* 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 potassium permanganate In N,N-dimethyl-formamide at 0 - 20℃; for 100.5 h; Inert atmosphere
At 0 °C to a solution of 10.0 g (0.046 mmol) of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in 200 ml of N,N-dimethylformamide 5.0 g (0.032 mmol) of KMnO4 was added, which took 30 min. The reaction mixture was stirred at room temperature for 100 h, and TLC (CCl3:CH3OH = 5:1) indicated the complete disappearance of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. The reaction mixture was evaporated under vacuum. The residue was washed with distilled water repeatedly to provide 8.1 g (83percent) of the title compound as a yellow powder. ESI-MS (m/e) 174 [M + H]+; 1H NMR (300 MHz, DMSO) δ/ppm = 10.81 (s, 1 H), 9.52 (s, 1 H), 8.43 (s, 1 H), 7.52 (m, 4 H); 13C NMR (75 MHz, DMSO) δ/ppm = 164.9, 152.3, 143.5, 136.2, 131.3, 129.7, 127.2, 125.8.
Reference:
[1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 5, p. 1672 - 1681
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 20, p. 4434 - 4436
[3] Patent: CN106986825, 2017, A,
[4] Journal of Agricultural and Food Chemistry, 2018, vol. 66, # 34, p. 8957 - 8965
2
[ 74163-81-8 ]
[ 27104-73-0 ]
Reference:
[1] Patent: CN106986825, 2017, A,
[2] Journal of Agricultural and Food Chemistry, 2018, vol. 66, # 34, p. 8957 - 8965
3
[ 74163-81-8 ]
[ 18881-17-9 ]
Reference:
[1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 20, p. 2883 - 2889
[2] Journal of Organic Chemistry, 1998, vol. 63, # 22, p. 7795 - 7804
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 18, p. 4033 - 4036
[4] Organic and Biomolecular Chemistry, 2018, vol. 16, # 38, p. 6961 - 6968
[5] Journal of Medicinal Chemistry, 1999, vol. 42, # 11, p. 1982 - 1990
[6] Chemical Communications, 2011, vol. 47, # 38, p. 10746 - 10748
[7] European Journal of Medicinal Chemistry, 2013, vol. 66, p. 407 - 414
4
[ 24424-99-5 ]
[ 74163-81-8 ]
[ 115962-35-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 144 h;
(S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (50.0 g, 282 mmol) was vigorously stirred in a mixture of 1,4-dioxane (1000 mL) and water (500 mL). Sodium bicarbonate (47.4 g, 564 mmol) and Boc anhydride (67.7 g, 310 mmol) were added and the reaction was stirred vigorously at room temperature for 6 days. The mixture was concentrated in vacuo and the residue dissolved in water (2000 mL). A 30percent w/v aqueous solution of sodium hydrogen sulfate monohydrate (300 mL) was added and the mixture extracted with chloroform (3 × 1000 mL). The pooled organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the desired compound (90.0 g, quantitative) as a thick syrup. LCMS-B: RT 3.64 min; m/z 178.1 [M-Boc+2H]+; m/z 276.1 [M- H]-
100%
With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 144 h;
(S)-1 ,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (50.0 g, 282 mmol) was vigorously stirred in a mixture of 1 ,4-dioxane (1000 mL) and water (500 mL). Sodium bicarbonate (47.4 g, 564 mmol) and Boc anhydride (67.7 g, 310 mmol) were added and the reaction was stirred vigorously at room temperature for 6 days. The mixture was concentrated in vacuo and the residue dissolved in water (2000 mL). A 30percent w/v aqueous solution of sodium hydrogen sulfate monohydrate (300 mL) was added and the mixture extracted with chloroform (3 * 1000 mL). The pooled organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the desired compound (90.0 g, quantitative) as a thick syrup. LCMS-B: RT 3.64 min; m/z 178.1 [M-Boc+2H]+; m/z 276.1 [M- H]-
100%
With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 144 h;
(S)-1 ,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (50.0 g, 282 mmol) was vigorously stirred in a mixture of 1,4-dioxane (1000 mL) and water (500 mL). Sodium bicarbonate (47.4 g, 564 mmol) and Boc anhydride (67.7 g, 310 mmol) were added and the reaction wasstirred vigorously at room temperature for 6 days. The mixture was concentrated in vacuo and the residue dissolved in water (2000 mL). A 30percent w/v aqueous solution of sodium hydrogen sulfate monohydrate (300 mL) was added and the mixture extracted with chloroform (3 x 1000 mL). The pooled organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the desired compound (90.0 g,quantitative) as a thick syrup. LCMS-B: RT 3.64 mm; m/z 178.1 [M-Boc+2H] m/z 276.1 [MH]
100%
With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 144 h;
(S)-1 ,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (50.0 g, 282 mmol) was vigorously stirred in a mixture of 1 ,4-dioxane (1000 mL) and water (500 mL). Sodium bicarbonate (47.4 g, 564 mmol) and Boc anhydride (67.7 g, 310 mmol) were added and the reaction was stirred vigorously at room temperature for 6 days. The mixture was concentrated in vacuo and the residue dissolved in water (2000 mL). A 30percent w/v aqueous solution of sodium hydrogen sulfate monohydrate (300 mL) was added and the mixture extracted with chloroform (3 * 1000 mL). The pooled organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the desired compound (90.0 g, (0503) quantitative) as a thick syrup. LCMS-B: RT 3.64 min; m/z 178.1 [M-Boc+2H]+; m/z 276.1 [M- H]-
96%
With sodium hydrogencarbonate In 1,4-dioxane; water
(S)-2-(tert-butoxycarbonyl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acidError. Objects cannot be created from editing field codes.(S)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (3g, 16.93mmol) was dissolved in a mixture of dioxane (30ml) and water (15ml) and the sodium hydrogen carbonate (2.81 g, 33.9mmol) was added. Boc20 (4.06g, 18.62mmol) was then added and the reaction mixture was left stirring overnight. The reaction mixture was partitioned between water and DCM. The aqueous layer was extracted twice more with DCM and then the combined organics were washed with water and brine, dried over MgS04 and concentrated in vacuo to afford (S)-2-(tert-butoxycarbonyl)-1 ,2,3,4-tetrahydroisoquinoline- 3-carboxylic acid as a colourless gum (4.5g, 16.23mmol, 96percent).
96%
With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 17 h;
(S)-1 ,2,3.4-Tetrahydroisoquinoline-3-carboxylic acid (5.00 g, 28.2 mmol) was vigorously stirred in 1 ,4-dioxane (100 mL) and water (50 mL). Sodium bicarbonate (4.74 mg, 56.4 mmol) and Boc anhydride (6.77 g, 31.0 mmol) were added and the mixture was stirred vigorously at room temperature. After 17 hours the mixture was concentrated in vacuo and the residue dissolved in water (200 mL). A 30percent w/v aqueous solution of sodium hydrogen sulfate monohydrate (30 mL) was added and the mixture extracted with chloroform (3 * 200 mL). The pooled organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the desired compound (7.50 g, 96percent yield) as a thick syrup. LCMS-B: RT 3.64 min; m/z 178.1 [M-Boc+2H]+; m/z 276.1 [M-H]-
80%
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 48 h;
To the suspension of 2.49 g (62.2 mmol) of NaOH, 62.2 mL of water, and 10.0 g (56.5 mmol) of 3S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, the solution of 14.8 g (67.8 mmol) of Boc2O in 40 mL of THF was added at 0 °C. The suspension was stirred at room temperature for 48 h to form a clean solution, and TLC (ethyl acetate/petroleum ether, 1:3) indicated complete disappearance of 3S-1,2,3,4-tetra-hydroisoquinoline-3-carboxylic acid. The reaction mixture was evaporated under vacuum, and the residue was dissolved in 100 ml of ethyl acetate. The solution was washed successively with 5percent aqueous solution of KHSO4 (30 mL .x. 3) and saturated aqueous solution of NaCl (30 mL .x. 3), and dried with anhydrous Na2SO4. After filtration, the filtrate was evaporated under vacuum and the residue was triturated with petroleum ether to give 12.5 g (80percent) of the title compound as a colorless powder. ESI-MS (m/e) 278 [M+H]+; inlMMLBox = -6.78 (c 1.0, methanol); 1H NMR (300 MHz, DMSO-d6) δ/ppm = 11.2 (s, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 8.2 Hz, 1H), 7.22 (t, J = 7.3 Hz, 1H), 4.14 (m, J = 5.2 Hz, 3H), 3.13 (m, J = 4.1 Hz, 2H), 2.72 (m, J = 4.5 Hz, 2H), 1.42 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ/ppm = 176.8, 169.8, 137.5, 132.8, 129.0, 127.8, 126.9, 125.2, 82.9, 60.7, 56.9, 51.3, 28.2, 25.5.
Reference:
[1] Patent: WO2017/153513, 2017, A1, . Location in patent: Page/Page column 78
[2] Patent: WO2017/153515, 2017, A1, . Location in patent: Page/Page column 62
[3] Patent: WO2017/153520, 2017, A1, . Location in patent: Page/Page column 44; 47
[4] Patent: WO2017/153519, 2017, A1, . Location in patent: Page/Page column 56; 59
[5] Tetrahedron Letters, 2001, vol. 42, # 43, p. 7559 - 7561
[6] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 21, p. 4828 - 4832
[7] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 21, p. 4833 - 4837
[8] Tetrahedron Letters, 2004, vol. 45, # 38, p. 7081 - 7085
[9] Organic Letters, 2016, vol. 18, # 19, p. 5070 - 5073
[10] Patent: WO2011/61318, 2011, A1, . Location in patent: Page/Page column 22
[11] Patent: WO2016/34673, 2016, A1, . Location in patent: Page/Page column 71; 74
[12] Journal of Materials Chemistry B, 2017, vol. 5, # 5, p. 917 - 927
[13] International Journal of Nanomedicine, 2018, vol. 13, p. 1139 - 1158
[14] Organic Letters, 2017, vol. 19, # 21, p. 5826 - 5829
[15] Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 6, p. 1719 - 1729
[16] European Journal of Organic Chemistry, 2002, # 23, p. 3936 - 3943
[17] European Journal of Medicinal Chemistry, 2009, vol. 44, # 12, p. 4904 - 4919
[18] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 2, p. 871 - 882
[19] Tetrahedron, 2014, vol. 70, # 23, p. 3707 - 3713
[20] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 24, p. 3623 - 3631
[21] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 20, p. 2883 - 2889
[22] Tetrahedron Asymmetry, 2010, vol. 21, # 9-10, p. 1238 - 1245
[23] Chinese Chemical Letters, 2012, vol. 23, # 3, p. 297 - 300
[24] Chemistry - A European Journal, 2015, vol. 21, # 51, p. 18589 - 18593
[25] Journal of Agricultural and Food Chemistry, 2018, vol. 66, # 34, p. 8957 - 8965
5
[ 1070-19-5 ]
[ 74163-81-8 ]
[ 115962-35-1 ]
Reference:
[1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 24, p. 7773 - 7788
The procedure was adapted from literature. A solution of 1 (phenylalanine) (2.0 g, 12.12 mmol) in HBr (10 mL) was heated to 40 °C. Formaldehyde (1.8 mL, 48.86 mmol) was then added dropwise. The reaction mixture was further heated to 70-80 °C for 3 hours (hrs), during which a white precipitate formed. The reaction was cooled the precipitate was filtered under vacuum and washed with cold ethanol. The white solid product was left under vacuum to dry. Yield = 89percent (1.78 g), Melting Point = 295-300 °C (decomposes); 1H NMR (MeOD) δ/ppm = 3.10 (q, J=11.41, 17.23 Hz , 1H), 3.35 (dd, J=5.28, 17.20 Hz, 1H), 4.34 (dd, J=5.38, 11.47 Hz, 1H), 4.37 (s, 2H), 7.14 (m, 4H) ; 13C NMR (MeOD) δ/ppm = 29.59, 45.60, 55.45, 127.74, 128.60, 128.72, 129.30, 130.14, 131.61, 170.95; LC-MS m/z = 178.08 [M+1] for C10H11NO2.
84%
With hydrogenchloride In chloroform; water at 80 - 90℃; for 10 h;
To the suspension of 5.0 g (0.03 mmol) of L-Phe in 50 mL of chloroform and 27 ml of formaldehyde, 45 mL of concentrated hydrochloric acid was added drop-wise. The reaction mixture was stirred at 80-90 °C for 10 h, and TLC (CHCl3/CH3OH, 10:1) indicates the complete disappearance of L-Phe. The reaction mixture was cooled to room temperature and the formed precipitates were collected by filtration. The collected solids were successively washed with water (30 mL .x. 3) and acetone (30 mL .x. 3) to give 4.5 g (84percent) of the title compound as a colorless powder. Mp 302-303 °C; inlMMLBox = -68 (c 1.0, H2O); ESI-MS (m/e) 178 [M+H]+; 1H NMR (300 MHz, CDCl3) δ/ppm = 11.0 (s, 1H), 7.25 (m, J = 6.4 Hz, 2H), 7.02 (d, J = 6.5 Hz, 1H), 6.98 (t, J = 6.6 Hz, 1H), 3.80 (m, 3H), 3.03 (d, J = 7.5 Hz, 1H), 2.78 (d, J = 8.4 Hz, 1H), 2.0 (s, 1H); 13C NMR (75 MHz, CDCl3) δ/ppm = 174.9, 136.2, 134.2, 127.2, 126.0, 57.6, 47.4, 29.4.
83.9%
With hydrogenchloride In chloroform; water at 80 - 90℃; for 10 h; Inert atmosphere
the suspension of 5.0 g (0.03 mmol) of l-Phe in 50 ml of chloroform and 27 ml of formaldehyde 45 ml of concentrated hydrochloric acid was added drop-wise. The reaction mixture was stirred at 80-90 °C for 10 h, and TLC (CHCl3/CH3OH, 10:1) indicates the complete disaprearance of l-Phe. The reaction mixture was cooled to room temperature and the formed precipitates were collected by filtration. The collected solids were successively washed with water (30 ml .x. 3) and acetone (30 ml .x. 3) to give 4.5 g (83.9percent) of the title compound as a colorless powder. Mp 302-303 °C; [α]D20 = -68 (c = 1.0, H2O); ESI-MS (m/e) 178 [M + H]+; 1H NMR (300 MHz, CDCl3) δ/ppm = 11.0 (s, 1H), 7.25 (m, J = 6.4 Hz, 2H), 7.02 (d, J = 6.5 Hz, 1H), 6.98 (t, J = 6.6 Hz, 1H), 3.80 (m, 3H), 3.03 (d, J = 7.5 Hz, 1H), 2.78 (d, J = 8.4 Hz, 1H), 2.0(s, 1H); 13C NMR (75 MHz, CDCl3) δ/ppm = 174.9, 136.2, 134.2, 127.2, 126.0, 57.6, 47.4, 29.4.
67.54%
With hydrogenchloride In water at 95℃; for 24 h;
A solution of HCl (320 ml)And HCHO (160 ml)Placed in 500ml eggplant bottle,After mixing, L-Phe (30.10 g, 182.45 mmol) was added,The reaction was terminated after reaction at 95 ° C for 24 h in an oil bath,Cool to room temperature.Ice bath with saturated NaOH to adjust the pH to 6 ~ 7, a large number of white solid precipitation.The white solid was filtered(21.80 g, 67.54percent).
Reference:
[1] Journal of Materials Chemistry B, 2017, vol. 5, # 5, p. 917 - 927
[2] International Journal of Nanomedicine, 2018, vol. 13, p. 1139 - 1158
[3] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 24, p. 7773 - 7788
[4] European Journal of Medicinal Chemistry, 2013, vol. 66, p. 407 - 414
[5] Organic and Biomolecular Chemistry, 2018, vol. 16, # 38, p. 6961 - 6968
[6] European Journal of Medicinal Chemistry, 2009, vol. 44, # 12, p. 4904 - 4919
[7] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 2, p. 871 - 882
[8] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 21, p. 9574 - 9587
[9] European Journal of Medicinal Chemistry, 2011, vol. 46, # 5, p. 1672 - 1681
[10] Synlett, 2011, # 20, p. 3005 - 3007
[11] Bulletin of the Chemical Society of Japan, 1991, vol. 64, # 12, p. 3729 - 3731
[12] Journal of the American Chemical Society, 1993, vol. 115, # 10, p. 3957 - 3965
[13] Chimia, 1996, vol. 50, # 11, p. 532 - 537
[14] Patent: CN106986825, 2017, A, . Location in patent: Paragraph 0023; 0027; 0028
[15] Journal of Organic Chemistry, 1998, vol. 63, # 22, p. 7795 - 7804
[16] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 3, p. 1019 - 1022
[17] Journal of Medicinal Chemistry, 1991, vol. 34, # 10, p. 3125 - 3132
[18] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2092 - 2097
[19] Tetrahedron Asymmetry, 2010, vol. 21, # 9-10, p. 1238 - 1245
[20] Journal of Medicinal Chemistry, 1983, vol. 26, # 9, p. 1267 - 1277
[21] Journal of Agricultural and Food Chemistry, 2018, vol. 66, # 34, p. 8957 - 8965
8
[ 77497-96-2 ]
[ 74163-81-8 ]
Reference:
[1] Synthesis, 1992, # 11, p. 1157 - 1160
[2] Chemical and Pharmaceutical Bulletin, 1983, vol. 31, # 1, p. 312 - 314
9
[ 367952-43-0 ]
[ 74163-81-8 ]
Reference:
[1] Synthesis, 2001, # 10, p. 1513 - 1518
10
[ 123053-49-6 ]
[ 74163-81-8 ]
Reference:
[1] Liebigs Annalen der Chemie, 1989, p. 1215 - 1232
11
[ 143767-56-0 ]
[ 74163-81-8 ]
Reference:
[1] Synthesis, 1992, # 11, p. 1157 - 1160
12
[ 50-00-0 ]
[ 63-91-2 ]
[ 7664-93-9 ]
[ 74163-81-8 ]
Reference:
[1] Patent: US6403561, 2002, B1,
13
[ 67123-97-1 ]
[ 74163-81-8 ]
Reference:
[1] Bulletin of the Chemical Society of Japan, 1991, vol. 64, # 12, p. 3729 - 3731
[2] Tetrahedron Asymmetry, 2001, vol. 12, # 10, p. 1399 - 1401
[3] Tetrahedron Asymmetry, 2001, vol. 12, # 10, p. 1399 - 1401
[4] Synthesis, 1992, # 11, p. 1157 - 1160
14
[ 150582-52-8 ]
[ 74163-81-8 ]
Reference:
[1] Synthesis, 2001, # 10, p. 1513 - 1518
[2] Synthesis, 2001, # 10, p. 1513 - 1518
15
[ 612-12-4 ]
[ 74163-81-8 ]
Reference:
[1] Synthesis, 1992, # 11, p. 1157 - 1160
[2] Synthesis, 1992, # 11, p. 1157 - 1160
16
[ 143767-55-9 ]
[ 74163-81-8 ]
Reference:
[1] Synthesis, 1992, # 11, p. 1157 - 1160
[2] Synthesis, 1992, # 11, p. 1157 - 1160
17
[ 367952-46-3 ]
[ 74163-81-8 ]
Reference:
[1] Synthesis, 2001, # 10, p. 1513 - 1518
18
[ 143767-54-8 ]
[ 74163-81-8 ]
Reference:
[1] Synthesis, 1992, # 11, p. 1157 - 1160
19
[ 307304-56-9 ]
[ 74163-81-8 ]
[ 103733-65-9 ]
Reference:
[1] Journal of Organic Chemistry, 2000, vol. 65, # 22, p. 7310 - 7322
20
[ 50-00-0 ]
[ 1009-67-2 ]
[ 74163-81-8 ]
Reference:
[1] Chinese Chemical Letters, 2012, vol. 23, # 3, p. 297 - 300
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 16.5 h;
(S)-2-((benzyloxy)carbonyl)-l, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid (3) To a 1 M aqueous solution of NaOH (3.20 g, 80.0 mmol in 80 mL of H20) at rt were added (S)-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (5.00 g, 28.2) and dioxane slowly until the suspension dissolves. Then benzylchloroformate was added (6.25 g, 5.59 xL, 36.7 mmol) drop wise over a period of 30 min at 0 °C. The reaction mixture was stirred for 16 h at room temperature. Dioxane was removed by evaporation and reaction mixture was acidified to pH 2 with 1M HC1 at 0 °C. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered and evaporated in vacuo to afford the title compound 3 (8.68, 27.9 mmol, 99percent) as a white foam. No further purification was required. 1H-NMR (360 MHz, CDC13): δ (ppm) 7.32-6.99 (m, 9H), 5.19-5.10 (m) and 4.91 (t, J = 4.9 Hz, 3H), 4.70 (d, J= 16.3 Hz), 4.50 (m, 1H), 3.22-3.07(m, 2H). 13C-NMR (150 MHz, CDC13): δ (ppm) 175.4 (CO, rotamer 2) and 175.0 (CO, rotamer 1), 155.4 (CO, rotamer 1) and 154.4 (CO, rotamer 2), 135.2 (Cq), 131.9 (Cq), 131.2 (Cq), 130.4 (CH, rotamer 1) and 130.3 (CH, rotamer 2), 127.5 (CH), 127.2 (CH), 127.1 (CH), 127.0 (CH, rotamer 1) and 126.9 (CH, rotamer 2), 126.1 (CH), 126.0 (CH), 125.4 (CH), 125.2 (CH), 66.8 (CH2, rotamer 1) and 66.6 (CH2, rotamer 2), 52.4 (CH, rotamer 2) and 52.0 (CH, rotamer 1), 43.5 (CH2, rotamer 2) and 43.3 (C, rotamer 2), 30.2 (CH2, rotamer 2) and 29.8 (CH2, rotamer 1). Ratio of rotamers is 3:2. MS (ESI) m/z (percent): 222 (14), (CnH10NO4) 200(11), (Ci0H10NO2) 176 (53), 130 (23), 104 (1 1), (C7H7) 91 (100). MS (ESI) m/z calcd for C18Hi7N04 [M]+, 311.12; found, 311.12. LC- MS (ESI) m/z calcd. for Ci8Hi7N04Na [M+Na , 334.1; found, 334.6. HPLC purity, 96percent, tR = 20.5 min, Gradient A.
Reference:
[1] Journal of Medicinal Chemistry, 2016, vol. 59, # 5, p. 2222 - 2243
[2] Patent: WO2017/63910, 2017, A1, . Location in patent: Page/Page column 20-21
[3] Journal of Organic Chemistry, 2001, vol. 66, # 23, p. 7575 - 7587
[4] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 17, p. 4371 - 4373
[5] Journal of Organic Chemistry, 2016, vol. 81, # 3, p. 956 - 968
[6] Chimia, 1996, vol. 50, # 11, p. 532 - 537
[7] European Journal of Organic Chemistry, 2012, # 17, p. 3331 - 3337
28
[ 13139-17-8 ]
[ 74163-81-8 ]
[ 79261-58-8 ]
Reference:
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 19, p. 3100 - 3108
General procedure: The experimental procedure was adapted from literature. A solution of 5 (1.5 g, 7.17 mmol) in methanol (MeOH) (60 mL) was cooled to 0 C. SOCl2 (3.6 mL, 50.19 mmol) was added slowly to the solution. The reaction mixture was then stirred at ambient temperature and left overnight. The solvent was removed in vacuo to give a pure yellowish solid. Yield = 96%, (1.5 g); Melting point = 227-229 C; 1H NMR (MeOD) delta/ppm = 2.95 (q, J=11.53 Hz, 1H), 3.13 (dd, J=5.20, 16.97 Hz, 1H), 3.78 (s, 3H), 4.18 (s, 2H), 4.30 (dd, J=5.30, 11.31 Hz, 1.0H), 6.53 (d, J=11.01 Hz, 2.0H); 13C NMR (MeOD) delta/ppm = 28.92, 45.40, 53.95, 55.75, 113.83, 116.06, 119.40, 122.53, 146.37, 146.92, 170.30; LC-MS m/z = 224.08 [M + 1] for C11H13NO4.
81%
With thionyl chloride; for 5h;Reflux;
(S)-1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid 4 (10.6 g, 60 mmol) was dissolved in anhydrous methanol (86 mL). Thionyl chloride (6.5 mL, 90 mmol) was added dropwise and reaction mixture was refluxed for 5 h. Methanol was evaporated and residue was partitioned in chloroform and saturated sodium bicarbonate solution. Water phase was additionally extracted with chloroform, and combined organics were dried over anhydrous MgSO4, filtered and concentrated to dryness to afford 9.2 g of 5-(S) (81% yield). 1H NMR (500 MHz, CDCl3) : 7.16 (br, 3H), 7.03 (br, 1H), 4.13 (br, 2H), 3.80 (br, 3H), 3.05 (br, 2H), 2.20 (br, 1H).
81%
With thionyl chloride; for 5h;Reflux;
(S)-1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid 4 (10.6 g, 60 mmol) was dissolved in anhydrous methanol (86 mL). Thionyl chloride (6.5 mL, 90 mmol) was added dropwise and reaction mixture was refluxed for 5 h. Methanol was evaporated and residue was partitioned in chloroform and saturated sodium bicarbonate solution. Water phase was additionally extracted with chloroform, and combined organics were dried over anhydrous MgSOi, filtered and concentrated to dryness to afford 9.2 g of 5 (81% yield). 1H NMR (500 MHz, CDCl3) delta: 7.16 (br, 3H), 7.03 (br, 1H), 4.13 (far, 2H), 3.80 (br, 3H), 3.05 (br, 2H), 2.20 (br, 1H).
78.40%
With thionyl chloride; for 0.5h;Cooling with ice;
Methanol (100 ml) was added to a 250 ml eggplant flask, and thionyl chloride (15 ml) was added dropwise under ice-salt bath. After stirring for 30 min,(3S) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1) (10.00 g, 56.50 mmol) was slowly added,Reaction 9-10h,The reaction solution was drained,A white solid (8.46 g, 78.40%) was obtained.
The procedure was adapted from literature. A solution of 1 (phenylalanine) (2.0 g, 12.12 mmol) in HBr (10 mL) was heated to 40 C. Formaldehyde (1.8 mL, 48.86 mmol) was then added dropwise. The reaction mixture was further heated to 70-80 C for 3 hours (hrs), during which a white precipitate formed. The reaction was cooled the precipitate was filtered under vacuum and washed with cold ethanol. The white solid product was left under vacuum to dry. Yield = 89% (1.78 g), Melting Point = 295-300 C (decomposes); 1H NMR (MeOD) delta/ppm = 3.10 (q, J=11.41, 17.23 Hz , 1H), 3.35 (dd, J=5.28, 17.20 Hz, 1H), 4.34 (dd, J=5.38, 11.47 Hz, 1H), 4.37 (s, 2H), 7.14 (m, 4H) ; 13C NMR (MeOD) delta/ppm = 29.59, 45.60, 55.45, 127.74, 128.60, 128.72, 129.30, 130.14, 131.61, 170.95; LC-MS m/z = 178.08 [M+1] for C10H11NO2.
84%
With hydrogenchloride; In chloroform; water; at 80 - 90℃; for 10h;
To the suspension of 5.0 g (0.03 mmol) of L-Phe in 50 mL of chloroform and 27 ml of formaldehyde, 45 mL of concentrated hydrochloric acid was added drop-wise. The reaction mixture was stirred at 80-90 C for 10 h, and TLC (CHCl3/CH3OH, 10:1) indicates the complete disappearance of L-Phe. The reaction mixture was cooled to room temperature and the formed precipitates were collected by filtration. The collected solids were successively washed with water (30 mL × 3) and acetone (30 mL × 3) to give 4.5 g (84%) of the title compound as a colorless powder. Mp 302-303 C; inlMMLBox = -68 (c 1.0, H2O); ESI-MS (m/e) 178 [M+H]+; 1H NMR (300 MHz, CDCl3) delta/ppm = 11.0 (s, 1H), 7.25 (m, J = 6.4 Hz, 2H), 7.02 (d, J = 6.5 Hz, 1H), 6.98 (t, J = 6.6 Hz, 1H), 3.80 (m, 3H), 3.03 (d, J = 7.5 Hz, 1H), 2.78 (d, J = 8.4 Hz, 1H), 2.0 (s, 1H); 13C NMR (75 MHz, CDCl3) delta/ppm = 174.9, 136.2, 134.2, 127.2, 126.0, 57.6, 47.4, 29.4.
83.9%
With hydrogenchloride; In chloroform; water; at 80 - 90℃; for 10h;Inert atmosphere;
the suspension of 5.0 g (0.03 mmol) of l-Phe in 50 ml of chloroform and 27 ml of formaldehyde 45 ml of concentrated hydrochloric acid was added drop-wise. The reaction mixture was stirred at 80-90 C for 10 h, and TLC (CHCl3/CH3OH, 10:1) indicates the complete disaprearance of l-Phe. The reaction mixture was cooled to room temperature and the formed precipitates were collected by filtration. The collected solids were successively washed with water (30 ml × 3) and acetone (30 ml × 3) to give 4.5 g (83.9%) of the title compound as a colorless powder. Mp 302-303 C; [alpha]D20 = -68 (c = 1.0, H2O); ESI-MS (m/e) 178 [M + H]+; 1H NMR (300 MHz, CDCl3) delta/ppm = 11.0 (s, 1H), 7.25 (m, J = 6.4 Hz, 2H), 7.02 (d, J = 6.5 Hz, 1H), 6.98 (t, J = 6.6 Hz, 1H), 3.80 (m, 3H), 3.03 (d, J = 7.5 Hz, 1H), 2.78 (d, J = 8.4 Hz, 1H), 2.0(s, 1H); 13C NMR (75 MHz, CDCl3) delta/ppm = 174.9, 136.2, 134.2, 127.2, 126.0, 57.6, 47.4, 29.4.
67.54%
With hydrogenchloride; In water; at 95℃; for 24h;
A solution of HCl (320 ml)And HCHO (160 ml)Placed in 500ml eggplant bottle,After mixing, L-Phe (30.10 g, 182.45 mmol) was added,The reaction was terminated after reaction at 95 C for 24 h in an oil bath,Cool to room temperature.Ice bath with saturated NaOH to adjust the pH to 6 ~ 7, a large number of white solid precipitation.The white solid was filtered(21.80 g, 67.54%).
With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 16.5h;
(S)-2-((benzyloxy)carbonyl)-l, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid (3) To a 1 M aqueous solution of NaOH (3.20 g, 80.0 mmol in 80 mL of H20) at rt were added (S)-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (5.00 g, 28.2) and dioxane slowly until the suspension dissolves. Then benzylchloroformate was added (6.25 g, 5.59 xL, 36.7 mmol) drop wise over a period of 30 min at 0 C. The reaction mixture was stirred for 16 h at room temperature. Dioxane was removed by evaporation and reaction mixture was acidified to pH 2 with 1M HC1 at 0 C. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered and evaporated in vacuo to afford the title compound 3 (8.68, 27.9 mmol, 99%) as a white foam. No further purification was required. 1H-NMR (360 MHz, CDC13): delta (ppm) 7.32-6.99 (m, 9H), 5.19-5.10 (m) and 4.91 (t, J = 4.9 Hz, 3H), 4.70 (d, J= 16.3 Hz), 4.50 (m, 1H), 3.22-3.07(m, 2H). 13C-NMR (150 MHz, CDC13): delta (ppm) 175.4 (CO, rotamer 2) and 175.0 (CO, rotamer 1), 155.4 (CO, rotamer 1) and 154.4 (CO, rotamer 2), 135.2 (Cq), 131.9 (Cq), 131.2 (Cq), 130.4 (CH, rotamer 1) and 130.3 (CH, rotamer 2), 127.5 (CH), 127.2 (CH), 127.1 (CH), 127.0 (CH, rotamer 1) and 126.9 (CH, rotamer 2), 126.1 (CH), 126.0 (CH), 125.4 (CH), 125.2 (CH), 66.8 (CH2, rotamer 1) and 66.6 (CH2, rotamer 2), 52.4 (CH, rotamer 2) and 52.0 (CH, rotamer 1), 43.5 (CH2, rotamer 2) and 43.3 (C, rotamer 2), 30.2 (CH2, rotamer 2) and 29.8 (CH2, rotamer 1). Ratio of rotamers is 3:2. MS (ESI) m/z (%): 222 (14), (CnH10NO4) 200(11), (Ci0H10NO2) 176 (53), 130 (23), 104 (1 1), (C7H7) 91 (100). MS (ESI) m/z calcd for C18Hi7N04 [M]+, 311.12; found, 311.12. LC- MS (ESI) m/z calcd. for Ci8Hi7N04Na [M+Na , 334.1; found, 334.6. HPLC purity, 96%, tR = 20.5 min, Gradient A.
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; for 144h;
(S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (50.0 g, 282 mmol) was vigorously stirred in a mixture of 1,4-dioxane (1000 mL) and water (500 mL). Sodium bicarbonate (47.4 g, 564 mmol) and Boc anhydride (67.7 g, 310 mmol) were added and the reaction was stirred vigorously at room temperature for 6 days. The mixture was concentrated in vacuo and the residue dissolved in water (2000 mL). A 30% w/v aqueous solution of sodium hydrogen sulfate monohydrate (300 mL) was added and the mixture extracted with chloroform (3 × 1000 mL). The pooled organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the desired compound (90.0 g, quantitative) as a thick syrup. LCMS-B: RT 3.64 min; m/z 178.1 [M-Boc+2H]+; m/z 276.1 [M- H]-
100%
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; for 144h;
(S)-1 ,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (50.0 g, 282 mmol) was vigorously stirred in a mixture of 1 ,4-dioxane (1000 mL) and water (500 mL). Sodium bicarbonate (47.4 g, 564 mmol) and Boc anhydride (67.7 g, 310 mmol) were added and the reaction was stirred vigorously at room temperature for 6 days. The mixture was concentrated in vacuo and the residue dissolved in water (2000 mL). A 30% w/v aqueous solution of sodium hydrogen sulfate monohydrate (300 mL) was added and the mixture extracted with chloroform (3 * 1000 mL). The pooled organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the desired compound (90.0 g, quantitative) as a thick syrup. LCMS-B: RT 3.64 min; m/z 178.1 [M-Boc+2H]+; m/z 276.1 [M- H]-
100%
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; for 144h;
(S)-1 ,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (50.0 g, 282 mmol) was vigorously stirred in a mixture of 1,4-dioxane (1000 mL) and water (500 mL). Sodium bicarbonate (47.4 g, 564 mmol) and Boc anhydride (67.7 g, 310 mmol) were added and the reaction wasstirred vigorously at room temperature for 6 days. The mixture was concentrated in vacuo and the residue dissolved in water (2000 mL). A 30% w/v aqueous solution of sodium hydrogen sulfate monohydrate (300 mL) was added and the mixture extracted with chloroform (3 x 1000 mL). The pooled organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the desired compound (90.0 g,quantitative) as a thick syrup. LCMS-B: RT 3.64 mm; m/z 178.1 [M-Boc+2H] m/z 276.1 [MH]
100%
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; for 144h;
(S)-1 ,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (50.0 g, 282 mmol) was vigorously stirred in a mixture of 1 ,4-dioxane (1000 mL) and water (500 mL). Sodium bicarbonate (47.4 g, 564 mmol) and Boc anhydride (67.7 g, 310 mmol) were added and the reaction was stirred vigorously at room temperature for 6 days. The mixture was concentrated in vacuo and the residue dissolved in water (2000 mL). A 30% w/v aqueous solution of sodium hydrogen sulfate monohydrate (300 mL) was added and the mixture extracted with chloroform (3 * 1000 mL). The pooled organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the desired compound (90.0 g, (0503) quantitative) as a thick syrup. LCMS-B: RT 3.64 min; m/z 178.1 [M-Boc+2H]+; m/z 276.1 [M- H]-
96%
With sodium hydrogencarbonate; In 1,4-dioxane; water;
(S)-2-(tert-butoxycarbonyl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acidError. Objects cannot be created from editing field codes.(S)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (3g, 16.93mmol) was dissolved in a mixture of dioxane (30ml) and water (15ml) and the sodium hydrogen carbonate (2.81 g, 33.9mmol) was added. Boc20 (4.06g, 18.62mmol) was then added and the reaction mixture was left stirring overnight. The reaction mixture was partitioned between water and DCM. The aqueous layer was extracted twice more with DCM and then the combined organics were washed with water and brine, dried over MgS04 and concentrated in vacuo to afford (S)-2-(tert-butoxycarbonyl)-1 ,2,3,4-tetrahydroisoquinoline- 3-carboxylic acid as a colourless gum (4.5g, 16.23mmol, 96%).
96%
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; for 17h;
(S)-1 ,2,3.4-Tetrahydroisoquinoline-3-carboxylic acid (5.00 g, 28.2 mmol) was vigorously stirred in 1 ,4-dioxane (100 mL) and water (50 mL). Sodium bicarbonate (4.74 mg, 56.4 mmol) and Boc anhydride (6.77 g, 31.0 mmol) were added and the mixture was stirred vigorously at room temperature. After 17 hours the mixture was concentrated in vacuo and the residue dissolved in water (200 mL). A 30% w/v aqueous solution of sodium hydrogen sulfate monohydrate (30 mL) was added and the mixture extracted with chloroform (3 * 200 mL). The pooled organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the desired compound (7.50 g, 96% yield) as a thick syrup. LCMS-B: RT 3.64 min; m/z 178.1 [M-Boc+2H]+; m/z 276.1 [M-H]-
80%
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 48h;
To the suspension of 2.49 g (62.2 mmol) of NaOH, 62.2 mL of water, and 10.0 g (56.5 mmol) of 3S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, the solution of 14.8 g (67.8 mmol) of Boc2O in 40 mL of THF was added at 0 C. The suspension was stirred at room temperature for 48 h to form a clean solution, and TLC (ethyl acetate/petroleum ether, 1:3) indicated complete disappearance of 3S-1,2,3,4-tetra-hydroisoquinoline-3-carboxylic acid. The reaction mixture was evaporated under vacuum, and the residue was dissolved in 100 ml of ethyl acetate. The solution was washed successively with 5% aqueous solution of KHSO4 (30 mL × 3) and saturated aqueous solution of NaCl (30 mL × 3), and dried with anhydrous Na2SO4. After filtration, the filtrate was evaporated under vacuum and the residue was triturated with petroleum ether to give 12.5 g (80%) of the title compound as a colorless powder. ESI-MS (m/e) 278 [M+H]+; inlMMLBox = -6.78 (c 1.0, methanol); 1H NMR (300 MHz, DMSO-d6) delta/ppm = 11.2 (s, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 8.2 Hz, 1H), 7.22 (t, J = 7.3 Hz, 1H), 4.14 (m, J = 5.2 Hz, 3H), 3.13 (m, J = 4.1 Hz, 2H), 2.72 (m, J = 4.5 Hz, 2H), 1.42 (s, 9H); 13C NMR (75 MHz, DMSO-d6) delta/ppm = 176.8, 169.8, 137.5, 132.8, 129.0, 127.8, 126.9, 125.2, 82.9, 60.7, 56.9, 51.3, 28.2, 25.5.
With sulfuric acid; nitric acid; at -20℃; for 0.5h;
Concentrated HN03(22mL)was added dropwise to a stirred solutionof 9A (30g, 170 mmol)in concentrated H2 S04 (120 mL) at -20C. The reaction mixture was stirredat -20C for0.5h then poured into ice water. The mixture was neutralization withammonium hydroxide,then filtered and washed with water to give 9B as a white solid (35 g, 93 %).
2-[2-({2-[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-3-carbonyl}-amino)-3-cyclohexyl-butyrylamino]-3-phenyl-propionic acid[ No CAS ]
2-[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid [1-(1-carbamoyl-2-phenyl-ethylcarbamoyl)-2-cyclohexyl-propyl]-amide[ No CAS ]
2-[2-({2-[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-3-carbonyl}-amino)-3-cyclohexyl-butyrylamino]-3-phenyl-propionic acid[ No CAS ]
2-[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid [1-(1-carbamoyl-2-phenyl-ethylcarbamoyl)-2-cyclohexyl-propyl]-amide[ No CAS ]
2-[2-({2-[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-3-carbonyl}-amino)-3-cyclohexyl-butyrylamino]-3-phenyl-propionic acid[ No CAS ]
2-[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid [1-(1-carbamoyl-2-phenyl-ethylcarbamoyl)-2-cyclohexyl-propyl]-amide[ No CAS ]
2-[2-({2-[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-3-carbonyl}-amino)-3-cyclohexyl-butyrylamino]-3-phenyl-propionic acid[ No CAS ]
2-[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid [1-(1-carbamoyl-2-phenyl-ethylcarbamoyl)-2-cyclohexyl-propyl]-amide[ No CAS ]
With chloro-trimethyl-silane; at 70℃; for 2h;Reflux;
(S)-1 ,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (1Og, 56mmol), TMSCI (39ml, 310mmol) and methanol (500ml) were refluxed together (at 7O0C) for 2 hours. The reaction mixture was evaporated to dryness and LCMS analysis indicated 100% conversion to (S)-1 ,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester, m/z 192 [M++H]+
With benzenesulfonamide; phosphorus pentachloride; triethylamine; In n-heptane; dichloromethane; water;
EXAMPLE 4 Synthesis of quinapril 5 ml of methylene chloride was added to a reaction flask containing 1.27 g (6 mmol) of phosphorus pentachloride. The temperature was then lowered to 0 C. and 1 g (3.6 mmol) of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine was added using a solid addition funnel. The reaction solution was then allowed to react at room temperature for 4 hours. 8 ml of heptane was added and stirred for 30 minutes. The solid obtained after filtration was dissolved in 10 ml of methylene chloride. 4 ml of methylene chloride and 2 ml (8 mmol) of BSA were added to a separate reaction flask containing 0.74 g (4.2 mmol) of (S)-(-)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. The reaction mixture was allowed to react at room temperature for 2 hours. 0.52 ml(3.7 mmol) of triethylamine was then added and the temperature was lowered to 0 C. The L-alanine acid chloride was then added into the reaction flask and stirred at room temperature overnight. 10 ml of water was then added and stirred. After extracting with methylene chloride, drying and concentrating, the title compound was obtained in a 83.9% yield. 1 H-NMR (400 MHz, CD3 OD): delta7.14-7.30 (m, 9H), 4.13-4.24 (m,2H), 3.90-4.02 (m,2H), 3.61(dt, 1H), 3.20(q,2H),2.87-2.96(m,2H), 2.44-2.71(m, 2H), 1.59-1.67(m,2H), 1.50(d,3H, 1.25(t,3H. MS(m/e): 439(M+1).
With potassium permanganate; In N,N-dimethyl-formamide; at 0 - 20℃; for 100.5h;Inert atmosphere;
At 0 C to a solution of 10.0 g (0.046 mmol) of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in 200 ml of N,N-dimethylformamide 5.0 g (0.032 mmol) of KMnO4 was added, which took 30 min. The reaction mixture was stirred at room temperature for 100 h, and TLC (CCl3:CH3OH = 5:1) indicated the complete disappearance of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. The reaction mixture was evaporated under vacuum. The residue was washed with distilled water repeatedly to provide 8.1 g (83%) of the title compound as a yellow powder. ESI-MS (m/e) 174 [M + H]+; 1H NMR (300 MHz, DMSO) delta/ppm = 10.81 (s, 1 H), 9.52 (s, 1 H), 8.43 (s, 1 H), 7.52 (m, 4 H); 13C NMR (75 MHz, DMSO) delta/ppm = 164.9, 152.3, 143.5, 136.2, 131.3, 129.7, 127.2, 125.8.
(S)-2-(2-fluorobenzyl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acidError. Objects cannot be created from editing field codes..(S)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2g, 1 1 .3mmol) and 2- fluorobenzaldehyde (2.4ml, 22.57mmol) were mixed in DMF and AcOH (1 .5ml) was added. The reaction mixture was stirred for 2h and then the sodium triacetoxyborohydride (4.8g, 22.57mmol) was added portionwise and the reaction mixture was left stirring overnight. LCMS analysis indicated complete conversion therefore the reaction mixture was diluted with water (10ml), MeOH (200ml) was added and this solution was treated on 2x20g SCX cartridges, eluting the product with 7M NH3 in MeOH. This yielded the product as a white solid. This solid was triturated with Et20, and then filtered off and dried, yielding (S)-2-(2-fluorobenzyl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2g, 7mmol, 62%) M.S. (ESI) (m/z): 286[M+H]+.
With thionyl chloride; at 0 - 50℃;Inert atmosphere;
Example 93(3R)-2-(2-(4-Chloro-3-(dibutylcarbamoyl)-5-methyl-lH-pyrazol-l-yl)-5-(naphthalen-2- ylsulfonylcarbamoyl)benzoyl)- 1 ,2,3 ,4-tetrahydroisoquinoline-3 -carboxylic acid(93) Intermediate 93 A: (R)-Methyl l,2,3,4-tetrahydroisoquinoline-3-carboxylatehydrochloride[00326] To (5)-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Aldrich, 500 mg, 2.82 mmol) in MeOH (2.8 mL) was added SOCl2 (824 mu,, 11.3 mmol) at 0 C. The resulting reaction mixture was allowed to warm to room temperature over 5 h and then stirred at 50 C overnight. The reaction mixture was then concentrated in vacuo to give the title compound (457 mg, 71%) as a white solid. ¾ NMR (CDC13) delta 7.30-7.23 (m, 2H), 7.20-7.13 (m, 2H), 4.78-4.69 (m, 1H), 4.56-4.45 (m, 1H), 4.43-4.35 (m, 1H), 3.87 (s, 3H), 3.49-3.43 (m, 2H); MS(ESI+) m/z 192.1 (M+H)+.
(S)-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With formic acid; for 4h;Reflux;
To a stirred solution of <strong>[74163-81-8](S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid</strong> (548mg, 3 mmol)in formic acid (1.7 mL) at ambient temperature was added 1.1 mL of 37% formaldehyde solutiondropwise over 15 min. The resultant mixture was stirred for 4 h at reflux. The solution wasevaporated to give a syrup, which was added diethyl ether (3 mL) and conc. HCl (0.8 mL) insequence with an ice-water bath. The resultant mixture was again evaporated to give a semisolid,26to which diethyl ether (5 mL) was added. The complex was treated under sonification and thesolid was collected by filtration to give 638 mg light yellow powder, in 93% yield. 1H NMR (400MHz, DMSO-d6) 7.267.30 (m, 3H), 7.22 (m, 1H), 4.61 (m, 1H), 4.47 (AB, J = 15.84 Hz, 2H),3.46 (dd, J = 5.48 Hz, 17.36 Hz, 1H), 3.26 (dd, J = 8.14 Hz, 17.30 Hz, 1H), 2.93 (s, 3H); 13CNMR (100 MHz, DMSO-d6) delta 168.84, 129.76, 128.51, 127.88, 127.68, 127.02, 126.48, 59.57,54.48, 52.69, 27.84. IR (Diamond, cm-1) numax 3349.0, 1731.8, 1197.8, 764.9. mp 183185 C.
(S)-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
To a stirred solution of <strong>[74163-81-8](S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid</strong> (548mg, 3 mmol) in formic acid (1.7 mL) at ambient temperature wasadded 1.1 mL of 37% formaldehyde solution dropwise over 15 min. The resultantmixture was stirred for 4 h at reflux. The solution was evaporated to give asyrup, which was added diethyl ether (3 mL) and conc. HCl (0.8 mL) in sequencewith an ice-water bath. The resultant mixture was again evaporated to give asemisolid, to which diethyl ether (5 mL) was added. The complex was treatedunder sonification and the solid was collected by filtration to give 638 mglight yellow powder, in 93% yield. 1HNMR (400 MHz, DMSO-d6) d 7.26-7.30 (m, 3H), 7.22 (m, 1H),4.61 (m, 1H), 4.47 (AB, J = 15.84 Hz,2H), 3.46 (dd, J = 5.48 Hz, 17.36 Hz,1H), 3.26 (dd, J = 8.14 Hz, 17.30 Hz,1H), 2.93 (s, 3H); 13C NMR (100 MHz, DMSO-d6) delta 168.84,129.76, 128.51, 127.88, 127.68, 127.02, 126.48, 59.57, 54.48, 52.69, 27.84. IR(Diamond, cm-1) numax 3349.0, 1731.8, 1197.8, 764.9. mp 183-185C
(S)-2-benzyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In isopropyl alcohol; at 80℃;
Step 1 : ( )-2-Benzyl- l ,2,3,4-tetrahvdroisoquinoline-3-carboxylic acid Benzyl bromide (2.05 g, 12 mmol) was added to a mixture of (5)-l , 2,3,4- tetrahydroisoquinoline-3-carboxylic acid (1.77 g, 10 mmol) and KappaOmicronEta (1.68 g, 30 mmol) in isopropyl alcohol (50 mL). The mixture was heated to 80 C overnight, cooled, and acidified to pH = 5-6. The product was precipitated as a white powder which was filtered and dried; MS (ESI) 268 (M + H).
Multi-step reaction with 4 steps
1: potassium permanganate / N,N-dimethyl-formamide / 20 °C / Cooling with ice
2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C / Cooling with ice; Schlenk technique
3: thionyl chloride / dichloromethane / 0.5 h / 20 °C / Cooling with ice
4: triethylamine / acetonitrile / 95 °C
Multi-step reaction with 3 steps
1.1: potassium permanganate / N,N-dimethyl-formamide / 72 h / 20 °C / Cooling with ice
2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C / Cooling with ice
3.1: thionyl chloride / dichloromethane / 6 h / 20 °C
3.2: 6 h / 95 °C