* 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.
Experimental procedure for the synthesis of 3: To a solution of 2 (0.051 mol, 10 g) dissolved in ethanol (100 mL), hydrazine hydrate (0.077 mol, 3.85 g) was added. The reaction mixture was refluxed for 8-10 hrs for completion of the reaction (monitored by TLC). The solvent was removed under reduced pressure and cooled by adding ice cold water. The resulting precipitate was filtered, washed with cold water and recrystallized from ethanol to get the desired compounds 3 (Yield = 8.56 g, 86percent).
Reference：
[1] Journal of the American Chemical Society, 2018,
[2] Bioorganic Chemistry, 2018, vol. 81, p. 389 - 395
[3] Pharmaceutical Chemistry Journal, 2001, vol. 35, # 12, p. 653 - 656
[4] Heterocyclic Communications, 2008, vol. 14, # 1-2, p. 101 - 105
[5] Organic and Biomolecular Chemistry, 2014, vol. 12, # 25, p. 4445 - 4453
[6] Patent: CN103864711, 2016, B, . Location in patent: Paragraph 0056; 0060; 0061
[7] RSC Advances, 2018, vol. 8, # 10, p. 5473 - 5483
3
[ 1459-93-4 ]
[ 7803-57-8 ]
[ 2760-98-7 ]
Yield
Reaction Conditions
Operation in experiment
85%
for 5 h; Reflux
A mixture of dimethyl ester of isophthalic acid (2.22 gm) and hydrazine hydrate (98percent, 2 cc) in methanol was refluxed for 5 hours and the reaction mixture was allowed to cool to room temperature. Then, the cooled reaction mixture was poured on to ice cold water. The dihydrazide of isophthalic acid thus obtained was filtered and recrystallized from ethanol. [1] Yield: (85percent), M.P=241C, (Scheme1). 1HNMR (400 MHz, CDCL3, ppm): 9.81 (s, 2H, -CO-NH-), 8.20 (s 1H ), 7.8(d, 2H, J=7.6 Hz), 7.5 (t, 1H, 7.2 Hz), 4.5 (s, 4H).
Reference：
[1] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2018, vol. 204, p. 225 - 231
4
[ 1459-93-4 ]
[ 2760-98-7 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1995, # 15, p. 1531 - 1532
5
[ 1459-93-4 ]
[ 626-18-6 ]
Yield
Reaction Conditions
Operation in experiment
99%
With C24H38Cl2N3PRu; hydrogen; sodium methylate In tetrahydrofuran at 25℃; for 16 h;
General procedure: Hydrogenation of Other Ester Compounds Catalyzed by Synthetic Preparation of Bipyridine Tetradshed Ruthenium Complex 5 The results are shown in Table 2:Table 2 Hydrogenation of other ester compounds a; A Reaction conditions: S / C = 1000,3.0 mmol Substrate, 3.0 μmol 5, 3.0 mL lPrOH, 0.3 mmol NaOMe, 5 MPa H2, 25 ° C. F Tetrahydrofuran as solvent.
95%
Stage #1: With lithium borohydride In tetrahydrofuran for 23 h; Inert atmosphere Stage #2: With acetic acid In tetrahydrofuran
Under Ar atmosphere, to dimethyl isophthalate (2.00 g, 10.30 mmol) were added dry THF (51.5 mL, 0.2M solution) and lithium borohydride (1.12 g, 51.5 mmol, 5 eq.), and stirred for 23 hours. Then, in an ice bath, to the mixture was added a few drops of acetic acid to neutralize the mixture, thereby quenching the reaction. The mixture was stirred for a while. Formed crystals were dissolved by adding MeOH. Although there was one spot of product as checked by TLC (Hex:EtOAc=1:1) during the reaction, after the reaction quenched, there were two spots of products on TLC. The solvent was distilled off under reduced pressure. Products were separated by silica gel column chromatography (only EtOAc) to give a compound (11) (1.36 g, 9.82 mmol, 95percent). 1H NMR(400MHz,CDCl3)δ[ppm]: 7.39-7.26 (4H, m, aromatic protons), 4.71 (4H, s, -CH2-O-), 1.70(2H, d, J = 76.8 Hz, OH) 13C NMR(100MHz,CDCl3)δ[ppm]: 139.28, 129.62, 128.47, 63.90 Mass(EI)m/z:138(M+), 120 107, 79, 65, 51. HRMS(EI)Calcd for C8H10O2138.06808 Found 138.06765. Anal. Calcd for C8H10O2:C, 69.54; H, 7.30. Found:C, 69.45; H, 7.23.
Reference：
[1] Green Chemistry, 2014, vol. 16, # 9, p. 4081 - 4085
[2] Patent: CN103980317, 2017, B, . Location in patent: Paragraph 0098; 0099; 0100; 0102; 0104
[3] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 5, p. 1974 - 1981
[4] Patent: EP2511260, 2012, A1, . Location in patent: Page/Page column 15
[5] Justus Liebigs Annalen der Chemie, 1977, p. 2036 - 2066
[6] Journal of Medicinal Chemistry, 1967, vol. 10, p. 491 - 495
[7] Australian Journal of Chemistry, 2011, vol. 64, # 3, p. 316 - 323
[8] Angewandte Chemie - International Edition, 2013, vol. 52, # 9, p. 2538 - 2542[9] Angew. Chem., 2013, vol. 125, # 9, p. 2598 - 2602,5
[10] ACS Catalysis, 2013, vol. 3, # 1, p. 32 - 40
6
[ 1459-93-4 ]
[ 51839-15-7 ]
Yield
Reaction Conditions
Operation in experiment
91%
at 36℃; for 12 h; Inert atmosphere
Iodine (18.29 g, 72 mmol) was added to a stirred solution of sodium periodate (8.8 g, 41 mmol) in 110 mL 96percent sulfuric acid at 36 °C under argon atmosphere. The resulting mixture was stirred for 30 minutes. To this mixture was added dimethyl isophthalate 1 (20 g, 103 mmol) and stirring was continued for 12 h. After completion of the reaction, the reaction mixture was poured into the mixture of crushed ice and dichloromethane (DCM). The organic layer was then separated and the aqueous layer repeatedly washed with dichloromethane. The collected organic layers were carefully washed with sodium bicarbonate, sodium thiosulfate and brine respectively. The combined organic layers were collected and dried over anhydrous sodium sulfate followed by evaporation to afford compound 2 as colorless crystalline material (30 g, 91 percent) which was used without further purification for the next step, mp: 99-101 °C; TLC (Ethyl acetate:pet ether, 5:95 v/v): Rf = 0.3; IR (CHC13) cm"1: 3023, 2955, 1727 (C=0), 1569; 1H NMR (CDC13, 400 MHz): δ 8.62 (s, 1H), 8.54 (s, 2H), 3.95 (s, 6H); 13C NMR (CDC13, 100 MHz); δ 164.76, 142.43, 132.16, 129.84, 93.40, 52.62.
Reference：
[1] Australian Journal of Chemistry, 1995, vol. 48, # 5, p. 967 - 986
[2] Journal of the American Chemical Society, 1980, vol. 102, p. 6862
[3] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 12, p. 1725 - 1729
[4] Australian Journal of Chemistry, 1985, vol. 38, # 11, p. 1705 - 1718
[5] Journal of the American Chemical Society, 1991, vol. 113, # 21, p. 7969 - 7979
11
[ 67-56-1 ]
[ 121-91-5 ]
[ 1459-93-4 ]
[ 51760-21-5 ]
Yield
Reaction Conditions
Operation in experiment
65.1%
Stage #1: at 150℃; for 7 h; Stage #2: at 120℃;
Into a 50 ml pressure and sealable glass tube, 1.66 g (10 mmol) of isopthalic acid, 6.00 g of 10 wt percent fuming sulfuric acid and 1.6 g (10 mmol) of bromine were charged, and the content was stirred at 150° C. for 7 hours. After the conclusion of the reaction, the content was cooled to room temperature, and placed in a beaker containing ice water to give a solid. The resulting solid was filtered off, washed with cooling, and further dried under reduced pressure to give a crude crystal of the aimed product. Then, dimethyl esters were derived from the crystal by heating and stirring it at 120° C. with 13.1 g (408 mmol) of methanol and 0.35 g (30 mol percent) of sulfuric acid in an autoclave. In succession, the esters were subjected to rectification to give 1.78 g (yeild: 65.1percent, vacuum boiling point: 159° C./4.8 mmHg) of aimed dimethyl 5-bromoisophthalate and 0.52 g (yield: 26.8percent, vacuum boiling point: 133° C./4.8mmHg) of dimethyl isophthalate corresponding to a raw material. The resulting crystals were identified as dimethyl 5-bromoisophthalate and 5-bromoisophthalic acid by MASS, 1H-NMR and melting point.
Into a 100 ml pressure and sealable glass tube, 9.70 g (50 mmol) of dimethyl isophthalate, 30.00 g of 10 wt percent fuming sulfuric acid and 10.40 g (100 mmol) of bromine were charged, and the content was stirred at 120° C. for 7 hours. After the conclusion of the reaction, the content was cooled to room temperature, and placed in a beaker containing ice water to give a solid. The resulting solid was filtered off, washed with cooling, and further dried under reduced pressure to give 11.95 g of a crude crystal of the aimed product (reaction yield: 50.4percent 5-bromoisophthalic acid, 19.6percent isophthalic acid, 4.9percent 2,5-dibromoisophthalic acid, 7.2percent 4,5-dibromoisophthalic acid, 7.0percent dimethyl 5-bromoisophthalate, 1.5percent dimethyl isophthalate, 0.9percent dimethyl 2,5-dibromoisophthalate and 0.2percent dimethyl 4,5-dibromoisophthalate). Then, dimethyl esters were derived from the crystal by heating and stirring it with 65.50 g (2.04 mol) of methanol and 1.75 g (30 mol percent) of sulfuric acid in an autoclave at 120° C. [0038] In succession, the esters were subjected to rectification to give 6.73 g (yield: 49.3percent, vacuum boiling point: 159° C./4.8mmHg) of aimed dimethyl 5-bromoisophthalate and 1.67 g (yield: 17.2percent, vacuum boiling point: 133° C./4.8mmHg) of dimethyl isophthalate corresponding to a raw material. The resulting crystals were identified as dimethyl 5-bromoisophthalate and 5-bromoisophthalic acid by MASS, 1H-NMR and melting point.
Reference：
[1] Organic and Biomolecular Chemistry, 2003, vol. 1, # 14, p. 2506 - 2511
[2] Organic Letters, 2013, vol. 15, # 22, p. 5818 - 5821
14
[ 1459-93-4 ]
[ 23351-91-9 ]
Yield
Reaction Conditions
Operation in experiment
50.4%
With bromine In (2S)-N-methyl-1-phenylpropan-2-amine hydrate
Example 18 Into a 100 ml pressure and sealable glass tube, 9.70 g (50 mmol) of dimethyl isophthalate, 30.00 g of 10 wtpercent fuming sulfuric acid and 10.40 g (100 mmol) of bromine were charged, and the content was stirred at 120°C for 7 hours. After the conclusion of the reaction, the content was cooled to room temperature, and placed in a beaker containing ice water to give a solid. The resulting solid was filtered off, washed with cooling, and further dried under reduced pressure to give 11.95 g of a crude crystal of the aimed product (reaction yield: 50.4percent 5-bromoisophthalic acid, 19.6percent isophthalic acid, 4.9percent 2,5-dibromoisophthalic acid, 7.2percent 4,5-dibromoisophthalic acid, 7.0percent dimethyl 5-bromoisophthalate, 1.5percent dimethyl isophthalate, 0.9percent dimethyl 2,5-dibromoisophthalate and 0.2percent dimethyl 4,5-dibromoisophthalate).
Reference：
[1] Patent: EP1293495, 2003, A1,
15
[ 1459-93-4 ]
[ 379711-35-0 ]
[ 379711-34-9 ]
[ 244768-63-6 ]
[ 121-91-5 ]
[ 51760-21-5 ]
[ 23351-91-9 ]
Yield
Reaction Conditions
Operation in experiment
50.4%
at 120℃; for 7 h;
Into a 100 ml pressure and sealable glass tube, 9.70 g (50 mmol) of dimethyl isophthalate, 30.00 g of 10 wt percent fuming sulfuric acid and 10.40 g (100 mmol) of bromine were charged, and the content was stirred at 120° C. for 7 hours. After the conclusion of the reaction, the content was cooled to room temperature, and placed in a beaker containing ice water to give a solid. The resulting solid was filtered off, washed with cooling, and further dried under reduced pressure to give 11.95 g of a crude crystal of the aimed product (reaction yield: 50.4percent 5-bromoisophthalic acid, 19.6percent isophthalic acid, 4.9percent 2,5-dibromoisophthalic acid, 7.2percent 4,5-dibromoisophthalic acid, 7.0percent dimethyl 5-bromoisophthalate, 1.5percent dimethyl isophthalate, 0.9percent dimethyl 2,5-dibromoisophthalate and 0.2percent dimethyl 4,5-dibromoisophthalate). Then, dimethyl esters were derived from the crystal by heating and stirring it with 65.50 g (2.04 mol) of methanol and 1.75 g (30 mol percent) of sulfuric acid in an autoclave at 120° C. [0038] In succession, the esters were subjected to rectification to give 6.73 g (yield: 49.3percent, vacuum boiling point: 159° C./4.8mmHg) of aimed dimethyl 5-bromoisophthalate and 1.67 g (yield: 17.2percent, vacuum boiling point: 133° C./4.8mmHg) of dimethyl isophthalate corresponding to a raw material. The resulting crystals were identified as dimethyl 5-bromoisophthalate and 5-bromoisophthalic acid by MASS, 1H-NMR and melting point.
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 14, p. 2621 - 2632
18
[ 1459-93-4 ]
[ 73183-34-3 ]
[ 944392-68-1 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 25, p. 8058 - 8061
[2] Angewandte Chemie - International Edition, 2012, vol. 51, # 2, p. 536 - 539
[3] Angewandte Chemie - International Edition, 2012, vol. 51, # 2, p. 540 - 543
[4] Chemistry--A European Journal, 2014, vol. 20, # 37, p. 11680 - 11684,5
19
[ 36768-62-4 ]
[ 1459-93-4 ]
[ 42774-15-2 ]
Yield
Reaction Conditions
Operation in experiment
98.5%
With sodium methylate In methanol at 60 - 110℃; for 1.5 h; Inert atmosphere; Large scale
In a horizontal forced mixer that works at a Froudenumber of 2.16 and has been equipped with plowshares, adistillation colunm and a protective gas connection, 2.5 molof dimethyl isophthalate (m.p. 64-66° C.) and 5 mol of4-amino-2,2,6,6-tetramethylpiperidine (in liquid form atroom temperature) are homogenized with one another at atemperature of 60° C. under nitrogen until a monophasicliquid mixture forms. After the addition of 59.4 g of asodium methoxide solution (25percent by weight in methanol),the reaction mixture is mixed at 110° C. for a duration of 90minutes. The alcohol from the catalyst formulation and thealcohol formed during the reaction are removed by distillation from the forced mixer. After the solid had been discharged and dried to constant weight, 1088.4 g (mass yield:9 8.5percent) of a white powder were isolated.
96.7%
With solid supported catalyst C1 In acetonitrile at 20 - 70℃; for 15 h;
To a suitable amount of organic solvent (a mixture of acetonitrile and polyethylene glycol 200 (PEG-200) in a volume ratio of 3:1), 100 mmol of the compound of the above formula (I) is added at room temperature.65 mmol of compound of formula (II) above, solid supported catalyst C1 (the amount of C1 is:The molar ratio of the compound of formula (I) to the nickel ion in C1 is 1:0.11), and then it is heated to 70°C under stirring.And continue stirring at this temperature for 15 hours; After work-up, work-up gives the compound of formula (III) as a white solid.That is, N,N'-bis(2,2,6,6-tetramethyl-4-piperidinyl)-1,3-benzenedicarboxamide,The yield is 96.7percent.
93.5%
at 190 - 230℃; for 7 h; Large scale
6.0 kg of dimethyl isophthalate, 21.0 kg of 2,2,6,6-tetramethyl-4-aminopiperidine was added to a 50 liter reactorIn the reactor all the materials off the entrance. The reaction was carried out at 190 ° C for 2 hours and then at 230 ° C for 5 hours. The temperature was lowered to below 180 ° C, and excess 2,2,6,6-tetramethyl-4-aminopiperidine was recovered by vacuum distillation under a vacuum pump. Then use water to generateN, N'-bis (2,2,6,6-tetramethyl-4-piperidinyl) -1,3-benzenedicarboxamide, filtered and dried to give 12.8 kg of acicular white crystalline product , Yield 93.5percent.
Reference：
[1] Patent: US2018/194727, 2018, A1, . Location in patent: Paragraph 0067; 0075; 0078
[2] Patent: CN107382828, 2017, A, . Location in patent: Paragraph 0075; 0076; 0077; 0078; 0079; 0080
[3] Patent: CN106905225, 2017, A, . Location in patent: Paragraph 0016
With 4-methyl-morpholine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride for 3h;
91%
With chloro-trimethyl-silane at 20℃; for 3h;
Experimental procedure for the synthesis of 2:
Experimental procedure for the synthesis of 2: To a solution of isophthalic acid (0.06 mol, 10.0 g) dissloved in methanol (100 mL), trimethylsilylchloride (0.06 mol, 7.6 mL) was added slowly. The reaction mixture was stirred for 3 hrs to complete the reaction (monitored by TLC). The solvent was removed under reduced pressure and the resultant precipitate was washed with ice cold water and filtered to yield the desired product 2. (Yield = 10.6g, 91%).
90%
for 12h; Heating / reflux;
6-24.15
Isophthalic acid (5 g, 30 mmol) was dissolved in methanol (50 ML). Catalytic amount of sulfuric acid was added therein. The reaction mixture was stirred at reflux for 12 hours to give isophthalic acid dimethyl ester (5.2 g, yield: 90%, white solid).
87%
With toluene-4-sulfonic acid
85%
With sulfuric acid Reflux;
Dimethyl isophthalate (14)
A solution of isophthalic acid (10.0 g, 60.2 mmol) and 3-4 drops of conc. H2SO4 in dry methanol (100 ml) was heated under reflux overnight. The methanol was evaporated at reduced pressure and the residue was neutralised with saturated NaHCO3 solution. The resulting solid was filtered off, washed with water and air-dried to get the dimethyl ester of isophthalic acid. Yield (10.0 g, 85%), m.p. 64 °C (lit.26 m.p. 67-68 °C). 1H NMR (300 MHz, CDCl3): d 8.66 (s, 1H, ArH), 8.20 (d, J = 7.4 Hz, 2H, ArH), 7.50 (t, J = 7.7 Hz, 1H, ArH), 3.92 (s, 6H, 2xCH3O). 13C NMR (75 MHz, CDCl3): d 166.22, 133.77, 130.68, 130.56, 128.59, 52.33.
80%
With hydrogenchloride for 2h; Reflux;
1 Synthesis of dimethyl isophthalate
Isophthalic acid (5.89g, 0.035 mol) was added to a 100 mL one-neck round-bottom flask, then 40 mL methanolic HCl 1M was poured into this flask. The reaction was reflux for 2h. Once finishing reaction, 100 mL hexane was added to the flask. Two layers were divided by separating funnel. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford desired product as a white powder with the yield of 80%. Dimethyl isophthalate: 1H NMR (500 MHz, Chloroform-d) δ = 8.68 (s, 1H), 8.25 (s, 1H), 8.23 (dd, J=8.0, 1.7, 2H), 7.59 - 7.50 (m, 1H), 3.95 (s, 8H); 13C NMR (126 MHz, Chloroform-d) δ = 166.38, 133.92, 130.83, 130.69, 128.75, 52.49.
78%
With Oxone In toluene at 60℃; for 48h; Green chemistry;
59%
With sulfuric acid Reflux;
With sulfuric acid
With hydrogenchloride
With sulfuric acid
With sulfuric acid for 12h; Reflux;
With sulfuric acid at 100℃; for 24h;
With thionyl chloride at 0 - 20℃;
2
SOCI2 (113.3 g, 0.96 mol) was added to 700 mt_ of dry methanol slowly at O0C. After stirring for 1 hour at room temperature, compound B1 (80 g, 0.48 mol) was added and stirred for 1.5 h. The mixture was concentrated and aqueous NaHCO3 solution was added for quench. The suspension was extracted with DCM twice. The combined organic layers was dried over Na2SO4, filtered and concentrated to give 85 g of compound B2 which was used into the next reaction without further purification.
With thionyl chloride at 20℃; for 1.5h;
B2
Synthesis of Compound B2: [Show Image] SOCl2 (113.3 g, 0.96 mol) was added to 700 mL of dry methanol slowly at 0°C. After stirring for 1 hour at room temperature, compound B1 (80 g, 0.48 mol) was added and stirred for 1.5 h. The mixture was concentrated and aqueous NaHCO3 solution was added for quench. The suspension was extracted with DCM twice. The combined organic layers was dried over Na2SO4, filtered and concentrated to give 85 g of compound B2 which was used into the next reaction without further purification.
With thionyl chloride at 20℃; for 20h; Cooling with ice;
Reflux; Acidic conditions;
With sulfuric acid for 24h; Reflux;
1.1
In a round bottom flask was added the formula indicated substituted phthalic 0.10 mol, was dissolved in 150mL of methanol and 15mL of concentrated sulfuric acid added, refluxed for 24 hours.Poured into 500mL of water, separated, washed with water, and dried to give a substituted dimethyl terephthalate.
With chloro-trimethyl-silane at 20℃; for 3h;
With sulfuric acid Reflux;
Synthesis of Dimethyl isophthalate (I)
Isophthalic acid (1.66 gm, 0.1 mmol) was added in super dry methanol (60 mL) containing 2-3 drops of concentrated H2SO4 and was reuxed till it dissolved. Then, the reaction mixture was poured onto ice cold water, immediately a solid started separated out from the clear solution. This solution was washed with sodium bicarbonate till the eervescence seized. The ester thus obtained was filtered and washed with water for several times (M.P: 64 C) [1].
With potassium hydroxide In methanol at 20℃; for 15h;
98%
With sodium hydroxide In methanol; acetone at 20℃; for 24h;
98%
Stage #1: dimethyl Isophthalate With methanol; sodium hydroxide In acetone at 20℃; for 25h; Inert atmosphere;
Stage #2: With hydrogenchloride; water
95%
With sodium hydroxide In methanol at 20℃; for 16h;
94%
hydrolysis with pig liver esterase;
90%
With sodium hydroxide In methanol; acetone at 25℃; for 9h; Inert atmosphere; Schlenk technique;
83%
With methanol; sodium hydroxide at 20℃;
3-(Methoxycarbonyl)benzoic acid (15)
Dimethylisophthalate 14 (9.7 g, 50 mmol) was added to a solution of NaOH (2.3 g, 60 mmol) in dry methanol (75 ml) and stirred at room temperature overnight. The solution so obtained was acidified with conc. HCl and evaporated to dryness. The solid formed was extracted with ethyl acetate (300 ml) and washed with water several times. The clear solution of ethyl acetate was dried over MgSO4 and evaporated to give the half-ester product. Yield (7.44 g, 83%), m.p. 188 °C (lit.27 m.p. 189 °C). 1H NMR (300 MHz, CDCl3): d 8.74 (s, 1H, ArH) 8.27 (d, J = 7.1 Hz, 2H, ArH), 7.55 (t, J = 7.1 Hz, 1H, ArH), 3.94 (s, 3H, CH3O).
79%
With potassium hydroxide In methanol at 0 - 25℃; for 72h;
73%
Stage #1: dimethyl Isophthalate With methanol; sodium hydroxide In acetone at 20℃; for 18h;
Stage #2: With hydrogenchloride; water
9
Example 9; 3-[N'-(2-Nitro-benzoyl)-hydrazinocarbonyl]-benzoic acid methyl ester (26); Isophthalic acid monomethyl ester (24). A solution of dimethyl isophthalate (25 g, 128.75 mmol) was dissolved in acetone (250 mL) and a solution of NaOH (5.4 g, 135 mmol) in methanol (50 mL) was added dropwise. A white precipitated was observed and the slurry was stirred for 18 h at room temperature. Then powdered NaOH (0.5 g) was added. The acetone was evaporated until dryness and the white residue was dissolved in water (250 mL), extracted with diethylether (2×100 mL). The aqueous solution was acidified with concentrated HCl to pH 45 and the white precipitate was filtered, dried under vacuum and the desired monoacid obtained (17 g, 94.36 mmol, 73% yield) as a white solid.
61%
With sodium hydroxide In methanol
55%
With sodium hydroxide In 1,4-dioxane; water at 20℃; Cooling with ice;
With sodium hydroxide
With methanol; barium dihydroxide for 15h;
With hydrogenchloride
With sodium hydroxide In methanol at 20℃;
With potassium hydroxide In methanol at 20℃;
With lithium hydroxide; water In tetrahydrofuran; methanol
32 EXAMPLE 32
This example describes the synthesis of compounds of the formula wherein RR and RS are each independently substituted or unsubstituted aliphatic or aromatic moiety, or RR and RS together form a substituted or unsubstituted cycloaliphatic or aromatic moiety. These compounds are prepared according to Scheme 15 and the procedure below. Esterfication of di-acid 15.2 with TMSCH2N2 gives the corresponding di-methyl ester 15.3. Basic hydrolysis (LiOH, 1 eq) of compound 15.3 yields mono-acid 15.4 which is then coupled with RRNHRS to yield compound 15.5. The basic hydrolysis (LiOH, H2O/THF/MeOH) of 15.5 gives acid 15.1. Compound 15.1, an acid of the formula RCCOOH, are used to make additional compounds of the invention. Table 11 shows exemplary compounds 15.1's.
Stage #1: dimethyl Isophthalate With sodium hydroxide In methanol at 20℃;
Stage #2: With water
2
To a solution of compound B2 (60 g, 0.31 mol) in 500 mL of MeOH was added a solution of NaOH (12.4 g, 0.31 mol) in 200 mL of MeOH. The mixture was stirred overnight at room temperature. It was concentrated and the residue was dissolved in 500 mL of water and extracted with Et2O. The aqueous solution was acidified with cone. HCI solution to pH = 2, the formed white precipitate was collected and dried under vacuum to give 46 g of crude compound B3 as a white solid.
Stage #1: dimethyl Isophthalate With sodium hydroxide In methanol at 20℃;
Stage #2: With hydrogenchloride In water
B3
Synthesis of Compound B3: [Show Image] To a solution of compound B2 (60 g, 0.31 mol) in 500 mL of MeOH was added a solution of NaOH (12.4 g, 0.31 mol) in 200 mL of MeOH. The mixture was stirred overnight at room temperature. It was concentrated and the residue was dissolved in 500 mL of water and extracted with Et2O. The aqueous solution was acidified with conc. HCl solution to pH = 2, the formed white precipitate was collected and dried under vacuum to give 46 g of crude compound B3 as a white solid.
18.25 g
Stage #1: dimethyl Isophthalate With sodium hydroxide In methanol; acetone at 20℃; Inert atmosphere;
Stage #2: With hydrogenchloride In water at 20℃; Inert atmosphere;
Methyl 3-hydroxymethylbenzoate (2d)
In a 3-necked 500 mL round-bottomed flask equipped with a mechanical stirrer was placed dimethyl isophthalate (20.00 g, 0.103 mol, 1 eq.) dissolved in acetone (200 mL). To this mixture was added dropwise over 20 min a sln of NaOH (4.33 g, 0.108 mol, 1.05 eq.) in MeOH (40 mL). The resulting milky suspension was stirred at r.t. overnight. Then, another portion of NaOH (0.433 g, 0.011 mol, 0.1 eq.) was added into the reaction and the suspension was stirred for another 5 hours. The solvent was removed under vacuum and the white precipitate thus obtained was dissolved in water (400 mL). Concentrated HCl (15 mL) was added dropwise until pH~1. Then, the suspension was filtered; the collected precipitate was washed with water (4×100 mL) and dried under vacuum at 65°C for 24 hours to give white solid 18.25 g. The obtained monomethyl isophthalate was used directly without further purification. In a 3 necked 500 mL round-bottomed flask equipped with a magnetic stirrer and a low temperature thermometer under a nitrogen atmosphere was placed monomethyl isophthalate (5.00 g, 0.027 mol, 1 eq.) dissolved in dry THF (125 mL). Then, this solution was placed in an ice-water bath and a solution of BH3•SMe2 (2M in THF, 70 mL, 0.14 mol, 5 eq.) was added dropwise slowly over 90 min to maintain the temperature in the solution below 7°C. After another 15 min, the cooling bath was removed and the solution was allowed to reach ambient temperature. After 5 hours, the reaction was carefully quenched (strong gas evolution) with small pieces of ice while cooling in an ice-water bath. When the gas evolution ceased, brine (50 mL) was added and the resulting mixture was extracted with diethyl ether (3×100 mL). The combined organic extracts were washed with diluted bleach (50 mL, original solution 9.6% bleach diluted 10 times), brine (50 mL) and dried (MgSO4). The solvent was removed under vacuum to give an oil which contained a small amount of white precipitate. Diethyl ether (20 mL) was added and the solid was removed by filtration and washed with Et2O (2×10 mL). The filtrate was concentrated to yield a pale yellow oil (4.48 g). The crude oil was then purified by silica gel column chromatography (PE:EA, 4:1 to 7:3) to afford methyl 3-hydroxymethylbenzoate (2d) as colorless oil (3.77 g, 82%). Rf = 0.17 (EtOAc:PE = 1:4); 1H NMR (300 MHz, CDCl3), δ (ppm): 8.00 (s, 1H, HAr), 7.93 (dt, J = 7.7, 1.4 Hz, 1H, HAr), 7.61 - 7.51 (m, 1H, HAr), 7.40 (t, J = 7.7 Hz, 1H, HAr), 4.71 (s, 2H, OCH2), 3.89 (s, 3H, OMe).
With water; sodium hydroxide In methanol at 20℃; for 16h; Inert atmosphere;
General procedure A for hydrolysis of diesters No.13a-f.
General procedure: An aqueous 1 M NaOH solution (1.0 eq)was added to a solution of diester No.12a-b (1.0 eq) in MeOH (1 mL/0.1 mmol of the diester). Afterstirring at room temperature for 16 h, the solution was acidified with aqueous 5% KHSO4 solution topH 3, diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). Combined organic extractswere washed with brine (20 mL), dried over anhydrous Na2SO4 and evaporated under reducedpressure to afford monoester.
With C24H38Cl2N3PRu; hydrogen; sodium methylate; In tetrahydrofuran; at 25℃; under 37503.8 Torr; for 16h;
General procedure: Hydrogenation of Other Ester Compounds Catalyzed by Synthetic Preparation of Bipyridine Tetradshed Ruthenium Complex 5 The results are shown in Table 2:Table 2 Hydrogenation of other ester compounds a; A Reaction conditions: S / C = 1000,3.0 mmol Substrate, 3.0 mumol 5, 3.0 mL lPrOH, 0.3 mmol NaOMe, 5 MPa H2, 25 C. F Tetrahydrofuran as solvent.
95%
Under Ar atmosphere, to dimethyl isophthalate (2.00 g, 10.30 mmol) were added dry THF (51.5 mL, 0.2M solution) and lithium borohydride (1.12 g, 51.5 mmol, 5 eq.), and stirred for 23 hours. Then, in an ice bath, to the mixture was added a few drops of acetic acid to neutralize the mixture, thereby quenching the reaction. The mixture was stirred for a while. Formed crystals were dissolved by adding MeOH. Although there was one spot of product as checked by TLC (Hex:EtOAc=1:1) during the reaction, after the reaction quenched, there were two spots of products on TLC. The solvent was distilled off under reduced pressure. Products were separated by silica gel column chromatography (only EtOAc) to give a compound (11) (1.36 g, 9.82 mmol, 95%). 1H NMR(400MHz,CDCl3)delta[ppm]: 7.39-7.26 (4H, m, aromatic protons), 4.71 (4H, s, -CH2-O-), 1.70(2H, d, J = 76.8 Hz, OH) 13C NMR(100MHz,CDCl3)delta[ppm]: 139.28, 129.62, 128.47, 63.90 Mass(EI)m/z:138(M+), 120 107, 79, 65, 51. HRMS(EI)Calcd for C8H10O2138.06808 Found 138.06765. Anal. Calcd for C8H10O2:C, 69.54; H, 7.30. Found:C, 69.45; H, 7.23.
With hydroxylamine hydrochloride; sodium hydroxide In methanol; water at 0 - 20℃; Inert atmosphere;
2 Example 2: Synthesis of m-phenylenediamine
Under the protection of nitrogen, add 19.4 g of methyl isophthalate, 100 ml of methanol and 50 ml of water into a 250 ml three-necked flask, add 13.9 g of hydroxylamine hydrochloride at room temperature, and then add dropwise under ice bath16.0 g of sodium hydroxide was dissolved in a solution of 50 ml of water. After the addition, the temperature was gradually raised from 0°C to room temperature and the reaction was stirred overnight. Subsequently, 100 ml of 2N hydrochloric acid was added to the reaction system to precipitate a white solid, which was washed with saturated brine, dried and concentrated to obtain 18.5 g of the target product, isophthaloyl hydroxamic acid, with a yield of 95%.
83%
With hydroxylamine hydrochloride; sodium hydroxide In methanol at 20℃;
69%
With hydroxylamine hydrochloride; sodium hydroxide In methanol at 0 - 20℃;
51%
With sodium hydroxide; hydroxylamine hydrochloride In methanol; water at 40℃;
With sodium methylate In N,N-dimethyl-formamide at -10 - 35℃; for 12h; Inert atmosphere;
1 Synthesis of bis β-diketone derivative A-001
Under nitrogen atmosphere, in 53 ml of N, N-dimethylformamide, 21.7 g of acetophenoneAnd 17.5 g of dimethyl isophthalate were dissolved and cooled to -10 ° C.12.2 g of sodium methoxide was gradually added over 2 hours, and after completion of the addition,The internal temperature was set to 20 ° C. and stirred for 2 hours.Further, the internal temperature was raised to 35 ° C. and the reaction was carried out for 8 hours. After confirming the end point of the reaction by HPLC,With the internal temperature set at 10 ° C or less,An acetic acid aqueous solution in which 16.2 g of glacial acetic acid was dissolved in 49 ml of water was gradually added to the reaction solution.After confirming that the pH is 7 or more,53 ml of toluene was charged into the reaction solution, and the internal temperature was raised to 60 ° C. After raising the temperature, stirring was stopped and the mixture was allowed to stand for 30 minutes, and the separated aqueous layer was discharged.After adding 26 ml of acetone to the reaction solution and suspending it for 1 hour at an internal temperature of 60 ° C.,After cooling to 35 ° C., the precipitated solid was filtered. Furthermore,Washed with 20 ml of acetone and 120 ml of warm water and dried,21.0 g of bis β-diketone derivative A-001 was obtained (yield 65.0%, HPLC simple area ratio 98.5%)
63.5%
With sodium amide In N,N-dimethyl-formamide at 0℃; for 15h; Inert atmosphere;
17 (Synthesis of Exemplified Compound A-001)
Exemplified compound A-001 was synthesized according to the following scheme. Under a nitrogen atmosphere, in 100 ml of N, N-dimethylformamide, 19.0 g of acetophenone and 12.0 g of dimethyl isophthalate were dissolved and cooled to -10 ° C. 8.0 g of NaNH 2 was gradually added over 3 hours. After completion of the addition, the mixture was stirred at -10 ° C. for 15 hours. After confirming the end point of the reaction by HPLC, dilute sulfuric acid in which 11 g of concentrated sulfuric acid was dissolved in 70 ml of water was gradually added to the reaction solution. The precipitated solid was filtered, washed with 150 ml of warm water, and washed with 50 ml of ethyl acetate. The crystals collected by filtration were washed with 30 ml of ethyl acetate, suspended for 4 hours at room temperature with 30 ml of water, filtered, washed with ethyl acetate and dried to obtain 14.3 g of exemplified compound A-001 (yield 62.5%, HPLC simple area ratio 98.5%).
With sodium hydride
With sodium hydride In tetrahydrofuran at 0 - 20℃; for 4h;
Experimental procedure for the synthesis of 3: To a solution of 2 (0.051 mol, 10 g) dissolved in ethanol (100 mL), hydrazine hydrate (0.077 mol, 3.85 g) was added. The reaction mixture was refluxed for 8-10 hrs for completion of the reaction (monitored by TLC). The solvent was removed under reduced pressure and cooled by adding ice cold water. The resulting precipitate was filtered, washed with cold water and recrystallized from ethanol to get the desired compounds 3 (Yield = 8.56 g, 86%).
With hydrazine hydrate; In methanol; at 20℃; for 29h;Reflux;
In a round bottom flask was added dimethyl terephthalate, 0.07mol substituted and 150 mL of methanol, add 100mL of hydrazine hydrate, refluxed for 24 hours, cooled to room temperature for 5 hours and filtered, washed with water, and dried to give phthalimido-substituted hydrazide.
Stage #1: 2-propynyl 2,3:4,6-di-O-isopropylidene-α-D-mannopyranoside With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 1h;
Stage #2: dimethyl Isophthalate In tetrahydrofuran; hexane at 20℃; for 24h;
polymer, η 0.62 dl/g at 25 deg C in 1 percent (w/w) dichloroacetic acid solution; monomer(s): dimethyl 1,1-biphenyl-4,4-dicarboxylate; diethylene glycol; dimethyl isophthalate[ No CAS ]
polymer, η 0.65 dl/g at 25 deg C in 1 percent (w/w) dichloroacetic acid solution; monomer(s): dimethyl 1,1-biphenyl-4,4-dicarboxylate; diethylene glycol; dimethyl isophthalate[ No CAS ]
polymer, η 0.66 dl/g at 25 deg C in 1 percent (w/w) dichloroacetic acid solution; monomer(s): dimethyl 1,1-biphenyl-4,4-dicarboxylate; diethylene glycol; dimethyl isophthalate[ No CAS ]
polymer, η 0.68 dl/g at 25 deg C in 1 percent (w/w) dichloroacetic acid solution; monomer(s): dimethyl 1,1-biphenyl-4,4-dicarboxylate; diethylene glycol; dimethyl isophthalate[ No CAS ]
polymer, η 0.69 dl/g at 25 deg C in 1 percent (w/w) dichloroacetic acid solution; monomer(s): dimethyl 1,1-biphenyl-4,4-dicarboxylate; diethylene glycol; dimethyl isophthalate[ No CAS ]
With sulfuric acid; sulfur trioxide; bromine; at 120℃; for 7h;
Into a 100 ml pressure and sealable glass tube, 9.70 g (50 mmol) of dimethyl isophthalate, 30.00 g of 10 wt percent fuming sulfuric acid and 10.40 g (100 mmol) of bromine were charged, and the content was stirred at 120° C. for 7 hours. After the conclusion of the reaction, the content was cooled to room temperature, and placed in a beaker containing ice water to give a solid. The resulting solid was filtered off, washed with cooling, and further dried under reduced pressure to give 11.95 g of a crude crystal of the aimed product (reaction yield: 50.4percent 5-bromoisophthalic acid, 19.6percent isophthalic acid, 4.9percent 2,5-dibromoisophthalic acid, 7.2percent 4,5-dibromoisophthalic acid, 7.0percent dimethyl 5-bromoisophthalate, 1.5percent dimethyl isophthalate, 0.9percent dimethyl 2,5-dibromoisophthalate and 0.2percent dimethyl 4,5-dibromoisophthalate). Then, dimethyl esters were derived from the crystal by heating and stirring it with 65.50 g (2.04 mol) of methanol and 1.75 g (30 mol percent) of sulfuric acid in an autoclave at 120° C. [0038] In succession, the esters were subjected to rectification to give 6.73 g (yield: 49.3percent, vacuum boiling point: 159° C./4.8mmHg) of aimed dimethyl 5-bromoisophthalate and 1.67 g (yield: 17.2percent, vacuum boiling point: 133° C./4.8mmHg) of dimethyl isophthalate corresponding to a raw material. The resulting crystals were identified as dimethyl 5-bromoisophthalate and 5-bromoisophthalic acid by MASS, 1H-NMR and melting point.
With sodium hydride In 1,2-dimethoxyethane; toluene at 100℃; for 4h;
89 PREPARATION 89; 3- (3-OXO-BUTYRYL)-BENZOIC acid methyl ester
A solution of dimethyl isophthalate (12 g, 61.85 mmole) and acetone (5 mL, 68 mmole) in a mixture OF TOLUENE/DIMETHOYETHANE (90ML/30 mL) was added to a suspension of NaH 60% (2.97 g, 74.23 mmole) in dry toluene (30 mL) under argon. The mixture was heated at 100 °C for 4 hours. The reaction mixture was cooled to rt and 25 mL of water were added. The mixture was poured into water (250 mL) and the pH adjusted to 3-4 with HCI 2N. The aqueous mixture was extracted with ethyl acetate (2x250 mL), washed with brine, dried over sodium sulphate and evaporated to afford a yellow solid which was purified by column cromatography (N-HEX/ETOAC 9: 1 to 8: 2) to afford the title compound (1.78 g, 11 % YIELD) as a yellow solid.
44.a Example 44. 3-S-5-CYCLOHEXYL-L- (3, 3-DIMETHYL-2-OXO-BUTYL)-2-OXO-1, 2-DIHYDRO-3H- 1, 3, 4-benzotriazepin-3-ylmethyl]-[1,3,4]oxadiazol-2-yl}-benzoic acid.; [0143] Step a.
3-(N'-{2-[5-Cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1, 2- DIHYDRO-3H-1, 3, 4-BENZOTRIAZEPIN-3-YL]-ACETYL}-HYDRAZINOCARBONYL)-BENZOIC acid methyl ester was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3, 3-dimethyl-2- oxo-butyl) -2-oxo-1,2-dihydro-3H-1, 3, 4-BENZOTRIAZEPIN-3-YL]-ACETYLAMINO}-BENZOIC acid methyl ester (Example 1) except that 3-hydrazinocarbonyl-benzoic acid methyl ester (prepared in two steps from isophthalic acid dimethyl ester) was used instead of 3-amino-benzoic acid methyl ester in step e.
With BF3 etherate; sodium hydrogencarbonate In dichloromethane; benzene
S.27.a 2nd Stage:
2nd Stage: Dimethyl isophthalate (Intermediate 1) 15 g (66 mmol) of dimethyl 4-amino-1-hydroxycyclohexa-3,5-diene-1,3-dicarboxylate obtained in the preceding stage and 600 ml of benzene are introduced into a 1-liter three-necked flask fitted with a reflux condenser, placed under an inert atmosphere and protected from moisture. 13.8 g (12 ml, 98 mmol) of BF3 etherate are added with stirring. The mixture is refluxed for 2 minutes and then cooled to room temperature and, after addition of saturated NaHCO3 solution (pH 9), the phases are separated by settling. The aqueous phase is re-extracted twice with dichloromethane. The organic phases are combined and dried over Na2SO4. After removal of the solvents under vacuum, the 13.8 g of residue are purified by chromatography using dichloromethane as elution solvent. The product is obtained as follows: Weight=8.5 g of a crystallyne residue, yield=62%, TLC: CH2Cl2. Rf=0.30, m.p.=130.1° C., NMR: CDCl3 1H δ (ppm) 3.87 (s,3H); 3.88 (s,3H); 6.30 (brs,2H); 6.65 (d,1H); 7.89 (dd,1H); 8.57 (d,1H).
1,3-bis(4,4-dimethyl-3-oxopentanoyl)-benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With sodium amide In diethyl ether at 0 - 20℃; for 4h;
61%
With hydrogenchloride In tetrahydrofuran; hexane
4 Synthesis of 1,3-bis(4,4-dimethyl-3-oxopentanoyl)-benzene
Example 4 Synthesis of 1,3-bis(4,4-dimethyl-3-oxopentanoyl)-benzene In a 100 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 1.5 gm (38 mmol) of 60% sodium hydride, 3.6 gm (36 mmol) of pinacolone, 3.0 gm (15.5 mmol) of dimethyl isophthalate, and 30 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream and refluxed with heating for 6 hours. After cooling the reaction mixture, 10 ml of 2N aqueous hydrochloric acid was added the product was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated to give a crude product. Recrystallization using hexane afforded 3.1 gm of the target compound as colorless crystals (yield: 61%). Melting Point: 106.0°-107.5° C. IR(νKBr, cm-1): 3124, 2974, 2872, 1611, 1563, 1482, 1431, 1290, 1227, 1134, 1095, 879, 804, 705. 1 H-NMR(CDCl3, δ): 1.27(18H, br.s), 6.34(2H, s), 7.55(1H, br.t, J=7.8Hz), 8.00 and 8.04(2H, dd, J=7.8Hz, J=1.5Hz), 8.38(1H, br.s). Elemental analysis Calculated (%) C: 72.70, H: 7.93 Found (%) C: 72.58, H: 7.95.
61%
With hydrogenchloride In tetrahydrofuran; hexane
4 Synthesis of 1,3-bis(4,4-dimethyl-3-oxopentanoyl)benzene
Example 4 Synthesis of 1,3-bis(4,4-dimethyl-3-oxopentanoyl)benzene In a 100 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 1.5 gm (38 mmol) of 60% sodium hydride, 3.6 gm (36 mmol) of pinacolone, 3.0 gm (15.5 mmol) of dimethyl isophthalate, and 30 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream and refluxed with heating for 6 hours. After cooling the reaction mixture, 10 ml of 2N aqueous hydrochloric acid was added the product was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated to give a crude product. Recrystallization using hexane afforded 3.1 gm of the target compound as colorless crystals (yield: 61%). Melting Point: 106.0°-107.5° C. IR(γKBr, cm-1): 3124, 2974, 2872, 1611, 1563, 1482, 1431, 1290, 1227, 1134, 1095, 879, 804, 705. 1 H-NMR(CDCl3, δ): 1.27(18 H, br.s), 6.34(2 H, s), 7.55(1 H, br.t, J=7.8 Hz), 8.00 and 8.04(2 H, dd, J=7.8 Hz, J=1.5 Hz), 8.38(1 H, br.s). Elemental analysis: Calculated (%) C: 72.70, H: 7.93; Found (%) C: 72.58, H: 7.95.
N,N'-bis(4,4-dimethoxybutyl)isophthalamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
In methanol; 5,5-dimethyl-1,3-cyclohexadiene
1 Preparation of N,N'-Bis(4,4-dimethoxybutyl)isophthalamide Using Dibutyl Tin Dimethoxide as Catalyst.
EXAMPLE 1 Preparation of N,N'-Bis(4,4-dimethoxybutyl)isophthalamide Using Dibutyl Tin Dimethoxide as Catalyst. A 250.00 g (1.29 mol) portion of dimethyl isophthalate was dissolved in 2000 g of mixed xylenes contained in a 5 L, three-necked, round-bottomed flask fitted with a Dean-Stark trap, a thermometer, an addition funnel, and a mechanical stirrer. With rapid stirring, 25.00 g (0.0847 mol) of dibutyl tin dimethoxide was added followed by raising the temperature of the solution to 130° C. 4,4-Dimethoxybutylamine (372.9 g, 2.80 mol) was then added dropwise to xylene solution through the course of 30 min. The reaction temperature was maintained at 130° C. for 5 hr while collecting ca. 190 g of a methanol/xylenes (ca. 1:1) distillate. (After gas chomatographic analysis of the distillate, it was determined that greater than 90% of the theoretical amount of methanol had been isolated.) The Dean-Stark trap was removed and a Claisen distillation head was fitted to the flask. Approximately 750 g of mixed xylenes were removed via atmospheric distillation, then the remaining solution was filtered while hot. Upon cooling, a white precipitate formed which was collected and recrystallized twice from mixed xylenes. After vacuum oven drying (55°-60° C./1.0 mm Hg) the product overnight, an isolated yield of 425 g (1.07 mol, 83.0% yield) was realized; mp 74.5°-75.5° C.; IR (KBr) 1630 (C=O), 1595, 1560, 1130, 1045, 915, 705 cm-1; 1 H NMR (CDCl3; 300 MHz) δ1.50-1.60 (m, 8H, --CH2 CH2 CH--), 3.22 (s, 12H, --OCH3), 3.31 (m, 4H, NH2 CH2 --), 4.26 (t, 2H J=4.8 Hz, CH2 CH--) 7.12 (t, 2H, J=5.6 Hz, --NH--CH2 --), 7.33 (t, 1H, J=7.7 Hz, ArH), 7.80 (d, 2H, J=7.7 Hz, ArH) 8.09 (s, 1H, ArH); 13 C NMR (CDCl3; 75.5 MHz) δ23.9, 29.6, 39.4, 52.5, 103.8, 125.0, 128.1, 129.5, 134.4, 166.7; MS (70 eV) m/z (rel. intensity) 100 (84.56), 104 (100.00), 163 (78.68), 232 (44.67), 274 (26.47), 333 (17.10); HRMS (FAB) 419.2158 (M+ Na).
N,N'-bis(2,2-dimethoxyethyl)isophthalamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
11 Preparation of N,N'-Bis(2,2-dimethoxyethyl)isophthalamide.
EXAMPLE 11 Preparation of N,N'-Bis(2,2-dimethoxyethyl)isophthalamide. Dimethyl isophthalate (42.72 g, 0.220 mol) was aminated with 50.00 g (0.476 mol) of 2,2-dimethoxyethylamine and 10.00 g (0.0339 mol) of dibutyl tin dimethoxide in 250 g of mixed xylenes according to the procedure used in Example 1. After a 6 hr reaction time at 135° C., the procedure afforded 70.41 g (0.207 mol, 94.0 % isolated yield) of N,N'-bis(2,2-dimethoxyethyl)isophthalamide after recrystallization from mixed xylenes, mp 76.5°-78° C.; IR (KBr) 1670 (C=O), 1640 (C=O), 1550, 1525, 1295, 1280, 1130, 1115, 1065 cm-1; MS (70 eV) m/z (rel. intensity)340 (M+) (0.07), 280 (1.06), 277 (1.03), 204 (2.24), 177 (1.22), 163 (1.06), 104 (5.87) 76 (8.12), 75 (100.00); HRMS (FAB) 341.1713 (MH+).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; methanol at 20℃; for 2h;
139.1
Methyl isophthalate (2.00 g, 11.1 mmol) was dissolved in THF (60 mL), and a 2.0 mol/L solution of dimethylamine (11.1 ml, 22.2 mmol) in methanol, EDC hydrochloride (4.27 g, 22.2 mmol) and 1-hydroxybenzotriazole monohydrate (3.40 g, 22.2 mmol) were added thereto, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate = 1:3) to afford methyl 3-(N,N-dimethylcarbamoyl)benzoate (2.30 g, 100 %).
11 EXAMPLE 11
EXAMPLE 11 Following the general procedure of Example 9, a slurry of 7.46 parts isophthalic acid in 80 parts dry dichloromethane was added to a mixture of 7.91 parts pyridine and 9.77 parts phosgene in 210 parts dry dichloromethane at 25° to 30° C. The ratio of equivalents of pyridine base/COOH acid group was 1.10. After carrying out the reaction and esterifying the resulting diacid chloride by the procedure described in Example 1 there was obtained a 100% yield of dimethyl isophthalate corresponding to a 100% yield of isophthaloyl chloride formed initially in the reaction.
With methylamine In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide
2.11 Methyl 3-[(methylamino)carbonyl]benzoate
Preparation 11 Methyl 3-[(methylamino)carbonyl]benzoate A slurry of methyl isophthalate (5.10g, 0.028mol) in CH2Cl2(100ml) at room temperature was treated with oxalyl chloride (6.0ml) followed by DMF (3 drops). The resultant mixture was stirred under reflux (90 mins). The resultant mixture was cooled to room temperature, the solvent removed by evaporation and the residue azeotroped with CH2Cl2. The resultant mixture was dissolved in THF (100ml), cooled to 0°C and treated with a solution of methylamine (2M, 28ml,56mmol) in THF. The mixture was allowed to warm to room temperature overnight, solvent removed by evaporation and resultant mixture was partitioned between ethyl acetate (200ml) and water (200ml). The organic layer separated and washed with sat aq NaHCO3, sat aq brine, and dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave the desired product (white solid, 4.60g, 79%). 1H NMR (CDCl3)δ 3.00 (d, 3H), 4.00 (s, 3H), 6.30 (s, br, 1H), 7.50 (t, 1H), 8.00 (d, 1H), 8.20 (d, 1H), 8.40 (s, 1H). LRMS m/z = 211.1 (M+18)+.
With methylamine In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide
2.11 Methyl 3-[(methylamino)carbonyl]benzoate
Preparation 11 Methyl 3-[(methylamino)carbonyl]benzoate A slurry of methyl isophthalate (5.10 g, 0.028 mol) in CH2Cl2 (100 ml) at room temperature was treated with oxalyl chloride (6.0 ml) followed by DMF (3 drops). The resultant mixture was stirred under reflux (90 mins). The resultant mixture was cooled to room temperature, the solvent removed by evaporation and the residue azeotroped with CH2Cl2. The resultant mixture was dissolved in THF (100 ml), cooled to 0° C. and treated with a solution of methylamine (2M, 28 ml,56 mmol) in THF. The mixture was allowed to warm to room temperature overnight, solvent removed by evaporation and resultant mixture was partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer separated and washed with sat aq NaHCO3, sat aq brine, and dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave the desired product (white solid, 4.60 g, 79%). 1H NMR (CDCl3) δ 3.00 (d, 3H), 4.00 (s, 3H), 6.30 (s, br, 1H), 7.50 (t, 1H), 8.00 (d, 1H), 8.20 (d, 1H), 8.40 (s, 1H). LRMS m/z=211.1 (M+18)+.
With bromine; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
Example 18 Into a 100 ml pressure and sealable glass tube, 9.70 g (50 mmol) of dimethyl isophthalate, 30.00 g of 10 wtpercent fuming sulfuric acid and 10.40 g (100 mmol) of bromine were charged, and the content was stirred at 120°C for 7 hours. After the conclusion of the reaction, the content was cooled to room temperature, and placed in a beaker containing ice water to give a solid. The resulting solid was filtered off, washed with cooling, and further dried under reduced pressure to give 11.95 g of a crude crystal of the aimed product (reaction yield: 50.4percent 5-bromoisophthalic acid, 19.6percent isophthalic acid, 4.9percent 2,5-dibromoisophthalic acid, 7.2percent 4,5-dibromoisophthalic acid, 7.0percent dimethyl 5-bromoisophthalate, 1.5percent dimethyl isophthalate, 0.9percent dimethyl 2,5-dibromoisophthalate and 0.2percent dimethyl 4,5-dibromoisophthalate).
1.1 Example 1
S1. Ethylmagnesium bromide (700 ml, 5.5 eq) was added to a three-necked flask, and a solution containing dimethyl isophthalate (50 g, 1.0 eq) in tetrahydrofuran (100 g) was added dropwise at 0 °C. After the addition is completed, the temperature is naturally raised to 25 ° C, and the system reacts for 2.5-4 h. After completion of the reaction, the reaction system was slowly poured into an aqueous solution of ammonium chloride, and the product was extracted with ethyl acetate (1000 g). The residue was recrystallized from n-heptane to give 3,3'-(1,3-phenylene)bis(3-pentanol) in a yield of 76.8%.
methyl 3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: dimethyl Isophthalate With lithium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 0.166667h;
Stage #2: 2-chloro-4-methylpyrimidine In tetrahydrofuran at 0℃; for 0.666667h;
Stage #3: With methanol In tetrahydrofuran at 0℃;
3.A
To a solution of dimethyl 1,3-benzenedicarboxylate (14.6 g, 75.2 mmol) in dry THF (75 mL) at 0° C., LiHMDS (1M in THF, 120 mL, 120 mmol) was added and the solution was allowed to stir for 10 min at 0° C. A solution of 2-chloro-4-methylpyrimidine (3.1 g, 24.1 mmol) in 10 mL of THF was then added dropwise to the reaction mixture at 0° C. over 10 min. The reaction mixture turns black. The solution was allowed to stir 30 minutes at 0° C. The reaction mixture was then quenched at 0° C. with MeOH and the solvent was removed in vacuo. The residue was diluted with EtOAc and washed with H2O. The H2O layer was extracted twice with EtOAc, dried with MgSO4 and evaporated onto silica gel. Purification by flash chromatography provided 6.1 g (87%) of the title product as a light yellow solid. MS (ESI): 291 [M+H]+.
Stage #1: isophthalic acid With sulfuric acid; sulfur trioxide; bromine at 150℃; for 7h;
Stage #2: methanol With sulfuric acid at 120℃;
17 EXAMPLE 17
Into a 50 ml pressure and sealable glass tube, 1.66 g (10 mmol) of isopthalic acid, 6.00 g of 10 wt % fuming sulfuric acid and 1.6 g (10 mmol) of bromine were charged, and the content was stirred at 150° C. for 7 hours. After the conclusion of the reaction, the content was cooled to room temperature, and placed in a beaker containing ice water to give a solid. The resulting solid was filtered off, washed with cooling, and further dried under reduced pressure to give a crude crystal of the aimed product. Then, dimethyl esters were derived from the crystal by heating and stirring it at 120° C. with 13.1 g (408 mmol) of methanol and 0.35 g (30 mol %) of sulfuric acid in an autoclave. In succession, the esters were subjected to rectification to give 1.78 g (yeild: 65.1%, vacuum boiling point: 159° C./4.8 mmHg) of aimed dimethyl 5-bromoisophthalate and 0.52 g (yield: 26.8%, vacuum boiling point: 133° C./4.8mmHg) of dimethyl isophthalate corresponding to a raw material. The resulting crystals were identified as dimethyl 5-bromoisophthalate and 5-bromoisophthalic acid by MASS, 1H-NMR and melting point.
Stage #1: dimethyl Isophthalate With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.166667h;
Stage #2: 2-chloro-4-methylpyrimidine In tetrahydrofuran for 0.666667h;
67.A
To a solution of dimethyl 1 ,3-benzenedicarboxylate (3.1 eq, 14.6 g, 75.2 mmol) in dry THF (75 mL) at 00C, LHMDS (1 M in THF, 5.0 eq, 120 mmol, 120 mL) was added and the solution was allowed to stir for 10 min at 00C. A solution of 2-chloro-4- methylpyrimidine (1.0 eq, 24.1 mmol, 3.1 g) in 10 mL of THF was then added dropwise to the reaction mixture at 0°C over 10 min. The mixture was allowed to stir 30 minutes at 00C. The reaction mixture was then quenched at 00C with MeOH and the solvent was removed in vacuo. The residue was diluted with EtOAc and washed with water. The water layer was extracted twice with EtOAc, dried with MgSO4, and evaporated onto silica gel. Purification by column chromatography (10-70% EtOAc in hexanes) provided 6.1 g of the title product of Step A as a light yellow solid (87%). MS (ESI): 291.1 [M+H]+.
Stage #1: dimethyl Isophthalate With bis(2,2,6,6-tetramethylpiperidinyl)zinc, lithium chloride, magnesium chloride complex In tetrahydrofuran at 80℃; for 2h; Microwave irradiation; Inert atmosphere;
Stage #2: 1-Chloro-4-iodobenzene With trifuran-2-yl-phosphane; bis(dibenzylideneacetone)-palladium(0) In tetrahydrofuran at 25℃; for 1h; Inert atmosphere;
With layered double hydroxide - supported L-methionine at 180℃; for 6h; Autoclave; chemoselective reaction;
With dimanganese decacarbonyl at 180℃; for 1h; Sealed tube;
General procedure for the reaction of dimethyl carbonate with carboxylic acids.
General procedure: 1-3 mmol of catalyst Mn 2 (CO) 10 , 100 mmol of the carboxylic acid, and 300-400 mmol of dimethyl carbonate were placed into a 17 mL stainless steel microreactor. The reactor was sealed, and the reaction mixture was heated at 180° for 1 h. After the reaction was complete, the reactor was cooled to room temperature and opened. The reaction mixture was filtered through a layer of Al 2 O 3 . Unreacted dimethyl carbonate was distilled off, the residue was distilled at atmospheric or reduced pressure, or crystallized.
With sodium periodate; sulfuric acid; iodine; at 36℃; for 12h;Inert atmosphere;
Iodine (18.29 g, 72 mmol) was added to a stirred solution of sodium periodate (8.8 g, 41 mmol) in 110 mL 96% sulfuric acid at 36 C under argon atmosphere. The resulting mixture was stirred for 30 minutes. To this mixture was added dimethyl isophthalate 1 (20 g, 103 mmol) and stirring was continued for 12 h. After completion of the reaction, the reaction mixture was poured into the mixture of crushed ice and dichloromethane (DCM). The organic layer was then separated and the aqueous layer repeatedly washed with dichloromethane. The collected organic layers were carefully washed with sodium bicarbonate, sodium thiosulfate and brine respectively. The combined organic layers were collected and dried over anhydrous sodium sulfate followed by evaporation to afford compound 2 as colorless crystalline material (30 g, 91 %) which was used without further purification for the next step, mp: 99-101 C; TLC (Ethyl acetate:pet ether, 5:95 v/v): Rf = 0.3; IR (CHC13) cm"1: 3023, 2955, 1727 (C=0), 1569; 1H NMR (CDC13, 400 MHz): delta 8.62 (s, 1H), 8.54 (s, 2H), 3.95 (s, 6H); 13C NMR (CDC13, 100 MHz); delta 164.76, 142.43, 132.16, 129.84, 93.40, 52.62.
With sodium hydride In tetrahydrofuran at 20℃; Cooling with ice;
84.84A
84-A. 3-[3-(4-Bromo-phenyl)-3-oxo-propionyl]-benzoic acid methyl ester.A mixture of isophthalic acid dimethyl ester (5.84 g, 30.1 mmol), 4-bromoacetophβnoϖe (5 g,25.1 mmol) In THF (70 ml) & cooled in an ice water bath. Sodium hydride d .20 g, 30.1 mrnoi) is added portionwise. The mixture is allowed to warm to ambient temperature and is stirred overnight. The pH of the mixture is then adjusted to 2-3 with the addition of saturated aqueous ammonium chloride solution and then 1 N aqueous hydrochloric acid. Solvents are removed under reduced pressure, and the residue is washed with ether and then heptane to afford product. MS (ESI) m/z = 383.8, 385.8 (M+1).
With sodium hydride In tetrahydrofuran at 0℃; Heating;
1.1.B
1-B. 3-{3-[4-(4-Methyl-piperazin-1-yl)-phenyl]-3-oxo-propionyl}-benzoic acid methyl ester.To a mixture of dimethylisophthafate (3.9 g, 20 mmoi) and sodium hydride (576 mg, 24 mmoi, 95%) in anhydrous tetrahydrofuran {40 mL) at O0C, is slowly added a solution of 1-[4- (4-methylpiperazin-1-yi)-phenyl]-ethanone 1-A (4.4g, 20 mmoi) in tetrahydrofuran (10 mL). The mixture is heated in a 50 0C oil bath and stirred for 5 hours, until LC-MS indicates that conversion is complete. The mixture is cooled to room temperature, and saturated ammonium chloride solution (20 mL) is added. The aqueous phase is extracted with dichloromethane (150 mL x 2). The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by flash column chromatography with 0 - 5% MeOH/DCM to afford product as a yellow solid.MS(ESI) m/z = 381.2 (M+1)
With sodium hydride In tetrahydrofuran Cooling with ice; Heating;
61.61B
61 -B. 3-[3-(4-Dimethoxymethyl-phenyl)-3-oxo-propionyl]-benzoic acid methyl ester.To a mixture of dimethylisophthalate (603 mg, 3.11 mmol) and sodium hydride (75 mg, 3.11 mmol, 95%) in anhydrous THF (4.5 mL) cooled in an ice water bath, is slowly added a solution of compound 61-A (500 mg, 2.59 mmol) in tetrahydrofuran (2 mL). The mixture is heated in a 500C oil bath and stirred for 5 hours. The mixture is cooled to ambient temperature and saturated aqueous ammonium chloride solution (5 mL) is added to quench the reaction. The aqueous phase is extracted with dichloromethane (2 x 50 mL) and the combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by flash column chromatography with 0 - 5% methanol in dichloromethane to afford product as a pale yellow solid. MS(ESI) m/z - 357.21 (M+1).
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; 1-(4,4'-di-tert-butyl-[2,2'-bipyridin]-6-yl)-2-(dimethyl(phenyl)silyl)-2,3-dihydro-1H-benzo[d][1,3,2]diazaborole;Inert atmosphere; Schlenk technique; Sealed tube;
General procedure: B2pin2, [IrCl(COD)]2 (1.0 mol%), preligand 1 (2.0 mol%), and (hetero)arene (0.2 mmol, ifsolid) were placed in a dried Schlenk flask (15 mL in volume) equipped with a stirring bar. Afterevacuating and refilling the flask with dry nitrogen three times, (hetero)arene (0.2 mmol, if liquid)and methoxycyclopentane (CAPE, 0.5 mL) were added with syringes under a stream of nitrogen.The resulting mixture was stirred at the corresponding temperature for the assigned time. After cooling to room temperature, the reaction mixture was concentrated and then purified by columnchromatography on silica gel to give the target product (The spectra data for the borylated compoundscan be seen in the Supplementary Material).
With Oxone; indium(lll) trifluoromethanesulfonate for 1.5h; Reflux;
t.2, entry 6
General procedure: The starting aldehydematerials (1 mmol) were dissolved in MeOH (5 mL),and Oxone (1 mmol) and 10 mol % of In(OTf)3 were added atroom temperature. The reaction mixture was heated at reflux,and was monitored for completion by TLC. After the reactionmixture was filtered, the filtrate was condensed using arotary evaporator. Flash column chromatography on silica gelfurnished the corresponding products, which were confirmedby spectroscopy.
90%
With Oxone at 60℃; for 0.666667h; Sonication;
2.1 Typical procedure for the oxidative esterification of aldehydes
General procedure: To a solution of aldehyde (1mmol) in 4mL of methanol was added Oxone (1mmol) and GO (0.2g). The resulting mixture was sonicated with an Elmasonic P ultrasonic cleaning unit (ultrasonic bath) with a frequency of 37kHz and 100% output power at 60°C for the time indicated in Table 3. The mixture was filtered through a sintered funnel and extracted with ethyl acetate (EtOAc). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. Purification was achieved by column chromatography using n-hexane/EtOAc: 100/3 as eluent. The spectroscopic data of the obtained acids were compared with authentic samples [5,15,40,41].
100 %Chromat.
Stage #1: methanol; Isophthalaldehyde With pyridine at 20℃; for 0.0833333h;
Stage #2: With N-Bromosuccinimide at 20℃; for 9h;
(2Z,2'Z)-1,1'-(1,3-phenylene)bis(3-(4-(decyloxy)phenyl)-3-hydroxyprop-2-en-1-one)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
Stage #1: 4-decyloxyacetophenone With sodium hydride In tetrahydrofuran Reflux; Inert atmosphere;
Stage #2: dimethyl Isophthalate In tetrahydrofuran for 24h; Reflux;
4.3.2. (2Z,2'Z)-1,1'-(1,3-Phenylene)bis(3-(4-(decyloxy)phenyl)-3-hydroxyprop-2-en-1-one) 2b (n=10)
General procedure: The solution of 4-dodecyloxyacetophenone (3.00 g, 9.02 mmol) and NaH (0.648 g, 0.027 mol) dissolved in 30 mL of dry THF or DME was stirred for 20 min under nitrogen atmosphere. The solution was gently heated to refluxing temperature, and stirred for 30 min. The solution was turned deep red. The solution of dimethyl isophthalate (0.875 g, 4.51 mmol) dissolved in 15 mL of THF was dropwise added, and the solution was then refluxed for 24 h. The solution was cooled and quenched carefully with distilled water. The dilute aqueous HCl (1.0 M) was added to raise the pH of the solution to acidic side. The solution was extracted twice with 50 mL of CH2Cl2/H2O (1/1). The organic layers were collected and dried over MgSO4. The products isolated as pale yellow solid were obtained by recrystallization from acetone/THF or CH3OH/THF. Yield 58-71%.
(2Z,2'Z)-1,1'-(1,3-phenylene)bis(3-(4-(dodecyloxy)phenyl)-3-hydroxyprop-2-en-1-one)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
Stage #1: 1-(4-dodecyloxy-phenyl)-ethanone With sodium hydride In tetrahydrofuran Reflux; Inert atmosphere;
Stage #2: dimethyl Isophthalate In tetrahydrofuran for 24h; Reflux;
4.3.1. (2Z,2'Z)-1,1'-(1,3-Phenylene)bis(3-(4-(dodecyloxy)phenyl)-3-hydroxyprop-2-en-1-one) 2b (n=12)
The solution of 4-dodecyloxyacetophenone (3.00 g, 9.02 mmol) and NaH (0.648 g, 0.027 mol) dissolved in 30 mL of dry THF or DME was stirred for 20 min under nitrogen atmosphere. The solution was gently heated to refluxing temperature, and stirred for 30 min. The solution was turned deep red. The solution of dimethyl isophthalate (0.875 g, 4.51 mmol) dissolved in 15 mL of THF was dropwise added, and the solution was then refluxed for 24 h. The solution was cooled and quenched carefully with distilled water. The dilute aqueous HCl (1.0 M) was added to raise the pH of the solution to acidic side. The solution was extracted twice with 50 mL of CH2Cl2/H2O (1/1). The organic layers were collected and dried over MgSO4. The products isolated as pale yellow solid were obtained by recrystallization from acetone/THF or CH3OH/THF. Yield 58-71%. 1H NMR (CDCl3): δ 0.86 (t, J=6.6 Hz, -CH3, 6H), 1.25-1.45 (m, -CH2, 40H), 1.77-1.82 (m, -CH2, 4H), 4.01 (t, J=6.5 Hz, -OCH2, 4H), 6.84 (s, -CH, 2H), 6.94 (d, J=9.0 Hz, Ar-H, 4H), 7.55 (t, J=7.8 Hz, Ar-H, 1H), 7.96 (d, J=8.7 Hz, Ar-H, 4H), 8.08 (d, J=6.6 Hz, Ar-H, 2H), 8.51 (s, Ar-H, 1H), 17.02 (s, -OH, 2H). 13C NMR (CDCl3): δ 13.12, 21.68, 24.99, 28.12, 28.35, 28.58, 28.64, 30.91, 67.33, 91.58, 113.51, 124.44, 126.60, 128.00, 128.45, 129.33, 135.22, 162.11, 182.07, 185.43.
(E)-methyl-3-(2-methyl-4-phenylbut-3-enoyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: (E)-(±)-1-(3-bromobut-1-enyl)benzene With magnesium In tetrahydrofuran at -5 - 10℃; for 1h; Inert atmosphere; Reflux;
Stage #2: dimethyl Isophthalate In tetrahydrofuran at -80 - 20℃;
Procedure 2
Magnesium (6.53 g, 25.75 mmol) was suspended in anhydrous THF (50 mL). The solution was cooled at -5 °C in a ice-salt bath and a solution of (E)-1-(3-bromobut-1-enyl)benzene 3 (5.43g, 25.75 mmol) in THF (30 mL) was added dropwise over 1h at such a rate that the internal reaction temperature did not exceed 0°C. Upon completion of the addition, the reaction mixture was stirred for 1h from 0 to -10 °C. The solution was cooled to - 80 °C in a liquid nitrogen-acetone freezing mixture. A solution of dimethylisophthalate (5 g, 25.75 mmol) in THF (40 mL) was added dropwise during 1h with vigorous stirring. Then the mixture was stirred at room temperature overnight. A 10% aqueous solution of H2SO4 (100mL) was added to the cooled reactionmixture. Two phases separated and the aqueous layer was extracted with ether (2x50 mL). The combined ethereal extracts were successively washed with a saturated aqueousNaHCO3 solution, water and finally dried over anhydrous magnesium sulfate. After removal of solvent, the resulting residue was purified on a silicagel column eluted with hexane/ethyl acetate 20:1 to give the corresponding aryl ketone(77%). []D20 = - 5.2° (c 0.1 AcOEt) with spectral data identical to those of product from procedure 1.
With sodium methylate; In methanol; at 60 - 110℃; for 1.5h;Inert atmosphere; Large scale;
In a horizontal forced mixer that works at a Froudenumber of 2.16 and has been equipped with plowshares, adistillation colunm and a protective gas connection, 2.5 molof dimethyl isophthalate (m.p. 64-66° C.) and 5 mol of4-amino-2,2,6,6-tetramethylpiperidine (in liquid form atroom temperature) are homogenized with one another at atemperature of 60° C. under nitrogen until a monophasicliquid mixture forms. After the addition of 59.4 g of asodium methoxide solution (25percent by weight in methanol),the reaction mixture is mixed at 110° C. for a duration of 90minutes. The alcohol from the catalyst formulation and thealcohol formed during the reaction are removed by distillation from the forced mixer. After the solid had been discharged and dried to constant weight, 1088.4 g (mass yield:9 8.5percent) of a white powder were isolated.
97.0%
In octane; at 150 - 160℃; under 6750.68 - 8250.83 Torr; for 15.0h;Autoclave; Inert atmosphere;
31.1 g (0.16 mol) of dimethyl isophthalate and 53.2 g (0.34 mol) of tetramethylpiperidinamine were weighed.The mixture was placed in a 1 L autoclave, and 540 ml of the recovered solvent n-octane of Example 4 was added, and the mixture was purged with nitrogen to close the feed port.Then, the temperature is stirred and the pressure is gradually increased as the temperature rises. The reaction is kept at 150-160 ° C, the absolute pressure is 0.9-1.1 MPa, and the heat preservation reaction is 15 h.Then, the mixture was cooled to room temperature, washed with n-octane, and then rinsed with water to give the objective product (III).The drying weight was 68.7 g, the yield was 97.0percent according to dimethyl isophthalate, and the GC detection content was 100percent.
96.7%
With solid supported catalyst C1; In acetonitrile; at 20 - 70℃; for 15.0h;
To a suitable amount of organic solvent (a mixture of acetonitrile and polyethylene glycol 200 (PEG-200) in a volume ratio of 3:1), 100 mmol of the compound of the above formula (I) is added at room temperature.65 mmol of compound of formula (II) above, solid supported catalyst C1 (the amount of C1 is:The molar ratio of the compound of formula (I) to the nickel ion in C1 is 1:0.11), and then it is heated to 70°C under stirring.And continue stirring at this temperature for 15 hours; After work-up, work-up gives the compound of formula (III) as a white solid.That is, N,N'-bis(2,2,6,6-tetramethyl-4-piperidinyl)-1,3-benzenedicarboxamide,The yield is 96.7percent.
93.5%
at 190 - 230℃; for 7.0h;Large scale;
6.0 kg of dimethyl isophthalate, 21.0 kg of 2,2,6,6-tetramethyl-4-aminopiperidine was added to a 50 liter reactorIn the reactor all the materials off the entrance. The reaction was carried out at 190 ° C for 2 hours and then at 230 ° C for 5 hours. The temperature was lowered to below 180 ° C, and excess 2,2,6,6-tetramethyl-4-aminopiperidine was recovered by vacuum distillation under a vacuum pump. Then use water to generateN, N'-bis (2,2,6,6-tetramethyl-4-piperidinyl) -1,3-benzenedicarboxamide, filtered and dried to give 12.8 kg of acicular white crystalline product , Yield 93.5percent.
1-[4-(1,2,2-triphenylethenyl)phenyl]ethan-1-one[ No CAS ]
6,6'-(1,3-phenylene)bis(2,2-difluoro-4-(4-(1,2,2-triphenylvinyl)phenyl)-2H-1,3,2-dioxaborinin-1-ium-2-uide)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
Stage #1: dimethyl Isophthalate; 1-[4-(1,2,2-triphenylethenyl)phenyl]ethan-1-one With sodium hydride In tetrahydrofuran at 60℃; for 24h; Inert atmosphere;
Stage #2: boron trifluoride diethyl etherate In dichloromethane for 2h; Reflux; Inert atmosphere;
2 2.2.1. 2,2-Difluoro-6-phenyl-4-(4-(1,2,2-triphenylvinyl)phenyl)-2H-1,3,2-dioxaborinin-1-ium-2-uide (TPEB)
General procedure: 1-(4-(1,2,2-triphenylvinyl)phenyl)ethanone (2 g, 5 mmol) andmethyl benzenecarboxylate (0.82 g, 6 mmol) were dissolved in dryTHF (50 mL) under an atmosphere of nitrogen. Then, NaH (0.4 g,10 mmol) was added. The mixture was stirred at 60° C for 24 h,followed by poured into ice water (300 mL). HCl (6 M, 10 mL) wasadded to neutralize excess NaH. The mixture was extracted withCH2Cl2 for three times, and the organic phase was combined anddried over magnesium sulfate. After removal of solvent, the residuewas used directly in the next step without purification. Then, thesolution of the ligand of the b-diketone ligand in dry dichloromethane(50 mL) was heated to reflux under an atmosphere ofnitrogen, and excess BF3Et2O (1.35 mL) was added. The mixturewas refluxed for 2 h. After the solvent was removed, the residuewas purified by column chromatography (silica) using petroleumether/CH2Cl2 (v/v 3/2) as eluent, followed by recrystallizationtwice from the mixed solvents of CH2Cl2 and light petroleum toafford TPEB (1.12 g, 43%) as bright orange solid.
With diisobutylaluminium hydride; disodium ethylenediamine tetraacetic acid In tetrahydrofuran; toluene at -45℃; for 2h; Inert atmosphere;
1 Example 1
Add 100 mL of tetrahydrofuran to the reaction flask.Then add 20.02 g (102.99 mmol) of dimethyl isophthalate and 0.50 g of EDTA-2Na to the inside.Nitrogen gas,Acetone dry ice cooled to -45 °C,Control temperature does not exceed -45 °C,257mL of 1.0M diisobutyl aluminum hydride toluene solution was added dropwise.After the addition, the reaction is incubated for 2 hours.Temperature control does not exceed 0 ° C drops 250mL potassium sodium tartrate saturated solution,filter,Liquid separation,The toluene phase is concentrated at 60-70°C,Concentrate to 5% of the original volume,There are a lot of solids out,filter,Drying of methyl 3-formylbenzoate 14.20 g at 50°CYield 84.02%,98.92% purity.
Multi-step reaction with 3 steps
1: sodium hydroxide / methanol / 16 h / 20 °C
2: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 2 h / 0 - 20 °C
3: dipyridinium dichromate / dichloromethane / 2 h / 20 °C / Inert atmosphere
[(η(3)-allyl)(chloro)dicarbonylbis(methyl cyanide)molybdenum(II)][ No CAS ]
[ 1459-93-4 ]
sodium cyclopentadienide[ No CAS ]
[(η3-C3H5)(η5-C5H4COC6H4COOH-3)Mo(CO)2][ No CAS ]
[1,3-{(η3-C3H5)Mo(CO)2(η5-C5H4CO)2}2C6H4][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 18%
2: 45%
Stage #1: dimethyl Isophthalate; sodium cyclopentadienide In tetrahydrofuran Inert atmosphere; Schlenk technique; Reflux;
Stage #2: [(η(3)-allyl)(chloro)dicarbonylbis(methyl cyanide)molybdenum(II)] In tetrahydrofuran at -80 - 20℃; Inert atmosphere; Schlenk technique;
Stage #3: hydrogenchloride Further stages;
6 4.6. Synthesis of [1,3-{(η3-C3H5)Mo(CO)2(η5-C5H4CO)2}2C6H4] (12) and [(η3-C3H5)(η5-C5H4COC6H4COOH-3)Mo(CO)2] (14)
4.6 Synthesis of [1,3-{(η3-C3H5)Mo(CO)2(η5-C5H4CO)2}2C6H4] (12) and [(η3-C3H5)(η5-C5H4COC6H4COOH-3)Mo(CO)2] (14) Solution of sodium cyclopentadienide (2.1 g, 24 mmol) in THF (50 ml) was treated dimethyl isophthalate (4; 3.1 g, 16 mmol) and heated under reflux overnight. After cooling to room temperature, volatiles were vacuum evaporated and crude product was washed with Et2O and vacuum dried to give 3.2 g of yellow powder. FTIR (ATR, cm-1): 1705 vs [ν(C=O)], 1511 br [ν(C=O)]. 0.8 g of this intermediate was dissolved in THF (20 ml), cooled to -80 °C and then added dropwise to a solution of [(η3-C3H5)Mo(CO)2(NCMe)2Cl] (1.6 g; 5.15 mmol) in THF (20 ml) precooled to -80 °C. The reaction mixture was stirred at room temperature overnight and then vacuum evaporated to dryness. The crude product was extracted with hot hexane (3 * 50 ml). The volatiles were vacuum evaporated and the final product was washed with cold hexane and vacuum dried. Appearance of 10 and 12 in molar ratio 3:1 mixture was confirmed by 1H NMR spectroscopy. This mixture was dissolved in solution of NaOMe (0.5 mol/l in MeOH, 40 ml, 20 mmol) and stirred for 2 h. The reaction mixture was treated with water (3 ml) and stirred overnight. After that, the mixture was diluted with water (50 ml) and washed with toluene (3 * 50 ml). The collected organic phases were dried with magnesium sulfate and volatiles were vacuum evaporated. Pure compound 12 was obtained after washing with cold hexane (5 ml) and vacuum drying. 12: Yield: 0.47 g (0.73 mmol, 18% based on dimethyl isophthalate). Yellow powder. Calcd for C28H22Mo2O6: C, 52.03; H, 3.43. Found: C, 52.20; H, 3.56. 1H NMR (CDCl3, 400 MHz, δ ppm): 8.08 (t, 4J(1H,1H) = 0.8 Hz, 1H, H2, C6H4), 7.93 (dd, 3J(1H,1H) = 7.8 Hz, 4J(1H,1H) = 0.8 Hz, 2H, H4,6 C6H4), 7.58 (t, 3J(1H,1H) = 7.8 Hz, 1H, H5, C6H4), 5.76 (t, 3J(1H,1H) = 4J(1H,1H) = 2.4 Hz, 4H, C5H4), 5.52 (t, 3J(1H,1H) = 4J(1H,1H) = 2.4 Hz, 4H, C5H4), 3.89 (s-br, 2H, C3H5), 2.80 (s-br, 4H, C3H5), 1.54 (s-br, 4H, C3H5). FTIR (ATR, cm-1): 1936 vs [νa(C≡O)], 1846 vs [νs(C≡O)], 1637 s [ν(C=O)]. The aqueous phase was treated with aqueous HCl (w = 35%) dropwise until the pH is acidic. Upon acidification yellow solid precipitates. The product was extracted with CH2Cl2 (50 ml), separated from aqueous phase and dried with magnesium sulfate. The volatiles were vacuum evaporated and the final product was washed with hexane (20 ml) and vacuum dried. 14: Yield: 0.73 g (1.80 mmol, 45% based on dimethyl isophthalate). Yellow powder. Calcd for C18H14MoO5: C, 53.22; H, 3.47. Found: C, 53.54; H, 3.57. 1H NMR (CD3OD, 400 MHz, δ ppm): 8.40 (s, 1H, H2, C6H4), 8.26 (d, 3J(1H,1H) = 7.7 Hz, 1H, H4,6, C6H4), 8.00 (d, 3J(1H,1H) = 7.7 Hz, 1H, H4,6, C6H4), 7.65 (t, 3J(1H,1H) = 7.7 Hz, 1H, H5, C6H4), 5.92 (t, 3J(1H,1H) = 4J(1H,1H) = 2.3 Hz, 2H, C5H4), 5.63 (t, 3J(1H,1H) = 4J(1H,1H) = 2.3 Hz, 2H, C5H4), 4.10 (s-br, 1H, C3H5), 2.82 (d, 3J(1H,1H) = 6.3 Hz, 2H, C3H5), 1.02 (s-br, 2H, C3H5). FTIR (ATR, cm-1): 1937 vs [νa(C≡O)], 1850 vs [νs(C≡O)], 1688 s [ν(C=O)], 1628 s [ν(C=O)]. Single crystals suitable for X-ray diffraction analysis were prepared by slow evaporation methanolic solution under inert atmosphere.
With dmap; benzotriazol-1-ol; 1,2-dichloro-ethane; N-ethyl-N,N-diisopropylamine In dichloromethane for 24h;
2
Methyl 3-((1H-benzo[d]imidazol-2-yl)carbamoyl)benzoate 7. A mixture of methyl isophthalate (500 mg, 2.8 mmol), aminobenzamidazole (369 mg, 2.8 mmol), HOBT (340 mg, 2.2 mmol), DMAP (34 mg, 0.28 mmol) and EDC (718 mg, 3.7 mmol) were dissolved in methylene chloride (5 mL), treated with Hunig's base (359 mg, 2.8 mmol) and stirred for 1 d. The reaction mixture was diluted with methanol, adsorbed onto silica gel and chromatographed (40 g Isco silica gel, 0 to 10% MeOH in CH2Cl2) to give pure product. The product was triturated with 20% ethyl acetate in hexanes to give 7 (352 mg, 42%) as a white powder. LC/MS gave a single peak with m/z=296.1 [M+1]+. 1H-NMR (dmso-d6) δ 12.51 (br s, 1H), 8.78 (br s, 1H), 8.39 (d, J=8 Hz, 1H), 8.13 (d, J=8 Hz, 1H), 7.66 (t, J=8 Hz, 1H), 7.42-7.46 (m, 2H), 7.15-7.19 (m, 2H), 3.91 (s, 3H).
A mixture of dimethyl ester of isophthalic acid (2.22 gm) and hydrazine hydrate (98%, 2 cc) in methanol was refluxed for 5 hours and the reaction mixture was allowed to cool to room temperature. Then, the cooled reaction mixture was poured on to ice cold water. The dihydrazide of isophthalic acid thus obtained was filtered and recrystallized from ethanol. [1] Yield: (85%), M.P=241C, (Scheme1). 1HNMR (400 MHz, CDCL 3, ppm): 9.81 (s, 2H, -CO-NH-), 8.20 (s 1H ), 7.8(d, 2H, J=7.6 Hz), 7.5 (t, 1H, 7.2 Hz), 4.5 (s, 4H).
3,3'-(1,3-phenylene)bis(1-(4-hexyloxyphenyl)-1,3-propanedione)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: dimethyl Isophthalate With sodium hydride In N,N-dimethyl-formamide; paraffin oil for 0.0833333h;
Stage #2: 4-hexyloxyacetophenone In N,N-dimethyl-formamide; paraffin oil for 0.333333h;
2.2
30 mL of dry N,N-dimethylformamide and 20.0 mmol (3.88 g) of 1, respectively, were placed in a 150 mL round bottom flask.Dimethyl phthalate, 50.0 mmol (4.00 g) of a 30% sodium hydride paraffin inclusion compound, dissolved after stirring for 5 minutes,45.0 mmol (9.91 g) of 4-n-hexyloxyacetophenone dissolved in 25 mL of dry N,N-dimethylformamide was added dropwise.After the addition is completed within 20 minutes,The post-processing method is referred to the synthesis method 3 in Embodiment 1,Obtaining the target product of 6.85g,The yield was 60%.
3,3'-(1,3-phenylene)bis(1-(4-(4-tert-butylbenzyloxy)phenyl)-1,3-propanedione)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
Stage #1: dimethyl Isophthalate With sodium hydride In N,N-dimethyl-formamide; paraffin oil for 0.0833333h;
Stage #2: 4-(4-tert-butylbenzyloxy)acetophenone In N,N-dimethyl-formamide; paraffin oil for 0.333333h;
3.2
Add 30 mL of dry N,N-dimethylformamide, 20 mmol (3.88 g) of dimethyl 1,3-benzeneate, 50 mmol (4.00 g) of 30% sodium hydride paraffin in a 150 mL round bottom flask. Object,After stirring for 5 minutes, 45 mmol (12.71 g) of 4-(4-tert-butylbenzyloxy)acetophenone dissolved in 25 mL of dry N,N-dimethylformamide was added dropwise.After the addition is completed within 20 minutes,The post-processing method is referred to the synthesis method 3 in Embodiment 1,Obtained the target product 7.64g,The yield was 55%.
3,3'-(1,3-phenylene)bis(1-(4-tert-butoxyphenyl)-1,3-propanedione)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
Stage #1: dimethyl Isophthalate With sodium hydride In N,N-dimethyl-formamide; paraffin oil for 0.0833333h;
Stage #2: 4-tert-butoxyacetophenone In N,N-dimethyl-formamide; paraffin oil at 60℃;
1.3.2
40 mL of anhydrous tetrahydrofuran, 20 mmol (3.88 g) of dimethyl 1,3-benzeneate, 50 mmol (4.00 g) of 30% sodium hydride paraffin inclusion complex were added to a 150 mL round bottom flask.After stirring for 5 minutes, 30 mL of a solution of 4-tert-butoxyacetophenone (45 mmol, 8.64 g) in tetrahydrofuran was added dropwise.After the addition was completed within 20 minutes, the reaction was heated to 60 ° C.Stir the reaction for 2 to 3 hours, and follow the reaction by TLC.Until the reaction is completed, the reaction mixture is slowly poured into water under stirring, and the pH of the solution is adjusted to be near neutral with concentrated hydrochloric acid.80 mL of dichloromethane was added and the aqueous layer was separated by layering.The organic layer was washed 3 times with 50 mL of saturated brine.The organic layer was dried and the solvent was removed under reduced pressure.Separation and purification by column chromatography gave the target product 6.17 g.The yield was 60%.
With (1,5-cyclooctadiene)(methoxy)iridium(l) dimer; N<SUP>1</SUP>-(pyridin-2-yl)benzene-1,2-diamine at 120℃; for 24h; Schlenk technique; Inert atmosphere;
1 Example 1a method for preparing methyl 3-formate-1-benzoic acid (bistrimethylsiloxymethylsilyl)methyl ester,Specific steps are as follows:
Methyl isophthalate (II) (388 mg, 2.0 mol, 1.0 equiv.),Catalyst [Ir(OMe)(COD)] 2 (IV) (34 mg, 0.05 mmol, 0.025 equiv.)And the ligand (V) (37 mg, 0.2 mmol, 0.05 equiv.) was added to the dried Schlenk tube with a stir bar, and the nitrogen was replaced by vacuum three times.Then adding bistrimethylsiloxymethylsilane (III) under nitrogen protection(888.0 mg, 4 mmol, 2.0 equiv.) and 5 mL of cyclopentyl methyl ether (CPME) solvent,The reaction mixture was heated to 120 ° C for 24 h.After falling to room temperature,The product (I) can be obtained by column chromatography (PE: EA = 20:1).(505.1g, 61%),
With Ac-Cys-OMe; bismuth(III) oxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 48h;Irradiation;
Iodide compound 7 (50 mg),Bismuth oxide (0.7mg, 1mol%),N-acetyl-L-cysteine methyl ester (8.3 mg, 0.3 equiv) was weighed into a 10 mL reaction tube.After deoxidation, the reaction solvent dichloromethane (1.6 ml) was added in order.And N,N-diisopropylethylamine (0.27 ml, 10 equiv),Reacted under 1W blue LED light,The reaction was terminated after the iodo compound 7 was consumed.Purification by column chromatography gave Compound 7a (29.1 mg).
di(3-hydroxy-2,2-dimethylpropyl) isophthalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With tetrabutyl titanium at 140 - 170℃; for 12h; Inert atmosphere;
1-4 Example 3
Add 130 g (0.67 mol) of dimethyl isophthalate to a three-necked flask.837 g (8.0 mol) of neopentyl glycol, raised to 140 ° C under nitrogen protection,Add 0.5g of tetrabutyl titanate, slowly heat to 170 ° C, and react at this temperature for 12h, during which time methanol is distilled off; the reaction solution is cooled to 140 ° C ~ 160 ° C,After removing excess neopentyl glycol by vacuum distillation, it was cooled to room temperature.The obtained crude product was added to a mixed solvent of 3 L of toluene and petroleum ether (volume ratio: 1:6), freeze-crystallized, filtered, and dried in vacuo to give a white solid.The yield was 77%.
N,N-dimethyl-α-oxo-(3-methoxycarbonyl)benzeneacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
Stage #1: dimethyl Isophthalate; N,N-dimethyl (trimethylsilyl)methanamide In toluene at 110℃; for 34h; Inert atmosphere; Schlenk technique; Sealed tube; Cooling with ice;
Stage #2: With hydrogenchloride In dichloromethane; water at 20℃; for 2h; Inert atmosphere; Schlenk technique;
2. General procedure for aminocarbonylation of carboxylic esters with carbamoylsilane
General procedure: A Schlenk tube fitted with a Teflon vacuum stopcock and micro stirbar was f lame-heatedunder vacuum and refilled with Ar. Carboxylic esters (0.5 mmol) and anhydrous toluene (1 .5mL) was added at ice bath temperature. After 20 min, N,N-dimethylcarbamoylsilane 2 (0 .6mmol) was added. The sealed reaction m ixture was stirred at 110 °C until no carbamoylsilane2 could be detected by TLC. For Table 1 and Table 2, the reaction mixture was addeddichloromethane (5 mL), water (2 mL) and concentrated hydrochloric acid (0.5 mL), thenstirred 2 hours at room temperature, the organic layer was decanted and the aqueous phaseextracted with dichloromethane (2 × 5 mL). The combined organic layers were dried overMgSO4 and evaporated to afford the crude product which was purif ied by columnchromatography on silica gel to afford α-ketoamides 3 or 5. For Table 3, entries 1-3, theresidue was directly isolated by Kugelrohr d istillation to give product 7a. For Table 3, entries4 and Scheme 2, volatiles were removed in vacuum, and the residue was chromatographedusing petroleum ether-EtOAc as eluent to yield products 7d and 9
N,N,N′,N′-tetramethyl-2-hydroxy-2-(3-methoxycarbonyl)phenylmalonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: dimethyl Isophthalate; N,N-dimethyl (trimethylsilyl)methanamide In toluene at 110℃; for 30h; Inert atmosphere; Schlenk technique; Sealed tube; Cooling with ice;
Stage #2: With hydrogenchloride In dichloromethane; water at 20℃; for 2h; Inert atmosphere; Schlenk technique;
2. General procedure for aminocarbonylation of carboxylic esters with carbamoylsilane
General procedure: A Schlenk tube fitted with a Teflon vacuum stopcock and micro stirbar was f lame-heatedunder vacuum and refilled with Ar. Carboxylic esters (0.5 mmol) and anhydrous toluene (1 .5mL) was added at ice bath temperature. After 20 min, N,N-dimethylcarbamoylsilane 2 (0 .6mmol) was added. The sealed reaction m ixture was stirred at 110 °C until no carbamoylsilane2 could be detected by TLC. For Table 1 and Table 2, the reaction mixture was addeddichloromethane (5 mL), water (2 mL) and concentrated hydrochloric acid (0.5 mL), thenstirred 2 hours at room temperature, the organic layer was decanted and the aqueous phaseextracted with dichloromethane (2 × 5 mL). The combined organic layers were dried overMgSO4 and evaporated to afford the crude product which was purif ied by columnchromatography on silica gel to afford α-ketoamides 3 or 5. For Table 3, entries 1-3, theresidue was directly isolated by Kugelrohr d istillation to give product 7a. For Table 3, entries4 and Scheme 2, volatiles were removed in vacuum, and the residue was chromatographedusing petroleum ether-EtOAc as eluent to yield products 7d and 9
With hydroxylamine hydrochloride; potassium hydroxide In methanol; water at 20 - 25℃;
2 Example 2Synthesis of potassium isophthaloyl hydroxamic acid:
At 20-25,Add 28g of potassium hydroxide aqueous solution (28g/35mL)Hydroxylamine hydrochloride solution (17.4g hydroxylamine hydrochloride/30mL methanolAnd 30mL water),After mixing well,Get a hydroxylamine solution,Then at 20-25,The hydroxylamine solution was slowly added dropwise to the methanol solution of dimethyl isophthalate (19.42g/160mL methanol).After stirring for 2.5-3.0 hours,No need to add acid to neutralize the reaction solution,Evaporate all solvents directly.Then wash the solid product with 80mL methanol-acetone (1:1v/v),Dry to obtain potassium isophthaloyl hydroxamic acid salt,Light yellow solid 35.6g (containing KCl),
Stage #1: m-xylene With manganese(IV) oxide; oxygen; cobalt(II) diacetate tetrahydrate at 156℃;
Stage #2: methanol
8-24 Example 18
The catalyst dissolved in the fresh meta-xylene added to the oxidation reactor is a mixture of MnO2 and Co(Ac)2·4H2O, the total concentration is 150ppm, the reaction temperature is 156°C, the reaction pressure is 1.0MPa, and the oxygen-containing gas is pure oxygen The difference is that the conversion rate of meta-xylene is controlled at 38%, and the mass percentage of methylbenzyl alcohol in the bottom liquid of the primary distillation tower is controlled at 0.05%. The mass percentage content of each component in the reaction solution obtained by HPLC analysis is listed in Table 1. The mass and composition of the obtained initial distillation tower bottom liquid and the content of toluic acid in the top mixture of the initial distillation tower are listed in the table 2. The above-mentioned preliminary distillation tower bottom liquid was rectified, 555.2 g of m-toluic acid product with a purity of 99.0% was obtained at the top of the tower, and 1552.3 g high-boiling tower bottom liquid with a m-toluic acid content of 84.6% by weight was obtained from the tower bottom. Using methanol as the esterification reagent, the high-boiling column still liquid is subjected to an esterification reaction to obtain an esterification reaction liquid whose main components are methyl m-toluate and dimethyl isophthalate, and the end of the reaction is m-methyl The content of benzoic acid is <0.5%. The obtained esterification reaction liquid was subjected to rectification and separation, and 1420.3 g of methyl m-toluate with a content of 99.0% and 262.8 g of dimethyl isophthalate with a content of 99.0% were sequentially obtained from the top of the tower. After calculation, based on the input m-xylene, the yield of m-toluic acid was 24.9%, the yield of methyl m-toluate was 57.7%, and the yield of dimethyl isophthalate was 8.3%. %, the total yield of the three is 90.9%.
Stage #1: 3-(5,5-dimethyl-1,3,2-dioxaborinanyl)-1-methoxycarbonylbenzene; di-<i>tert</i>-butyl dicarbonate With 4,4'-dimethyl-2,2'-bipyridines; lithium methanolate; copper(l) chloride In N,N-dimethyl acetamide at 30℃; for 6h; Inert atmosphere; Schlenk technique;
Stage #2: methyl iodide In N,N-dimethyl acetamide at 30℃; for 2h; Schlenk technique;
Methyl (Het)arylcarboxylates 3a-y, 5a-e; General Procedure
General procedure: A 15 mL Schlenk tube equipped with a stirrer bar was chargedwith CuCl (10 mol%), L7 (13 mol%), LiOMe (2.5 equiv), and theappropriate boronic ester 1 or 4 (0.375 mmol). The vessel wasthen evacuated and filled with Ar (three cycles). DMA (0.5 mL)and (Boc)2O (0.25 mmol) were added sequentially under Ar, andthe mixture was stirred at 30 for 6 h. MeI (5 equiv) was thenadded in air, and the mixture was stirred at 30 for additional2 h. The mixture was finally diluted with EtOAc and washedwith sat. aq NaCl (20 mL). The aqueous phase was furtherextracted with EtOAc (3 × 20 mL), and the combined organicphases were dried (Na2SO4) and concentrated. The residue waspurified by column chromatography [silica gel EtOAc-hexane(1:100 to 1:50)].
(S)-2-amino-N-(1,3-benzothiazol-5-yl)-N-methyl-3-amphetamine[ No CAS ]
methyl (S)-3-((1-(benzothiazol-5-yl(methyl)amino)-1-oxo-3-phenylpropane-2-yl)carbamoyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.64 g
Stage #1: dimethyl Isophthalate With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane for 0.5h; Cooling with ice;
Stage #2: (S)-2-amino-N-(1,3-benzothiazol-5-yl)-N-methyl-3-amphetamine With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 6h;
4 Example 4: Intermediate Preparation of methyl (S)-3-((1-(benzothiazol-5-yl(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)benzoate (5)
In a 100mL round bottom flask was added monomethyl isophthalate (0.48g, 2.67mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.27g, 3.33mmol), and add 30mL dichloromethane to make Dissolve, then stir for 30min under ice bath conditions, Then Intermediate 4 (0.69g, 2.22mmol) was dissolved in 10mL of dichloromethane and added dropwise to the reaction system with a constant pressure dropping funnel; after that, N,N-diisopropylethylamine (0.57g, 4.44mmol) was added to the reaction system and returned to room temperature to react for 6h. After the reaction was monitored by TLC, the solvent was evaporated under reduced pressure, 30 mL of saturated sodium chloride solution was added, and the mixture was extracted with dichloromethane (30 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20mL×2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained was separated by silica gel column chromatography (eluent EA:PE=1:3). Intermediate (S)-3-((1-(Benzothiazol-5-yl(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)methyl benzoate (5 ) 0.64g, yellow solid, the yield is 60.8%.
With tert.-butylhydroperoxide; oxygen; potassium carbonate at 150℃; for 48h; Autoclave; Green chemistry;
2.2. Procedures for the oxidative cleavage of C- -C bonds to esters
General procedure: In the typical oxidation reaction, the substrate (0.25 mmol), catalyst(10 mol%), K2CO3 (20 mol%), TBHP (2.2 equiv.) and MeOH (4 mL) wereplaced in a round-bottomed flask. The mixture was then transferred tothe autoclave. The autoclave was closed and purged with oxygen for 3times. Finally, the autoclave was pressurized in oxygen atmosphere for48 h and stirred at 150 C. After the reaction was completed, the autoclavewas cooled to room temperature, the internal standard compound(biphenyl, 15 mg) and MeOH (2 mL) were added. The reaction solutionwas analyzed on GC and confirmed by GC-MS. Or the yield was determinedby 1HNMR using dibromomethane (10 mg) as the internalstandard.
N<SUP>1</SUP>,N<SUP>3</SUP>-bis(p-tolylsulfinyl)isophthalamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
Stage #1: p-tolylsulfinyl amide With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667h; Schlenk technique;
Stage #2: dimethyl Isophthalate In tetrahydrofuran; hexane at -78 - 50℃; for 5h; Schlenk technique;
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