* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 33, p. 10652 - 10658
[2] ChemCatChem, 2013, vol. 5, # 8, p. 2183 - 2186
2
[ 10349-57-2 ]
[ 5382-49-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 2, p. 670 - 676
[2] ChemCatChem, 2013, vol. 5, # 8, p. 2183 - 2186
[3] Angewandte Chemie - International Edition, 2017, vol. 56, # 12, p. 3216 - 3220[4] Angew. Chem., 2017, vol. 129, # 12, p. 3264 - 3268,5
[5] Catalysis Science and Technology, 2017, vol. 7, # 10, p. 1981 - 1985
[6] ACS Catalysis, 2018, vol. 8, # 5, p. 4545 - 4557
[7] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1988, vol. 24, p. 65 - 67[8] Khimiya Geterotsiklicheskikh Soedinenii, 1988, vol. 24, # 1, p. 77 - 79
[9] Tetrahedron Letters, 2004, vol. 45, # 16, p. 3215 - 3217
[10] Chemische Berichte, 1902, vol. 35, p. 2613
[11] Patent: US5385909, 1995, A,
[12] Patent: US2004/122001, 2004, A1,
[13] ACS Catalysis, 2018, vol. 8, # 1, p. 17 - 21
3
[ 851202-94-3 ]
[ 5382-49-0 ]
Yield
Reaction Conditions
Operation in experiment
61%
for 18 h; Heating / reflux
l-Acetyl-1, 2,3, 4-tetrahydro-quinoline-6-carbonitrile (50 mmol) was refluxed in HC1 (8M) (150 mL) for 18h. The mixture was cooled and pH adjusted to approx. 3 with NaOH. The product precipitated and was removed by filtration, washed with water and dried. Yield: 61percent 1H NMR (D6-DMSO) : 1.79 (m, 2H); 2.68 (m, 2H) ; 3.23 (m, 2H); 5.45 (br, 1H) ; 6. 48 (d, 1H) ; 7.45-7. 50 (2H).
Example 24a; Pyridin-3-ylmethyl 6-(2-amino-5-(thiophen-2-yl)phenylcarbamoyl)-3,4-dihydroquino-line- l(2H)-carboxylate (216); Scheme 24; Step 1 : Methyl l,2,3,4-tetrahvdroquinoline-6-carboxylate (212); [0827] A mixture of 50percent potassium hydroxide in H2O (30 mL) and diethyl ether (100 mL), stirred at 0 0C, was treated portion- wise with solid iV-nitroso-jV-methyl urea (3.Og, 29.1 mmol).The reaction mixture was stirred for 30 min then transferred into a separatory funnel, the aqueous layer was discarded and the yellow etheral phase (diazomethane solution) was cooled to -78 0C in an Erlenmeyer flask. To a solution of acid 211 (1.Og, 5.65 mmol) in THF (100 mL), stirred at0 0C, was added the etheral solution of diazomethane (kept at -78 0C) drop wise. After the addition, the reaction mixture was stirred at 0 0C for 2 h then at room temperature for 4 h, and concentrated to give title compound 212 as a reddish solid (100percent yield).[0828] 1H NMR (DMSO-d6) δ (ppm): 7.47 to 7.45 (m, 2H), 6.63 (s, IH), 6.42 (d, J= 8.4 Hz,IH), 3.71 (s, 3H), 3.24-3.21 (m, 2H), 2.67 (t, J= 6.3 Hz, 2H), 1.80-1.74 (m, 2H).
Step 1 Methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate 1,2,3,4-tetrahydroquinoline-6-carboxylic acid (50 g, 282 mmol) was dissolved in MeOH (500 mL) in a 2 L flask, to which AcCl (100 mL) was added at 0° C., followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate (45 g).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 2, p. 670 - 676
[2] Patent: US2016/355483, 2016, A1, . Location in patent: Paragraph 0323-0324
A 500 ml. RBF was charged with 1 ,2,3,4-tetrahydroquinoline-6-carboxylic acid (10 g, 0.064 mol) ethanol (200 ml_, 0.3 M) and the reaction mixture was treated dropwise with sulfonyl chloride (8.4 ml_, 14.0 g, 0.104 mol, 1 .6 equiv.). The reaction mixture was warmed to 85 C and stirred for 4 h. The reaction was complete by LCMS analysis and was allowed to cool to RT. mixture was cooled to RT and poured into 800 mL of water. The solution was then made basic with the addition of solid NaHC03. The resulting precipitate was collected by vacuum filtration and dried under reduced pressure to afford ethyl, 1 ,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid (10.6 g, 13.1 g theoretical, 80.9%). 1 H NMR (CDCI3): d 7.64 (m 2H), 6.37 (d 1 H), 4.27 (q 2H), 3.33 (t 2H), 2.75 (t 2H), 1.92 (m 2H), 1.33 (t 3H); LCMS: (APCI) m/e 206 (M+H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); 1,2-dichloro-ethane; at 60℃; for 96.0h;
1, 2,3, 4-Tetrahydro-quinoline-6-carboxylic acid (17 mmol) was dissolved in DMF (5mL) and 1,2-dichloroethane (15 mL) was added, followed by DIPEA (17 mmoL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17 munol), l-hydroxybenzohiazole (17 mmol) and 2-aminothiazole (17 mmol). Stirred at 60 C for 96h, then HC1 (17 mmol) and water (20 mL) was added. The organic solvent was removed by evaporation, and the aqueous phase was extracted with ethyl acetate. The organics were dried over MgS04, filtered and evaporated. The crude product was purified by flash chromatography on silica with gradient (heptane/ethyl acetate) elution. Yield: 10% (3% overall) 1H NMR (D6-DMSO) : 1.80 (m, 2H); 2.70 (m, 2H); 3.24 (m, 2H); 6.46 (d, 1H); 6.56 (s, 1H) ; 7.16 (d, 1H); 7.49 (d, 1H); 7.65-7. 72 (2H).
With hydrogenchloride; water; for 18.0h;Heating / reflux;
l-Acetyl-1, 2,3, 4-tetrahydro-quinoline-6-carbonitrile (50 mmol) was refluxed in HC1 (8M) (150 mL) for 18h. The mixture was cooled and pH adjusted to approx. 3 with NaOH. The product precipitated and was removed by filtration, washed with water and dried. Yield: 61% 1H NMR (D6-DMSO) : 1.79 (m, 2H); 2.68 (m, 2H) ; 3.23 (m, 2H); 5.45 (br, 1H) ; 6. 48 (d, 1H) ; 7.45-7. 50 (2H).
1 -[(9H-fluoren-9-ylmethoxy)carbonyl]-<strong>[5382-49-0]1,2,3,4-tetrahydroquinoline-6-carboxylic acid</strong> EPO <DP n="100"/> To a mixture of I^S^-tetrahydroquinoline-theta-carboxylic acid (1.03g, 5.8mmol) in 1 ,4-dioxane (12ml) and 0.5M aqueous sodium hydroxide solution (12ml) was added 9- fluorenylmethoxycarbonyl chloride (1.68g, 6.5mmol). The mixture was partitioned between 1 M HCI (aq) and dichloromethane. The aqueous layer was extracted with dichloromethane and the combined organic extracts were washed with water then brine and dried over sodium sulfate. The solvent was removed in vacuo and the crude product purified by flash column chromatography on silica to give 1-[(9H-fluoren-9-ylmethoxy)carbonyl]-1, 2,3,4- tetrahydroquinoline-6-carboxylic acid as a white solid (2.Og; 86%).
86%
With sodium hydroxide; In 1,4-dioxane; water;
.15 1-[(9H-fluoren-9-ylmethoxy)carbonyl1-1 ,2,3,4-tetrahydroquinoline-6-carboxylic acid; To a mixture of 1 ,2,3,4-tetrahydroquinoline-6-carboxylic acid (1.03 g, 5.8 mmol) in 1 ,4-dioxane (12 ml) and 0.5M aqueous sodium hydroxide solution (12 ml) was added 9- fluorenylmethoxycarbonyl chloride (1.68 g, 6.5 mmol). The mixture was partitioned between 1 M HCI (aq) and dichloromethane. The aqueous layer was extracted with dichloromethane and the combined organic extracts were washed with water then brine and dried over sodium sulfate. The solvent was removed in vacuo and the crude product purified by flash column chromatography on silica to give 1-[(9H-fluoren-9-ylmethoxy)carbonyl]-1 , 2,3,4- tetrahydroquinoline-6-carboxylic acid as a white solid (2.Og; 86%).
76%
With sodium hydroxide; In 1,4-dioxane; water; at 20℃;
A mixture of 1 ,2,3,4-tetrahydroquinoline-6-carboxylic acid (5 g, 28.2 mmol) in 1 ,4-dioxane (30 ml.) and 0.5 M aqueous sodium hydroxide solution (30 ml.) was treated with 9-fluorenylmethoxycarbonyl chloride (8.3 g, 31 mmol) and stirred at RT overnight. The mixture was partitioned between 1 M HCI (50 ml.) and dichloromethane (50 ml_). The aqueous layer was extracted with dichloromethane (3 x 20 ml.) and the combined organic layer was washed with water (30 ml.) then brine (30 ml.) and dried over sodium sulfate. The solvent was removed in vacuo and the crude product purified by flash column chromatography on silica to give 1-[(9H-fluoren-9-ylmethoxy)carbonyl]-1 , 2,3,4- tetrahydroquinoline-6-carboxylic acid, 6S-23 (8.57 g, 76% yield) as a white solid. The material was used in the next step without further purification
1-[(2,4-diamino-6-pteridinyl)methyl]1,2,3,4-tetrahydro-6-quinolinecarboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ISOPROPYLAMIDE; water;
Reference Example 41 Synthesis of [1-[(2,4-diamino-6-pteridinyl)methyl]<strong>[5382-49-0]1,2,3,4-tetrahydro-6-quinolinecarboxylic acid</strong> In dimethylacetamide (3 ml) were suspended 6-bromomethyl-2,4-diaminopteridine hydrobromide.isopropanol adduct (178 mg) and <strong>[5382-49-0]1,2,3,4-tetrahydro-6-quinolinecarboxylic acid</strong> (55 mg), and the suspension was stirred at 60 to 65 C. overnight. After cooling, water (10 ml) was added to the reaction mixture, and the mixture was adjusted to pH=3.5 with 1N-hydrochloric acid under ice-water cooling and allowed to stand at cool place overnight. Deposited precipitates were collected by filtration to obtain the title compound (70 mg). 1 H-NMR (DMSO-d6, delta): 2.08 (2H, t, J=8 Hz), 2.88 (2H, t, J=8 Hz), 3.68 (2H, t, J=8 Hz), 4.72 (2H, s), 6.62 (1H, d, J=9 Hz), 7.48 (2H, m), 8.51 (1H, s).
<strong>[5382-49-0]1,2,3,4-Tetrahydroquinoline-6-carboxylic acid</strong> (2.49 g, 1.0 eq) was dissolved in EtOH (200mL). 30% Formaldehyde (4 mL) and 10% Pd/C (2.0 g) were added. The reaction was hydrogenated at 50 psi overnight. The catalyst was filtered off and the solvent evaporated to provide crude 1-methyl-<strong>[5382-49-0]1,2,3,4-tetrahydroquinoline-6-carboxylic acid</strong> which was purified via flash column chromatography using hexane/ethyl acetate 50/50-100% ethyl acetate to provide 1.44 g (54%) of the desired product. 1 H NMR (200 MHz, DMSO) delta1.89 (m, 2H), 2.71 (t, 2H), 2.9 (s, 2H), 3.3 (t, 2H), 6.52 (d, 1H), 7.46 (s, 1H), 7.6 (dd, 1H).
b) Allyl 1-Allyl-1,2,3,4-tetrahydroquinoline-6-carboxylate To a solution of <strong>[5382-49-0]1,2,3,4-tetrahydroquinoline-6-carboxylic acid</strong> (5.3 g, 29.9 mmol) in dried DMF (100 mL) at -10 C. was added sodium hydride (2 g 60% dispersion, 50 mmol). The suspension was stirred at -10 C. until gas evolution ceased (approx. 30 min), then treated with allyl bromide (4 mL, 46.2 mmol) and allowed to warm to room temperature over 2 hours. The suspension was treated with further sodium hydride (2 g 60% dispersion, 50 mmol) and the temperature raised to 65 C. for 2 hours, then treated with further allyl bromide (4 mL, 46.2 mmol). The mixture was stirred at room temperature overnight, then poured into ice water (1000 mL), and the aqueous mixture extracted with ether (3*250 mL) and chloroform (250 mL). The combined organic extracts were dried (MgSO4), filtered, and the solvent removed in vacuo to yield the title compound as an oil suitable for further use without purification.
With thionyl chloride; at 0℃; for 3.0h;Heating / reflux;
Example 11; Sodium salt of 1-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinoline-6-carboxylic Acid (Compound No. 79); 11.1: Methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate Hydrochloride; 0.93 g of <strong>[5382-49-0]1,2,3,4-tetrahydroquinoline-6-carboxylic acid</strong> and 100 ml of methanol are placed in a 500 ml round-bottomed flask under a nitrogen atmosphere. 0.46 ml of thionyl chloride is added at 0 C. and then the reaction mixture is stirred at reflux for three hours. After evaporating the solvent, the residue is triturated in ethyl ether and then the solid obtained is filtered off and dried under vacuum. 1.13 g of methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate hydrochloride are obtained.M+H+=192.3
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