* 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.
With palladium 10% on activated carbon; hydrogen In ethyl acetate at 70℃;
a. 5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-amine (74). A 0.05 M solution of1,1 ,4,4-tetramethyl-6-nitro- 1,2,3 ,4-tetrahydronaphthalene (73) (2.5 g, 10.7 mmol) in ethyl acetate(210 mL) was passed through a 10percent PdJC cartridge at 1.0 mL/minute, twice, in the ThalesNano Hcube® at 70 °C and 2-5 bar pressure. The resulting solution was concentrated in vacuo to give 74(2.1532 g, 99percent) as a yellow, crystalline solid, m.p. 58-60 °C: ‘H NMR (400 MHz, CDC13) 7.11 (d, J= 8.4, 1H), 6.65 (d, J= 2.4, 1H), 6.54 (dd, J= 8.4, 2.4, ill), 3.62 (br s, 2H), 1.66 (s, 4H), 1.26 (s, 611), 1.25 (s, 611); ‘3C NMR (100.6 MHz, CDC13) ö 145.8, 143.3, 135.4, 127.3, 113.7, 112.9, 35.2,34.1, 33.5, 31.9, 31.7; IR (neat) 3405, 3208, 2952, 2920, 1612, 1499 cm’; LC-MS-CI (M+H)+ calcd for C,4H22N 204.1752, found 204.1747.
99%
With palladium 10% on activated carbon; hydrogen In ethyl acetate at 70℃; Flow reactor
A 0.05 M solution of 1,1,4,4-tetramethyl-6-nitro-1,2,3,4-tetrahydronaphthalene (32) (2.5 g, 10.7 mmol) in ethyl acetate (210 mL) was passed through a 10percent Pd/C cartridge at 1.0 mL/minute, twice, in the ThalesNano H-cube® at 70° C. and 2-5 bar pressure. The resulting solution was concentrated in vacuo to give compound 33 (2.1532 g, 99percent) as a yellow, crystalline solid, m.p. 58-60° C.: 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J=8.4, 1H), 6.65 (d, J=2.4, 1H), 6.54 (dd, J=8.4, 2.4, 1H), 3.62 (br s, 2H), 1.66 (s, 4H), 1.26 (s, 6H), 1.25 (s, 6H); 13C NMR (100.6 MHz, CDCl3) δ 145.8, 143.3, 135.4, 127.3, 113.7, 112.9, 35.2, 34.1, 33.5, 31.9, 31.7; IR (neat) 3405, 3208, 2952, 2920, 1612, 1499 cm-1; LC-MS-CI (M+H)+ calcd for C14H22N 204.1752, found 204.1747.
75%
With iron; calcium chloride In ethanol at 78℃; Inert atmosphere
To a solution of nitro-1,2,3,4-tetrahydronaphthalenes 30(5.0 mmol) in 95percent ethanol (35 mL mmol-1), powdered iron(150 mmol) and CaCl2 (50 mmol) were added. The mixturewas refluxed at 78 °C for 48 h. The reaction mixture wasextracted with ethyl acetate and the organic phase dried overanhydrous MgSO4. The solvent was then removed undervacuum. The product was purified by flash chromatographyusing hexane/ethyl acetate 90:10 as eluent. The product 31was obtained as a brown crystal in 75percent yield. mp 71 °C;1H NMR (300 MHz, CDCl3) δ 1.21 (s, 6H, 2CH3), 1.23 (s,6H, 2CH3), 1.62 (s, 4H, CH2), 3.48 (ls, 2H, NH2), 6.61 (d,1H, J 2.7 Hz, Ar-H), 6.50 (dd, 1H, J 8.1, 2.7 Hz, Ar-H),7.08 (d, 1H, J 8.1 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) δ 31.80, 32.00, 33.53, 34.20, 35.23, 112.88, 113.62, 127.37,135.38, 143.58, 145.82.
46%
With iron; acetic acid In water at 60℃; for 3.25 h;
A mixture of HNO3 [63percent] (0.94 mL) and H2SO4 (1.5 mL) was added to 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene5 (2.0 g, 10.6 mmol) at -10°C and the reaction mixture was stirred for 1 h. The reaction mixture was poured into ice:water and the product was extracted with CH2Cl2. The organic layer was washed with NaOH (1N), H2O, brine, dried over MgSO4 to give after solvent evaporation 1,1,4,4-tetramethyl-6-nitro-1,2,3,4-tetrahydro-naphthalene (1.87 g, 76 percent). ref. Kagechika, H., Kawachi, E., Hashimoto, Y., Shudo, K., Himi T., J. Med. Chem., 31, 2182-2192, 1988. To a stirred solution of 1,1,4,4-tetramethyl-6-nitro-1,2,3,4-tetrahydro-naphthalene (0.593 g, 2.5 mmol) in glacial acetic acid ( 10 mL) was added iron powder (0.77, 13.8 mmol) over a period of 15 min. The reaction mixture was stirred at 60°C for 3 hours. The volatiles were evaporated and the resulting oil was partitioned between EtOAc and water. Organics extracts were washed with brine, dried over MgSO4 to obtain 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine6 (0.232 g, 46percent yield) as a brown solid. [] MW: 203.32; Yield: 35 percent; Brown Solid; Mp (°C): 67.1H NMR (CDCl3,δ): 1.23 (s, 6H, 2xCH3), 1.25 (s, 6H, 2xCH3), 1.64 (s, 4H, 2xCH2), 3.50 (s, 2H, NH2), 6.52 (dd, 1H, J = 8.32 Hz, J = 2.53 Hz, ArH), 6.63 (d, 1H, J = 2.52 Hz, ArH), 7.10 (d, 1H, J = 8.33 Hz, ArH).MS-ESI: m/z (rel. int.) 204.0 ([MH]+, 100).HPLC: Method A, detection 254 nm, RT = 4.8 min, Peak area 90 percent.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 9, p. 2352 - 2356
[2] Patent: WO2015/130973, 2015, A1, . Location in patent: Page/Page column 34; 35
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 19, p. 8924 - 8940
[4] Patent: US2018/207156, 2018, A1, . Location in patent: Paragraph 0114; 0119
[5] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 15, p. 7277 - 7290
[6] Organic Letters, 2013, vol. 15, # 6, p. 1378 - 1381
[7] Heterocycles, 2010, vol. 81, # 11, p. 2465 - 2470
[8] Journal of the Brazilian Chemical Society, 2018, vol. 29, # 1, p. 109 - 124
[9] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2182 - 2192
[10] Patent: EP1541549, 2005, A1, . Location in patent: Page/Page column 15; 38
[11] Letters in Drug Design and Discovery, 2016, vol. 13, # 8, p. 729 - 733
2
[ 6683-46-1 ]
[ 92050-16-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 9, p. 2352 - 2356
[2] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2182 - 2192
[3] Patent: US4703110, 1987, A,
[4] Heterocycles, 2010, vol. 81, # 11, p. 2465 - 2470
[5] Organic Letters, 2013, vol. 15, # 6, p. 1378 - 1381
[6] Letters in Drug Design and Discovery, 2016, vol. 13, # 8, p. 729 - 733
3
[ 139162-43-9 ]
[ 92050-16-3 ]
Yield
Reaction Conditions
Operation in experiment
70%
With hydrogenchloride In water at 100℃; for 10.5 h;
Compound (23) (2.50 g) obtained in Step 6-2 was added to a 6 N hydrochloric acid aqueous solution (50 mL), and the mixture was stirred at 100 ° C. for 10.5 hours. After returning to room temperature, the reaction solution was rendered alkaline with 6 N aqueous sodium hydroxide solution under ice cooling and extracted with diethyl ether.The organic layer was separated, washed with saturated brine, and dried with anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 4: 1) to give the title compound (24) (1.45 g, yield 70percent) as light As a brown solid.
Reference：
[1] Patent: JP2017/71567, 2017, A, . Location in patent: Paragraph 0183-0184; 0187
4
[ 6223-78-5 ]
[ 92050-16-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 9, p. 2352 - 2356
[2] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2182 - 2192
[3] Journal of Organic Chemistry, 1960, vol. 25, p. 708 - 711
[4] Letters in Drug Design and Discovery, 2016, vol. 13, # 8, p. 729 - 733
[5] Patent: JP2017/71567, 2017, A,
[6] Journal of the Brazilian Chemical Society, 2018, vol. 29, # 1, p. 109 - 124
5
[ 6683-46-1 ]
[ 92050-16-3 ]
Reference：
[1] Patent: US2003/125383, 2003, A1,
6
[ 110-03-2 ]
[ 92050-16-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2182 - 2192
[2] Letters in Drug Design and Discovery, 2016, vol. 13, # 8, p. 729 - 733
[3] Patent: JP2017/71567, 2017, A,
[4] Journal of the Brazilian Chemical Society, 2018, vol. 29, # 1, p. 109 - 124
7
[ 6683-46-1 ]
[ 92050-16-3 ]
[ 102121-55-1 ]
Reference：
[1] Patent: US5087743, 1992, A,
[2] Patent: US5128479, 1992, A,
8
[ 27452-17-1 ]
[ 92050-16-3 ]
Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 5, p. 748 - 753
9
[ 103031-30-7 ]
[ 92050-16-3 ]
Reference：
[1] Journal of Organic Chemistry, 1960, vol. 25, p. 708 - 711
10
[ 6683-48-3 ]
[ 92050-16-3 ]
Reference：
[1] Journal of Organic Chemistry, 1960, vol. 25, p. 708 - 711
11
[ 108-88-3 ]
[ 92050-16-3 ]
Reference：
[1] Journal of Organic Chemistry, 1960, vol. 25, p. 708 - 711
12
[ 94497-53-7 ]
[ 92050-16-3 ]
Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 5, p. 748 - 753
13
[ 92050-16-3 ]
[ 94497-51-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2182 - 2192
[2] Letters in Drug Design and Discovery, 2016, vol. 13, # 8, p. 729 - 733
14
[ 92050-16-3 ]
[ 27452-17-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2013, vol. 61, # 2, p. 237 - 241
Terephthalic acid monomethyl ester (194 mg, 1.08 mmol) was dissolved in SOCl2 (5.39 mL) at 0C. A drop of DMF was added and the mixture was stirred for 30 min. The SOCl2 was removed under vacuum and the crude acid chloride was dissolved in pyridine (12.5 mL). 5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine 6 (200 g, 0.98 mmol) and DMAP (12 mg, 0.1 mmol) was added and the mixture was heated at 60 C for 2 h with stirring. The mixture was poured into H2O and the product was extracted with EtOAc. Them organic layer was washed successively with HCl 2M, saturated NaHCO3, saturated NaCl, dried over MgSO4 and filtrated to give after evaporation N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-terephthalamic acid methyl ester 7 (316 mg, 88 % yield) as a white solid. [] MW: 365.47; Yield 88 %; White Solid; Mp: 211C.Rf. 0.9 (EtOAc:Cyclohexane = 50:50).1H NMR (CDCl3,delta): 1.28 (s, 6H, 2xCH3), 1.30 (s, 6H, 2xCH3), 1.70 (s, 4H, 2xCH2), 3.96 (s, 3H, OCH3), 7.32 (d, 1H, J = 8.50 Hz, ArH), 7.45 (d, 1H, J = 8.28 Hz, ArH), 7.53 (s, 1H, ArH), 7.80 (s, 1H, ArH), 7.92 (d, 2H, J = 8.15 Hz, ArH), 8.14 (d, 2H, J = 8.12 Hz, ArH).MS-ESI: m/z (rel. int.) 366.0 ([MH]+, 100).HPLC: Method A, detection 254 nm, RT = 7.5 min, Peak area 90.6 %.
EXAMPLE 3 The nitration of 1.2 g of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene with nitric acid/sulfuric acid mixture in sulfuric acid gave a 2-nitro derivative having a melting point of 71-72 C. (0.9 g, recrystallized from methanol). The reduction of the obtained nitro derivative with Pd-C as catalyst in alcohol gave 2-amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene having a melting point of 72-73 C. (recrystallized from hexane).
The intermediate 2-amino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene was prepared by reduction of 2-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (Kagechika, H. et al., J. Med. Chem., 31, 2182-2192 (1998)) in a similar manner to that described in step (b) of Example J-1.
50
[ 5781-53-3 ]
[ 92050-16-3 ]
[ 853728-70-8 ]
Yield
Reaction Conditions
Operation in experiment
90%
With triethylamine; In dichloromethane; at 60℃; for 3h;
To a solution of 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-amine 6 in CH2Cl2 (20 mL) was added Et3N (0.684 mL), and methoxyoxalylchloride (0.452 ml). The solution was stirred at 60 C for 3 h and all the volatiles were evaporated to obtain a white solid that was purified using silica gel chromatography with EtOAc:Cyclohexane = 15:85 to yield to methyl (1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-7-ylcarbamoyl)formate24 (0.637 g, 90% yield). [] MW: 289.37; Yield: 90%; White Solid; Mp (C): 216.Rf: 0.20 (EtOAc:Cyclohexane = 15:85).1H-NMR (CDCl3,delta): 1.27 (s, 6H, 2xCH3), 1.28 (s, 6H, 2xCH3), 1.68 (s, 4H, 2xCH2), 3.96 (s, 3H, OCH3), 7.31 (d, 1H, J = 8.46 Hz, ArH), 7.46 (dd, 1H, J = 8.46 Hz, J = 2.36 Hz, ArH), 7.51 (d, 1H, J = 2.26 Hz, ArH), 8.83 (s, 1H, NH).MS-ESI m/z (rel. int.): 290.1 ([MH]+, 100).HPLC: Method A, detection UV 254 nm, RT = 6.80 min, peak area 99.0 %.
Example 7 Synthesis of 4-[3-Pentyl-3-(5,5,8,8-Tetramethyl-5,6,7,8-Tetrahydro-Naphthalen-2-yl)-Ureido]-Benzoic Acid (27) A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (10.0 g, 49.3 mmole) in 150 mL of pyridine was cooled to 0 C. and trifluoroacetic anhydride (34.2 mL) was added dropwise. The reaction mixture was stirred at 0 C. for two hour, diluted with 300 mL ethyl acetate and washed with two 250 mL portions of water. The organic phase was dried over MgSO4, filtered and concentrated in vacuo, to give a yellow oil. The product was purified by flash chromatography (SiO2, 1:6 ethyl acetate/hexanes) to afford 15.05 g of 2,2,2-trifluoro-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (29) as a colorless oil.
With triethylamine; In dichioromethane; dichloromethane;
Example 3 Synthesis of 4-[3-Hexyl-3-(5,5,8,8-Tetramethyl-5,6,7,8-Tetrahydro-Naphthalen-2-yl)-Ureido]-Benzoic Acid (13) A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (0.5 g, 2.46 mmole) in 20 mL of dichioromethane was treated successively with 0.51 mL of triethylamine (1.5 eq.) and 0.35 mL of hexanoyl chloride (1 eq.). The reaction mixture was stirred at room temperature for two hours, diluted with an additional 20 mL of dichloromethane and washed with two 50 mL portions of water and one 50 mL portion of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo, giving 740 mg (100%) of hexanoic acid (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide (15) as a pale yellow oil.
With sodium hydroxide; formaldehyd; hydrogen; sodium cyanoborohydride;palladium; In dichloromethane; acetic acid; acetonitrile;
b. 2-Dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene. To a solution of 2-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (79.0 g, 0.339 mol) in dichloromethane as added 1 g of 10% palladium on carbon and the mixture was hydrogenated at 40-50 psi of hydrogen for 20 hrs. The catalyst was removed by filtration and the organic and the aqueous layers were separated. The aqueous layer was made alkaline by addition of 1N NaOH and extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and evaporated to give <strong>[92050-16-3]2-amino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene</strong> as a red-orange solid which was used in the next step without further purification. To a solution of <strong>[92050-16-3]2-amino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene</strong> (70.10 g, 0.345 mol) and formaldehyde (280 mL, 10 eq) in 2 L of acetonitrile cooled to 0 C. was added sodium cyanoborohydride (65 g, 3 eq.) in portions while maintaining the temperature between 10-20 C. Glacial acetic acid was added to adjust the pH to 7. The reaction was stirred for 2 hrs at room temperature and the resulting mixture was partitioned between 1N NaOH and EtOAc, the organic phase was washed with water and brine, dried over sodium sulfate, filtered and evaporated. Chromatography on silica gel (hexanes/EtOAc 95:5) gave 54.90 g (70%, 2 steps) of 2-dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene. 1H-NMR (300 MHz, CDCl3): 1.25 (s, 6 H), 1.29 (s, 6 H), 1.66 (s, 4 H), 2.91 (s, 6 H), 6.62 (dd, J=3.0 Hz, J=8.7 Hz, 1 H), 6.67 (d, J=2.7 Hz, 1 H), 7.19 (d, J=8.7 Hz, 1 H).
6-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene[ No CAS ]
5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamnine[ No CAS ]
[ 92050-16-3 ]
Yield
Reaction Conditions
Operation in experiment
17.641 g (85%)
palladium-carbon; In ethanol;
1.4 g of 10% Pd/C was added to a solution of 6-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (3) (23.93 g, 102.6 mmole) in 1 L of ethanol. The resulting suspension was maintained under 1 atmosphere of H2 for 15 hours. The reaction mixture was then filtered over Celite (2X) and concentrated in vacuo. The residue was taken up in 200 mL ether and dried over MgSO4. Filtration and concentration in vacuo gave a light brown solid, which was purified by flash chromatography (SiO2, 5%-20%, ethyl acetatelhexanes) to provide 17.641 g (85%) of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamnine (1) as a pale yellow solid. M.P.: 68-69 C.
Example 2 Synthesis of 4-[3-phenethyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoic Acid (5) A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (0.5 g, 2.46 mmole) in 20 mL of dicloromethane was treated successively with 0.51 mL of triethylamine (1.5 eq.) and 0.33 mL of phenylacetyl chloride (1 eq.), stirred at room temperature for two hours and then diluted with an additional 20 mL of dichloromethane. The organic solution was washed with two 50 mL portions of water and one 50 mL portion of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give 790 mg (100%) of phenylacetic acid (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide (7) as a pale yellow foam.
Example 13 Synthesis of 6-[3-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen -2-yl)-ureido]-nicotinic Acid (49) A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (1.0 g, 4.93 mmole) in 12 mL tetrahydrofuran (THF) was cooled to -78 C. and treated dropwise with 2.5 M n-butyllithium solution (2.2 mL) and allowed to warm to -20 C. over a one hour period. Iodopentane (1.28 mL) was introduced at -20 C., the mixture stirred at room temperature for three hours, poured into 50 mL of a saturated aqueous sodium bicarbonate solution and extracted with three portions of 50 mL of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a brown oil. The product was purified by flash chromatography (SiO2, 5% ethyl acetate/hexanes) providing 1.1 g (82%) of pentyl -(5,5,8,8-tetramethyl -5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (51) as a colorless oil.
With pyridine; potassium hydroxide; trifluoroacetic anhydride; In ethanol; dichloromethane; water; dimethyl sulfoxide;
a) 10 g of <strong>[92050-16-3]5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine</strong> were dissolved in 140 ml of methylene chloride. After the addition of 50 ml of pyridine, the reaction mixture was cooled to 0C, treated dropwise with 34 ml of trifluoroacetic anhydride, stirred at 0C for 2 hours, poured on ice water and extracted with ether. The organic phase was washed with water, dried (Na2SO4) and the solvent evaporated to give an orange oil which was purified with flash chromatography (silica gel, eluent hexane/ethyl acetate=4:1) and crystallized from hexane to yield 15 g of white crystals, m.p. 154-155 C. The compound was dissolved in 100 ml of DMSO and treated with 3.4 g of potassium hydroxide. The reaction mixture was cooled to 0 C., treated dropwise with 12 g of iodopentane dissolved in 15 ml of DMSO and stirred at room temperature for 24 hours. The crude product which was received after the usual workup (ice water/ether), was purified by column chromatography (silica gel, hexane/10% ethyl acetate) to give 13.9 g of a colorless oil. The crude oil was dissolved in 140 ml of ethanol, treated with a solution of 10 g of potassium hydroxide in 20 ml of water and stirred at room temperature for 2 hours. The reaction mixture was poured on ice water, extracted with ether, dried (Na2SO4) and the solvent evaporated. The oily residue was filtered through silica gel (eluent hexane/10% ethyl acetate) to give 9.8 g of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine as a slightly yellow oil.
A solution of 4-methoxycarbonylphenyl-pentyl-carbamoyl chloride (45) (180 mg, 0.63 mmole) in 5 mL pyridine was treated with 130 mg of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen -2-ylamine (1.05 eq.) and stirred at 40 C. for 15 hours. The reaction mixture was concentrated in vacuo to give an orange oil which was purified by flash chromatography (SiO2,10%-20% ethyl acetate/hexanes) to provide 190 mg (67%) of methyl 4-[1-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (47) as a colorless oil.
6-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene[ No CAS ]
[ 6683-46-1 ]
[ 92050-16-3 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; nitric acid; acetic acid;palladium-carbon; In ethanol; acetic anhydride;
Example 1 Synthesis of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (20.0 g, 106.2 mmole) in 85 ml of acetic anhydride at 0 C. was treated with 12.2 mL of acetic acid followed by 11.1 mL of nitric acid (70%) and was allowed to warm to room temperature. After 24 hours the reaction mixture was poured onto 300 mL ice-water and extracted with three 150 mL portions of ether. The combined organic extracts were washed with four 100 mL portions of 15% aqueous sodium hydroxide solution, two 200 mL portions of water and one 200 mL portion of saturated aqueous sodium chloride solution. The organic phase was dried, filtered and concentrated in vacuo, giving 23.93 g (97%) of 6-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (3) as a pale yellow solid. 1.4 g of Pd/C (10%) was added to a solution of 6-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (3) (23.93 g, 102.6 mmole) in 1 L of ethanol. The resulting suspension was maintained under 1 atmosphere for 15 hours. The mixture was filtered over Celite (2*) and concentrated in vacuo. The residue was taken up in 200 mL ether and dried over MgSO4. Filtration and concentration in vacuo gave a light brown solid, which was purified by flash chromatography (SiO2, 5%-20%, ethyl acetate/hexanes), providing 17.641 g (85%) of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) as a pale yellow solid. M.P.: 68-69 C.
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamino)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 4-methyl-morpholine; hydrogenchloride; In 1,4-dioxane; ethanol;
EXAMPLE 5 Preparation of 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamino)benzoic acid 1.02 g (5 mmol) of <strong>[92050-16-3]5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine</strong>, 1.24 g (5 mmol) of 4-iodobenzoic acid, 820 mul (7.5 mmol) of N-methylmorpholine, 360 mg (2.5 mmol) of Cu2 O and 15 ml of dioxane were introduced successively into a round-bottomed flask. The entire contents were heated at reflux for 24 hours, the reaction medium poured into 15 ml of 5N hydrochloric acid, the precipitate filtered and the latter washed with water. The solids were triturated in ethyl alcohol, filtered and dried. 200 mg (12%) of the expected acid of melting point 262-4 C. were then recovered.
allyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylcarbamoylmethyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(d) Allyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylcarbamoylmethyl)benzoate. In a manner similar to Example 4(c), by reaction of 2 g (10 mmol) of <strong>[92050-16-3]5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine</strong> with 2.2 g (10 mmol) of 4-(allyloxycarbonyl)phenylacetic acid, 3.7 g (92%) of the expected ester, melting point 49-50 C. are obtained.
5-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]pyridine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; thionyl chloride; In water; benzene;
Example 1 5-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl-carbamoyl)pyridine-2-carboxylic acid Pyridine-2,5-dicarboxylic acid 2-monomethyl ester (139 mg) was dissolved in 5 ml of dry benzene and the solution was refluxed for 1 hour after 1 ml of thionyl chloride was added. The solvent and excess thionyl chloride were removed by evaporation under a reduced pressure, and then the residue was dried. The residue was dissolved in newly added benzene (5 ml), and the solution was left to stand overnight after <strong>[92050-16-3]5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine</strong> (156 mg) was dissolved in the mixture of 5 ml benzene and 1 ml pyridine was added. The reaction mixture was added with water and extracted with ethyl acetate. The extract was washed with water and dried, and then the solvent was removed to give methyl 5(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenylcarbamoyl) pyridine-2-carboxylate (218 mg, yield 78%). Recrystallization from methanol gave needles having a melting point of 207-208 C. The methyl ester obtained (74.4 mg) was treated with ethanolic sodium hydroxide (2N) and the mixture was then neutralized. The theoretical amount of 5-(5,6,7,8-tetrahydro5,5,8,8-tetramethyl-2-naphthalenylcarbamoyl)pyridine-2-carboxylic acid was obtained. Recrystallization from ethyl acetate and n-hexane gave prisms having a melting point of 200--201 C. (69.5 mg, yield 97%).
With pyridine; thionyl chloride; In water; benzene;
Example 1 5-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenylcarbamoyl)pyridine-2-carboxylic acid Pyridine-2,5-dicarboxylic acid 2-monomethyl ester (139 mg) was dissolved in 5 ml of dry benzene and the solution was refluxed for 1 hour after 1 ml of thionyl chloride was added. The solvent and excess thionyl chloride were removed by evaporation under a reduced pressure, and then the residue was dried. The residue was dissolved in newly added benzene (5 ml), and the solution was left to stand overnight after <strong>[92050-16-3]5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine</strong> (156 mg) was dissolved in the mixture of 5 ml benzene and 1 ml pyridine was added. The reaction mixture wad added with water and extracted with ethyl acetate. The extract was washed with water and dried, and then the solvent was removed to give methyl 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenylcarbamoyl) pyridine-2-carboxylate (218 mg, yield 78%). Recrystallization from methanol gave needles having a melting point of 207-208 C. The methyl ester obtained (74.4 mg) was treated with ethanolic sodium hydroxide (2N) and the mixture was then neutralized. The theoretical amount of 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenylcarbamoyl)pyridine-2-carboxylic acid was obtained. Recrystallization from ethyl acetate and n-hexane gave prisms having a,melting point of 200-201 C (69.5 mg, yield 97%).
magnesium sulfate; In hexane; dichloromethane; ethyl acetate;
N-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl)-2-naphthalenyl 4-ethoxycarbonyl benzaldimine (Compound 4) A solution of 2-amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (Compound 20, 0.088 g, 0.43 mmol) and <strong>[713-57-5]ethyl 4-carboxybenzoate</strong> (Compound 28 0.077 g, 0.43 mmol) in CH2 Cl2 (3.0 ml) was stirred at room temperature in the presence of MgSO4 for 12 h. After concentration, the reaction mixture was purified by flash column chromatography (silica gel, 10% ethyl acetate in hexane) to yield yellow solids. These were recrystallized from 10% ethyl acetate in hexane to give the title compound as pale yellow crystals (0.081 g, 52%). 1 H NMR d 1.32 (d, 12H), 1.43 (t, J=7.2 Hz, 3H), 4.42 (q, J=7.1 Hz, 2H), 7.04 (dd, J1 =2.3 Hz, J2 =8.4 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.35 (d, J =8.4 Hz, 1H), 7.97 (d, J= 8.4 Hz, 2H), 8.14 (d, J=8.2 Hz, 2H), 8.54 (s, 1H).
N-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl)-2-naphthalenyl 4-carboxy benzaldimine (Compound 2) A solution of <strong>[92050-16-3]2-amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene</strong> (Compound 20, 0.106 g, 0.52 mmol) together with 4-carboxybenzaldehyde (Compound 26, 0.071 g, 0.47 mmol) in THF (5.0 ml) was stirred at room temperature in the presence of MgSO4 for 2 days. The reaction mixture was filtered through celite and the clear yellow solution was concentrated under reduced pressure to give yellow solids. The solids were successively washed with hexane until no tetramethyltetralin amine presented in the hexane layer (checked by TLC). The title compound was obtained as a light yellow solid (0.093 g, 60%). 1 H NMR d 1.32 (d, 12H), 1.72 (s, 4H), 7.06 (dd, J1 =2.2 Hz, J2 =8.4 Hz, 1H), 7.24 (d, J=2.2 Hz, 1H), 7.36 (d, J=8.3 Hz, 1H), 8.01 (d, J=8.4 Hz, 2H), 8.21 (d, J=8.4 Hz, 2H), 8.56 (s, 1H).
methyl 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamino)naphthoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In 1,4-dioxane; sulfuric acid;
(a) Preparation of methyl 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamino)naphthoate: 4.04 g (19.9 mmol) of <strong>[92050-16-3]5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine</strong>, 5 g (19.9 mmol) of 6-bromo-2-naphthoic acid, 3.3 ml (30 mmol) of N-methyl-morpholine, 2.9 g (19.9 mmol) of Cu2 O and 60 ml of dioxane were introduced in succession into a round-bottomed flask. The mixture was heated at reflux for 24 hours, the reaction medium was poured into 60 ml of 5N hydrochloric acid, and the precipitate was filtered off, washed with water and dried. The solid was purified by chromatography on a silica column eluted with ethyl acetate and, after evaporation of the solvents, 1.2 g of the expected acid was recovered, which was converted into the methyl ester by reacting same with 50 ml of methyl alcohol in the presence of 100 mul of concentrated sulfuric acid. 720 mg (10%) of methyl 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamino)-naphthoate were obtained, in the form of a chestnut-brown oil.
With hydrogenchloride; potassium hydroxide; sodium cyanoborohydride; dimethyl sulfoxide; In tetrahydrofuran; methanol; ethanol; water; ethyl acetate; toluene;
EXAMPLE 11 N-(4-carboxybenzyl)-<strong>[92050-16-3]5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine</strong> 8.1 g (40 mmol) of <strong>[92050-16-3]5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine</strong> and 6.6 g (40 mmol) of methyl 4-formylbenzoate in 100 ml of toluene were refluxed for 30 min, the solvent was evaporated off, the residue was taken up in 200 ml of 1:1 tetrahydrofuran/methanol, and 3.2 g (50 mmol) of sodium cyanoborohydride were added at room temperature. After the mixture had been stirred for 2 hours, the solvent was evaporated off under reduced pressure, the residue was taken up in 200 ml of ethyl acetate, and the organic phase was washed with water, dried over magnesium sulfate and evaporated. Recrystallization of the residue from ethanol yielded 9.6 g of N-(4-carbomethoxybenzyl)-<strong>[92050-16-3]5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine</strong> of melting point 104-107 C. 2 g of this ester and 2.5 g of potassium hydroxide in 45 ml of 5:1:3 ethanol/dimethyl sulfoxide/water were refluxed for 1 hour. At room temperature, 20 ml of 2N hydrochloric acid were added to the solution. The precipitate was filtered off, recrystallized from methanol and yielded 1.1 g of the title compound of melting point 225-231 C.
N-(5,6,7,8-tetrahydro-5,5,8.8-tetramethyl-2-naphthyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In tetrahydrofuran; pyridine; ice-water;
EXAMPLE 9 2.5 g of <strong>[92050-16-3]5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine</strong> were dissolved in 50 ml of pyridine and treated at room temperature with a solution of 1.7 g of benzoyl chloride in 20 ml of tetrahydrofuran. After stirring at room temperature for two hours the reaction mixture was poured on to ice-water and, after acidification with 3N hydrochloric acid, extracted with ethyl acetate. The oil obtained after drying and evaporating the organic phase was crystallized from hexane/ethyl acetate and gave 3 g of N-(5,6,7,8-tetrahydro-5,5,8.8-tetramethyl-2-naphthyl)benzamide in white crystals, m.p. 146 C.-148 C.
p-(2-morpholinoethoxy)-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With thionyl chloride; In tetrahydrofuran; pyridine; ice-water;
EXAMPLE 11 6.1 g of p-(2-morpholinoethoxy)benzoic acid were covered with 100 ml of thionyl chloride and heated at reflux for 1 hour. After evaporating the excess thionyl chloride the residue was suspended in 100 ml of tetrahydrofuran and added dropwise to a solution of 4.9 g of <strong>[92050-16-3]5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine</strong> in 150 ml of pyridine. After stirring at room temperature for 20 hours the reaction mixture was poured on to ice-water and extracted with ethyl acetate. After repeatedly washing the organic phase with water, drying over sodium sulphate and evaporating the solvent there was obtained a crystalline crude product which was purified by filtration over a silica gel column (eluding agent hexane/ethyl acetate =1:1, then ethyl acetate) and crystallization from hexane/ethyl acetate. There were obtained 8.6 g of p-(2-morpholinoethoxy)-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)benzamide, m.p. 130 C.-132 C.
With nitric acid; acetic anhydride; In acetic acid;
EXAMPLE B 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine 77.2 ml of glacial acetic acid and 20.8 ml of nitric acid (98% strength) were mixed while cooling and then added dropwise within 2 hours to a solution of 65.8 g (0.35 mol) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 154 ml of glacial acetic acid and 257 ml of acetic anhydride in a salt/ice bath. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. The solution was then poured into water, and the precipitate was filtered off with suction, washed with water and dried. 79.7 g of crude 2-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene of melting point 46-50 C. were obtained.
With nitric acid; acetic anhydride; In acetic acid;
Example H 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine 77.2 ml of glacial acetic acid and 20.8 ml of nitric acid (98% strength) were mixed while cooling and then added dropwise within 2 hours to a solution of 65.8 g (0.35 mol) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 154 ml of glacial acetic acid and 257 ml of acetic anhydride in a salt/ice bath. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. The solution was then poured into water, and the precipitate was filtered off with suction, washed with water and dried. 79.7 g of crude 2-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene of melting point 46-50 C. were obtained.
With triethylamine; In dichloromethane; at 20℃;Cooling with ice;
Example 15 : Propionic acid ester analogue (21) of Am-80 [Show Image] A solution of 4-[2-(methoxycarbonyl)ethyl]benzoic acid (77 mg, 0.370 mmol) and thionyl chloride (135 mu l, 1.85 mmol) in benzene (3 ml) was refluxed by heating for 1 hour. The resultant was treated in the same manner as that of Example 13 to obtain an acid chloride. This acid chloride was dissolved in dichloromethane (1 ml), this solution was added dropwise with a solution of the compound 20 (50 mg, 0.246 mmol) and triethylamine (171 mu I, 1.23 mmol) in dichloromethane (1 ml) under ice cooling, and the mixture was stirred for 10 minutes, and further stirred at room temperature for 4 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous sodium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography [eluted with benzene-ethyl acetate (8:1)], and recrystallized to obtain the title compound 21 (94 mg, 97%). Compound 21: colorless prisms, melting point: 135-136C (dichloromethane-hexane) MS (m/z): 393 (M+, 35), 378 (100), 362 (5), 191 (76), 131 (35), 103 (18), 91 (10), 59 (7), 43 (10) IR (KBr) cm-1: 1707, 1659 1H-NMR (CDCl3) delta : 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 2.67 (2H, t, J=7.5 Hz), 3.02 (2H, t, J=7.5 Hz), 3.68 (3H, s), 7.30 (1H, d, J=8.5 Hz), 7.32 (2H, A2B2, J=8 Hz), 7.41 (1H, dd, J=8.5, 2.5 Hz), 7.53 (1H, d, J=2.5 Hz), 7.69 (1H, br s, CONH), 7.80 (2H, A2B2, J=8 Hz)
With triethylamine; In dichloromethane; at 20℃; for 4.16h;Cooling with ice;
Example 15; Propionic Acid Ester Analogue (21) of Am-80; A solution of 4-[2-(methoxycarbonyl)ethyl]benzoic acid (77 mg, 0.370 mmol) and thionyl chloride (135 mul, 1.85 mmol) in benzene (3 ml) was refluxed by heating for 1 hour. The resultant was treated in the same manner as that of Example 13 to obtain an acid chloride. This acid chloride was dissolved in dichloromethane (1 ml), this solution was added dropwise with a solution of the compound 20 (50 mg, 0.246 mmol) and triethylamine (171 mul, 1.23 mmol) in dichloromethane (1 ml) under ice cooling, and the mixture was stirred for 10 minutes, and further stirred at room temperature for 4 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous sodium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography [eluted with benzene-ethyl acetate (8:1)], and recrystallized to obtain the title compound 21 (94 mg, 97%).Compound 21: colorless prisms, melting point: 135-136 C. (dichloromethane-hexane)MS (m/z): 393 (M+, 35), 378 (100), 362 (5), 191 (76), 131 (35), 103 (18), 91 (10), 59 (7), 43 (10)IR (KBr) cm-1: 1707, 16591H-NMR (CDCl3) delta: 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 2.67 (2H, t, J=7.5 Hz), 3.02 (2H, t, J=7.5 Hz), 3.68 (3H, s), 7.30 (1H, d, J=8.5 Hz), 7.32 (2H, A2B2, J=8 Hz), 7.41 (1H, dd, J=8.5, 2.5 Hz), 7.53 (1H, d, J=2.5 Hz), 7.69 (1H, br s, CONH), 7.80 (2H, A2B2, J=8 Hz)
With toluene-4-sulfonic acid; In 1,4-dioxane; at 111℃; for 14h;Inert atmosphere;
b. Methyl 6-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinate (75). To a 100 mL, one-neck, round-bottomed flask equipped with a magnetic stir bar and charged with 74 (0.8047 g, 3.958 mmol), methyl 6-chloronicotinate (0.6897, 4.02 mmol), and p-TsOH (0.7605 g,4.0 mmol) was added 1 ,4-dioxane (15 mL). The flask was fitted with a reflux condenser, evacuated and back-filled with nitrogen, heated to reflux and stirred in an oil bath at 111 °C for 14 h. After cooling the reaction to r.t., the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude product that was purified by column chromatography (150 mL Si02, 10percent ethyl acetate:hexanes) to give 75 (0.8152 g, 61percent) as a white crystalline solid, m.p. 167-171 °C: ?H NMR (400 MHz, CDC13) oe 8.81 (dd, J 2.0, 0.4, 1H), 8.02 (dd, J_ 8.8, 2.0, 1H), 7.94 (s, 111), 7.31 (a, J 7.6, 111), 7.21 (d, J 2.4, 1H), 7.12 (dd, J 8.4, 2.4, 1H), 6.82 (dd, J 8.8, 0.4, 1H), 3.87 (s, 3H), 1.70 (s, 411), 1.29 (s, 12H); ?3C NMR (100.6 MHz, CDC13) oe 166.0, 159.4, 151.2, 146.3, 141.5, 138.9, 136.1, 127.5, 120.4, 120.0, 116.3, 106.0, 51.6, 35.0, 34.9, 34.3, 33.9, 31.8, 31.7; IR (neat) 3224, 2954, 1715, 1597, 1535, 1261 cm?; ES-MS (M+Na)+ caled for C21H26N7O2Na 361.1892, found 361.1899.
61%
With toluene-4-sulfonic acid; In 1,4-dioxane; at 111℃;Inert atmosphere;
To a 100 mL, one-neck, round-bottomed flask equipped with a magnetic stir bar and charged with 33 (0.8047 g, 3.958 mmol), methyl 6-chloronicotinate (34) (0.6897, 4.02 mmol), and p-TsOH (0.7605 g, 4.0 mmol) was added 1,4-dioxane (15 mL). The flask was fitted with a reflux condenser, evacuated and back-filled with nitrogen, heated to reflux and stirred in an oil bath at 111° C. for 14 hours. After cooling the reaction to room temperature, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude product that was purified by column chromatography (150 mL SiO2, 10percent ethyl acetate:hexanes) to give compound 35 (0.8152 g, 61percent) as a white crystalline solid, m.p. 167-171° C.: 1H NMR (400 MHz, CDCl3) delta 8.81 (dd, J=2.0, 0.4, 1H), 8.02 (dd, J=8.8, 2.0, 1H), 7.94 (s, 1H), 7.31 (d, J=7.6, 1H), 7.21 (d, J=2.4, 1H), 7.12 (dd, J=8.4, 2.4, 1H), 6.82 (dd, J=8.8, 0.4, 1H), 3.87 (s, 3H), 1.70 (s, 4H), 1.29 (s, 12H); 13C NMR (100.6 MHz, CDCl3) delta 166.0, 159.4, 151.2, 146.3, 141.5, 138.9, 136.1, 127.5, 120.4, 120.0, 116.3, 106.0, 51.6, 35.0, 34.9, 34.3, 33.9, 31.8, 31.7; IR (neat) 3224, 2954, 1715, 1597, 1535, 1261 cm-1; ES-MS (M+Na)+ calcd for C21H26N2O2Na 361.1892, found 361.1899.
methyl 2-fluoro-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120 - 125℃; for 22.0h;Inert atmosphere;
a. Methyl 2-fluoro-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)amino)benzoate (103). To a solution of 6 (0.8098 g, 3.98 mmol), 2 (1.1254 g, 4.02 mmol), CsCO3 (3.12 g, 9.58 mmol), rac-BINAP (0.1901 g, 0.305 mmol) in toluene (4.5 mL) in a 100 mL round-bottomed flask was added Pd2(dba)3 (0.1783 g, 0.19 mmol). The solution was sparged with nitrogen for 5 mm., then a reflux condenser was fitted to the flask, the atmosphere was evacuated and back-filled with nitrogen (three times), and the reaction was heated to reflux with stirring in an oil bath (125-120 C) for 22h. After cooling the reaction to room temperature, excess cesium carbonate and other solid particulates were filtered and washed with ethyl acetate, and the organic filtrate was concentrated in vacuo to give a crude product that was purified by column chromatography (150 mL Si02, 3.7% ethyl acetate:hexanes) to give 103 (0.7449 g, 52%) as a crystalline solid, m.p. 121.8- 136.7 C: ?H NMR (400 MHz, CDC13) oe 7.80 (t, J= 8.4, 111), 7.27 (d, J= 8.4,1H), 7.08 (d, J 2.4, 1H), 6.96 (dd, J 8.4, 2.4, 1H), 6.65 (dd, J 8.8, 2.4, 1H), 6.62 (dd, J 12.4, 2.4, 1H), 5.95 (br s, 1H), 3.87 (s, 3H), 1.69 (s, 4H), 1.28 (s, 611), 1.27 (s, 6H); ?3C NMR (100.6 MHz, CDC13) 165.2,164.9, 164.8, 162.6, 150.8, 150.7, 146.4, 141.2, 137.0, 133.6, 133.5, 127.6, 119.8, 119.4, 110.0,108.0, 107.9, 101.4, 101.1, 51.7, 34.9, 34.9, 34.3, 33.9, 31.8, 31.7; IR (neat) 3344, 2956, 1703, 1620, 1601, 1273 cm?; ES-MS (M+Na)+ calcd for C22H26FNO2Na 378.1845, found 378.1848.
methyl 2-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With toluene-4-sulfonic acid; In 1,4-dioxane; at 111℃; for 14h;Inert atmosphere;
a. Methyl 2-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidine-5- carboxylate (82). To a 100 mL, one-neck, round-bottomed flask equipped with a magnetic stir bar and charged with 74 (0.8047 g, 3.958 mmol), methyl 6-chioronicotinate (0.6897, 4.02 mmol), andpTsOH (0.8 101 g, 3.98 mmol) was added 1,4-dioxane (15 mL). The flask was fitted with a reflux condenser, evacuated and back-filled with nitrogen, heated to reflux and stirred in an oil bath at 111C for 14 h. After cooling the reaction to r.t., the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude product that was purified by column chromatography (150 mL Si02, 10% ethyl acetate:hexanes to 12% ethyl acetate:hexanes) to give 82(1.0177 g, 75%) as a white crystalline solid, m.p. 143.2-149.3 C: ?H NMR (400 MHz, CDC13) 6 8.95 (s, 2H), 8.25 (br s, 1H), 7.47 (dd, J 8.4, 2.4, 1H), 7.42 (d, J 2.0, 111), 7.32 (d, J 8.4, 1H), 3.90 (s, 3H), 1.69 (s, 4H), 1.30 (s, 6H), 1.28 (s, 6H); ?3C NMR (100.6 MHz, CDC13) 6164.7, 161.4, 145.7, 141.1, 135.3, 127.1, 118.8, 118.7, 114.7, 51.9, 35.0, 34.3, 33.9, 31.8, 31.8; JR (neat) 3254, 2954, 1720, 1597, 1526, 1433, 1289, 1258, 1123 cm?; ES-MS (M+Na)+ calcd for C20H25N3O2Na 362.1844, found 362.1844.
tert-butyl 4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)carbamoyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 38h;
Compound (26) (113 mg), EDCI (119 mg) and HOBt · H 2 0 (95.0 mg) were dissolved in N, N-dimethylformamide (5 mL)Compound (24) (124 mg) was added and the mixture was stirred at room temperature for 38 hours.The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine.The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 10: 1 to 5: 1)To give the title compound (54) (226 mg, q.y.) as a pale yellow solid.
4-(((((4-(methyl(2-phenylcyclopropyl)amino)ethyl)carbamoyl)oxy)benzyl)(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)benzoic acid[ No CAS ]
In a 50 mL round-bottomed flask T-14 (100 mg, 0.52 mmol) was dissolved in dry CH2CI2 (3 mL) under argon. Added were oxalyl chloride (67 pL, 0.78 mmol 1.5 equiv) and one drop of DMF. The reaction was heated to 40°C for 1 h. Then the solvents were evaporated to dryness and 2 mL of CH2CI2 added. This solution was added dropwise to a solution of 1 ,1 ,4,4-tetramethyl-6-amino tetraline (105 mg, 0.52 mmol, 1 equiv) and Et3N (0.22 mL, 1.56 mmol, 3 equiv) in CH2CI2 (5 mL). The mixture was stirred for 5 h at room temperature, then EtOAc was added (30 mL), and the solution washed with 2M HCI (2 x 10 mL) and finally with 1 M NaOH (10 mL). The organic layer was dried (MgS04) and evaporated. The residue was purified via column chromatography (CH2CI2) to afford the title compound T-16 (167 mg, 85percent) as a colorless solid.
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