* 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.
The [(2-chloroethoxy)-methylene]bis[4-chlorobenzene] as prepared in PREPARATION II above (11.02 g), ethyl 3-piperidinecarboxylate (5.49 g), KI (0.3 g), and K2 CO3 (9.73 g) are placed in 120 ml acetone and refluxed for about 63 hr. TLC (silica, 30percent ethyl acetate: 70percent hexane as eluent) is used to monitor completion of reaction. The contents are cooled, and acetone is removed. The residual oil is dissolved in ether, and washed with H2 O, brine, then dried over MgSO4. The ether is evaporated to an oil (16 g) which is chromatographed on silica using 25percent ethyl acetate: 75percent hexane as eluent. 8.13 g of the desired product, 3-piperidinecarboxylic acid, 1-[2-[bis(4-chlorophenyl)methoxy]ethyl]-, ethyl ester, is obtained for a 55percent yield. NMR spectrum is consistent with that expected for product.
Reference：
[1] Patent: US4910312, 1990, A,
3
[ 120-43-4 ]
[ 584-08-7 ]
[ 75-26-3 ]
[ 4318-42-7 ]
Reference：
[1] Patent: US5354747, 1994, A,
[2] Patent: US5461047, 1995, A,
4
[ 4704-77-2 ]
[ 584-08-7 ]
[ 36236-76-7 ]
Yield
Reaction Conditions
Operation in experiment
53.5%
With sulfuric acid In acetone
EXAMPLE 21 (+-)-N-(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl-N,N-dimethyl-β-hydroxyethyl ammonium bromide Into a 500 milliliter round bottom flask equipped with a magnetic stir bar and drying tube, a solution of 28.0 grams (0.181 mole) of 3-bromo-1,2-propanediol in 200 milliliters of acetone was added. Then, 0.5 milliliter of concentrated sulfuric acid was added and the reaction allowed to proceed at room temperature for 24 hours with continuous stirring. The reaction mixture was neutralized with 13.0 grams of K2 CO3 for 30 minutes, the solution was filtered and the solvent evaporated in vacuo. The resulting oil was dissolved in 150 milliliter of ether, extracted three times with 150 milliliter portions of water and the organic layer dried over anhydrous sodium sulfate. The filtered ether was evaporated in vacuo and 100 milliliters of hexanes was added, resulting in two layers. The upper layer was decanted and evaporated in vacuo to provide 19.1 grams (53.5percent) of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl bromide.
Step 3: 1-(2-Phenylpropyl)piperazin-2-one In the same way as that described in Example 2, Step 3, using 2-[(bromoacetyl)(2-phenylpropyl)amino]ethyl carbamic acid tert-butyl ester (1.64 g, 4.11 mmol), trifluoroacetic acid (4 mL) and CH2 Cl2 (40 mL), followed by K2 CO3 (1.1 g, 8.2 mmol) and EtOH (100 mL). The piperazinone (668 mg, 75percent) was isolated as a colourless oil. 1 H NMR (250 MHz, CDCl3) δ1.28 (3H, d, J=6.8 Hz), 2.72-2.93 (3H, m), 3.04-3.26 (3H, m), 3.28 (1H, d, J=17.3 Hz), 3.52 (1H, d, J=17.3 Hz), 3.85-3.93 (1H, m), 7.19-7.35 (5H, m).
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 43, p. 13426 - 13430[2] Angew. Chem., 2017, vol. 129, p. 13611 - 13615,5
10
[ 5006-66-6 ]
[ 7789-69-7 ]
[ 584-08-7 ]
[ 74-95-3 ]
[ 26218-78-0 ]
Reference：
[1] Patent: US5420270, 1995, A,
11
[ 63837-11-6 ]
[ 124-38-9 ]
[ 584-08-7 ]
[ 24851-69-2 ]
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 43, p. 13426 - 13430[2] Angew. Chem., 2017, vol. 129, p. 13611 - 13615,5
12
[ 110-89-4 ]
[ 584-08-7 ]
[ 107-91-5 ]
[ 109-94-4 ]
[ 4241-27-4 ]
Reference：
[1] Patent: US5521179, 1996, A,
13
[ 584-08-7 ]
[ 609-15-4 ]
[ 20485-39-6 ]
Yield
Reaction Conditions
Operation in experiment
31%
With formamide In benzene
EXAMPLE 1 Preparation of Ethyl 4-Methyl-5-Oxazolecarboxylate This compound was prepared according to the procedure described in French Pat. No. 1,543,853. A mixture of 50.0 g (0.337 moles) of ethyl chloroacetoacetate and 42.0 g (0.933 moles) of formamide was stirred at 120°-135° for 18 hr. Thereafter, the mixture was cooled using an ice bath to 10° C. 300 ml of 1 N K2 CO3 was added dropwise with gas evolution noted. After complete addition of K2 CO3 solution, the reaction mixture was stirred with 200 ml of benzene/ether (2:1) and saturated with NaCl. The insoluble material was filtered and the benzene/ether layer was separated and washed with water, dried (MgSO4) and concentrated under reduced pressure. The brown residue was distilled on a Kugelrohr to give 14.8 g of white solid, mp 31°-33° C.; yield 31percent; nmr (CDCl3) 8.0 (s,1H,C2 H), 44 (q, J=7 Hz, 2H,CH2), 2.5 (s,3H,CH3), 1.4 (t,3H,CH3).
Reference：
[1] Patent: US4303439, 1981, A,
14
[ 288-32-4 ]
[ 1194-02-1 ]
[ 584-08-7 ]
[ 25372-03-6 ]
Reference：
[1] Patent: US5736548, 1998, A,
15
[ 75-09-2 ]
[ 584-08-7 ]
[ 2258-42-6 ]
[ 5270-94-0 ]
Reference：
[1] Patent: US5276152, 1994, A,
16
[ 591-20-8 ]
[ 584-08-7 ]
[ 100-44-7 ]
[ 53087-13-1 ]
Reference：
[1] Patent: US5952350, 1999, A,
[2] Patent: US5843940, 1998, A,
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 26, p. 10774 - 10777
20
[ 1634-04-4 ]
[ 6638-79-5 ]
[ 584-08-7 ]
[ 79-04-9 ]
[ 67442-07-3 ]
Reference：
[1] Patent: US5786515, 1998, A,
21
[ 99-66-1 ]
[ 584-08-7 ]
[ 2695-47-8 ]
[ 13319-71-6 ]
Reference：
[1] Patent: US4238389, 1980, A,
22
[ 124-38-9 ]
[ 51437-00-4 ]
[ 584-08-7 ]
[ 403-15-6 ]
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 43, p. 13426 - 13430[2] Angew. Chem., 2017, vol. 129, p. 13611 - 13615,5
23
[ 2420-16-8 ]
[ 584-08-7 ]
[ 74-88-4 ]
[ 4903-09-7 ]
Reference：
[1] Patent: US6031003, 2000, A,
[2] Patent: US5763569, 1998, A,
[3] Patent: US5688938, 1997, A,
24
[ 586-30-1 ]
[ 584-08-7 ]
[ 3556-83-0 ]
Reference：
[1] Patent: US4532343, 1985, A,
25
[ 586-30-1 ]
[ 584-08-7 ]
[ 121-44-8 ]
[ 3556-83-0 ]
Reference：
[1] Patent: US6127356, 2000, A,
26
[ 37687-57-3 ]
[ 584-08-7 ]
[ 5417-17-4 ]
Yield
Reaction Conditions
Operation in experiment
96%
With sodium hydroxide In chloroform; water; acetonitrile
Step 2 Synthesis of 2-chloro-3,4-dimethoxybenzaldehyde 184 g (0.986 mol) of 2-chloro-3-hydroxy-4-methoxybenzaldehyde was dissolved in 2 l of CH3 CN. 204 g (1.476 mol) of K2 CO3 and 298 g (2.096 mol) of CH3 I were added to the solution, which was heated under reflux for 4 hours. After cooling, the crystals were separated by filtration and the mother liquor was concentrated under reduced pressure. 800 ml of water and 600 ml of CHCl3 were added to the residue to conduct extraction. The CHCl3 layer was washed with 500 ml of 10percent NaOH and a saturated Nacl aqueous solution. It was dehydrated over MgSO4 and concentrated to dryness under reduced pressure to obtain 189.49 g (96percent) of 2-chloro-3,4-dimethoxybenzaldehyde. mp 70°~72° C. NMR (90 MHz, CDCl3) δ:3.88 (3H, s), 3.96 (3H, s), 6.92 (1H, d), 7.72 (1H, d), 10.28 (1H, s)
Reference：
[1] Patent: US5292521, 1994, A,
27
[ 121-71-1 ]
[ 7732-18-5 ]
[ 584-08-7 ]
[ 100-44-7 ]
[ 34068-01-4 ]
Reference：
[1] Patent: US4404222, 1983, A,
[2] Patent: US4407819, 1983, A,
28
[ 100-39-0 ]
[ 584-08-7 ]
[ 490-78-8 ]
[ 30992-63-3 ]
Reference：
[1] Patent: US5248685, 1993, A,
29
[ 582-17-2 ]
[ 584-08-7 ]
[ 3469-26-9 ]
Reference：
[1] Patent: US5712312, 1998, A,
30
[ 584-08-7 ]
[ 106-93-4 ]
[ 105-53-3 ]
[ 1559-02-0 ]
Reference：
[1] Patent: US2010/239576, 2010, A1,
31
[ 372-20-3 ]
[ 584-08-7 ]
[ 75-03-6 ]
[ 458-03-7 ]
Reference：
[1] Patent: US5593993, 1997, A,
32
[ 100-02-7 ]
[ 70384-51-9 ]
[ 584-08-7 ]
[ 6482-24-2 ]
[ 22483-40-5 ]
Reference：
[1] Patent: US5585394, 1996, A,
33
[ 2150-44-9 ]
[ 584-08-7 ]
[ 74-88-4 ]
[ 19520-74-2 ]
Reference：
[1] Patent: US5998470, 1999, A,
34
[ 50-86-2 ]
[ 584-08-7 ]
[ 77-78-1 ]
[ 4093-29-2 ]
Reference：
[1] Patent: US4138492, 1979, A,
35
[ 876-02-8 ]
[ 584-08-7 ]
[ 74-88-4 ]
[ 10024-90-5 ]
Reference：
[1] Patent: US6001884, 1999, A,
[2] Patent: US6031003, 2000, A,
[3] Patent: US5688938, 1997, A,
[4] Patent: US5763569, 1998, A,
36
[ 480-66-0 ]
[ 584-08-7 ]
[ 100-44-7 ]
[ 18065-05-9 ]
Reference：
[1] Patent: US4267165, 1981, A,
[2] Patent: US4290957, 1981, A,
[3] Patent: US4348333, 1982, A,
[4] Patent: US4226804, 1980, A,
37
[ 1878-67-7 ]
[ 584-08-7 ]
[ 14062-30-7 ]
Reference：
[1] Patent: US6025388, 2000, A,
38
[ 584-08-7 ]
[ 614-75-5 ]
[ 74-88-4 ]
[ 27798-60-3 ]
Reference：
[1] Patent: US5656629, 1997, A,
39
[ 14199-15-6 ]
[ 584-08-7 ]
[ 100-44-7 ]
[ 68641-16-7 ]
Reference：
[1] Patent: US4672071, 1987, A,
[2] Patent: US4761420, 1988, A,
40
[ 3943-89-3 ]
[ 100-39-0 ]
[ 584-08-7 ]
[ 1570-05-4 ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium hydroxide In methanol; water; butanone
(B) 3,4-DIBENZYLOXYBENZOIC ACID To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5 g (0.76 mole) of K2 CO3 and 168.8 g (0.76 mole) of benzyl bromide. The mixture was refluxed for 16 hours and filtered. Evaporation of the filtration gave an oil. This oil was mixed with 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours. The methanol was evaporated and the reaction mixture was acidified with concentrated HCl. The precipitate was filtered to give 101 g (92percent) of the desired product; m.p. 184°-185° C. The NMR and IR spectra were consistent with the assigned structure.
92%
With potassium hydroxide In methanol; water; butanone
3,4-Dibenzyloxybenzoic Acid To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5 g (0.76 mole) of K2 CO3 and 168.8 g (0.76 mole) of benzyl bromide. The mixture was refluxed for 16 hours and filtered. Evaporation of the filtration gave an oil. This oil was mixed with 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours. The methanol was evaporated and the reaction mixture was acidified with concentrated HCl. The precipitate was filtered to give 101 g (92percent) of the desired product; m.p. 184°-5° C. The NMR and IR spectra were consistent with the assigned structure.
92%
With potassium hydroxide In methanol; water; butanone
(b) 3,4-Dibenzyloxybenzoic Acid To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5 g (0.76 mole) of K2 CO3 and 168.8 g (0.76 mole) of benzyl bromide. The mixture was refluxed for 16 hours and filtered. Evaporation of the filtration gave an oil. This oil was mixed with 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours. The methanol was evaporated and the reaction mixture was acidified with concentrated HCl. The precipitate was filtered to give 101 g (92percent) of the desired product; m.p. 184°-185° C. The NMR and IR spectra were consistent with the assigned structure.
Reference：
[1] Patent: US4582855, 1986, A,
[2] Patent: US4402974, 1983, A,
[3] Patent: US4798892, 1989, A,
41
[ 3964-56-5 ]
[ 584-08-7 ]
[ 50638-47-6 ]
Reference：
[1] Patent: US5739166, 1998, A,
42
[ 124-38-9 ]
[ 584-08-7 ]
[ 5391-88-8 ]
[ 97364-15-3 ]
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 43, p. 13426 - 13430[2] Angew. Chem., 2017, vol. 129, p. 13611 - 13615,5
43
[ 3262-72-4 ]
[ 584-08-7 ]
[ 2766-43-0 ]
Reference：
[1] Patent: US5380945, 1995, A,
44
[ 1722-12-9 ]
[ 57260-73-8 ]
[ 584-08-7 ]
[ 137583-05-2 ]
Reference：
[1] Patent: US6159964, 2000, A,
45
[ 584-08-7 ]
[ 72537-17-8 ]
[ 89402-42-6 ]
Reference：
[1] Patent: US4625035, 1986, A,
[2] Patent: US4480102, 1984, A,
46
[ 124-38-9 ]
[ 584-08-7 ]
[ 72537-17-8 ]
[ 89402-42-6 ]
Reference：
[1] Patent: US4480102, 1984, A,
47
[ 584-08-7 ]
[ 147-85-3 ]
[ 27957-91-1 ]
Reference：
[1] Patent: US5424444, 1995, A,
[2] Patent: US5508418, 1996, A,
[3] Patent: US5516912, 1996, A,
48
[ 124-38-9 ]
[ 584-08-7 ]
[ 25216-74-4 ]
[ 111331-82-9 ]
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 43, p. 13426 - 13430[2] Angew. Chem., 2017, vol. 129, p. 13611 - 13615,5
49
[ 181955-94-2 ]
[ 584-08-7 ]
[ 7757-82-6 ]
[ 85817-34-1 ]
Yield
Reaction Conditions
Operation in experiment
78%
With sodium cyanoborohydride; benzaldehyde; acetic acid In tetrahydrofuran; methanol
3. 4-Benzyl-2-hydroxymethylpiperazine To a cooled (0° C.) and stirred solution of Intermediate 1 (22 g, 57 mmol), acetic acid (9.7 mL, 171 mmol) and sodium cyanoborohydride (7.16 g, 114 mmol) in methanol (440 mL) was added benzaldehyde (5.8 mL, 57 mmol). The cooling bath was removed and the mixture stirred at room temperature for 3 h. Saturated K2 CO3 solution (200 mL) was added and the mixture stirred for 15 min. The solvents were evaporated and the residue partitioned between CH2 Cl2 (2*400 mL) and water (500 mL). The combined organic layers were dried (Na2 SO4) and evaporated. The residue was chromatographed on silica gel, eluding with CH2 Cl2: MeOH (95:5) to afford an inseparable mixture of 4-benzylpiperazine-2-carboxylic acid methyl ester and the corresponding ethyl ester (5.33 g, 40percent), in a 7:1 ratio respectively. To a solution of the esters (5.33 g, 22.8 mmol) in THF (200 mL) was added LiAl H4 (22.8 mL of a 1.0M solution in ether) dropwise at -10° C. Stirring was continued at -10° C. for 2.5 h. After this time saturated Na2 SO4 solution (30 mL) was added and the cooling bath removed. Stirring was continued at room temperature for 10 min then the mixture was filtered and the filtrate evaporated. The residue was chromatographed on silica gel, eluding with CH2 Cl2:MeOH:NH3 (90:8:1-->60:8:1) to afford the title compound (3.7 g, 78percent) as a colourless oil. 1 H NMR (360 MHz, CDCl3) δ 1.89-1.95 (1H, m), 2.08-2.30 (3H, m), 2.68-2.71 (2H, m), 2.86-3.04 (3H, m), 3.45-3.60 (4H, m), 7.13-7.32 (5H, m). MS (ES+) 207 (M+1).
b 2-Chloro4-pyridinecarboxaldehyde A suspension of 2-chloro-4-hydroxymethylpyridine (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in ethyl acetate was refluxed for 3 h. Another portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) was added and heating was continued another 3.5 h. The reaction mixture was cooled, filtered through a pad of celite, concentrated under reduced and chromatographed with 0.5-4percent CH3 OH/CH2 Cl2. The combined fractions were washed with NaHCO3 (sat.), 10percent Na2 S2 O3, and NaCl (sat.), dried, filtered and evaporated to give the title compound as a light yellow solid (5.3 g, 67percent yield). 1 H NMR (CDCl3): δ10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J=5.0 Hz).
67%
With N-Bromosuccinimide In ethyl acetate
b 2-Chloro-4-pyridinecarboxaldehyde A suspension of 2-chloro-4-hydroxymethylpyridine (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in ethyl acetate was refluxed for 3 h. Another portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) was added and heating was continued another 3.5 h. The reaction mixture was cooled, filtered through a pad of celite, concentrated under reduced and chromatographed with 0.5-4percent CH3 OH/CH2 Cl2. The combined fractions were washed with NaHCO3 (sat.), 10percent Na2 S2 O3, and NaCl (sat.), dried, filtered and evaporated to give the title compound as a light yellow solid (5.3 g, 67percent yield). 1 H NMR (CDCl3): δ10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H,J=5.0 Hz).
Reference：
[1] Patent: US5977103, 1999, A,
[2] Patent: US5756499, 1998, A,
56
[ 100704-10-7 ]
[ 497-19-8 ]
[ 584-08-7 ]
[ 101066-61-9 ]
Yield
Reaction Conditions
Operation in experiment
67%
With N-Bromosuccinimide In ethyl acetate
b 2-Chloro-4-pyridinecarboxaldehyde A suspension of 2-chloro-4-pyridinemethanol (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in EtOAc was refluxed for 3 h. A Second portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) were added and the reaction was heated to reflux for an additional 3.5 h, cooled and filtered through a pad of celite. The filtrate, after concentrattion to a small volume, was subjected to flash chromatography eluding with 0.5-4percent CH3 OH/CH2 Cl2. The fractions containing product were combined, washed successively with sat aq NaHCO3 10percent Na2 S2 O3, and brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a light yellow solid; yield 5.3 g (67percent). 1 H NMR (CDCl3) δ 10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J=5.0 Hz).
67%
With N-Bromosuccinimide In ethyl acetate
b 2-Chloro-4-pyridinecarboxaldehyde A suspension of 2-chloro-4-pyridinemethanol (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in EtOAc was refluxed for 3 h. A second portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) were added and the reaction was heated to reflux for an additional 3.5 h, cooled and filtered through a pad of celite. The filtrate, after concentration to a small volume, was subjected to flash chromatography eluding with 0.5-4percent CH3 OH/CH2 Cl2. The fractions containing product were combined, washed successively with sat aq NaHCO3 10percent Na2 S2 O3, and brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a light yellow solid; yield 5.3 g (67percent). 1 H NMR,,(CDCl3) δ 10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J=5.0 Hz).
Reference：
[1] Patent: US5658903, 1997, A,
[2] Patent: US5739143, 1998, A,
57
[ 53250-83-2 ]
[ 504-02-9 ]
[ 584-08-7 ]
[ 75-86-5 ]
[ 99105-77-8 ]
Reference：
[1] Patent: US5318947, 1994, A,
58
[ 110-91-8 ]
[ 119312-61-7 ]
[ 584-08-7 ]
[ 119313-12-1 ]
Reference：
[1] Patent: US5077402, 1991, A,
59
[ 2457-50-3 ]
[ 7677-24-9 ]
[ 584-08-7 ]
[ 79-44-7 ]
[ 159307-02-5 ]
Reference：
[1] Patent: US5350696, 1994, A,
[2] Patent: US5559214, 1996, A,
[3] Patent: US5760191, 1998, A,
60
[ 124-38-9 ]
[ 41604-19-7 ]
[ 584-08-7 ]
[ 137045-30-8 ]
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 43, p. 13426 - 13430[2] Angew. Chem., 2017, vol. 129, p. 13611 - 13615,5
b) 5-Ethynyl-pyrimidine; Potassium carbonate (7.38 g, 53.4 mmol) was added in one portion to a stirred solution of <strong>[216309-28-3]5-trimethylsilanylethynyl-pyrimidine</strong> (4.71 g, 26.7 mmol) in methanol (10 ml). The reaction mixture was stirred for 2 hours at room temperature then concentrated in vacuo. The residue was suspended in dichloromethane and the inorganic solids were removed by filtration. The filtrate was concentrated in vacuo to remove ca. 95percent of the solvent to afford 5-ethynyl-pyrimidine as a brown oil in crude form. This material was used in the subsequent Sonogashira reaction without further purification.
PART A -- Preparation of methyl 3-fluoro-4-[2-(2-ethoxyethoxy)-ethoxy]-benzoate. Into a 500-ml, round-bottom flask equipped with a magnetic stirrer, heating mantle and condenser were placed 5.7 g (33.5 mmol) <strong>[403-01-0]methyl 3-fluoro-4-hydroxybenzoate</strong>, 8.5 g (43.2 mmol) 1-bromo-2-(2-ethoxyethoxy)-ethane, 23.2 g of powdered anhydrous potassium carbonate and 350 ml acetonitrile. After stirring the reaction mixture under reflux for four hours, TLC analysis showed that none of the phenolic starting material remained. Three hundred ml of the acetonitrile was then distilled off and 300 ml dichloromethane was added. The reaction mixture was filtered through Celite and the solids were washed thoroughly with dichloromethane. Evaporation of the filtrate yielded product in the form of a yellow oil. Purification by flash chromatography on silica gel with 4percent ethyl ether in dichloromethane, followed by low temperature recrystallization from pentane, yielded 0.55 g of white crystals, 89percent, m.p. 33-36.5°C. The structure was confirmed by infrared, nuclear magnetic resonance and mass spectral analyses.
4,4'-Bis-[9-(3,6-diphenylcarbazolyl)]-1-1,1'-biphenyl[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE II Synthesis of 4,4'-Bis-[9-(3,6-diphenylcarbazolyl)]-1-1,1'-biphenyl In a 50 milliliter round bottom flask there were added 4,4'-diiodo-1,1'-biphenyl (2.1 grams), 3,6-diphenyl carbazole (3.3 grams), potassium carbonate powder (1.4 grams), copper sulfate pentahydrate (0.06 grams), and 5 milliliters of tridecane. The resulting mixture was heated to 230° C. and stirred at this temperature under argon for 24 hours. After cooling to room temperature (~23° C.), the solids content resulting was ground into slurry, which slurry was then transferred to a filtration funnel, washed with hexane to remove the tridecane, followed by washing with 3 percent hydrochloric acid and water. The solid resulting was then dissolved in hot toluene. The insoluble residue was filtered hot. After cooling to room temperature, the product was crystallized from the solution to yield 2.3 grams of 4,4'-bis-[9-(3,6-diphenylcarbazolyl)]-1,1'-biphenyl as a yellowish powder. This compound had a melting point of 294° C. Its chemical structure was confirmed by proton analysis.
N-(1-ethylpyrazol-5-yl)-4-nitroanthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.5 g (63%)
Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 2-chloro-4-nitrobenzoic acid (4.03 g, 0.02 mol), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol), DMF (25 ml), K2 CO3 (2.76 g, 0.02 mol) and Cu(OAc)2. H2 O (0.5 g) is refluxed for 24 hours. The reaction mixture is cooled to room temperature, poured into ice water and then acidified with acetic acid to a pH of 5. A solid forms which is collected by filtration and dried to afford 3.5 g (63%) of N-(1-ethylpyrazol-5-yl)-4-nitroanthranilic acid.
Example A N-(Benzyloxycarbonyl)-3-(2-thienyl)-D,L-alanine Into a 500 ml flask was placed 3.0 g of 3-(2-Thienyl)-D,L-alanine (optically active material in the L-form is available from Aldrich or SIGMA and could be used to obtain an optically active product) in 75 ml H2 O/60 ml dioxane, and 5.6 g K2 CO3 was added, followed by 2.85 ml of carbobenzyloxy chloride. The mixture was stirred rapidly for 1 hour. TLC (21/7/7/9, EtOAc/AcOH/CH3 CN/H2 O: showed that the starting material was gone. A new higher Rf product was seen. The dioxane was concentrated off and the aqueous layer was washed with Et2 O (75 ml). The aqueous layer was mixed with CH2 Cl2 (150 ml) and acidified to pH=2.0 with 5 N HCl. The desired N-(Benzyloxycarbonyl)-3-(2-thienyl-D,L-alanine was extracted with CH2 Cl2. The organic layer was separated and dried with Na2 SO4, filtered, and concentrated to give 5.05 g of desired N-(Benzyloxycarbonyl)-3-(2-thienyl)-D,L-alanine (98% yield). 1 H NMR (300 MHz, CDCl3): delta 7.37 (m, 5H); 7.18 (d, J=4 Hz, 1H); 6.95 (m, 1H); 6.83 (m, 1H); 5.35 (d, J=8 Hz, 1M); 5.15 (s, 2H); 4.7 (m, 1H); and 3.4 (m, 2H).
98%
In 1,4-dioxane; water;
Example A N-(Benzyloxycarbonyl)-3-(2-thienyl)-D,L-alanine Into a 500 ml flask was placed 3.0 g of 3-(2-thienyl)-D,L-alanine (optically active material in the L-form is available from Aldrich or SIGMA and could be used to obtain an optically active product) in 75 ml H2 O/60 ml dioxane, and 5.6 g K2 CO3 was added, followed by 2.85 ml of carbobenzyloxy chloride. The mixture was stirred rapidly for 1 hour. TLC (21/7/7/9, EtOAc/AcOH/CH3 CN/H2 O) showed that the starting material was gone. A new higher Rf product was seen. The dioxane was concentrated off and the aqueous layer was washed with Et2 O (75 ml). The aqueous layer was mixed with CH2 Cl2 (150 ml) and acidified to pH=2.0 with 5 N HCl. The desired N-(Benzyloxycarbonyl)-3-(2-thienyl)-D,L-alanine was extracted with CH2 Cl2. The organic layer was separated and dried with Na2 SO4, filtered, and concentrated to give 5.05 g of desired N-(Benzyloxycarbonyl)-3-(2-thienyl)-D,L-alanine (98% yield). 1 H NMR (300 MHz, CDCl3): delta7.37 (m, 5H); 7.18 (d, J=4Hz, 1H); 6.95 (m, 1H); 6.83 (m, 1H); 5.35 (d, J=8Hz, 1M); 5.15 (s, 2H); 4.7 (m, 1H); and 3.4 (m, 2H).
3,5,-Dibromo-5'-methyl-[1,2']bipyridinyl-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper; sodium hydrogencarbonate;
Step 2 3,5,-Dibromo-5'-methyl-[1,2']bipyridinyl-2-one 3,5,-Dibromo-2-pyridinol (1.47 g, 5.81 mmol), 2-bromo-5-methylpyridine (1.00 g, 5.81 mmol), copper (0.008 g, 0.116 mmol) and K2 CO3 (0.883 g, 6.39 mmol) were heated at 180 C. for 18 hrs. The brown reaction mixture was cooled, diluted with EtOAc and stirred with saturated NaHCO3 for 1 hr. The aqueous layer was extracted with EtOAc (2*) and the combined organic extracts were washed with brine, dried (Na2 SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH2 Cl2 10:90 to 30:70 gradient elution) to afford the title compound as a white solid. 1 H NMR (400 MHz, CDCl3) delta 8.36 (s, 1H), 8.07(d, J=2.6 Hz, 1H), 7.86 (d, J=2.6 Hz, 1H), 7.83(d, 8.4 Hz, 1H), 7.66(d, J=8.4 Hz, 1H), and 2.41(s,3H) ppm.
5-bromopyrazine-2-carboxylic acid methyl ester[ No CAS ]
[ 75-09-2 ]
[ 4214-79-3 ]
[ 584-08-7 ]
5-(5-chloro-2-oxo-2H-pyridin-1-yl)-pyrazine-2-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper; In 5,5-dimethyl-1,3-cyclohexadiene; ethyl acetate;
Step 2 5-(5-chloro-2-oxo-2H-pyridin-1-yl)-pyrazine-2-carboxylic acid methyl ester <strong>[4214-79-3]5-Chloro-2-pyridinol</strong> (1.43 g, 11.05 mmol), the bromide from step 1 (2.39 g, 11.05 mmol), copper (0.021 g, 0.33 mmol) and K2 CO3 (1.68 g, 12.15 mmol) were heated at 120° C. for 3 hrs. Xylene (2 ml) was added and heating was continued at 1 reflux for 2 hrs. The reaction mixture was cooled, diluted with EtOAc and water and the pH was adjusted to 9 with NH4 Cl. The aqueous layer was extracted with EtOAc (2*) and the combined organic extracts were washed with brine, dried (Na2 SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: hexanes 20:80 to EtOAc: CH2 Cl2 10:90 gradient elution) to afford the title compound as a solid. 1 H NMR (400 MHz, CDCl3) delta 9.60 (d, J=1.3 Hz, 1H), 9.23 (d, J=1.3 Hz,1H), 8.13 (d, J=2.9 Hz,1H), 7.38(dd, J=9.8 and 2.9 Hz, 1H), 6.66(d, J=9.7 Hz, 1H) and 4.07 (s, 3H) ppm.
Step 1 5-Chloro-5'-methyl-[1,2']bipyridinyl-2-one <strong>[4214-79-3]5-Chloro-2-pyridinol</strong> (2.26 g, 17.4 mmol), 2-bromo-5-methylpyridine (3.00 g, 17.4 mmol), copper (0.022 g, 0.35 mmol) and K2 CO3 (2.66 g, 19.2 mmol) were heated at 180° C. for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (2*) and the combined organic extracts were washed with brine, dried (Na2 SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH2 Cl2 20:80 to 50:50 gradient elution) to afford the title compound as a white solid. 1 H NMR (400 MHz, CDCl3) delta 8.37 (s, 1H), 7.96(d, J=3.0 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.65(dd, J=2.4 and 8.2 Hz, 1H), 7.32(dd, J=2.9 and 9.7 Hz, 1H), 6.61(d, J=9.7 Hz, 1H) and 2.39(s,3H)ppm.
5'-hydroxymethyl-6-methyl-[1,2']bipyridinyl-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper;
Step 2 5'-Hydroxymethyl-6-methyl-[1,2']bipyridinyl-2-one 2-bromo(5-hydroxymethyl)pyridine (3.00 g, 15.95 mmol), 6-methylpyridone (2.08 g, 19.14 mmol), Copper (2.64, 19.14 mmol) and K2 CO3 (0.635 g, 10.0 mmol) were heated at 140 C. for 3 hrs. Added CHC13 to reaction when still warm and let stirred overnight. Filtered the mixture through a frit, concentrated in vacuo and the residue was chromatographed (silica gel, 0-4% MeOH-EtOAc solution). Obtained the title compound as a brown oil.
(a) A mixture of 2,5-dibromobenzoic acid (25 g, 0.09 mol), DMF (200 ml), 5-amino-1-ethylpyrazole (10 g, 0.09 mol), Cu(OAc)2 (1 g) and K2 CO3 (12.3 g, 0.09 mol) is heated at reflux for about 2 days. The reaction mixture is poured into water, acidified with acetic acid, and the precipitate which forms is collected by filtration to afford 12.6 g of N-(1-ethylpyrazol-5-yl)-5-bromoanthranilic acid.
Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 2,5-dibromobenzoic acid (25 g, 0.09 mol), DMF (200 ml), 5-amino-1-ethylpyrazole (10 g, 0.09 mol), Cu(OAc)2 (1 g) and K2 CO3 (12.3 g, 0.09 mol) was heated at reflux for about 2 days. The reaction mixture was poured into water, acidified with acetic acid and the precipitate which formed was collected by filtration to afford 12.6 g of N-(1-ethylpyrazol-5-yl)-5-bromoanthranilic acid.
N-(1-ethylpyrazol-5-yl)-3-bromoanthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 5-amino-1-ethylpyrazole (33.7 g, 0.3 mol), 2,5-dibromobenzoic acid (84 g, 0.3 mol), K2 CO3 (41.4 g, 0.3 mol), Cu(OAc)2 (1 g) and DMF (500 ml) is refluxed overnight. The reaction mixture is poured into ice water (4 L), and is then acidified with acetic acid. The solid which forms is collected by filtration and dried to afford 35 g of a mixture of N-(1-ethylpyrazol-5-yl)-3-bromoanthranilic acid and N-(1-ethylpyrazol-5-yl)-5-bromoanthranilic acid.
Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 5-amino-1-ethylpyrazole (33.7 g, 0.3 mol), 2,5-dibromobenzoic acid (84 g, 0.3 mol), K2 CO3 (41.4 g, 0.3 mol), Cu(OAc)2 (1 g) and DMF (500 mL) was refluxed overnight. The reaction mixture was poured into ice-water (4 L) and was then acidified with acetic acid. The solid which formed was collected by filtration and dried to afford 35 g of a mixture of N-(1-ethylpyrazol-5-yl)-3-bromoanthranilic acid and N-(1-ethylpyrazol-5-yl)-5-bromoanthranilic acid.
N-(1-ethylpyrazole-5-yl)-5-acetamidoanthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 5-acetamido-2-bromobenzoic acid (7 g, 27 mmol), DMF (25 ml), Cu(OAc)2 (0.2 g), 5-amino-1-ethyl-pyrazole (3 g, 27 mmol) and K2 CO3 (3.7 g, 27 mm is refluxed for about 2 days. The reaction mixture is poured into water, acidified with acetic acid and cooled. A solid forms which is collected by filtration to afford 2 g of N-(1-ethylpyrazole-5-yl)-5-acetamidoanthranilic acid.
Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 5-acetamido-2-bromobenzoic acid (7 g, 27 mmol), DMF (25 ml), Cu(OAc)2 (0.2 g), 5-amino-1-ethyl-pyrazole (3 g, 27 mmol) and K2 CO3 (3.7 g, 27 mmol) was refluxed for about 2 days. The reaction mixture was poured into water, acidified with acetic acid and cooled. A solid formed which was collected by filtration to afford 2 g of N-(1-ethylpyrazole-5-yl)-5-acetamidoanthranilic acid.
N-(1-ethylpyrazol-5-yl)-5-(methylsulfonyl)anthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Cu(OAc)2; In N,N-dimethyl-formamide;
(b) A mixture of 2-chloro-5-(methylsulfonyl)benzoic acid (5.0 g, 21.4 mmol), 5-amino-1-ethylpyrazole (2.4 g, 21.4 mmol), DMF (50 ml), Cu(OAc)2 (0.5 g) and K2 CO3 (2.76 g, 20 mmol) is heated at reflux overnight. The reaction mixture is poured into water, acidified with acetic acid and extracted with CH2 Cl2. The CH2 Cl2 layer is evaporated to afford N-(1-ethylpyrazol-5-yl)-5-(methylsulfonyl)anthranilic acid.
Cu(OAc)2; In N,N-dimethyl-formamide;
(b) A mixture of 2-chloro-5-(methylsulfonyl)benzoic acid (5.0 g, 21.4 mmol), 5-amino-1-ethylpyrazole (2.4 g, 21.4 mmol), DMF (50 ml), Cu(OAc)2 (0.5 g) and K2 CO3 (2.76 g, 20 mmol) was heated at reflux overnight. The reaction mixture was poured into water, acidified with acetic acid and extracted with CH2 Cl2. The CH2 Cl2 layer was evaporated to afford N-(1-ethylpyrazol-5-yl)-5-(methylsulfonyl)anthranilic acid.
N-(1-ethylpyrazol-5-yl)-4,5-dimethoxyanthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12.8 g (97%)
Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 5-amino-1-ethylpyrazole (5.0 g, 45 mmol), 2-bromo-4,5-dimethoxybenzoic acid (11.76 g, 45 mmol), K2 CO3 (6.21 g, 45 mmol), Cu(OAc)2 (0.8 g, 400 mmol) and DMF (125 ml) is refluxed overnight. The reaction mixture is cooled, poured into water and acidified with acetic acid. The resulting solid is collected by filtration and dried to afford 12.8 g (97%) of N-(1-ethylpyrazol-5-yl)-4,5-dimethoxyanthranilic acid.
12.8 g (97%)
Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 5-amino-1-ethylpyrazole (5.0 g, 45 mmol), 2-bromo-4,5-dimethoxybenzoic acid (11.76 g, 45 mmol), K2 CO3 (6.21 g, 45 mmol), Cu(OAc)2 (0.8 g, 400 mmol) and DMF (125 ml) was refluxed overnight. The reaction mixture was cooled, poured into water and acidified with acetic acid. The resulting solid was collected by filtration and dried to afford 12.8 g (97%) of N-(1-ethylpyrazol-5-yl)-4,5-dimethoxyanthranilic acid.
N-(1-ethylpyrazol-5-yl)-4-carboxyanthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Cu(OAc)2; In 1,2-dimethoxyethane;
(a) A mixture of 2-bromoterephthalic acid (4.8 g, 0.02 mol), DME (50 ml), Cu(OAc)2 (0.2 g), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol) and K2 CO3 (2.71 g, 0.02 mol) is heated at 135 C. overnight, then at reflux overnight. The reaction mixture is poured into water, acidified with acetic acid and the precipitate which forms is collected by filtration and dried to afford 2.5 g of N-(1-ethylpyrazol-5-yl)-4-carboxyanthranilic acid.
Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 2-bromoterephthalic acid (4.8 g, 0.02 mol), DMF (50 ml), Cu(OAc)2 (0.2 g), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol) and K2 CO3 (2.71 g, 0.02 mol) was heated at 135 C. overnight, then at reflux overnight. The reaction mixture was poured into water, acidified with acetic acid and the precipitate which formed was collected by filtration and dried to afford 2.5 g of N-(1-ethylpyrazol-5-yl)-4-carboxyanthranilic acid.
N-(1-ethylpyrazol-5-yl)-5-nitroanthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.8 g (68%)
In N,N-dimethyl-formamide;
(a) A mixture of 2-chloro-5-nitrobenzoic acid (4.03 g, 0.02 mol), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol), DMF (25 ml), K2 CO3 (2.76 g, 0.02 mol) and Cu(OAc)2 H2 O (0.5 g) is refluxed for 24 hours. The reaction mixture is cooled to room temperature, poured into ice waterl and acidified with acetic acid to a pH of 5. A solid forms which is collected by filtration and dried to afford 3.8 g (68%) of N-(1-ethylpyrazol-5-yl)-5-nitroanthranilic acid.
With trichlorophosphate;Cu(OAc)2; In dichloromethane; N,N-dimethyl-formamide;
(c) A mixture of 2-iodo-4-methoxybenzoic acid (13.6 g, 48.9 mmol), 5-amino-1-ethylpyrazole (5.5 g, 49 mmol), DMF (100 ml), K2 CO3 (6.9 g, 0.05 mol) and Cu(OAc)2 (0.5 g) is refluxed overnight. The reaction mixture is poured into water (500 ml) and acidified with acetic acid to a pH of 5-6. The product slowly crystallized from the solution and is collected by filtration and washed with water. The solid is taken up in CH2 Cl2 /methanol, dried, filtered and evaporated. The residue is combined with POCl3 (60 ml) and refluxed overnight. The reaction mixture is cooled, poured into water and neutralized with concentrated NH4 OH. The mixture is extracted with CH2 Cl2, and the CH2 Cl2 extracts are evaporated, and the residue is purified by column chromatography on silica gel eluding with ethyl acetate to afford 5 g of 1-ethyl-4-chloro-7-methoxy-1H-pyrazolo[3,4-b]quinoline, m.p. 114-115 C.
With trichlorophosphate;Cu(OAc)2; In dichloromethane; N,N-dimethyl-formamide;
(c) A mixture of 2-iodo-4-methoxybenzoic acid (13.6 g, 48.9 mmol), 5-amino-1-ethylpyrazole (5.5 g, 49 mmol), DMF (100 ml), K2 CO3 (6.9 g, 0.05 mol) and Cu(OAc)2 (0.5 g) was refluxed overnight. The reaction mixture was poured into water (500 ml) and acidified with acetic acid to a pH of 5-6. The product slowly crystallized from the solution and was collected by filtration and washed with water. The solid was taken up in CH2 Cl2 /methanol, dried, filtered and evaporated. The residue was combined with POCl3 (60 ml) and refluxed overnight. The reaction mixture was cooled, poured into water and neutralized with concentrated NH4 OH. The mixture was extracted with CH2 Cl2, and the CH2 Cl2 extracts were evaporated and the residue was purified by column chromatography on silica gel eluding with ethyl acetate to afford 5 g of 1-ethyl-4-chloro-7-methoxy-1H-pyrazolo[3,4-b]quinoline, m.p. 114-115 C.
Step 1 5-Chloro-1-(4-hydroxymethyl-phenyl)-1H-pyridin-2-one <strong>[4214-79-3]5-Chloro-2-pyridinol</strong> (0.61 g, 4.7 mmol), 4-iodobenzyl-alcohol (1.00 g, 4.27 mmol), Copper (0.27 g, 4.27 mmol) and K2 CO3 (0.65 g, 4.70 mmol) were heated at 180° C. for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (2*) and the combined organic extracts were washed with brine, dried (Na2 SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc as eluent) to afford the title compound as a white solid. 1 H NMR (400 MHz, CD3 OD) delta 7.74 (d, J=2.7 Hz, 1H), 7.59 (dd, J=3.0 and 9.6 Hz, 1H), 7.51 (d, J=8.6 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 6.61 (d, J=9.4 Hz, 1H) and 4.67(s,1H) ppm.
Ethyl (3-bromophenyl)acetate (Compound B1) 100 g (463 mmol) of 3-bromophenylacetic acid was converted into the title compound (yellow oil) using 2 g of conc. H2 SO4 and 500 ml of ethanol by refluxing the reaction for 16 hours. Thereafter, the reaction mixture was cooled to ambient temperature, stirred with solid K2 CO3 for 30 minutes and then filtered. The filtrate was concentrated in vacuo, diluted with Et2 O, washed with 10% aqueous NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo to give the title compound. PMR (CDCl3): delta 1.26 (3H, t, J=7.0 Hz), 3.56 (2H, s), 4.16 (2H, q, J=7.0 Hz), 7.16-7.26 (2H, m), 7.38-7.46 (2H, m).
3-Chloro-4-methoxybenzaldehyde A mixture of 3-chloro-4-hydroxybenzaldehyde (25 g, 160 mmol), iodomethane (27.25 g, 192 mmol), K2 CO3 (granular, anhydrous) (110.6 g, 800 mmol), and acetone (300 mL) was refluxed for 3 hours. The reaction mixture was then cooled to room temperature. Diethyl ether (500 mL) was added and the mixture was filtered through paper to remove the inorganic solids. the filtrate was evaporated under reduced pressure, dissolved in diethyl ether (800 mL), and washed with 0.1 N NaOH (3*100 mL). The organic layer was dried (Na2 SO4) and evaporated under vacuum to yield 24 g, 92percent yield of crude product. This material was further purified by chromatography on silica gel (50 mm*30 cm) (elution with hexane-EtOAc, 5:1) to give 15.02 g, 56percent yield of a white solid: TLC (hexane-EtOAc, 5:1) Rf =0.24; GC Rt =4.75 min; MS (EI) m/z 170(M+), 172(M+2).
56%
In diethyl ether; acetone;
3-Chloro-4-methoxybenzaldehyde A mixture of 3-chloro-4-hydroxybenzaldehyde (25 g, 160 mmol), iodomethane (27.25 g, 192 mmol), K2 CO3 (granular, anhydrous) (110.6 g, 800 mmol), and acetone (300 mL) was refluxed for 3 hours. The reaction mixture was then cooled to room temperature. Diethyl ether (500 mL) was added and the mixture was filtered through paper to remove the inorganic solids. the filtrate was evaporated under reduced pressure, dissolved in diethyl ether (800 mL), and washed with 0.1N NaOH (3*100 mL). The organic layer was dried (Na2 SO4) and evaporated under vacuum to yield 24 g, 92percent yield of crude product. This material was further purified by chromatography on silica gel (50 mm*30 cm) (elution with hexane-EtOAc, 5:1) to give 15.02 g, 56percent yield of a white solid: TLC (hexane-EtOAc, 5:1) Rf =0.24; GC Rt =4.75 min; MS (EI) m/z 170(M+), 172(M+2).
With sodium hydroxide; lithium aluminium tetrahydride; In tetrahydrofuran; ethanol; ethyl acetate;
EXAMPLE 18A STR36 Intermediate: 1-Benzyl-4-oxiranylpiperidine A slurry of 4-piperidinyl ethyl ester (6.36 mol), K2 CO3 (10.98 mol) and benzyl chloride (7.63 mol) in ethanol (5 L) was stirred at room temperature under nitrogen for forty-eight hours. The pale yellow slurry was filtered through celite. The filtrate was concentrated to an orange oil which was stirred with EtOAc (3 L) and H2 O (1.5 L) for five minutes. The organic layer was isolated, washed with H2 O (2*500 mL) and brine (1*500 ml) dried (MgSO4) and filtered. The filtrate was concentrated to give ethyl N-benzyl isonipecotate as an orange oil. LAH (1M solution in THF, 4.37 mol) was diluted with THF (4 L), the solution was chilled to 0° C. via IPA/dry-ice bath, under nitrogen. A solution of ethyl N-benzyl isonipecotate (2.95 mol) in THF (4 L) was added over two hours. The cold bath was removed and the solution was stirred for three hours before heating at reflux for eighteen hours. The heating mantle was removed and the solution was stirred at room temperature for eighteen hours before being quenched at 0° C. by the dropwise addition of: EtOAc (110 mL), H2 O (164 mL), 10percent aqueous sodium hydroxide (246 mL) and H2 O (410 mL). The slurry was stirred at room temperature for eighteen hours and filtered which provided N-Benzyl-4-hydroxymethylpiperidine.
Example 6 (Production of optically active 4-methyl-1,3-dioxolan-2-one) Under a flow of nitrogen, a 100 ml four-neck flask equipped with a reflux condenser was fed with 9.45 g (0.124 mol; optical purity: 99.2%e.e.) of R-1,2-propanediol, 0.86 g (0.00622 mol, 0.05 equiv.) of potassium carbonate and 26.87 g (0.298 mol, 2.4 equiv.) of dimethyl carbonate. The mixture was stirred at 60 C. for 1 hour, and there was formed the object compound R-4-methyl-1,3-dioxolan-2-one with a 90% conversion of 1,2 -propanediol. The conversion approximately agreed with the conversion calculated from the equilibrium constant. Then, the heating and stirring were continued for another 30 minutes and consequently the reaction mixture went into suspension, having a pale-red color. The reaction mixture was cooled with an ice bath, and 0.62 g (1 equiv. relative to K2 CO3) of concentrated sulfuric acid (98 weight % purity) was added thereto to precipitate white solids out. The white solids were suction-filtered off through filter paper (5A size). The distillates having boiling points of 70 C. or lower were evaporated off from the filtrate at atmospheric pressure, then, the resultant residue was subjected to further distillation under reduced pressure (5 mmHg) using a Vigreaux column (200 mm) to collect the distillates having boiling points of between 91 to 92 C., and there was obtained R-4-methyl-1,3-dioxolan-2-one. The yield of R-4-methyl-1,3-dioxolan-2-one was 8.35 g, its purity was 98.5% (by gas chromatography), and its optical purity was 99.2%e.e. (by high performance liquid chromatography).
b 2-Chloro4-pyridinecarboxaldehyde A suspension of 2-chloro-4-hydroxymethylpyridine (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in ethyl acetate was refluxed for 3 h. Another portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) was added and heating was continued another 3.5 h. The reaction mixture was cooled, filtered through a pad of celite, concentrated under reduced and chromatographed with 0.5-4% CH3 OH/CH2 Cl2. The combined fractions were washed with NaHCO3 (sat.), 10% Na2 S2 O3, and NaCl (sat.), dried, filtered and evaporated to give the title compound as a light yellow solid (5.3 g, 67% yield). 1 H NMR (CDCl3): delta10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J=5.0 Hz).
67%
With N-Bromosuccinimide; In ethyl acetate;
b 2-Chloro-4-pyridinecarboxaldehyde A suspension of 2-chloro-4-hydroxymethylpyridine (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in ethyl acetate was refluxed for 3 h. Another portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) was added and heating was continued another 3.5 h. The reaction mixture was cooled, filtered through a pad of celite, concentrated under reduced and chromatographed with 0.5-4% CH3 OH/CH2 Cl2. The combined fractions were washed with NaHCO3 (sat.), 10% Na2 S2 O3, and NaCl (sat.), dried, filtered and evaporated to give the title compound as a light yellow solid (5.3 g, 67% yield). 1 H NMR (CDCl3): delta10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H,J=5.0 Hz).
Preparation of 1-(1-methyl-imidazolin-2-yl)-piperazine: 1.86 of Boc-piperazine were combined with 25 ml of water, 25 ml of methanol, 2.77 g of K2 CO3 and 1.5 g of <strong>[64205-92-1]imidazoline-2-sulphonic acid</strong> and stirred for 2 days at RT. After dilution with water the mixture was extracted with EE and chromatographed over silica gel. 0.8 g of 1-(imidazolin-2-yl)-4-Boc-piperazine were obtained.
3-[4-[1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium iodide; In acetonitrile;
EXAMPLE 36 3-[4-[1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone hydrochloride A mixture of 3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone (3.50 g), <strong>[87691-88-1]1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride</strong> (3.70 g), K2 CO3 (6.34 g), NaI (330 mg) and acetonitrile (175 mL) was heated at 95 C. (bath temperature) under nitrogen. After 21 hours, TLC analysis (silica gel, 5% MeOH/CH2 Cl2) showed the absence of starting bromide and the presence of a major product, Rf =0.33. The reaction mixture was cooled to room temperature, ethyl acetate (150 mL) was added, and the mixture filtered. The filtrate was concentrated in vacuo to an oil which was triturated with ethyl acetate. The mixture was filtered again and the filtrate, after concentration, was chromatographed (Waters Prep 500, one silica gel column, 3% MeOH/CH2 CL2) to give 3.48 g of a viscous oil. The oil was dissolved in diethyl ether (500 mL), the solution filtered to remove a fluffy solid, and the filtrate acidified to pH=1 (hydrion paper) with an HCl/diethyl ether solution. The resultant salt (3.23 g) was recrystallized from ethanol/ethyl acetate yielding 2.29 g of white needles, mp 222-227 C. ANALYSIS: Calculated for C20 H28 N4 OS2 ·HCl: 54.46%C; 6.63%H; 12.70%N; 8.04%Cl. Found: 53.93%C; 6.73%H; 12.58%N; 8.57%Cl.
With sodium iodide; In acetonitrile;
EXAMPLE 36 3-[4-[1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone hydrochloride A mixture of 3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone (3.50 g), <strong>[87691-88-1]1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride</strong> (3.70 g), K2 CO3 (6.34 g), NaI (330 mg) and acetonitrile (175 mL) was heated at 95 C. (bath temperature) under nitrogen. After 21 hours, TLC analysis (silica gel, 5% MeOH/CH2 Cl2) showed the absence of starting bromide and the presence of a major product, Rf =0.33. The reaction mixture was cooled to room temperature, ethyl acetate (150 mL) was added, and the mixture filtered. The filtrate was concentrated in vacuo to an oil which was triturated with ethyl acetate. The mixture was filtered again and the filtrate, after concentration, was chromatographed (Waters Prep 500, one silica gel column, 3% MeOH/CH2 CL2) to give 3.48 g of a viscous oil. The oil was dissolved in diethyl ether (500 mL), the solution filtered to remove a fluffy solid, and the filtrate acidified to pH=1 (hydrion paper) with an HCl/diethyl ether solution. The resultant salt (3.23 g) was recrystallized from ethanol/ethyl acetate yielding 2.29 g of white needles, mp 222-227 C. ANALYSIS: Calculated for C20 H28 N4 OS2 *HCl: 54.46%C; 6.63%H; 12.70%N; 8.04%Cl. Found: 53.93%C; 6.73%H; 12.58%N; 8.57%Cl.
3-(4-(1-[1,2-benzisothiazol-3-yl]-4-piperazinyl)butyl)-5-methyl-4-thiazolidinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium iodide; In acetonitrile;
EXAMPLE 61 3-(4-(1-[1,2-Benzisothiazol-3-yl]-4-piperazinyl)butyl)-5-methyl-4-thiazolidinone A mixture of 3-(4-bromobutyl)-5-methyl-4-thiazolidinone (4.00 g), <strong>[87691-88-1]1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride</strong> (4.46 g), K2 CO3 (8.00 g) and NaI (300 mg) in acetonitrile (210 ml) was heated at 40-45 C. for 64 hours and the product was processed in substantially the same manner as in Example 10 to afford 3.64 g of crystals, m.p. 113-115 C. ANALYSIS: Calculated for C19 H26 N4 OS2: 58.43%C; 6.71%H; 14.34%N. Found: 58.32%C; 6.69%H; 14.29%N.
3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-1-thia-3-azaspiro-[4.4]-nonan-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium iodide; In acetonitrile;
EXAMPLE 75 3-[4-[1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl]butyl]-1-thia-3-azaspiro[4.4]nonan-4-one A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]-nonan-4-one (4.50 g), <strong>[87691-88-1]1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride</strong> (4.33 g), K2 CO3 (7.45 g) and NaI (560 mg), in acetonitrile (220 ml) was heated at 65 C. for 14.5 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.25 g of crystals, m.p. 200-203 C. ANALYSIS: Calculated for C22 H30 N4 OS2 ·HCl: 56.57%C; 6.69%H; 11.99%N; 7.59%Cl. Found: 56.15%C; 6.75%H; 12.11%N; 7.88%Cl.
With sodium iodide; In acetonitrile;
EXAMPLE 75 3-[4-[1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl]-butyl]-1-thia-3-azaspiro[4.4]nonan-4-one A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]-nonan-4-one (4.50 g), <strong>[87691-88-1]1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride</strong> (4.33 g), K2 CO3 (7.45 g) and NaI (560 mg), in acetonitrile (220 ml) was heated at 65 C. for 14.5 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.25 g of crystals, m.p. 200-203 C. ANALYSIS: Calculated for C22 H30 N4 OS2 *HCl: 56.57%C; 6.69%H; 11.99%N; 7.59%Cl. Found: 56.15%C; 6.75%H; 12.11%N; 7.88%Cl.
3-(4-(1-[1,2-benzisothiazol-3-yl]-4-piperazinyl)butyl)-1-thia-3-azaspiro[4.5]decan-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium iodide; In acetonitrile;
EXAMPLE 80 3-(4-(1-[1,2-Benzisothiazol-3-yl]-4-piperazinyl)butyl)1-thia-3-azaspiro[4.5]decan-4-one A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]nonan-4-one (4.00 g), <strong>[87691-88-1]1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride</strong> (3.67 g), K2 CO3 (7.00 g) and NaI (300 mg) in acetonitrile (220 ml) was heated at 70 C. for 20 hours and the product was processed in substantially the same manner as in Example 10 to afford 3.01 g of crystalline solid, m.p. 209 C. ANALYSIS: Calculated for C23 H32 N4 OS2 ·HCl: 57.42%C; 6.91%H; 11.64%N; 7.37%Cl. Found: 57.51%C; 6.82%H; 11.75%N; 7.30%Cl.
With sodium iodide; In acetonitrile;
EXAMPLE 80 3-(4-(1-[1,2-Benzisothiazol-3-yl]-4-piperazinyl)butyl)-1-thia-3-azaspiro[4.5]decan-4-one A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]nonan-4-one (4.00 g), <strong>[87691-88-1]1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride</strong> (3.67 g), K2 CO3 (7.00 g) and NaI (300 mg) in acetonitrile (220 ml) was heated at 70 C. for 20 hours and the product was processed in substantially the same manner as in Example 10 to afford 3.01 g of crystalline solid, m.p. 209 C. ANALYSIS: Calculated for C23 H32 N4 OS2 *HCl: 57.42%C; 6.91%H; 11.64%N; 7.37%Cl. Found: 57.51%C; 6.82%H; 11.75%N; 7.30%Cl.
3-(4-(1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl)butyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium iodide; In acetonitrile;
EXAMPLE 79 3-(4-(1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl)butyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one hydrochloride A mixture of 3-(4-bromobutyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one (3.84 g), <strong>[87691-88-1]1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride</strong> (3.49 g), K2 CO3 (5.90 g) and NaI (280 mg) in acetonitrile (215 ml) was heated at between 65-80 C. for 16.5 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.86 g of crystals, m.p. 210-215 C. ANALYSIS: Calculated for C23 H32 N4 OS2 ·HCl: 57.42%C; 6.91%H; 11.64%N; 7.37%Cl. Found: 57.21%C; 6.87%H; 11.63%N; 7.03%Cl.
With sodium iodide; In acetonitrile;
EXAMPLE 79 3-(4-(1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl)butyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one hydrochloride A mixture of 3-(4-bromobutyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one (3.84 g), <strong>[87691-88-1]1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride</strong> (3.49 g), K2 CO3 (5.90 g) and NaI (280 mg) in acetonitrile (215 ml) was heated at between 65-80 C. for 16.5 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.86 g of crystals, m.p. 210-215 C. ANALYSIS: Calculated for C23 H32 N4 OS2 *HCl: 57.42%C; 6.91%H; 11.64%N; 7.37%Cl. Found: 57.21%C; 6.87%H; 11.63%N; 7.03%Cl.
3-(4-bromobutyl)-5-(2,2,2-trifluoroethyl)-4-thiazolidinone[ No CAS ]
3-(4-(1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl)butyl)-5-(2,2,2-trifluoroethyl)-4-thiazolidinone hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium iodide; In acetonitrile;
EXAMPLE 63 3-(4-(1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl)butyl)-5-(2,2,2-trifluoroethyl)-4-thiazolidinone hydrochloride A mixture of 3-(4-bromobutyl)-5-(2,2,2-trifluoroethyl)-4-thiazolidinone (3.20 g), <strong>[87691-88-1]1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride</strong> (2.81 g), K2 CO3 (4.83 g) and NaI (250 mg) in acetonitrile (280 ml) was heated at 70 C. for 15 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.30 g of crystals, m.p. 188-200 C. ANALYSIS: Calculated for C20 H25 F3 N4 OS2 ·HCl: 48.52%C; 5.29%H; 11.32%N; 7.16%Cl. Found: 48.51%C; 5.32%H; 11.20%N; 7.28%Cl.
With sodium iodide; In acetonitrile;
EXAMPLE 63 3-(4-(1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl)butyl)-5-(2,2,2-trifluorethyl)-4-thiazolidinone hydrochloride A mixture of 3-(4-bromobutyl)-5-(2,2,2-trifluoroethyl)-4-thiazolidinone (3.20 g), <strong>[87691-88-1]1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride</strong> (2.81 g), K2 CO3 (4.83 g) and NaI (250 mg) in acetonitrile (280 ml) was heated at 70 C. for 15 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.30 g of crystals, m.p. 188-200 C. ANALYSIS: Calculated for C20 H25 F3 N4 OS2 ·HCl: 48.52% C; 5.29% H; 11.32% N; 7.16% Cl. Found: 48.51% C; 5.32% H; 11.20 % N; 7.28% Cl.
methyl (Z)-4-<<2-butyl-5-<(1-butyl-3-<(2-amino-4-thiazolyl)methyl>-2,5-dioxo-4-imidazolidinylidene)methyl>-1H-imidazol-1-yl>methyl>benzoate dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dichloromethane; N,N-dimethyl-formamide;
EXAMPLE 62 Methyl Z-4-[[2-butyl-5-[[1-butyl-3-[(2-amino-4-thiazolyl)methyl]-2,5-dioxo -4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate dihydrochloride To a solution of methyl Z-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene) methyl]-1H-imidazol-1-yl]methyl]benzoate (0.569 g, 1.2 mmol) in DMF (5 mL) is added K2 CO3 (2.0 g, 15 mmol). After stirring for 5 minutes 2-amino-4-chloromethylthiazole hydrochloride (0.222 g, 1.2 mmol) is added. The mixture is stirred for 48 hours and the filtered. The filtrate is concentrated in vacuo and dissolved in methylene chloride (30 mL). This solution is washed with water and drived over K2 CO3 and charcoal. A viscous oil is obtained by evaporation of the solvents in vacuo. This oil is dissolved in ether and treated with ethereal HCl to precipitate a gum which is collected by decantation. This gum is recrystallized from 2-propanol/ether. Anal. Calcd. for C28 H34 N6 O4 S. 2HCl. 2H2 O: C, 50.90; H, 6.10; N, 12.87. Found: C, 51.23; H, 6.10; N, 12.67. mp 171°-174° C.; MS (CI) 551 (M+1).
EXAMPLE 44 1-[4-(3-Bromopropoxy)-3-bromophenyl]ethanone A stirred mixture of <strong>[1836-06-2]3-bromo-4-hydroxyacetophenone</strong> (4.5 g, 21.2 mmoles), K2 CO3 (4 g) and 1,3-dibromopropane (7.6 g) in acetonitrile (200 ml) was heated at reflux for 2 hr. At the end of the reaction, the solvent was removed and the residue was dissolved in dichloromethane (400 ml) and filtered. The dichloromethane solution was concentrated to an oil. The oil was added to isopropyl ether and stirred to cause crystallization (4.1 g; 58%). The solid was recrystallized from isopropyl ether to give 3.5 g of 1-[4-(3-bromopropoxy)-3-bromophenyl]ethanone as glistening crystals, m.p.=83-84 C.
In dichloromethane; acetonitrile;
EXAMPLE 44 1-[4-(3-Bromopropoxy)-3-bromophenyl]ethanone A stirred mixture of <strong>[1836-06-2]3-bromo-4-hydroxyacetophenone</strong> (4.5 g, 21.2 mmol), K2 CO3 (4 g) and 1,3-dibromopropane (7.6 g) in acetonitrile (200 ml) was heated at reflux for 2 hours. At the end of the reaction, the solvent was removed and the residue was dissolved in dichloromethane (400 ml) and filtered. The dichloromethane solution was concentrated to an oil. The oil was added to isopropyl ether and stirred to cause crystallization (4.1 g; 58%). The solid was recrystallized from isopropyl ether to give 3.5 g of 1-[4-(3-bromopropoxy)-3-bromophenyl]ethanone as glistening crystals, m.p.=83-84 C. ANALYSIS: Calculated for C11 H12 Br2 O2: 39.31%C, 3.60%H, Found: 39.80%C, 3.55%H.
In dichloromethane; acetonitrile;
EXAMPLE 44 1-[4-(3-Bromopropoxy)-3-bromophenyl]ethanone A stirred mixture of 3-bromo4-hydroxyacetophenone (4.5 g, 21.2 mmol), K2 CO3 (4 g) and 1,3-dibromopropane (7.6 g) in acetonitrile (200 ml) was heated at reflux for 2 hours. At the end of the reaction, the solvent was removed and the residue was dissolved in dichloromethane (400 ml) and filtered. The dichloromethane solution was concentrated to an oil. The oil was added to isopropyl ether and stirred to cause crystallization (4.1 g; 58%). The solid was recrystallized from isopropyl ether to give 3.5 g of 1-[4-(3-bromopropoxy)-3-bromophenyl]ethanone as glistening crystals, m.p.=83-84 C. ANALYSIS: Calculated for C11 H12 Br2 O2: 39.31%C 3.60%H; Found: 39.80%C 3.55%H
With hydrogenchloride; thionyl chloride; triethylamine; In 1,4-dioxane; N-methyl-acetamide; ethyl acetate; acetonitrile;
Example 1 2-[2-chloro-4- (methylsulfonyl) benzoyl]-1,3-cyclohexanedione 42.5 g of 2-chloro-4-methylsulfonylbenzoic acid were boiled in 160 ml of dioxane with 5 drops of dimethylformamide and 25.1 ml of thionyl chloride until the evolution of gas subsided. The solvent was stripped off with the exclusion of moisture on a rotary evaporator. To the oily residue there were added at 0° C. 19.7 g of 1,3-cyclohexanedione in 250 ml of acetonitrile, and 63.1 ml of triethylamine were then added dropwise at this temperature. Stirring was continued for 15 minutes, 15.3 ml of acetone cyanohydrin were added, and the mixture was allowed to stand overnight. The reaction mixture was concentrated under reduced pressure on a rotary evaporator, the residue was taken up in ethyl acetate/water, and the organic phase was washed with 2N hydrochloric acid. The product was extracted from the organic phase using 5percent K2 CO3 solution, and precipitated at a pH of 2-3 using concentrated hydrochloric acid, with cooling. After filtration with suction and drying, 48.4 g of 2-[2-chloro-4-(methylsulfonyl)benzoyl]-1,3-cyclohexanedione of melting point 141°-142° C. were obtained.
With sodium tetrahydroborate; formaldehyd;sulfuric acid; In methanol;
EXAMPLE 8 Another Preparation of N-Methyl-L-proline Methyl Ester The L-proline is dissolved in methanol, the solution is cooled to 0 C. and 36% aqueous formaldehyde is added with stirring. To this solution is then added powdered NaBH4 in portions while maintaining the temperature between -5 and +5 C. The reaction is filtered, the filter cake extracted with solvent and combined with the filtrate, and the solvents evaporated to dryness. The residual N-methyl-L-proline is then dissolved in and reacted with methanol in the presence of H2 SO4 at reflux for 4-24 hr. The reaction mixture is cooled to 0 C., and with vigorous stirring a solution of K2 CO3 is slowly added to the mixture, until the pH is between pH 7 and 8, then the title product is extracted from the basic mixture and isolated after drying and removal of the solvent.
With sodium tetrahydroborate; formaldehyd;sulfuric acid; In methanol;
EXAMPLE 8 Another Preparation of N-Methyl-L-proline methyl ester The L-proline is dissolved in methanol, the solution is cooled to 0 C. and 36% aqueous formaldehyde is added with stirring. To this solution is then added powdered NaBH4 in portions while maintaining the temperature between -5 and +5 C. The reaction is filtered, the filter cake extracted with solvent and combined with the filtrate, and the solvents evaporated to dryness. The residual N-methyl-L-proline is then dissolved in and reacted with methanol in the presence of H2 SO4 at reflux for 4-24 hr. The reaction mixture is cooled to 0 C., and with vigorous stirring a solution of K2 CO3 is slowly added to the mixture, until the pH is between pH 7 and 8, then the title product is extracted from the basic mixture and isolated after drying and removal of the solvent.
(4-nitro-2,6-dichlorophenyl)-2-bromoacetamide[ No CAS ]
[ 584-08-7 ]
[ 112257-24-6 ]
[ 159484-66-9 ]
2-(aminocarbonyl)-N-(4-nitro-2,6-dichlorophenyl)-4-(tert-butoxycarbonyl)-1-piperazineacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
In N,N-dimethyl-formamide;
EXAMPLE 11 2-(aminocarbonyl)-N-(4-nitro-2,6-dichlorophenyl)-4-(tert-but oxycarbonyl)-1-piperazineacetamide (III) A mixture of (4-nitro-2,6-dichlorophenyl)-2-bromoacetamide (2.57 g, 7.84 mmol), 2-aminocarbonyl-4-tert-butoxycarbonylpiperazine (1.80 g, 7.86 mmol), and K2 CO3 (4.35 g) in 50 mL of DMF was stirred at room temperature for 24 hours. The resulting mixture was partitioned between ethyl actate and water, and the aqueous extract vigorously re-extracted with ethyl acetate. After removal of solvent in vacuo, the combined ethyl acetate extracts yielded 2.59 g of residue. This was recrystallized in methylene chloride-hexane to yield III as a white solid (1.67 g, 45% yield): m.p.>123 C. (dec.); 1 H NMR (300 MHz, CDCl3) delta 1.45 (s, 9H), 2.47-2.55 (m, 1H), 3.05-3.10 (m, 1H), 3.15-3.35 (m, 4H), 3.50-3.56 (d, 1H), 3.83 (broad s, 1H), 4.00-4.04 (m, 1H), 5.59 (broad s, 1H), 6.12 (broad s, 1H), 8.24 (s, 2H), 9.40 (broad s, 1H); MS (FAB) m/z 476 (M+).
N-(1-ethylpyrazol-5-yl)-4-nitroanthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.5 g (63%)
In N,N-dimethyl-formamide;
(a) A mixture of 2-chloro-4-nitrobenzoic acid (4.03 g, 0.02 mol), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol), DMF (25 ml), K2 CO3 (2.76 g, 0.02 mol) and Cu(OAc)2.H2 O (0.5 g) was refluxed for 24 hours. The reaction mixture was cooled to room temperature, poured into ice-water and then acidified with acetic acid to a pH of 5. A solid formed which was collected by filtration and dried to afford 3.5 g (63%) of N-(1-ethylpyrazol-5-yl)-4-nitroanthranilic acid.
With hydrogenchloride; sodium hydroxide; In water; ethyl acetate; acetone;
A 4-(2-Methoxyethoxy)-1-nitrobenzene A mixture of 40 g of 4-nitrophenol, 41 g of 1-bromo-2-methoxyethane, 45 g of K2 CO3 and 80 ml of tris[2-(2-methoxyethoxy)ethyl]amine in 80 ml of acetone is refluxed for 20 hours. An insoluble material is filtered off and the filtrate is concentrated under vacuum. The residue is taken up with water and the precipitate formed is filtered off and washed with water. The precipitate is dissolved in AcOEt, washed with a 1N solution of NaOH, with water, with a 1N solution of HCl and with water and dried over Na2 SO4 and the solvent is evaporated off under vacuum to give 59 g of the expected product, which is used as such in the next step.
<strong>[3934-84-7]3,4-Dihydroxy-5-methoxybenzoic acid</strong> (50 mM), K2 CO3 (300 mM) and allyl bromide (200 mM) in DMF (100 ml) was stirred vigorously at 80 C. for 21/2 hours. The mixture was filtered and the filtrate partitioned between ethyl acetate and water. The organic phase was washed with brine and evaporated to give allyl 3,4-diallyloxy-5-methoxybenzoate as a crude oil: NMR (CDCl3) 3.89(s, 3H); 4.61(m, 4H); 4.82(m, 2H); 5.31(m, 6H); 6.06(m, 3H); 7.32(s, 2H).
Cis(+)-3-acetyloxy-2,3-dihydro-5-(2-methyl-3-dimethylaminopropyl)-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one oxalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With oxalic acid; acetic anhydride; In acetone;
EXAMPLE 3 Cis(+)-3-acetyloxy-2,3-dihydro-5-(2-methyl-3-dimethylaminopropyl)-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one oxalate (diastereoisomer B) 5 g cis(+)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one, 2.9 g 2-methyl-3-dimethylaminopropylchloride hydrochloride, 5.7 g K2 CO3, 1.4 ml H2 O were reacted in 75 ml acetone, according to the procedure as in Example 1 (a), then reacted with 70 ml acetic anhydride, (see Example 1 (b)). The crude was treated with ethyl ether and the so obtained solid is filtered off and the solution was evaporated to dryness. This procedure was repeated. 4.3 g residue were dissolved in isopropyl alcohol and treated with 1.2 g oxalic acid. A solid, which was crystallized from acetone-ethyl ether, was obtained; m.p. 84°-89° C.; [alpha]D20 =119.3 (H2 O).
2. Intermediate 2: 4-(4-tert-Butyloxycarbonyl)piperazin-1-yl Butanal Dimethyl Acetal A mixture of <strong>[29882-07-3]4-chlorobutanal dimethyl acetal</strong> (J. Chem. Soc., Perkin Trans. 1, 1981, 251-255; 4.1 g, 26.9 mmol), K2 CO3 (4.08 g, 29.6 mmol) and tert-butyl-1-piperazinecarboxylate (5.00 g, 26.9 mmol), in anhydrous DMF (100 ml) was heated at 100° C. for 24 h. The mixture was cooled to room temperature, water (75 ml) added and extracted with ethyl acetate (5*100 ml). The combined extracts were washed with water (*3), dried (Na2 SO4) and evaporated. The crude product was chromatographed on silica gel eluding with ethyl acetate to give the title-product (3.41 g, 42percent). delta (250 MHz, CDCl3) 1.46 (9H, s, OC(Me)3); 1.50-1.68 (4H, m, 2 of CH2); 2.32-2.42 (6H, m, 3 of CH2); 3.30 (6H, s, (OMe)2); 3.40-3.48 (4H, m, 2 of CH2); 4.38 (1H, t, J=6 Hz, CH).
N-(1-ethylpyrazol-5-yl)-5-nitroanthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.8 g (68%)
In N,N-dimethyl-formamide;
(a) A mixture of 2-chloro-5-nitrobenzoic acid (4.03 g, 0.02 mol), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol), DMF (25 ml), K2 CO3 (2.76 g, 0.02 mol) and Cu(OAc)2.H2 O (0.5 g) was refluxed for 24 hours. The reaction mixture was cooled to room temperature, poured into ice-water and acidified with acetic acid to a pH of 5. A solid formed which was collected by filtration and dried to afford 3.8 g (68%) of N-(1-ethylpyrazol-5-yl)-5-nitroanthranilic acid.
EXAMPLE 35 6-Benzyloxychroman-4-one A mixture of 42.9 g (261 mmol) of the title product of Example 34, 48.7 g (352 mmol) of K2 CO3, and 32.0 mL (269 mmol) of benzyl bromide in 250 mL acetone was heated to reflux under N2. After 20 hours, the reaction mixture was cooled to room temperature, diluted with 1.5 L ethyl acetate, and filtered through Celite (trademark). The filtrate was concentrated, chromatographed (one time with CH2 Cl2, one time with 1:3 ethyl acetate-hexanes) on silica gel, and triturated with 10% diethyl ether in hexanes to give 58.37 g of the title product as a tan powder. 88% yield. 1 H NMR (300 m Hz, CDCl3): delta5.05 (s, 2H); 4.5 (t, 2H); 2.79 (t, 2H). MS (Cl, NH3): 255 M+H, Base.
In hexane; acetone;
Step 1: 6-Benzyloxy-4-chromanone A mixture of 6-hydroxy-4-chromanone (18.6 g, 113 mmol), benzyl bromide (20 g, 116 mmol), and K2 CO3 (21 g, 152 mmol) in acetone (110 ml) was refluxed for 20 hrs. The mixture was cooled, diluted with EtOAc, and filtered through celite. The filtrate was concentrated to an oil, which was triturated with 10% Et2 O in hexane (150 ml) to gives, after filtration and washing, 28 g (87%) of the title compound.
2a 1.0 eq. of <strong>[16357-40-7]3-acetyl-4-hydroxybenzoic acid</strong> preparation, see[1a)] was reacted with 2.2 eq. each of K2 CO3 and methyl iodide in absolute acetone to form methyl 3-acetyl-4-methoxybenzoate. Colorless crystals, mp 54°-58° C.
With sodium hydroxide; In ethyl acetate; butanone;
a) 5.15 g (0.034 mol) <strong>[3610-02-4]4-hydroxybenzothiophene</strong> was dissolved in 130 ml methylethylketone and admixed with 9.4 g (0.068 mol) K2 CO3 and 20 g (0.068 mol) 5-methyl-2-phenyl-4-(2-bromoethyl)oxazole. The preparation was boiled for 72 hours under reflux, evaporated, taken up in ethyl acetate and extracted three times by shaking with 2N NaOH. After cooling and evaporation of the organic phase, it was crystallized from ethyl acetate/isohexane. 8.8 g 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzothiophene of melting point 130-132 C. is obtained.
N-(1-ethylpyrazol-5-yl)-5-methoxyanthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 2-bromo-5-methoxybenzoic acid (141.5 g, 0.61 mol), 5-amino-1-ethylpyrazole (68 g, 0.61 mol), K2 CO3 (84.2 g, 0.61 mol), DMF (500 mL) and Cu(OAc)2 (3 g) was refluxed for about 2 days. The reaction mixture was cooled and then was poured into water (1500 mL). The mixture was acidified with acetic acid and the resulting solid was collected by filtration and dried to afford 110 g of N-(1-ethylpyrazol-5-yl)-5-methoxyanthranilic acid.
2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine[ No CAS ]
[ 40258-78-4 ]
[ 584-08-7 ]
[ 110-17-8 ]
2-[2-[4-(6,Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amino]ethyl acetate fumarate[ No CAS ]
[ 60-29-7 ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; acetonitrile;
EXAMPLE 132 2-[2-[4-(6,Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amino]ethyl acetate fumarate A mixture of 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.0 g, 7.6 mmol), K2 CO3 (1.38 g, 10 mmol) and bromoethyl acetate (1.40 g, 8.3 mmol) in acetonitrile (50 ml) was heated at reflux for 4 hours. At the end, the insolubles were filtered off and rinsed with DCM. The solvent was evaporated down. The crude mixture was purified by flash chromatography over a silica gel column (Sorbsil C-30, 30 g; eluted with 2percent CH3 OH in DCM, 800 ml). The oil (1.15 g) thus obtained was treated with a solution of fumaric acid (358 mg) in ethanol. Crystallization was induced by adding drops of ethyl ether, yield: 1.09 g, m.p.=116°-118° C. Analysis: Calculated for C18 H24 FN3 O3.C4 H4 O4: 56.77percent C 6.06percent H 9.03percent N Found: 56.32percent C 5.97percent H 8.94percent N
2,4-bis(8-quinolinylmethylthio)-5,5-dimethyl-5H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol (EtOH); chloroform;
EXAMPLE 62 2,4-bis-(8-quinolinylmethylthio)-5,5-dimethyl-5H-imidazole Initially, 3 g of 8-bromomethylquinoline was added to a solution of 1 g of 5,5-dimethyl-2,4-dithiohydantoin in 50 mL of ethanol (EtOH). The reaction mixture was stirred at the room temperature for 1.5 hour, and concentrated in vacuo. To the residue, 100 mL of CHCl3 was added. The mixture was washed with an aqueous solution of K2 CO3, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatograph (CHCl3). Recrystallization from diethyl ether gave the desired compound in the form of a needle-like crystal. The yield of this compound was 2.3 g with a yield ratio of 83.3percent, and the melting point was 101°-104° C. A result of a 1 H-NMR analysis of the compound is as follows: 1 H-NMR (CDCl3, delta, ppm, TMS) 1.33 (6H, s, --CH3 *2), 5.08 (2H, s, --CH2 --Ar), 5.12 (2H, s, --CH2 --Ar), 7.18~9.04 (12H, m, Ar)
b 2-Chloro-4-pyridinecarboxaldehyde A suspension of 2-chloro-4-pyridinemethanol (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in EtOAc was refluxed for 3 h. A Second portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) were added and the reaction was heated to reflux for an additional 3.5 h, cooled and filtered through a pad of celite. The filtrate, after concentrattion to a small volume, was subjected to flash chromatography eluding with 0.5-4% CH3 OH/CH2 Cl2. The fractions containing product were combined, washed successively with sat aq NaHCO3 10% Na2 S2 O3, and brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a light yellow solid; yield 5.3 g (67%). 1 H NMR (CDCl3) delta 10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J=5.0 Hz).
5.3 g (67%)
With N-Bromosuccinimide; In ethyl acetate;
b 2-Chloro-4-pyridinecarboxaldehyde A suspension of 2-chloro-4-pyridinemethanol (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in EtOAc was refluxed for 3 h. A second portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) were added and the reaction was heated to reflux for an additional 3.5 h, cooled and filtered through a pad of celite. The filtrate, after concentration to a small volume, was subjected to flash chromatography eluding with 0.5-4% CH3 OH/CH2 Cl2. The fractions containing product were combined, washed successively with sat aq NaHCO3 10% Na2 S2 O3, and brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a light yellow solid; yield 5.3 g (67%). 1 H NMR,,(CDCl3) delta 10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J=5.0 Hz).
3a 1.0 eq. of <strong>[16357-40-7]3-acetyl-4-hydroxybenzoic acid</strong> was reacted with 2.2 eq. each of K2 CO3 and isopropyl bromide in absolute DMF to form isopropyl 3-acetyl-4-isopropoxybenzoate. Yellowish oil, MS (ES): 265 (M+1).
Methyl (1RS,2RS,3RS)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate[ No CAS ]
[ 584-08-7 ]
Methyl (1RS,2SR,3RS)-3-[2-[(4-formylpyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
In ethyl acetate; N,N-dimethyl-formamide;
a Methyl (1RS,2SR,3RS)-3-[2-[(4-Formylpyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate To a solution of Methyl (1RS,2SR,3RS)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (300 mg, 0.63 mmol) in DMF (4 mL) was added K2 CO3 (109 mg, 0.79 mmol) and <strong>[40273-47-0]3-fluoro-4-formylpyridine</strong> (150 mg, 1.2 mmol). The reaction mixture was heated to reflux under Argon for 2 h. After cooling to room temperature it was partitioned between 3N HCl and ethyl acetate. The ethyl acetate extract was washed with water, aqueous NaHCO3 and brine and dried (Mg2 SO4). The solvent was removed in vacuo. The residue was purified by flash column chromatography (silica gel, gradient elution from 10% to 20% ethyl acetate/hexanes) to afford the title compound (128 mg, 42%).
(c) K2 CO3 (13.94 g, 0.101 mol) was dissolved in water (67 ml) and then 2-iodo-4-methoxybenzoic acid (25.3 g, 0. 091 mol) was added, followed by 5-amino-1-ethylpyrazole (11.2 g, 0.101 mol) and finally copper (2.7 g). The reaction mixture was refluxed for 20 hours, cooled to room temperature and then water (350 ml) was added and the mixture was refluxed for 0.75 hours. The reaction mixture was cooled, and the product was collected by filtration, recrystallized from ethanol, and dried in an oven at 40 C. to afford 13.37 g (56%) of N-(1-ethylpyrazol-5-yl) -4-methoxyanthranilic acid, m.p. 130-135 C.
EXAMPLE 7 Preparation of N-methoxy-N-methylchloroacetamide (3b). To a cold (0° C.), stirred solution of K2 CO3 (62.4 g, 450 mmol) in H2 O (250 mL) was added, successively, N,O-dimethylhydroxylamine hydrochloride (20 g, 205 mmol) and organic solvent (250 mL, toluene or MTBE). The resulting two phase mixture was cooled to -5° C. and chloroacetyl chloride (19.6 ml, 246 mmol) was added over 5 min (solution temperature maintained below 0° C.). The vigorously stirred mixture was allowed to warm to 15° C. over 30 min, the layers were separated, and the aqueous layer was extracted with organic solvent (3*100 mL, toluene or MTBE). The combined organic extracts were concentrated (MTBE used as solvent) to give the amide 3b (26.8 g, 95percent) as a white solid. Alternatively, the combined organic extracts (toluene used as solvent) were concentrated to 250 mL to effect azeotropic drying (water content 100 mug/mL) and the solution of 3b was used directly in reactions with organometallic reagents.
(b) Alternatively, the product can be obtained as follows: To a mixture of imidazole (5.13 g, 75.35 mmol), K2 CO3 (11.45 g) and DMSO (50 ml) at room temperature was added to 4-fluorobenzonitrile (10.04 g) in one portion. The reaction mixture was stirred at room temperature for 1 hour, and then was warmed on a steam for 2 hours. The reaction mixture was cooled to room temperature, and poured into cold water. A precipitate formed which was collected by filtration and washed with water and recrystallized from CHCl3 /hexane to afford 4.07 g of 4-(1-imidazolyl)benzonitrile, m.p. 146°-148° C.
With I2; hydroxylamine hydrochloride; In hexane; water; dimethyl sulfoxide;
Part A: 3-cyano-6-pyridaldoxime 5-Cyano-2-picoline (25 g, 0.21 mol) and I2 were heated under reflux in DMSO (200 mL) for 1 h. After cooling to RT, hydroxylamine hydrochloride (16 g, 0.23 mol), K2 CO3 (29 g, 0.21 mol), and water (21 mL) were added. The resulting mixture was heated to 80 C. for 2.5 h, cooled, diluted with water (100 mL) and much acetone, and absorbed onto silica gel by concentration. Chromatography on silica gel, eluding with 0% to 50% EtOAc in hexane, afforded 12.2 g of a tan solid; mp 204-207 C. (dec); HRMS, e/z Calc. for (M+H)+: 148.0511. Found: 148.0516.
5-chloro-6-methylpyrazine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
Example 48 5-CHLORO-6-METHYL-2-PYRAZINECARBOXYLIC ACID A mixture of <strong>[77168-85-5]methyl 5-chloro-6-methyl-2-pyrazine carboxylate</strong> (0.16 g, 0.86 mmol), K2 CO3 (0.31 g, 2.18 mmol) and H2 O was stirred for 2 h at room temperature. The reaction was filtered and acidified (20percent HCl), and the resulting solid collected to provide the title compound (0.057 g, 39percent yield); m.p. 116°-117° C.
With potassium hydroxide; In methanol; water; butanone;
(B) 3,4-DIBENZYLOXYBENZOIC ACID To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5 g (0.76 mole) of K2 CO3 and 168.8 g (0.76 mole) of benzyl bromide. The mixture was refluxed for 16 hours and filtered. Evaporation of the filtration gave an oil. This oil was mixed with 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours. The methanol was evaporated and the reaction mixture was acidified with concentrated HCl. The precipitate was filtered to give 101 g (92percent) of the desired product; m.p. 184°-185° C. The NMR and IR spectra were consistent with the assigned structure.
101 g (92%)
With potassium hydroxide; In methanol; water; butanone;
3,4-Dibenzyloxybenzoic Acid To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5 g (0.76 mole) of K2 CO3 and 168.8 g (0.76 mole) of benzyl bromide. The mixture was refluxed for 16 hours and filtered. Evaporation of the filtration gave an oil. This oil was mixed with 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours. The methanol was evaporated and the reaction mixture was acidified with concentrated HCl. The precipitate was filtered to give 101 g (92percent) of the desired product; m.p. 184°-5° C. The NMR and IR spectra were consistent with the assigned structure.
101 g (92%)
With potassium hydroxide; In methanol; water; butanone;
(b) 3,4-Dibenzyloxybenzoic Acid To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5 g (0.76 mole) of K2 CO3 and 168.8 g (0.76 mole) of benzyl bromide. The mixture was refluxed for 16 hours and filtered. Evaporation of the filtration gave an oil. This oil was mixed with 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours. The methanol was evaporated and the reaction mixture was acidified with concentrated HCl. The precipitate was filtered to give 101 g (92percent) of the desired product; m.p. 184°-185° C. The NMR and IR spectra were consistent with the assigned structure.
EXAMPLE 3a 1-(phenylmethyl)-2-methyl-3-(phenylmethoxy) 4-pyridone 73 g of the product of Example 2 were dissolved in 4 liters of ethanol (dry). 25 g K2 CO3 powderized and 70 g benzylbromide were added. After refluxing for 4 hours and filtration, the solvent was distilled off and the residue extracted with 4 liters of hot petroleum ether in 3 parts. After cooling to room temperature and filtration the petroleum ether filtrate was concentrated to 2 liters and cooled to -10° C. 31 g of white crystals of the title compound of Example 3 were obtained. The formed title compound 3A was insoluble in petroleum ether at room temperature white crystals. 70percent of total yield.
methyl-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetoxyacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16.5 g (94%)
In N-methyl-acetamide;
EXAMPLE 12 Methyl(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetoxyacetate A mixture of 15 g (0.052 m) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid in 100 ml of dimethylformamide and 3.87 g (0.028 m) of K2 CO3 was warmed to an internal temperature of 50° C. in an atmosphere of nitrogen for 1.5 hours. To this mixture, 9.41 g (0.062 m) of methyl bromoacetate was added dropwise and the mixture was held at 50° C. overnight. The reaction mixture was poured into water and extracted with ether. The ether extract was washed with 5percent NaHCO3 and water, dried over Na2 SO4, filtered and evaporated to give 16.5 g (94percent) of an oil of methyl(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetoxyacetate. ANALYSIS: Calculated for C19 H16 O6: 67.05percentC; 4.74percentH; Found: 66.88percentC; 4.74percentH
16.5 g (94%)
In N-methyl-acetamide;
EXAMPLE 12 Methyl-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetoxyacetate A mixture of 15 g (0.052 m) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid in 100 ml of dimethylformamide and 3.87 g (0.028 m) of K2 CO3 was warmed to an internal temperature of 50° C. in an atmosphere of nitrogen for 1.5 hours. To this mixture, 9.41 g (0.062 m) of methyl bromoacetate was added dropwise and the mixture kept at 50° C. overnight. The reaction mixture was poured into water and extracted with ether. The ether extract was washed with 5percent NaHCO3 and water, dried over Na2 SO4, filtered and evaporated to give 16.5 g (94percent) of an oil of methyl-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetoxyacetate. ANALYSIS: Calculated for C19 H16 O6: 67.05percentC. 4.74percentH. Found: 66.88percentC, 4.74percentH.
2-methyl-4-(2,4-dibenzyloxyphenyl)-2-buten-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With CuI; In acetone;
EXAMPLE 18 2-Methyl-4-(2,4-dibenzyloxyphenyl)-2-Buten-1-ol A mixture of 7.5 g (0.039 mol) of <strong>[14381-51-2]1-bromo-2,3-dihydroxybenzene</strong>, 11.2 g (0.082 mol) of K2 CO3, and 14 g (0.082 mol) of benzyl bromide in 70 ml of acetone was stirred at room temperature overnight, or until all starting material disappeared as indicated by TLC. The reaction mixture was poured into water and the aqueous solution was extracted with ether. The organic layer was separated, dried over MgSO4 and concentrated to give 14.5 g product as white solid. This compound, 1-bromo-2,4-dibenzyloxybenzene, as formed in accordance with the above procedure is conveniently summarized by the following reaction: STR9 A solution of 5.5 g (0.015 mol) of 1-bromo-2,4-dibenzyloxybenzene and 3.7 g (0.025 mol) of CH3 I in 20 ml of ether was added dropwise to 950 mg of Mg turning. The reaction mixture was refluxed for 2 hours and then cooled to -10° C. One gram of CuI was added, and stirring was continued at -10° C. for 30 min. A solution of 3.5 g (01042 mol) of 3-methyl-3,4-epoxy-1-butene in 10 ml of ether was then added dropwise to the reaction mixture, and stirring continued for another hour at -10° C. The reaction was quenced by satd. NH4 Cl solution. The organic layer was separated, dried over MgSO4 and concentrated. Purification of the crude product by dry column chromatography gave 1.6 g of product (a mixture of cis/trans isomer 8:2) as white solid; m.p. 83°-85° C. The product, 2-methyl-4-(2,4-dibenzyloxyphenyl)-2-buten-1-ol, formed from 1-homo-2,4-dibenzyloxybenzene, is conveniently depicted by the following reaction: STR10
2-chloro-1-(2-nitrophenoxy)-4-trifluoromethylbenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56.1 g (88%)
In dimethyl sulfoxide;
EXAMPLE 88 Preparation of 2-(2-chloro-4-trifluoromethylphenoxy)nitrobenzene A mixture of 29.4 g (0.200 mol) of 2-fluoro nitrobenzene, 41.0 g (0.200 mol) of <strong>[35852-58-5]2-chloro-4-trifluoromethylphenol</strong> and 30.0 g (0.220 mol) of K2 CO3 in 150 ml of DMSO was heated at 100° C. for 6 hours. The reaction mixture was poured over ice and extracted with ether. The organic phase was washed with water and saturated aqueous NaCl and dried (MgSO4). The solvent was removed by evaporation at reduced pressure to yield 56.1 g (88percent) of the desired product as a yellow oil. IR and 1 H NMR spectra were in agreement with the assigned structure. Analysis: Calculated for C13 H7 ClF3 NO3: C, 49.15; H, 2.22; N, 4.41; Found: C, 49.47; H, 2.07; N, 4.13.
56.1 g (88%)
In dimethyl sulfoxide;
EXAMPLE 104 Preparation of 2-(2-chloro-4-trifluoromethylphenoxy)nitrobenzene A mixture of 29.4 g (0.200 mol) of 2-fluoro nitrobenzene, 41.0 g (0.200 mol) of <strong>[35852-58-5]2-chloro-4-trifluoromethylphenol</strong> and 30.0 g (0.220 mol) of K2 CO3 in 150 ml of DMSO was heated at 100° C. for six hours. The reaction mixture was poured over ice and extracted with ether. The organic phase was washed with water and saturated aqueous NaCl and dried (MgSO4). The solvent was removed by evaporation at reduced pressure to yield 56.1 g (88percent) of the desired product as a yellow oil. IR and 1 H NMR spectra were in agreement with the assigned structure. Analysis: Calculated for C13 H7 ClF3 NO3: C, 49.15; H, 2.22; N, 4.41. Found: C, 49.47; H, 2.07; N, 4.13.
7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylic acid[ No CAS ]
[ 40258-78-4 ]
[ 584-08-7 ]
1-Acetoxyethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.29 g (70%)
In methanol; chloroform; N,N-dimethyl-formamide;
EXAMPLE 10 1-Acetoxyethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylate (Ib, R2 =CH3, R3 =CH3, R4 =AX*) *AX=--CH(CH3)OCOCH3 To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylic acid (1.55 g, 3.54 mmoles) and K2 CO3 (636 mg, 4.6 mmoles) in DMF (4 ml) was added at 5° C. <strong>[40258-78-4]1-bromoethyl acetate</strong> (769 mg, 4.6 mmoles). The mixture was stirred at 5° C. for 1 hour, diluted with ethyl acetate (300 ml), washed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was dissolved in chloroform and chromatographed on a silica gel column (50 g) with 1percent methanol in CHCl3. The desired fractions were combined and concentrated to a small volume. The resdiue was triturated with isopropyl ether to give 1.29 g (70percent) of the title compound as the isopropyl ether solvate. Estimated purity 90percent (by HPLC). Mp. 103°-110° C. (dec.). IR: numax (KBr) in cm-1 1770 (br.), 1670, 1620.
7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(E)-1-butenyl]-3-cephem-4-carboxylic acid[ No CAS ]
[ 40258-78-4 ]
[ 584-08-7 ]
1-Acetoxyethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(E)-1-butenyl]-3-cephem-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77 mg (49%)
In methanol; chloroform; N,N-dimethyl-formamide;
EXAMPLE 16 1-Acetoxyethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(E)-1-butenyl]-3-cephem-4-carboxylate (Ib, R2 =CH3, R3 =CH3, R4 =AX E isomer) To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(E)-1-butenyl]-3-cephem-4-carboxylic acid (130 mg, 0.3 mmole) and K2 CO3 (55 mg, 0.4 mmole) in DMF (2.5 ml) was added at 5° C. <strong>[40258-78-4]1-bromoethyl acetate</strong> (67 mg, 0.4 mmole). The mixture was stirred at 5° C. for 1 hour, diluted with ethyl acetate (25 ml), washed successively with water and an aqueous NaCl solution, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was dissolved in chloroform and chromatographed on a silica gel column with 1percent methanol in CHCl3. The desired fractions were combined and concentrated in vacuo to yield 77 mg (49percent) of the title compound. Estimated purity 90percent (by HPLC). Mp. 110°-115° C. IR: numax (KBr) in cm-1 1760 (br.), 1670, 1510.
2-(3,4,5-trichlorophenoxy)-5-nitrobenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
In ethanol; nitrogen; water; acetone; acetonitrile;
EXAMPLE 17 2-(3,4,5-Trichlorophenoxy)-5-nitrobenzonitrile In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 8.68 g (0.0475 moles) of 2-chloro-5-nitrobenzonitrile 9.67 g (0.0489 moles) of <strong>[609-19-8]3,4,5-trichlorophenol</strong>, 6.75 g (0.0489 moles) of anhydrous K2 CO3, and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was cooled to room temperature and diluted with 150 ml of water. The product separated as a solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized from a mixture of 200 ml of absolute ethanol and 100 ml of acetone to give 11.62 g (71percent yield) of purified 2-(3,4,5-trichlorophenoxy)-5-nitrobenzonitrile as small white crystals, mp 162°-164° C.
2,6-Dichloro-4-(2,5-dichloro-4-methylmercapto-phenoxy)-pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; acetone;
(b) 2,6-Dichloro-4-(2,5-dichloro-4-methylmercaptophenoxy)-pyridine Quantities of 19.3 gm (0.1 mol) of <strong>[25194-01-8]2,6-dichloro-4-nitropyridine</strong> and 23.1 gm (0.11 mol) of 2,5-dichloro-4-methylmercaptophenol were dissolved in 100 ml of acetone, 13.8 gm (0.1 mol) of K2 CO3 were added, and the resulting mixture was stirred for 3 hours under reflux. It was then stirred into 500 ml of water, and the precipitate formed was recovered by suction filtration. Yield: 32.5 gm (91.5% of theory). M.p.: 144-146 C. Analysis: C12 H7 Cl4 NOS (355.08) Calc.: C 40.59 H 1.99, N 3.95; Found: C 40.78 H 2.30, N 3.85.
a. 4-Ethoxy-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester 1-Ethyl-4-hydroxy-6-methyl-1H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid ethyl ester was prepared according to Example 1b, using 5-amino-1-ethylpyrazole in place of 5-amino-1-n-pentylpyrazole, and 44 g (17.6 mM) of the hydroxy compound were dissolved in 250 ml of dry DMF. Ground anhydrous K2 CO3 (26.1 g, 1.1 eq) was added to the DMF solution followed by the addition of ethyl iodide (14.5 ml, 1.1 eq). The reaction mixture was stirred at 60 C. for 4 hours at which time an additional 4.5 ml of ethyl iodide were added. The reaction mixture was stirred for an additional 3 hours and then cooled to rt. The mixture was poured into 1 liter of water and extracted three times with EtOAc, 300 ml each. The extracts were combined and washed twice with water, 500 ml each, and once with brine (500 ml). The organic layer was dried over anhydrous MgSO4, filtered and evaporated to leave 47.21 g of a white solid; mp=55.5-56.5 C.
EXAMPLE E2 4-Bromo-2-chloro-6-methylanisole 4-Bromo-2-chloro-6-methylphenol (50 g, 0.225 mole) and K2 CO3 (31.8 g, 0.23 mole) were combined in acetone (300 ml). Dimethyl sulfate (32 ml, 0.34 mole) was added dropwise and the mixture stirred 22 hours at room temperature, filtered and concentrated to an oil in vacuo. The oil was taken up in 250 ml ether, washed 2*2N NaOH, 1* saturated NaHCO3, 2* brine, dried over MgSO4, reconcentrated to an oil and distilled to yield purified title product, 42.9 g, b.p. 122-124/0.9 mm, pnmr/CDCl3 /delta/TMS:2.3 (s, 3H), 3.8 (s, 3H), 7.3 (q, 2H).
EXAMPLE 1 Preparation of 2,3,5,6-tetrahydro-8H-imidazo[2,1-c] [1,4]-thiazine A solution of 23.4 g. (0.20 moles) of <strong>[20196-21-8]3-thiomorpholinone</strong> in 150 ml. dry CH2 Cl2 is added dropwise with stirring to a solution of 44 grams of triethyloxonium fluoroborate in 100 ml. of CH2 Cl2 maintained at 0-5C. Stirring is continued for six hours as temperature is allowed to come to 25C; K2 CO3 (46 g.) is added and the methylene chloride solution is decanted and the residue of K2 CO3 is washed with CH2 Cl2. The combined organic solutions are dried over anhydrous K2 CO3, filtered and solvent evaporated. Distillation of the concentrate gives 17.9 g. of the lactam ether. The lactam ether is added to a solution of 24.6 grams (0.12 moles) of 2-bromo-ethylamine hydrobromide in 150 ml. absolute ethanol and the resulting solution heated on a steam bath for two hours. The solvent is evaporated and the residue washed with ether. The resulting crystalline material is washed with acetone and air dried under suction. The crude crystalline product (28.5 g.) is dissolved in 200 ml. ethanol and sodium methoxide (.07 mole in 50 ml. methanol is added; the resulting solution is heated under reflux with stirring for two hours prior to evaporation of the solvent under reduced pressure. To the residue is added 75 ml. water and the solution made basic with potassium carbonate; the basic solution is extracted with chloroform (3 * 100 ml.). The combined extracts are dried over anhydrous Na2 SO4, filtered and the solvent evaporated. Distillation of the concentrate gives 2,3,5,6-tetrahydro-8H-imidazo[2,1-c] [1,4] thiazine (11.3 g.). The hydrochloride and oxalate salts are prepared, respectively, by dissolving 1 g. of the product in the minimum volume of absolute ethanol at 45C. and adding dropwise an aqueous 1 molar solution of the respective acid; the resulting salts are collected by filtration, washed with ethanol and dried.
EXAMPLE IX Allyl N-(m-nitrobenzenesulfonyl) carbamate was prepared by reacting 20.2 grams (0.10 mole) of <strong>[121-52-8]m-nitrobenzenesulfonamide</strong> with 12 grams (0.10 mole) of allyl chlorocarbonate in the presence of anhydrous K2 CO3 in acetone according to the procedure described in Example VI. The product was a pale yellow oil which solidified on cooling. Weight of the final product was 5 grams which represented a yield of 17.8%. Melting point was 84-86C.
EXAMPLE 1 Manufacture of O,O-dimethyl-O-(3,4,5-trichlorophenyl)-thiophosphate 29.6g <strong>[609-19-8]3,4,5-trichlorophenol</strong> were dissolved in 250 ml methylethyl ketone. 25.0g anhydrous K2 CO3 were added thereto and the mixture stirred for 1 hour at room temperature. Thereafter within about a quarter of an hour 26.0g dimethylchlorothiophosphate were dropped into the reaction mixture. The mixture was then stirred for 1 hour at room temperature and then for 5 hours at 70° C. After cooling the reaction mixture was poured into 500ml water, the product extracted with 200 ml benzene, washed with water and dried. After distilling off the solvent, 46.2g of an almost colourless product were obtained. Analysis for C8 H8 Cl3 O3 PS:
EXAMPLE 12 Methyl 2-methoxy-4-acetamidobenzoate 34 grs (0.17 mol) 4-acetamidosalicylic acid, 57.96 grs (0.42 mol) K2 CO3 and 250 ml acetone were introduced into a 500 cc flask and heated to 40 C. Then, maintaining the same temperature, 51.40 grs (0.408 mol) methyl sulphate was added in approximately 15 minutes, and the mixture was heated under reflux for 5 hours. The mixture was cooled, the K2 SO4 precipitate was filtered and the acetone solution was concentrated to 1/3 of its original volume. Dilution with ethyl ether gave a crystalline solid which was filtered, weight 34 grs. m.p. = 130-132 C. Yield = 89%.
With n-butyllithium; LiAlH4; NaH; diisopropylamine; In tetrahydrofuran; water;
EXAMPLE 1A Preparation of 7-Carboxy-7-propyl-1-decene by the Alkylation of Valproic Acid with 6-Bromo-1-hexene Under an argon blanket, sodium hydride (1 g, 50% oil, 0.022 mole) was washed twice with hexane and the washings decanted. To the washed NaH was added 50 ml of THF (freshly distilled from LiAlH4) and followed by the dropwise addition of valproic acid (2.88 g, 0.02 mole) in 20 ml of THF. The rate of addition was adjusted according to the amount of hydrogen evolved. The sodium salt was cooled in a salt ice bath to 0 and then diisopropylamine (2 g, 0.02 mole, distilled over CaH2) was added. The mixture was heated to 55 for 15 minutes, and then cooled to room temperature in two hours. The solution was then cooled to -1 and n-butyllithium (10 ml, 0.02 mole) was added while keeping the temperature between about 0-5. After 15 minutes, the reaction mixture was warmed to 35 for 33 minutes and again cooled to 0. To the cold reaction mixture was added dropwise cold (0-2) 6-bromo-1-hexene (3.2 g, 0.02 mole) in 20 ml of THF. The resulting solution was cooled in an ice bath for 30 minutes, then maintained at 33 for an hour. NaBr precipitated and the reaction mixture was allowed to stir overnight at room temperature. A sample of the solution was taken and shaken with D2 O; nmr showed no tertiary hydrogen present. The reaction mixture was then cooled in an ice bath, 25 ml of water was added and the mixture was extracted with 50 ml of ether. The ethereal solution had 50 ml of 5% K2 CO3 added to it and then was extracted with 2*50 ml of hexane. The basic aqueous solution in an ice bath was acidified with concentrated HCl to pH 1, saturated with salt, and then extracted with 2*50 ml of ether. The ethereal solution was washed with 3*10 ml of brine, dried (MgSO4) and concentrated to give 2.9 g of an oil. Tlc on silica (10% methanol in chloroform) gave a Rf 0.76 visualized by bromocresol green stain.
A. Ethyl 3-(3,4-Dimethoxyphenyl)alaninate A 47 g (0.21 mole) portion of <strong>[55-59-4]3,4-dimethoxyphenylalanine</strong> in 450 ml of absolute ethanol was treated with 31 ml of concentrated H2 SO4. The reaction mixture was refluxed for 5 hours and poured into 1.6 l. of H2 O. The solution was basified with a solution of 61 g of K2 CO3 in 200 ml of water. The basified solution was extracted with three 600 ml portions of ethyl acetate. The combined extracts were washed with 1.4 l. of water, dried over MgSO4 overnight and filtered. The filtrate was concentrated under reduced pressure to give 27 g (51%) of the desired product, a light yellow-brown viscous oil which crystallized upon refrigeration.
2-chloro-4-((cyclopentyl)methyloxy)toluene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; N,N-dimethyl-formamide;
Preparation Example 7-1 To a solution of <strong>[615-62-3]3-chloro-4-methylphenol</strong> (1.00 g) in N,N-dimethylformamide (8 ml) was added potassium carbonate powder (1.44 g) and the mixture was heated to 80°C. Thereto was added cyclopentylmethyl methanesulfonate (1.57 g) and the mixture was stirred at 120°C for 3 hr. The reaction mixture was cooled to room temperature. Water was added and the mixture was extracted 3 times with hexane. The organic layers were combined and washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography (silica gel, hexane) to give 2-chloro-4-((cyclopentyl)methyloxy)toluene(1.46 g) as a colorless oil. 1H-NMR(CDCl3): 1.22-1.93(8H, m), 2.29(3H, s), 2.34(1H, sept, J7Hz), 3.78(2H, d, J=7Hz), 6.71(1H, dd, J=8 and 2Hz), 6.91(1H, d, J=2Hz), 7.09(1H, d, J=8Hz).
4-(1-Azetidinyl)butanal dimethylacetal A mixture of azetidine (2.0 g, 35.0 mmol), 4-chlorobutanal dimethylacetal (5.88 g, 39.0 mmol) and K2 CO3 (5.38 g, 39.0 mmol), in anhydrous DMF (100ml), was stirred at room temperature for 72 h. Water (50 ml) was added and the mixture extracted with EtOAc (3*150 ml). The combined extracts were washed with H2 O (3*50ml), dried (Na2 SO4) and evaporated. The crude product was purified by distillation (1.2 g). delta (360 MHz, CDCl3) 1.35-1.42 (2H, m, CH2), 1.57-1.64 (2H, m, CH2), 2.00-2.40 (2H, m, CH2), 2.36 (2H, t, J=9.0 Hz, CH2), 3.15 (4H, m, t, J=7.0 Hz, 2 of CH2), 3.33 (6H, s, 2 of OMe), 4.35 (1H, t, J=5.7 Hz, CH).
With hydrogenchloride; ammonium chloride; sodium hydrogencarbonate; In ethanol; water; acetonitrile;
2-(3H-spiro[2-benzofuran-1,1'-cyclobutan]-6-yloxy)pyrimidin-5-amine To a solution of spiro[1H-isobenzofuran-3,1'-cyclobutane]-5-ol (Intermediate 24, 50 mg, 0.28 mmol) in dry acetonitrile (4 mL) dipotassium carbonate (58.8 mg, 0.43 mmol) and then <strong>[10320-42-0]2-chloro-5-nitro-pyrimidine</strong> (43.0 mg, 0.27 mmol) were added and the reaction mixture was stirred for 4 hours at room temperature. The reaction was diluted with ethyl acetate (20 ml) and washed with an aqueous saturated solution of ammonium chloride (2*10 ml). The organic layer was dried (Na2SO4), filtered and evaporated. The residue was dissolved in ethanol (5 mL)/water (1 mL). Iron (95.0 mg, 1.7 mmol) and an aqueous 6M solution of hydrogen chloride (0.05 ml, 0.3 mmol) were added and the reaction mixture was stirred at 50° C. for 3 hours. The catalyst was filtered off and the solution was diluted with an aqueous saturated solution of NaHCO3 (10 ml) and extracted with ethyl acetate (2*15 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 10 g as column and cyclohexane/ethyl acetate from 60:40 to 0:100 as eluent affording the title compound (24 mg) as a light yellow solid. LC/MS: QC-3_MIN: Rt=1.875 min; m/z 270 [M+H]+.
2,2'-(5-bromo-1,3-phenylene)bis(oxy)bis(3-methylpyridine)[ No CAS ]
[ 584-08-7 ]
[ 534-17-8 ]
[ 108-95-2 ]
2,2'-(5-phenoxy-1,3-phenylene)bis(oxy)bis(3-methylpyridine)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 4. NX-43 The synthesis of 2,2'-(5-phenoxy-1,3-phenylene)bis(oxy)bis(3-methylpyridine) (NX-43) was a two-step process as detailed below. Potassium Carbonate was added to a solution of 5-bromobenzene-1,3-diol and <strong>[2369-18-8]2-fluoro-3-methylpyridine</strong> in dimethyl formamide. The reaction mixture was irradiated with microwave at 200 C. for 4 h. Reaction mixture was diluted with ice cold water and extracted with ethyl acetate. The combined organic layer was dried with sodium sulphate and evaporated under reduced pressure to obtain 2,2'-(5-bromo-1,3-phenylene)bis(oxy)bis(3-methylpyridine). Cesium Carbonate was added to a solution of 2,2'-(5-bromo-1,3-phenylene)bis(oxy)bis(3-methylpyridine), phenol, catalytic copper iodide and dimethyl glycine in DMF and the reaction mixture was irradiated with microwave at 150 C. for 3 h. Reaction mixture was diluted with ice cold water and extracted with ethyl acetate. The combined organic layer was dried with sodium sulphate and evaporated under reduced pressure to obtain 2,2'-(5-phenoxy-1,3-phenylene)bis(oxy)bis(3-methylpyridine). H NMR (400 MHz, CDCl3-d6): 8.02 (d, J=3.6 Hz, 2H), 7.50 (d, J=7.2 Hz, 2H), 7.35-7.31 (m, 2H), 7.12-7.10 (m, 3H), 6.93-6.90 (m, 2H), 6.61-6.60 (m, 1H), 6.566-6.56 (t, J=2.4 Hz, 2H), 2.29 (S, 6H).
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