclohex-1-ene With dihydrogen peroxide In water; acetonitrile at 20℃; for 24.83h;
Stage #2: With sodium hydroxide In diethyl ether; water; acetonitrile
Stage #3: With hydrogenchloride In water
7 1-me
1-methyl-1-cyclohexene -> 6-oxoheptanoic acid To a mixture of [Mn2O3(tmtacn)2](PF6)2.H2O (8.1 mg, 10 μmol) and 2,6-dichlorobenzoic acid (57.3 mg, 0.30 mmol) in CH3CN (7 ml) was added H2O2 (30 μl of a 50 % aq. solution, 0.53 mmol) at room temperature and the resulting mixture was stirred for 20 min. Subsequently 1-methyl-1-cyclohexene (962 mg, 10 mmol) was added together with CH3CN (3 ml). H2O2 (3.22 ml of a 50 % aq. solution, 56.8 mmol) was then added at room temperature using a syringe pump (0.14 ml/hr) . A second amount of [Mn2O3(tmtacn)2](PF6)2.H2O (8.1 mg, 10 μmol) was added to the reaction mixture 6.5 hours after the addition of hydrogen peroxide had commenced and a third amount of [Mn2O3(tmtacn)2](PF6)2.H2O (8.1 mg, 10 μmol) was added to the reaction mixture 18 hours after the addition of hydrogen peroxide had commenced. When the addition of hydrogen peroxide was completed, the mixture was stirred for an additional hour. Water (10 ml) and diethyl ether (10 ml) were added to the combined filtrates, followed by solid sodium bisulfite (ca. 1 gram) to remove excess H2O2 (removal was confirmed by commercially available peroxide test strips). The pH of the aqueous layer was set to pH > 10 by adding some solid NaOH. The organic layer was separated and the aqueous layer was washed with diethyl ether (3x15 ml). The pH of the aqueous layer was subsequently set to pH < 1.5 with some 35% HCl (aq.) and was extracted with diethyl ether (5x10 ml). The combined extracts were washed with brine (15 ml) and subsequently dried over anhydrous Na2SO4. The solvents were evaporated in vacuo yielding 146 mg of a solid with a purity of circa 14% (determined by 1H NMR). 6-Oxoheptanoic acid was thus obtained in about 1.4% yield. 1H NMR (400 MHz, acetone-d6): δ 1.55-159 (m, 4H), 2.08 (s, 3H), 2.27-2.31 (m, 2H), 2.46-2.49 (m, 2H). Purity was confirmed with GC (FID detector). GC-MS(EI) showed the presence of 6-oxoheptanoic acid as well: m/z 144.1 [M+], 126.0, 111.0, 98.0, 84.0, 73.0, 58.0, 43.0.
With acetic acid at 0 - 5℃; durch Ozonolyse, anschliessendes Kochen mit 30prozentig. H2O2;
With potassium permanganate Oxydation;
With water; oxygen; silica gel; ozone at -78℃;
84 %Spectr.
With tetrafluoroboric acid; iodomesitylene; 3-chloro-benzenecarboperoxoic acid In dichloromethane; 1,1,1,3',3',3'-hexafluoro-propanol; water at 20℃; for 49h; Inert atmosphere;
With dihydrogen peroxide; 2,6-dichlorobenzoic acid In water; acetonitrile at 20℃; for 41.5h;
7
Experiment 7: 1-methyl- 1-cyclohexene -> 6-oxoheptanoic acidTo a mixture of [Mn203 ( tmtacn) 2] (PF6)2.H20 (8.1 mg, 10 ymol) and 2, 6-dichlorobenzoic acid (57.3 mg, 0.30 mmol) in CH3CN (7 ml) was added H202 (30 μ of a 50 % aq. solution, 0.53 mmol) at room temperature and the resulting mixture was stirred for 20 min. Subsequently 1-methyl-l-cyclohexene (962 mg, 10 mmol) was added together with CH3CN (3 ml). H202 (3.22 ml of a 50 % aq. solution, 56.8 mmol) was then added at room temperature using a syringe pump (0.14 ml/hr) . A second amount of [Mn203 (tmtacn) 2] (PF6)2.H20 (8.1 mg, 10 μϖιο) was added to the reaction mixture 6.5 hours after the addition of hydrogen peroxide had commenced and a third amount of[Mn203 (tmtacn) 2] (PF6)2.H20 (8.1 mg, 10 μϖιο) was added to the reaction mixture 18 hours after the addition of hydrogen peroxide had commenced. When the addition of hydrogen peroxide was completed, the mixture was stirred for an additional hour. Water (10 ml) and diethyl ether (10 ml) were added to the combined filtrates, followed by solid sodium bisulfite (ca. 1 gram) to remove excess H202 (removal was confirmed by commercially available peroxide test strips) . The pH of the aqueous layer was set to pH > 10 by adding some solid NaOH. The organic layer was separated and the aqueous layer was washed with diethyl ether (3x15 ml) .The pH of the aqueous layer was subsequently set to pH < 1.5 with some 35% HC1 (aq. ) and was extracted with diethyl ether (5x10 ml) . The combined extracts were washed with brine (15 ml) and subsequently dried over anhydrous Na2S04. Thesolvents were evaporated in vacuo yielding 146 mg of a solid with a purity of circa 14% (determined by H MR) .6-0xoheptanoic acid was thus obtained in about 1.4% yield. 1H NMR (400 MHz , acetone-d6) : δ 1.55-159 (m, 4H) , 2.08 (s, 3H) , 2.27-2.31 (m, 2H) , 2.46-2.49 (m, 2H) . Purity was confirmed with GC (FID detector) . GC-MS(EI) showed the presence of 6- oxoheptanoic acid as well: m/z 144.1 [M+] , 126.0, 111.0, 98.0, 84.0, 73.0, 58.0, 43.0.N.B. NMR showed other compounds as well, including 2,6- dichlorobenzoic acid.
With ozone In carbon dioxide at 20℃; for 0.00166667h;
5
(Example 5)An oxygen-containing compound was produced using a reaction apparatus similar to that shown in Fig. 3, except that the decomposition reaction section 11, decomposer preheating tube 12, decomposition reaction vessel 13, and decomposer tank 14 illustrated were not provided, and that the ozonization reaction section 1 also functioned as a decomposition reaction section.The pressure of a pressure-regulating valve 30 was set to 10 MPa, and a high-pressure carbon dioxide solution in which 0.088 M of ozone having an oxygen content of less than 1% was dissolved was supplied at a flow rate of 2 mL/min from a supply device 20 for supplying ozone and high-pressure carbon dioxide.1-Methylcyclohexene was supplied from a raw-material tank 4 using a high-pressure pump, and the raw material was preheated in a reaction vessel 3 at 20°C. The preheated raw material was then combined with the high-pressure carbon dioxide solution of ozone, and continuous ozonization and thermal decomposition reactions proceeded in a stainless steel coil-shaped ozonization reaction section 1 (which also functioned as a decomposition reaction section) having an inside diameter of 1 mm and a length of 26 cm and set to 20°C. The residence time corresponding to the reaction time was about 6 seconds. The product was passed via the pressure-regulating valve 30 and was dissolved in acetone placed in a gas-liquid separation device 40. Quantification of the acetone solution by FT-NMR using coumarin as an internal standard confirmed that 1.35 mmol of 6-oxoheptanoic acid was produced in 30 minutes
92 %Chromat.
With dihydrogen peroxide In water; <i>tert</i>-butyl alcohol at 80℃; for 24h;
With hexaaquaruthenium(II) tosylate; oxygen; acetic acid In water at 55℃; for 24h;
87%
With aurin; water; copper(II) bis(trifluoromethanesulfonate) In acetonitrile for 48h; Schlenk technique; Irradiation;
86%
With water; oxygen In benzene at 60℃; for 20h;
86%
With oxygen; copper dichloride In acetic acid at 80℃; for 5h;
77%
With sulfuric acid; K-10 montmorillonite; oxygen In acetic acid at 70℃; for 30h;
2.4 Catalytic tests
General procedure: All catalytic tests were carried out using Schlenk techniques (20 mL) which was attached to a vacuum line with a manometer and a gas inlet. Prior to each catalytic test, the clay was dried at 373 K for 2 h. In a typical experiment, the Schlenk was charged with the solvent (5.0 mL; solvent: CH3CN, H2O, CH3OH, CH3COOH or a mixture of CH3COOH and H2O) and K-10MT (0.20 g). In some tests H2SO4 (0-0.37 mmol) was also added. The substrate (5.0 mmol) was then added and the vessel was immersed in an oil bath preheated at 70 °C. O2 was introduced at atmospheric pressure and the mixture was stirred magnetically for 24 h. Three parallel catalytic experiments were carried out for each test.
75%
With oxygen In water; acetic acid at 60℃; for 1h;
70%
With oxygen; acetic acid In water at 60℃; for 4h; variation of time and AcOH concn.; other cycloalkanones;
70%
With oxygen; acetic acid In water at 60℃; for 4h;
53%
With 1-(4-(trifluoromethyl)phenyl)-1H-phenanthro[9,10-d]imidazol-3-ium trifluoromethanesulfonate; hydroquinone In chlorobenzene at 60℃; for 48h;
44%
With hydrogenchloride; sodium nitrite In tetrahydrofuran; water at -5 - 20℃; for 10h;
25%
With oxygen In acetic acid at 65℃; for 69h;
With chromium(VI) oxide; sulfuric acid
With potassium permanganate; water
With Adipic acid; air; manganese(II) nitrate at 65℃;
With sulfuric acid; chromic acid Oxydation;
With water; oxygen im Licht;
With oxygen; sodium methylate In methanol; 1,2-dimethoxyethane
With N,N,N,N,N,N-hexamethylphosphoric triamide; potassium <i>tert</i>-butylate; oxygen In <i>tert</i>-butyl alcohol
35 %Chromat.
With dihydrogen peroxide In water; <i>tert</i>-butyl alcohol at 80℃; for 24h;
With iron(III) chloride; oxygen; dimethyl sulfoxide at 55℃; for 24h; chemoselective reaction;
With thionyl chloride In <i>N</i>-methyl-acetamide; benzene
11.a a.
a. 6-Oxo-heptanoyl chloride 6-Oxo-heptanoic acid (20.1g; 0.14 mole), thionyl chloride (18.3g; 11.2 ml; 0.154 mole) and dry benzene (300 ml) together with dimethylformamide (three drops) were stirred at room temperature for 22 hours. The halogenating reagent and benzene were removed on the rotary evaporator. A further 100 ml of benzene was added and the solution was again evaporated under reduced pressure (to remove last traces of thionyl chloride). The quantitatively formed liquid acid chloride was used directly in step (b).
With pivaloyl chloride
With thionyl chloride for 2h;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane Inert atmosphere;
6-oxo-heptanoic acid (4-{9-[6-(<i>tert</i>-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-tetrahydro-furo[3,4-<i>d</i>][1,3]dioxol-4-yl]-9<i>H</i>-purin-6-ylamino}-butyl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 6-oxoheptanoic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at 0℃; for 0.25h;
Stage #2: N6-(4-aminobutyl)-9-[5-O-(tert-butyldimethylsilyl)-2,3-O-isopropylidene-β-D-ribofuranosyl]purine In tetrahydrofuran at 20℃; for 2h;
Stage #1: 6-oxoheptanoic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran for 0.25h;
Stage #2: N6-(4-aminobutyl)-9-[5-O-(tert-butyldimethylsilyl)-2,3-O-isopropylidene-β-D-ribofuranosyl]purine In tetrahydrofuran for 2h;
I.2
Coupling to the Methyl Ketone Chain and Deprotection in 5'6-Oxo-heptanoic acid (288 mg, 2 mmol) is dissolved in 5 ml of anhydrous THF. The solution is placed at 0° C. under argon. N-Methylmorpholine (223 p1, 2 mmol) is then added, followed by isobutyl dichloroformiate (258 μl; 2 mmol) 5 min later. After 15 minutes, the aminated nucleoside is added. After 2 hours, the THF is evaporated off and the residue is taken up with ether. This is washed with a 1 N aqueous NaOH solution and then with water saturated with NaCl. After drying over Na2SO4 and evaporation, an oil is obtained. The desilylation is carried out by taking the oil up in 10 ml of THF, to which TBAF (3.25 ml of a 1M solution in THF) is added. After one hour, the solvent is evaporated off. The residue is solubilized in dichloromethane and washing is carried out with water saturated with NaCl. After drying and evaporation, the residue is chromatographed on silica gel (eluent: CH2Cl2, then CH2Cl2/MeOH: 95/5).After evaporation, 870 mg of the nucleoside carrying the methyl ketone function and deprotected in 5' (1.7 mmol, 85% over 2 steps) is obtained. It is carried by proton NMR, carbon 13 NMR and mass spectrometry.
Stage #1: 6-oxoheptanoic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at 0℃; for 0.25h;
Stage #2: Propargylamine In tetrahydrofuran at 20℃; for 0.5h;
80%
With 4-methyl-morpholine In tetrahydrofuran at 0 - 20℃; for 0.5h;
I.1
Synthesis of the Methyl Ketone ChainThe methyl ketone unit is introduced onto the arm by peptide coupling between propargylamine and 6-oxo-heptanoic acid. 6-Oxoheptanoic acid (2.75 g, 18.16 mmol) is solubilized in 40 ml of anhydrous THF. The solution is placed at 0° C. under an argon atmosphere. N-methyl-, morpholine (2 ml, 18.16 mmol) is then added, followed by propargylamine (1.25 ml, 18.16 mmol) 15 min later, and the mixture is allowed to return to room temperature. After reaction for 30 minutes, the precipitate is filtered and evaporated to dryness.The residue obtained is taken up in dichloromethane and is washed with a 0.1 N aqueous sodium hydroxide solution, then with a 1 N aqueous hydrochloric acid solution and finally with water saturated with sodium chloride.After drying over Na2SO4, the dichloromethane is evaporated off and the residue is chromatographed on silica gel (eluent: ethyl acetate). The product is thus obtained in the form of a white powder (2.6 g, 14.4 mmol; 80%).The methyl ketone chain was characterized by proton NMR, carbon 13 NMR and mass spectrometry.
52%
Stage #1: 6-oxoheptanoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane for 0.0333333h;
Stage #2: With benzotriazol-1-ol In dichloromethane for 0.0333333h;
Stage #3: Propargylamine In dichloromethane at 20℃; for 16h;
4-[5-methoxy-2-methyl-1-(pyridine-2-carbonyl)-1<i>H</i>-indol-3-yl]-butyric acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26.8%
Stage #1: 4-methoxyphenylhydrazine hydrochloride With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃;
Stage #2: pyridine-2-carbonyl chloride With pyridine at 80℃;
Stage #3: 6-oxoheptanoic acid With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
4-[1-(4-dimethylamino-benzoyl)-5-methoxy-2-methyl-1<i>H</i>-indol-3-yl]-butyric acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16.2%
Stage #1: 4-methoxyphenylhydrazine hydrochloride With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃;
Stage #2: 4-(dimethylamino)benzoyl chloride With pyridine at 80℃;
Stage #3: 6-oxoheptanoic acid With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
4-[1-(furan-2-carbonyl)-2-methyl-5-sulfo-1<i>H</i>-indol-3-yl]-butyric acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5%
Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃;
Stage #2: 2-furancarbonyl chloride With pyridine at 80℃;
Stage #3: 6-oxoheptanoic acid With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
Stage #1: p-tolylhydrazine hydrochloride With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃;
Stage #2: 4-chloro-benzoyl chloride With pyridine at 80℃;
Stage #3: 6-oxoheptanoic acid With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
Stage #1: 4-methoxyphenylhydrazine hydrochloride With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃;
Stage #2: 4-chloro-benzoyl chloride With pyridine at 80℃;
Stage #3: 6-oxoheptanoic acid With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
46%
Stage #1: 4-methoxyphenylhydrazine hydrochloride With aldehyde resin; triethylamine In dichloromethane at 45℃;
Stage #2: 4-chloro-benzoyl chloride With pyridine at 80℃;
Stage #3: 6-oxoheptanoic acid With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
4-[1-(4-chloro-benzoyl)-2-methyl-5-sulfo-1<i>H</i>-indol-3-yl]-butyric acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5%
Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃;
Stage #2: 4-chloro-benzoyl chloride With pyridine at 80℃;
Stage #3: 6-oxoheptanoic acid With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
4-[1-(biphenyl-4-carbonyl)-2-methyl-5-sulfo-1<i>H</i>-indol-3-yl]-butyric acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5%
Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃;
Stage #2: 4-biphenyl-carboxylic acid chloride With pyridine at 80℃;
Stage #3: 6-oxoheptanoic acid With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
4-[1-(4-bromo-benzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]-butyric acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
Stage #1: 4-methoxyphenylhydrazine hydrochloride With aldehyde resin; triethylamine In dichloromethane at 45℃;
Stage #2: 4-chlorobenzoyl chloride With pyridine at 80℃;
Stage #3: 6-oxoheptanoic acid With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
31%
Stage #1: 4-methoxyphenylhydrazine hydrochloride With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃;
Stage #2: 4-chlorobenzoyl chloride With pyridine at 80℃;
Stage #3: 6-oxoheptanoic acid With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
(1S,5R)-5-Methyl-6-oxa-bicyclo[3.2.0]heptan-7-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3%
With 2-chloro-1-methyl-pyridinium iodide; triethylamine In acetonitrile at 25℃;
48 % Spectr.
With 2-bromo-N-n-propylpyridinium 1,1,1-trifluoromethanesulfonate; 4-pyrrolidin-1-ylpyridine; N-ethyl-N,N-diisopropylamine In dichloromethane at 23℃; for 12h;
Stage #1: 6-oxoheptanoic acid In methanol at 50℃;
Stage #2: With bromine In methanol for 3h; Heating / reflux;
30
Dissolve 5-acetyl valeric acid (16.0 g, 111.1 mmol) in MEOH (200 ME) AND warm the mixture near 50°C. Add bromine (5.7 mL, 111. 1 mmol) and heat the mixture at reflux for 3 hours. Concentrate the mixture and dissolve the resulting oil in ET2O. Wash the organic solution with water and aqueous NAHCO3 and dry over NA2S04. Concentration gives the crude mixture of 7-bromo-6-oxo-heptanoic acid methyl ester and 5-BROM-6- oxo-heptanoic acid methyl ester (25.3 g, 96%).
With sulfuric acid; In methanol; 1,2-dichloro-ethane;
6-Oxo-heptanoic acid methyl ester (2-2) A solution of 5-acetylvaleric acid 2-1 (200 g, 1.38 mole) in 1,2-dichloroethane/methanol (1000 mL/400 mL) was treated with concentrated sulfuric acid (3.69 mL, 6.78 g, 69 mmol) and refluxed for 12 h. The solution was cooled to room temperature and washed with saturated aqueous NaHCO3 (2*400 mL). The aqueous washes were back extracted with dichloromethane (200 mL), and the combined organic extracts were washed with brine. The solution was dried over MgSO4, filtered, and concentrated to give about 218 g of the methyl ester 2-2 as a colorless oil. 1H NMR (300 MHz, CDCl3): delta3.62 (s, 3H), 2.41 (t, 2H), 2.31 (t, 3H), 2.12 (s, 3H), 1.59 (m, 4H) ppm.
With potassium hydroxide; In diethyl ether; dichloromethane;
Step A 6-Oxo-heptanoic Acid Methyl Ester (1-2) To a rapidly stirred mixture of diethyl ether (175 ml) and 40percent KOH (52 ml) at 0° C. was added MNNG (15.4 g, 105 mmol). The mixture was stirred for 10 minutes. The ethereal layer was transferred to a solution of 6-oxo-heptanoic acid 1-1 (5.0 g, 34.68 mmol) and CH2Cl2 at 0° C. The solution was purged with argon for 30 minutes and then concentrated. Flash chromatography (silica, 30percent to 50percent EtOAc/hexanes) gave ester 1-2 as a clear oil. TLC Rf=0.88 (silica, EtOAc). 1H NMR (300 MHz, CDCl3) delta 3.67 (s, 3H), 2.46 (m,2H), 2.33 (m, 2H), 2.14 (s, 3H), 1.62 (m, 4H).
With potassium hydroxide; In diethyl ether; dichloromethane;
Step A 6-Oxo-heptanoic acid methyl ester (1-2) To a rapidly stirred mixture of diethyl ether (175 ml) and 40percent KOH (52 ml) at 0° C. was added MNNG (15.4 g, 105 mmol). The mixture was stirred for 10 minutes. The ethereal layer was transferred to a solution of 6-oxo-heptanoic acid 1-1 (5.0 g, 34.68 mmol) and CH2Cl2 at 0° C. The solution was purged with argon for 30 minutes and then concentrated. Flash chromatography (silica, 30-50percent EtOAc/hexanes) gave ester 1-2 as a clear oil. TLC Rf=0.88 (silica, EtOAc). 1H NMR (300 MHz, CDCl3) delta3.67 (s, 3H), 2.46 (m,2H), 2.33 (m, 2H), 2.14 (s, 3H), 1.62 (m, 4H).
7-[((1-methylpropoxy)carbonyl)oxy]-2-oxoheptane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 4-methyl-morpholine In dichloromethane
8.A A.
A. 7-[((1-Methylpropoxy)carbonyl)oxy]-2-oxoheptane 11.2 g (0.07 mole) of 6-ketoheptanoic acid was dissolved in 100 ml of dichloromethane and 10 g of N-methylmorpholine was added. The reaction mixture was cooled in an ice bath, stirred and kept under a nitrogen atmosphere. 11.6 g (0.085 mole) of isobutyl chloroformate dissolved in 25 ml of dichloromethane was slowly added over a period of 15 minutes. The reaction mixture was allowed to proceed for one hour. The reaction mixture was evaporated to an oily solid and used in subsequent reactions.
With 4-methyl-morpholine; N-butylamine In tetrahydrofuran
(Compound IV, n=4, Y=n-butylamino)
6-Oxoheptanoic Acid n-Butylamide (Compound IV, n=4, Y=n-butylamino) The title compound was prepared by the method described for 6-oxoheptanoic acid p-toluide (IV, n=4, Y=p-methylanilino) using the following quantities: δ-acetyl-n-valeric acid (2.5 g, 1.75 mmol), N-methylmorpholine (1.9 ml, 17.5 mmol), isobutyl chloroformate (2.25 ml, 17.5 mmol), n-butylamine (1.7 ml, 17.5 mmol), tetrahydrofuran (15 ml). Recrystallization from ethyl acetate/hexanes gave 1.3 g of the desired compound as white needles, which were pure by thin layer chromatography (95:5:3 chloroform/methanol/acetic acid, Rf =0.52) m.p. 53°-54° C.
(Compound IV, n=4, Y=p-trifluoromethylanilino)
6-Oxoheptanoic Acid p-Trifluoromethylanilide (Compound IV, n=4, Y=p-trifluoromethylanilino) The title compound was prepared by the method described for 6-oxoheptanoic acid p-toluide (IV, n=4, Y=p-methylanilino) except that the reaction was refluxed overnight. The following quantities were used: δ-acetyl-n-valeric acid (1.0 g, 6.9 mmol), N-methylmorpholine (1.52, 13.8 mmol), isobutyl chloroformate (0.90 ml, 6.9 mmol), p-trifluoromethylaniline hydrochloride (1.37 g, 6.9 mmol), tetrahydrofuran (50 ml). Recrystallization from ethyl acetate/hexanes gave 1.6 g of the desired compound as pale yellow platelets, which were pure by thin layer chromatography (60:40 ethyl acetate/hexanes Rf =0.40) m.p. 138°-140° C.
[00242] n-Butyllithium (10.8 ml of 2.5 M in hexanes, 27 mmol, 1.3 equiv) was added to a solution of methyltriphenylphosphonium bromide (9.7 g, 27 mmol, 1.3 equiv) in dimethyl sulfoxide (50 ml) at 0 0C, and the mixture was stirred at room temperature for 1 h. It was added to a solution of 6-oxo-heptanoic acid 70 (3 g, 20.82 mmol, 1 equiv) and n-butyllithium (8.33 ml of 2.5 M in hexanes, 20.82 mmol, 1 equiv) in THF (30 ml). The mixture was stirred at room temperature for 48 hr. Water was added and the mixture was acidified with 2 N HCl and extracted with methylene chloride (3 x 50 ml). The organic layer was washed with 10% sodium hydroxide solution. The aqueous layer was acidified with 2.0 N HCl and extracted with ethyl acetate (3 x 60 ml). The organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (10% EtOAc / hexanes) gave pure acid 123 (2.32 g, 78%) as a colorless oil: TLC R/= 0.47 (silica gel, 25% EtOAc / hexanes); 1H NMR (600 MHz, CDCl3) delta 4.688 (s, IH), 4.653 (s, IH), 2.36-2.33 (t, 3J = 7.8 Hz, 2H), 2.03-1.99 (t, 3J= 7.8 Hz, 2H), 1.687 (s, 3H), 1.64-1.58 (m, 2H), 1.50-1.44 (m, 2H); 13C NMR (IOO MHz, CDCl3) delta 180.696, 145.56, 110.362, 37.54, 34.182, 27.098, 24.436, 22.477; HRMS calcd for C42H70O5Si2 + Na+ ; found [M + Na+].
bis(tetrabutylammonium)-closo-dodecahydroxy-dodecaborate[ No CAS ]
[ 17341-25-2 ]
disodium-closo-dodeca-(5-acetylpentanoyloxy)-dodecaborate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With 1,1'-carbonyldiimidazole In 1,2-dichloro-ethane under N2 or Ar; carboxylic acid and carbonyldiimidazole added to 1,2-dichloroethane; stirred (room temp., 2 h); B compd. in 1,2-dichloroethane added; heated to reflux for 14 d; monitored by (11)B NMR spectra; soln. transferred; stirred with resins (StratoSpheres PL-DETA, for 5 h and Amberlite IRC-50, 2 h); subjected to flash chromy. (silica gel, MeOH); cation exchanged to Na salt;
n-Butyllithium (10.8 ml of 2.5 M in hexanes, 27 mmol, 1.3 equiv) was added to a solution of methyltriphenylphosphonium bromide (9.7 g, 27 mmol, 1.3 equiv) in dimethyl sulfoxide (50 ml) at 0 0C, and the mixture was stirred at room temperature for 1 h. It was added to a solution of 6-oxo-heptanoic acid 6 (3 g, 20.82 mmol, 1 equiv) and n-butyllithium (8.33 ml of 2.5 M in hexanes, 20.82 mmol, 1 equiv) in THF (30 ml). The mixture was stirred at room temperature for 48 hr. Water was added and the mixture was acidified with 2 N HCl and extracted with methylene chloride (3 x 50 ml). The organic layer was washed with 10% sodium hydroxide solution. The aqueous layer was acidified with 2 N HCl and extracted with ethyl acetate (3 x 60 ml). The organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (10% EtOAc/hexanes) gave pure acid 7 (2.32 g, 78%) as a colorless oil: TLC R/= 0.47 (silica gel, 25% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) delta 4.69 (s, IH), 4.65 (s, IH), <n="17"/>2.34 (t, J= 7.8 Hz, 2H), 2.01 (t, J= 7.8 Hz, 2H), 1.69 (s, 3H), 1.64-1.58 (m, 2H), 1.50-1.44 (m, 2H); 13C NMR (IOO MHz, CDCl3) delta 180.7, 145.6, 110.4, 37.5, 34.2, 27.1, 24.4, 22.5.
93A
Put 8.80 g (55.63 mmol) 6-oxoheptanoic acid and 6.741 g (55.63 mmol) (R)-(+)-1-phenylethylamine together in 100 ml toluene at RT. Add a catalytic amount (approx. 50 mg) of p-toluenesulphonic acid and heat overnight with stirring on a water separator. Then partially concentrate by evaporation, filter off any solids using a paper filter, and fully concentrate the filtrate by evaporation. Dissolve the residue in 170 ml methanol. Add approx. 1.7 g Raney Nickel (moist with water) and hydrogenate for 48 h at 4 bar. Next, filter on diatomite and concentrate the filtrate by evaporation. Purify the residue by column chromatography on silica gel (solvent: dichloromethane/methanol 95:5), obtaining 4.15 g (48.5% of theor.) of the target compound, which is reacted without further characterization.
1-(2-bromophenyl)hydrazine hydrochloride[ No CAS ]
[ 1232860-64-8 ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 6-oxoheptanoic acid; 1-(2-bromophenyl)hydrazine hydrochloride In ethanol at 50℃; for 0.666667h;
Stage #2: ethanol With sulfuric acid for 16h; Reflux;
Stage #3: With sodium hydrogencarbonate In water
1
Example 1; Ethyl 4-(7-bromo-2-methyl-1H-indol-3-yl)butanoateTo a solution of (2-bromophenyl)hydrazine hydrochloride (14 g) in ethanol (60 mL), 5-acetylvaleric acid (9.0 g) was added. The reaction mixture was stirred at 50° C. for 40 minutes, and concentrated sulfuric acid (6.0 mL) was added thereto, followed by heating under reflux for 16 hours. The reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution which was then extracted with ethyl acetate and dried over anhydrous sodium sulfate, followed by concentratration under reduced pressure. The resulting residue was purified by column chromatography (hexane:ethyl acetate=8:1) to obtain the title compound (15 g) having the following physical properties.TLC:Rf 0.54 (hexane:ethyl acetate=3:1)1H-NMR (CDCl3): δ 1.23, 1.89-2.00, 2.31, 2.39, 2.72, 4.10, 6.95, 7.24, 7.43, 7.91
3-hydroxy-2-(6-oxo-heptanoylamino)-propionic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 6-oxoheptanoic acid With triethylamine; isobutyl chloroformate In tetrahydrofuran at -30℃; for 1h; Inert atmosphere;
Stage #2: methyl 2-amino-3-hydroxypropanoate hydrochloride In tetrahydrofuran at -30 - 20℃; for 2h; Inert atmosphere;
3-Hydroxy-2-(6-oxo-heptanoylamino)-propionic acid methyl ester:; In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 6-oxo-heptanoic acid (2.00 g, 13.32 mmol) in THF (82 mL) at -30 0C was treated sequentially with Et3N (3.89 mL, 27.97 mmol) followed by isobutyl chloroformate (1.95 mL, 14.65 mmol). After stirring for 1 h at -30 0C, serine methylester hydrochloride (2.32 g, 14.65 mmol was added and the reaction mixture was allowed to warm gradually to rt and stirred for an additional 2 h at rt. The resulting suspension was filtered, the solid washed with THF and the filtrate was concentrated under reduced pressure. Purification of the residue by FC (97:3 EA-MeOH) gave the title compound as a colorless oil. TLC: rf (97:3 EA-MeOH) = 0.26. LC-MS-conditions 02: tR = 0.56 min [M+H]+ = 246.44.
Stage #1: 6-oxoheptanoic acid With triethylamine; isobutyl chloroformate In tetrahydrofuran at -30℃; for 1h; Inert atmosphere;
Stage #2: methyl 2-amino-3-hydroxypropanoate hydrochloride In tetrahydrofuran at -30 - 20℃; for 2h; Inert atmosphere;
3-Hydroxy-2-(6-oxo-heptanoylamino)-propionic acid methyl esterIn a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 6-oxo-heptanoic acid (2.00 g, 13.32 mmol) in THF (82 mL) at -30° C. was treated sequentially with Et3N (3.89 mL, 27.97 mmol) followed by isobutyl chloroformate (1.95 mL, 14.65 mmol). After stirring for 1 h at -30° C., serine methylester hydrochloride (2.32 g, 14.65 mmol was added and the reaction mixture was allowed to warm gradually to rt and stirred for an additional 2 h at rt. The resulting suspension was filtered, the solid washed with THF and the filtrate was concentrated under reduced pressure. Purification of the residue by FC (97:3 EA-MeOH) gave the title compound as a colorless oil. TLC:rf (97:3 EA-MeOH)=0.26. LC-MS-conditions 02: tR=0.56 min [M+H]+=246.44.
With trifluorormethanesulfonic acid In dichloromethane at -10 - 20℃;
3A
Example 3Atert-Butyl 6-oxoheptanoate 10.0 g (about 90% pure, 62.4 mmol) of 6-oxoheptanoic acid are initially charged in 71.8 ml of cyclohexane, and 20.46 g (93.6 mmol) of tert-butyl 2,2,2-trichloroacetimidate and 15 ml of dichloromethane are added. At -10° C., 0.55 ml (6.24 mmol) of trifluoromethanesulfonic acid is slowly added dropwise to the solution. The resulting suspension is stirred overnight and warmed to RT over this period. The insoluble precipitate is removed by filtration and the filtrate is washed twice with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 5:1). On standing, a solid precipitates from the resulting product overnight. This solid is removed by filtration. This gives 4.51 g of product (36.1% of theory).GC-MS (method 1): Rt=4.1 min; m/z=144 (M-56)+ MS (DCI): m/z=218 (M+NH4)+ 1H-NMR (400 MHz, DMSO-d6): δ=2.46-2.42 (m, 2H), 2.20-2.15 (m, 2H), 2.08 (s, 3H), 1.47-1.40 (m, 4H), 1.41 (s, 9H).
With trifluorormethanesulfonic acid In dichloromethane at -10 - 20℃;
11a
Example 11ATert-Butyl 6-oxoheptanoate 10.0 g (about 90% pure, 62.4 mmol) of 6-oxoheptanoic acid were initially charged in 71.8 ml of cyclohexane, and 20.46 g (93.6 mmol) of tert-butyl 2,2,2-trichloroacetimidate and 15 ml of dichloromethane were added. At -10° C. 0.55 ml (6.24 mmol) of trifluoromethanesulfonic acid were slowly added dropwise to the solution. The resulting suspension was stirred overnight with warming to RT. The insoluble precipitate was then removed by filtration. The filtrate was washed twice with sodium bicarbonate solution and with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 5:1). On standing overnight, a solid precipitated from the product obtained in this manner. This solid was removed by filtration with suction and discarded. The target product, obtained in the form of the filtrate, was not purified any further. This gave 4.51 g (36.1% of theory) of the title compound.GC-MS (Method 1): Rt=4.1 min; m/z=144 (M-C4H8)+.MS (DCI): m/z=218 (M+NH4)+.1H-NMR (400 MHz, DMSO-d6): δ=2.46-2.42 (m, 2H), 2.20-2.15 (m, 2H), 2.08 (s, 3H), 1.47-1.40 (m, 4H), 1.41 (s, 9H).
Stage #1: 6-amino-3-bromo-2H-chromen-2-one With hydrogenchloride; sodium nitrite In water at -5℃; for 0.5h;
Stage #2: With hydrogenchloride; tin(II) chloride dihdyrate In water at -5℃; for 5h;
Stage #3: 6-oxoheptanoic acid With acetic acid In water at 80℃; for 4h;
6.1.11. 2-(8-Bromo-2-methyl-7-oxo-3,7-dihydropyrano[3,2-e]indol-1-yl)acetic acid (21a)
General procedure: To a solution of the 6-amino-3-bromocoumarin (19) (239 mg, 1.0 mmol) in HCl (37%, 1.0 mL) was added NaNO2 (83 mg, 1.20 mmol) in H2O (0.5 mL) at -5 °C. After being stirred at this temperature for 30 min, the resulting mixture was treated with a pre-cooled (-10 to -5 °C) solution of stannous chloride dihydrate (452 mg, 2.0 mmol) in HCl (37%, 0.5 mL). The mixture was stirred at -5 °C for an additional 5 h. The reaction mixture was filtered. The solid was added into a solution of 20a (278 mg, 2.4 mmol) in HOAc (5 mL). The mixture was then heated to 80 °C for 4 h. The solvent was evaporated in vacuo, and the residue was diluted with H2O (10 mL) and EtOAc (50 mL). The mixture was adjusted to pH 8 by the addition of saturated NaHCO3 solution. The organic phase was separated and washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash column chromatography (dichloromethane/methanol=25/1) to afford 21a as a yellow solid (117 mg, 35%).
General procedure: To a solution of alkyne (1.0 mmol) in PEG-400/H2O(4:1) was added [Ru(p-cymene)Cl2]2 (0.01 mmol), and themixture stirred at room temperature. Upon completion of thereaction (monitoring by TLC), the reaction mixture was dilutedwith Et2O (10 mL), stirred for 10 min, and allowed to stand in anice-salt bath to solidify the PEG-400. The organic layer wasdecanted, dried over anhydrous Na2SO4, filtered, and concentratedunder reduced pressure. The residue obtained was purifiedby silica gel flash column chromatography (ethyl acetate-petroleum ether) to give the pure product.
Stage #1: 6-oxoheptanoic acid; 2-bromophenylhydrazine hydrochloride In ethanol at 50℃; for 0.666667h;
Stage #2: ethanol With sulfuric acid for 16h; Reflux;
1 Ethyl 4-(7-bromo-2-methyl-1H-indol-3-yl)butanoate
Example 1 Ethyl 4-(7-bromo-2-methyl-1H-indol-3-yl)butanoate To a solution of (2-bromophenyl)hydrazine hydrochloride (14 g) in ethanol (60 mL), 5-acetylvaleric acid (9.0 g) was added. The reaction mixture was stirred at 50° C. for 40 minutes, and concentrated sulfuric acid (6.0 mL) was added thereto, followed by heating under reflux for 16 hours. The reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution which was then extracted with ethyl acetate and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The resulting residue was purified by column chromatography (hexane:ethyl acetate=8:1) to obtain the title compound (15 g) having the following physical properties. TLC:Rf 0.54 (hexane:ethyl acetate=3:1) 1H-NMR (CDCl3): δ 1.23, 1.89-2.00, 2.31, 2.39, 2.72, 4.10, 6.95, 7.24, 7.43, 7.91.
2-(Trimethylsilyl)-1,3-dithiane (1.467g, 7.629 mmol, 2 equivalents) was dissolved in tetrahydrofuran (10 mL) under inert atmosphere, cooled to -78 C, and treated with n-butyllithium (1.6 M in hexanes, 4.77 mL, 7.629 mmol, 2 equivalents). The resulting solution was stirred at -78 C for 30 minutes, then at room temperature for 30 minutes. The solution was then cooled back to -78 C and treated with 6-oxoheptanoic acid (0.6070g, 3.789 mmol, 1 equivalent, dissolved in 10 mL of tetrahydrofuran). After 15 minutes, cold bath was removed and the reaction was allowed to warm to room temperature as it stirred overnight. The reaction was quenched the following morning with 3 M aqueous hydrochloric acid to a pH of approximately 6. Ether was added, and the layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was chromatographed through silica gel with hexanes and ethyl acetate to give the desired product (67%) as a colorless oil.
Methyl 6-oxoheptanoate (24) 1,8-Diazabicyclo[5.4.0]undec-7-ene (3.4 mL, 22.86 mmol) was added to a solution of 6-oxoheptanoic acid 23 (1.1 g, 7.63 mmol) in acetone (15 mL) at 23° C. After stirring for 15 min iodomethane (2.4 mL, 38.3 mmol) was added. The reaction was stirred for 1 h and then the solvent was removed in vacuo. The residue was purified by flash column chromatography (silica gel, 7:3 hex/EtOAc) to provide 1.18 g (95percent) of the methyl ester 24 (see scheme 4).
6-oxoheptanoic acid trimethylsilyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine at 50℃; for 1h;
Silylation
General procedure: Compounds (1 mg) to be silylated were taken up in 300 μL of a mixture of pyridine and BSTFA (N,O-Bis(trimethylsilyl)trifluoroacetamide, Supelco Inc., St QuentinFallavier, France) (2:1, vol/vol) and allowed to react at 50°C for 1 h. After evaporation to dryness (to eliminate pyridine), the residue was dissolved in ethylacetate (2mL/mg) and BSTFA (0.1 mL) (to avoid desilylation) and analyzed by gas chromatography/mass spectrometry (GC/MS)
In tetrahydrofuran; toluene at -78 - -10℃; Inert atmosphere;
3.1 Preparation of 6-Hydroxy-6-methyl-heptanoic acid
To a 250 mL 3-neck round bottom flask equipped with a magnetic stirrer, addition funnel, condenser, thermocouple and nitrogen inlet was charged 5-acetylvaleric acid 18 (1.0 g; 6.9 mmol) and anhydrous THF (50 mL). This solution was stirred and chilled to -78 °C via dry ice/acetone bath. To this cold solution 1.4 M MeMgl in THF/toluene (29 mL; 40 mmol; 5.8 eq) was added slowly via addition funnel over 15 min. The reaction was stirred at -78 °C for 2 h, then slowly warmed to - 10 °C and saturated aq. NH4C1 solution was added to quench the excess Grignard. The biphasic mixture was warmed to ambient temperature, diluted with ethyl acetate, the organic layer was discarded. The aqueous layer was acidified with 1 M HC1 and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with brine, dried over Na2S04, filtered and concentrated to afford 0.63 g (57% yield) as a clear colorless oil. 1H- NMR (500 MHz, CDC13): δ 2.39 - 2.36 (m, 2H), 1.68 - 1.62 (m, 2H), 1.51 - 1.47 (m, 2H), 1.45 - 1.40 (m, 2H), 1.21 (s, 6H).
6-oxo-N,N-bis(pyridin-2-ylmethyl)heptanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.166667h;
With iron(III) chloride In dichloromethane at 20℃; for 0.0833333h; Inert atmosphere; Green chemistry;
Deprotection of 2,4-DMPM-Protected Ester (6)
General procedure: To a solution of the 2,4-DMPM ester (0.2 mmol) in CH2Cl2 (1 mL) was added FeCl3(0.01 mmol), then stirred at room temperature under argon. After being stirred until the reaction was completed, the reaction mixture was directly filtrated through a small amount of a silica-gel pad and washed with Et2O. The filtrate was concentrated in vacuoto give the sufficiently-pure carboxylic acid. When some peaks derived from undetermined side-products were observed in the 1H-NMR spectra, the analytically-pure deprotected carboxylic acid was obtained after the normal silica-gel column chromatography (Table 3).
Stage #1: 6-oxoheptanoic acid With 10% Pt/activated carbon; water-d2 In isopropyl alcohol at 120℃; for 24h;
Stage #2: With water; sodium hydroxide at 70℃; for 24h;
To a rapidly stirred mixture of diethyl ether (175 ml) and 40percent KOH (52 ml) at0°C was added IVTNNG (15.4 g, 105 mmol). The mixture was stirred for 10 minutes. Theethereal layer was transferred to a solution of 6-oxo-heptanoic acid 4-1 (5.0 g, 34.68 mmol) and CH2C12 at 0°C. The solution was purged with argon for 30 minutes and then concentrated. Flash chromatography (silica, 30percent to 50percent EtOAc/hexanes) gave ester 4-2 as a clear oil.TLC Rf= 0.88 (silica, EtOAc).?HNMR(3001V11{z, CDC13)oe 3.67 (s, 3H), 2.46 (m,2H), 2.33 (m, 2H), 2.14(s, 3H), 1.62(m,4H).
With sulfuric acid In water at 20℃; for 15h; Cooling with ice;
1 (1) 6,6-bis(4-hydroxyphenyl)heptanoic acid (a) is formed by condensation reaction of phenol with 5-acetylpentanoic acid as a starting material. The synthesis steps are as follows:
9.4 g (10 mmol) of phenol was weighed, 5-acetylpentanoic acid 7.2 g (50 mmol) Placed in 50ml two-necked flask,Add 4 ml of water,Stir to dissolve, ice bath,Stirring add concentrated sulfuric acid 10ml,The reaction was stirred at room temperature for 15 h;The reaction solution was added 50ml of water, extracted with ether; the organic phase was extracted with saturated sodium bicarbonate, the aqueous phase retained after completion of the extraction, the aqueous phase was adjusted pH 4-5, extracted with ether, the organic phase by rotary evaporation with a rotary evaporator to give product 6,6-bis(4-hydroxyphenyl)heptanoic acid, 9.43 g.
9.43 g
With sulfuric acid In water at 20℃; for 15h; Cooling with ice;
1.1 Example 1
with phenol as raw material and5-acetylpentanoic acid is generated by condensation reaction6,6-bis (4-hydroxyphenyl) heptanoic acid (a), with the following steps:9.4 g (10 mmol) of phenol was weighed,5-acetylpentanoic acid 7.2 g (50 mmol) was placed in a 50 ml two-necked flask,Add 4ml of water, stir to dissolve, ice bath, stirring under the concentrated sulfuric acid 10ml,Stirring at room temperature for 15 h; the reaction solution was added to 50 ml of water,Extracted with ether; the organic phase was extracted with saturated sodium bicarbonate, the aqueous phase was retained,After extraction, the pH of the aqueous phase was adjusted to 4-5, extracted with ether,The organic phase was spin-dried with a rotary evaporator to give 9.43 g of product 6,6-bis (4-hydroxyphenyl) heptanoic acid.
9.43 g
With sulfuric acid In water at 20℃; for 15h; Cooling with ice;
1 preparation of 6,6-bis(4-hydroxyphenyl)heptanoic acid
9.4 g (10 mmol) of phenol was weighed,5-acetylpentanoic acid 7.2 g (50 mmol)Placed in 50ml two-necked flask,Add 4 ml of water,Stirring to dissolve,Ice bath,Stirring add concentrated sulfuric acid 10ml,The reaction was stirred at room temperature for 15 h;The reaction solution was added with 50 ml of water,Extraction with ether;The organic phase was extracted with saturated sodium bicarbonate,Keep the water,After extraction is complete,Adjust the water phase pH4-5,Extracted with ether,The organic phase was spin-dried with a rotary evaporator,To give 9.43 g of product 6,6-bis (4-hydroxyphenyl) heptanoic acid.
9.43 g
With sulfuric acid In water at 20℃; for 15h; Cooling with ice;
1.1 (1) condensation reaction of phenol with 5-acetylvaleric acid to produce 6,6-bis (4-hydroxyphenyl) heptanoic acid (a)Proceed as follows:
Weigh phenol 9.4g (10mmol),7.2 g (50 mmol) of 5-acetylvaleric acid,Placed in 50ml two-necked flask,Add 4ml of water,Stirring to dissolve,Ice bath, stirring under the addition of concentrated sulfuric acid 10ml,The reaction was stirred at room temperature for 15h;The reaction mixture was added with 50 ml of water and extracted with diethyl ether. The organic phase was extracted with saturated sodium bicarbonate to retain the aqueous phase. After the extraction was completed, the aqueous phase was adjusted to pH 4-5 and extracted with ether. The organic phase was spin-9.43 g of the product 6,6-bis (4-hydroxyphenyl) heptanoic acid was obtained.
With hydroxylamine-O-sulfonic acid In ammonia at -78 - 20℃; for 12h; Sealed tube; liquid NH3;
3.2.1. Acidic Substrates (1a-e)
General procedure: Ketone (2 mmol) was dissolved in liquid NH3 (8 mL) in a sealed tube at -78 °C.Hydroxylamine-O-sulfonic acid (1.1 equiv.) was carefully added at the same temperature. After closingthe tube, the reaction mixture was stirred at room temperature for 12 h, before it was cooled at -78 °Cand subsequently opened. KOH (3.3 equiv. for 1a-d and 4.3 equiv. for 1e) was added to liquid NH3mixture and then the tube was sealed. The reaction mixture was further stirred at room temperatureunder air for 2 h. The ammonia was gradually removed at room temperature in a fume hood.The residue was dissolved with water (30 mL) which was adjust pH to 2 with HCl aq, then extractedtwice with Et2O (30 mL). The organic layer was washed with brine, dried over MgSO4, and evaporated.The residue was subjected to silica-gel column chromatography to afford the diazirinyl products.
Stage #1: 1-methylcyclohex-1-ene With dodecyltrimethylammonium phosphotungstate; dihydrogen peroxide In toluene at 60℃; for 12h;
Stage #2: With dihydrogen peroxide In toluene at 80℃; for 12h;
5 Example 5: Olefin as starting material
General procedure: In a typical reaction, 0.75 mL toluene containing 2 mol/L cyclohexene, 2 mol/L 1-methyl cyclohexene or 2 mol/L 4-methyl cyclohexene is separately mixed with 2.25 mL water containing 1.2 eq. H2O2, 0.05 g dodecylpolyoxometalate of Example 2 and 0.01 g dodecyl phosphoric acid (buffer solution) . The system was emulsified at 11500 rpm for 1 min and heated at 60 C for 12 h. 0.05 g 80/20 C18/C3SO3H amphiphilic silica nanoparticles and another 3.5 eq. H2O2batch were added to the system which was re-emulsified at 11500 rpm for 2 min, and the reaction was continued at 80 C, 500 rpm for 12 h. The products obtained were identified by NMR and HPLC and conversion. The selectivity of each product are listed in Table 3.
N-(4-((4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzyl)-6-oxoheptanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h;
To a solution of 6-oxoheptanoic acid (36 mg, 0.25 mmol) in DCM (5.0 mL) was added EDC (48 mg, 0.25 mmol). Sequentially, l-(4-(aminomethyl)benzyl)-2-butyl-l//-imidazo[4,5-c]quinolin- 4-amine (50 mg, 0.14 mmol), EhN (21 mg, 0.15 mmol) and DMAP (3.0 mg, 0.025 mmol) were added and stirred for 16h at room temperature. The solution was partitioned between DCM (30 mL) and water (15 mL). The organic layer was washed with sat'd NH4CI (15 mL), sat'd NaHCCh (2 x 15 mL), dried over Na2S04, filtered and concentrated. Upon drying, the product was isolated as a light yellow/brown foamy solid. HPLC purity at 220 nm, > 95.0% AUC. MS (ESI) calculated for C29H35N5O2, m/z 485.3, found 486.2.
(E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-(piperazin-1-yl)propoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide[ No CAS ]
(E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-(4-(6-oxoheptanoyl)piperazin-1-yl)propoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In N,N-dimethyl-formamide for 2h;
1
To 6-oxoheptanoic acid (0.80 mg, 0.056 mmol) in DMF (0.5 mL) was added ()-l-(4-(5- carbamoyl-2-(I -cthyl-3-rncthyl- 1 / -pyrazolc-5-carboxamido)-7-(3-(pipcrazin- 1 -yl)propoxy)- 1H- bcnzo[c/]imidazol- 1 -yl)but-2-cn- 1 -yl)-2-(I -cthyl-3-rncthyl- 1 //-pyrazole-5-carboxamido)-7-methoxy- 1H- bc n zo [c/] i m i dazo I c-5 -car bo xam i dc (5 mg, 0.0059 mmol). DIEA (3.0 mg, 0.023 mmol) was added followed by HATU (2.0 mg, 0.0056 mmol). The solution was stirred for 2 hours. The DMF was removed, the sample was dried under vacuum, and used in the subsequent step without further purification or characterization. HPLC purity at 220 nm, > 95.0% AUC. MS (ESI) calculated for C49H62N14O8, m/z 974.5, found 488 (m/2).
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 for 2h;
1 Compound E
Compound E, (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-7-(3-(4-(6-oxoheptanoyl)piperazin-1-yl)propoxy)-1H-benzo[d]imidazol-1-yl)but-2- en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5- carboxamide, referred to as pip-diABZI-HA (or sometimes herein as “diABZI”). Note: A ketone, 6-oxohepantanoic acid (HA), was introduced to enable linkage to star polymers through a pH- sensitive hydrazone bond. To 6-oxoheptanoic acid (0.80 mg, 0.056 mmol) in DMF (0.5 mL) was added (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-(piperazin-1- yl)propoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide (5 mg, 0.0059 mmol). DIEA (3.0 mg, 0.023 mmol) was added followed by HATU (2.0 mg, 0.0056 mmol). The solution was stirred for 2 hours. The DMF was removed, the sample was dried under vacuum, and used in the subsequent step without further purification or characterization. HPLC purity at 220 nm, > 95.0% AUC. MS (ESI) calculated for C49H62N14O8, m/z 974.5, found 488 (m/2)
With 1,2-bis((2S,5S)-2,5-diphenylphospholan-1-yl)ethane; hydrogen; nickel(II) acetate tetrahydrate In 2,2,2-trifluoroethanol at 50℃; for 24h; Overall yield = 87 percent;
2 Example 2:
General procedure: 1.8mg of nickel triflate and 1.25mg of (S,S)-Ph-BPE were added to a 10ml Schlenk reaction tube or autoclave, 2ml of trifluoroethanol was added and stirred at room temperature for 20 minutes, then 0.25mmol of different fats were added Family gamma- or delta-ketoacid substrates. Under the hydrogen pressure of 1-50 atm, the reaction temperature was 65°C for 24 hours. After the reaction, the product was then analyzed by gas chromatography, and the results were shown in Table 4:
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