* 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] Organic Preparations and Procedures International, 1994, vol. 26, # 4, p. 429 - 438
2
[ 67123-97-1 ]
[ 119-65-3 ]
[ 6624-49-3 ]
Reference：
[1] Journal of the American Chemical Society, 1981, vol. 103, # 15, p. 4642 - 4643
[2] Journal of the American Chemical Society, 1981, vol. 103, # 15, p. 4642 - 4643
3
[ 67123-97-1 ]
[ 6624-49-3 ]
Reference：
[1] Patent: CN107137355, 2017, A,
4
[ 67123-97-1 ]
[ 50458-77-0 ]
Reference：
[1] Organic Preparations and Procedures International, 1994, vol. 26, # 4, p. 429 - 438
With hydrogenchloride In water for 4.5 h; Heating / reflux
A suspension of D,L-phenylalanine (50 g, 3.03 mol) in con. HCl (325 mL) and 37percent formaldehyde (110 mL) was heated to a gentle reflux with vigorous stirring for 30 min. Additional formaldehyde (50 ml) and con. HCl (110 mL) was added and continuously heated for 4 hours. The reaction mixture was cooled to room temperature and the solid product was collected by filtration, washed with methanol (30 mL), and dried to give the known 3-carboxy-1,2,3,4-tetrahydroquinoline, 64.09 g (98.9percent): mp 295-298° C. (>326° C., dec.) (Julian P L, J. Chem. Soc. 1948, 70,180-183) as an enantiomeric mixture; 1H NMR (DMSO-d6) δ 3.10-3.18 (1H, m, CH), 3.28-3.34 (1H, m, CH), 4.27 (2H, s, CH2), 4.39 (1H, m, CH), 7.25-7.27 (4H, m, 4*ArH), 9.89 (1H, brs, exchangeable, NH); 10.06 (1H, brs, exchangeable, OH); MS: m/z 177.0 (M+H)+.
33%
With hydrogenchloride In water for 6 h; Reflux
To the solution of 187 phenylalanine 37 (16.5g, 0.1mol) in 94 HCl (150mL), 33percent 188 formaldehyde solution (70mL, 1mol) was added. The reaction mixture was stirred at refluxing for 6h and TLC analysis indicated that the reaction was completed. The mixture was filtered to give white 189 solid 11 in 33percent yield. m.p. 245–247°C; 1H-NMR (300MHz, DMOS-d6): δ 10.07 (s, 1H, -COOH), 7.27 (s, 4H, Ar-H), 4.43–4.40 (m, 2H, -CH2-), 3.81 (s, 1H, -CH-), 3. 45–3.10 (m, 2H, -CH2-).
Reference：
[1] Patent: US2009/117125, 2009, A1, . Location in patent: Page/Page column 15
[2] Bulletin of the Chemical Society of Japan, 1991, vol. 64, # 12, p. 3729 - 3731
[3] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1325 - 1344
[4] Journal of the American Chemical Society, 1948, vol. 70, p. 180,182
[5] Journal of Organic Chemistry, 1951, vol. 16, p. 430
[6] Journal of Medicinal Chemistry, 1983, vol. 26, # 9, p. 1267 - 1277
[7] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 17, p. 3978 - 3981
[8] Patent: US4500713, 1985, A,
7
[ 673-06-3 ]
[ 67123-97-1 ]
Reference：
[1] Patent: US5914319, 1999, A,
[2] Patent: US5455229, 1995, A,
[3] Patent: US5455229, 1995, A,
[4] Patent: US5705487, 1998, A,
[5] Patent: US5707966, 1998, A,
[6] Patent: US5726159, 1998, A,
[7] Patent: US5436229, 1995, A,
8
[ 50-00-0 ]
[ 63-91-2 ]
[ 67123-97-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1986, vol. 29, # 5, p. 784 - 796
[2] Patent: US5200416, 1993, A,
[3] Arzneimittel-Forschung/Drug Research, 1986, vol. 36, # 1, p. 10 - 13
[4] Patent: CN107137355, 2017, A, . Location in patent: Paragraph 0088; 0089
Reference：
[1] Journal of Medicinal Chemistry, 1993, vol. 36, # 3, p. 314 - 319
15
[ 143767-54-8 ]
[ 67123-97-1 ]
Reference：
[1] Synthesis, 1992, # 11, p. 1157 - 1160
[2] European Journal of Medicinal Chemistry, 2001, vol. 36, # 3, p. 265 - 286
16
[ 143767-55-9 ]
[ 67123-97-1 ]
Reference：
[1] Synthesis, 1992, # 11, p. 1157 - 1160
[2] European Journal of Medicinal Chemistry, 2001, vol. 36, # 3, p. 265 - 286
[3] Synthesis, 1992, # 11, p. 1157 - 1160
17
[ 612-12-4 ]
[ 67123-97-1 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2001, vol. 36, # 3, p. 265 - 286
[2] Synthesis, 1992, # 11, p. 1157 - 1160
[3] Synthesis, 1992, # 11, p. 1157 - 1160
18
[ 109-87-5 ]
[ 150-30-1 ]
[ 67123-97-1 ]
Reference：
[1] Chemische Berichte, 1911, vol. 44, p. 2034
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 10, p. 1185
19
[ 67123-97-1 ]
[ 27104-73-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 17, p. 3978 - 3981
[2] Organic Preparations and Procedures International, 1994, vol. 26, # 4, p. 429 - 438
[3] Journal of Medicinal Chemistry, 1982, vol. 25, # 9, p. 1081 - 1091
[4] Patent: CN107137355, 2017, A,
20
[ 67123-97-1 ]
[ 54329-54-3 ]
Yield
Reaction Conditions
Operation in experiment
53%
With hydrogenchloride; formaldehyd In formic acid; water
PREPARATION 3 2-Methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid A solution of 0.364 g (2.07 mmol) of 3-carboxy-1,2,3,4-tetrahydroisoquinoline in 25 mL of formic acid was combined with 2.5 mL of 37percent formaldehyde. The resulting mixture was allowed to reflux for approximately 17 hours. After cooling, the mixture was contentrated under reduced pressure to provide a gum. This gum was dissolved in 3.0 mL of water, adjusted to a pH 2 using hydrochloric acid and then purified using ion-exchange chromatography (Dowex 50x-8, 100 meshcation) to provide 0.21 g of a yellow powder. Yield: 53percent 1 H NMR (DMSO-d6): δ2.56 (S, 3H), 3.01 (m, 2H), 3.48 (t, 1H), 3.9 (dd, 2H) 7.05 (m, 1H), 7.13 (m, 3H). MS (FD): m/e 192 (M+2).
With sodium hydroxide; boron trifluoride In tetrahydrofuran; methanol
Step 1 Synthesis of S-(1,2,3,4-Tetrahydro-Isoquinoline-3-yl)-Methanol STR38 Borane-methyl sulfide complex (31.0 mmol) was added to the gently refluxing solution of S-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid (5.0 g, 28.22 mmol) and boron trifluoride ethorate (28.22 mmol) in THF (100 ML) under nitrogen. The solution was then refluxed overnight. The reaction mixture was cooled to 0° C. and quenched by slow addition of methanol (5 ML). the solvent was evaporated and the residue was dissolved in aqueous solution of sodium hydroxide (6 M) and reflux for 2 hr. the mixture was filtered through a cerite pad. The filtrate was extracted with chloroform, washed with brine, dried over MgSO4 and evaporated. The crude product was recrystallized from CHCl3 to give the desired product as crystals (4.0 g, 87percent). 1 H NMR (CDCl3) δ: 7.10 (4 H, m), 4.06 (2H, s), 3.77 (1H, dd, J=10.95 Hz, J=3.64 Hz), 3.52 (1H, dd, J=10.95 Hz, J=7.80 Hz), 3.08 (1H, m), 2.70 (1H, dd, J=16.27 Hz, J=4.26 Hz), 2.59 (1H, dd, J=16.27 Hz, J=10.85 Hz). 13 C NMR (CDCl3) δ: 128.43, 125.34, 125.14, 124.98, 64.81, 54.18, 46.97, 30.05.
A mixture of this product (11 g), potassium acetate (19.6 g) and dry ethanol (200 ml) was heated to reflux and a solution of iodine (25.4 g) in dry ethanol (250 ml) was added over a period of 3 hours to the heated mixture. The mixture was heated to reflux for 16 hours, cooled and filtered and the filtrate was evaporated. The residue was partitioned between ethyl acetate and a dilute aqueous sodium thiosulphate solution. The organic layer was dried (Na2 SO4) and evaporated. The residue was purified by column chromatography eluding with ethyl acetate to give ethyl isoquinoline-3-carboxylate (3 g).
With iodine; potassium acetate; In ethanol;
A mixture of this product (11 g), potassium acetate (19.6 g) and dry ethanol (200 ml) was heated to reflux and a solution of iodine (25.4 g) in dry ethanol (250 ml) was added over a period of 3 hours to the heated mixture. The mixture was heated to reflux for 16 hours, cooled and filtered and the filtrate was evaporated. The residue was partitioned between ethyl acetate and a dilute aqueous sodium thiosulphate solution. The organic layer was dried (Na2SO4) and evaporated. The residue was purified by column chromatography eluding with ethyl acetate to give ethyl isoquinoline-3-carboxylate (3 g).
A mixture of the compound tetrahydroisoquinoline carboxylic acid (21.44 mmol), dioxane (40 ml), water (200 ml) and sodium hydroxide (2:1:1, 10 ml, 1 M) was cooled in an ice bath and stirred overnight. To the resulting reaction mixture was added di-tert-butoxy carbonyl anhydride (23.58 mmol) and stirred overnight. The mixture was concentrated under reduced pressure and subsequently cooled in an ice-bath. The residue thus obtained was diluted with ethylacetate and acidified with dilute potassium hydrogen sulphate solution to a pH of 2-3. The aqueous phase was extracted with ethylacetate, washed with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to furnish the title compound. 1H NMR (CDCl3) delta: 7.25-7.14 (4H, m), 5.09-4.5 (2H, m), 4.47-4.42 (1H, m), 3.2-3.14 (2H, m), 1.50-1.40 (9H, m); Mass: 278 (M++1); IR (cm-1); 3425, 2977, 1700, 1406, 1165, 753.
With sodium hydroxide; boron trifluoride; In tetrahydrofuran; methanol;
Step 1 Synthesis of S-(1,2,3,4-Tetrahydro-Isoquinoline-3-yl)-Methanol STR38 Borane-methyl sulfide complex (31.0 mmol) was added to the gently refluxing solution of S-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid (5.0 g, 28.22 mmol) and boron trifluoride ethorate (28.22 mmol) in THF (100 ML) under nitrogen. The solution was then refluxed overnight. The reaction mixture was cooled to 0 C. and quenched by slow addition of methanol (5 ML). the solvent was evaporated and the residue was dissolved in aqueous solution of sodium hydroxide (6 M) and reflux for 2 hr. the mixture was filtered through a cerite pad. The filtrate was extracted with chloroform, washed with brine, dried over MgSO4 and evaporated. The crude product was recrystallized from CHCl3 to give the desired product as crystals (4.0 g, 87%). 1 H NMR (CDCl3) delta: 7.10 (4 H, m), 4.06 (2H, s), 3.77 (1H, dd, J=10.95 Hz, J=3.64 Hz), 3.52 (1H, dd, J=10.95 Hz, J=7.80 Hz), 3.08 (1H, m), 2.70 (1H, dd, J=16.27 Hz, J=4.26 Hz), 2.59 (1H, dd, J=16.27 Hz, J=10.85 Hz). 13 C NMR (CDCl3) delta: 128.43, 125.34, 125.14, 124.98, 64.81, 54.18, 46.97, 30.05.
With sodium hydroxide; In water; tert-butyl alcohol;
A. N-Boc-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid A solution of 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (855 mg, 4.83 mmol), (Boc)2 O (1.37 g, 6.28 mmol), and 1N NaOH (6 mL) in a mixture of t-BuOH (12 mL) and water (12 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water (30 mL) and washed with ether-hexanes (1:1, 2*25 mL). The organic layer was back-extracted with 10% NaHCO3. The combined aqueous layers were carefully acidified to pH 2-3 and extracted with EtOAc (3*30 mL). The combined organic extracts were washed with water and saturated aqueous NaCl, dried (MgSO4), and concentrated to provide the title compound (1.27 g) as a white solid.
With sodium hydroxide; In water; tert-butyl alcohol;
A. N-Boc-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid A solution of 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (855 mg, 4.83 mmol), (Boc)2 O (1.37 g, 6.28 mmol), and 1N NaOH (6 mL) in a mixture of t-BuOH (12 mL) and water (12 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water (30 mL) and washed with ether-hexanes (1:1,2*25 mL). The organic layer was back-extracted with 10% NaHCO3. The combined aqueous layers were carefully acidified to pH 2-3 and extracted with EtOAc (3*30 mL). The combined organic extracts were washed with water and saturated aqueous NaCl, dried (MgSO4), and concentrated to provide the title compound (1.27 g) as a white solid.
N-(4-nitro-3-trifluoromethylphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: A mixture of racemic 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid10(5-10 mmol), K2CO3(3 equiv.) and the appropriate fluoronitroaryl derivative (1 equiv.) was heated (80C) in dimethylsulphoxide with stirring (3 h). The coloured mixture was poured into water, and then acidified with dilute hydrochloric acid. The mixture was extracted with CH2Cl2(x 3) and the combined organic layers were washed several times with water, dried (MgSO4) and evaporated giving the carboxylic acid derivative11which was used without further purification.
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