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Chemical Structure| 74163-81-8
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Product Details of [ 74163-81-8 ]

CAS No. :74163-81-8 MDL No. :MFCD00144533
Formula : C10H11NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :BWKMGYQJPOAASG-VIFPVBQESA-N
M.W : 177.20 Pubchem ID :2733226
Synonyms :
L-Porretine;L-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid

Calculated chemistry of [ 74163-81-8 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.3
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 52.36
TPSA : 49.33 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -8.33 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.36
Log Po/w (XLOGP3) : -1.33
Log Po/w (WLOGP) : 0.25
Log Po/w (MLOGP) : -1.2
Log Po/w (SILICOS-IT) : 1.35
Consensus Log Po/w : 0.09

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.38
Solubility : 74.5 mg/ml ; 0.42 mol/l
Class : Very soluble
Log S (Ali) : 0.79
Solubility : 1100.0 mg/ml ; 6.21 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -2.42
Solubility : 0.674 mg/ml ; 0.0038 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.01

Safety of [ 74163-81-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 74163-81-8 ]

* 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.

  • Upstream synthesis route of [ 74163-81-8 ]
  • Downstream synthetic route of [ 74163-81-8 ]

[ 74163-81-8 ] Synthesis Path-Upstream   1~28

  • 1
  • [ 74163-81-8 ]
  • [ 6624-49-3 ]
YieldReaction ConditionsOperation in experiment
83% 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 ]
YieldReaction ConditionsOperation 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
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Reference: [1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 24, p. 7773 - 7788
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Reference: [1] Heterocycles, 2014, vol. 89, # 8, p. 1844 - 1859
  • 7
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YieldReaction ConditionsOperation in experiment
89% at 40 - 80℃; for 3 h; 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
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[2] Chemical and Pharmaceutical Bulletin, 1983, vol. 31, # 1, p. 312 - 314
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Reference: [1] Liebigs Annalen der Chemie, 1989, p. 1215 - 1232
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Reference: [1] Synthesis, 1992, # 11, p. 1157 - 1160
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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
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Reference: [1] Synthesis, 2001, # 10, p. 1513 - 1518
[2] Synthesis, 2001, # 10, p. 1513 - 1518
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Reference: [1] Synthesis, 1992, # 11, p. 1157 - 1160
[2] Synthesis, 1992, # 11, p. 1157 - 1160
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Reference: [1] Synthesis, 1992, # 11, p. 1157 - 1160
[2] Synthesis, 1992, # 11, p. 1157 - 1160
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Reference: [1] Synthesis, 2001, # 10, p. 1513 - 1518
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Reference: [1] Synthesis, 1992, # 11, p. 1157 - 1160
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Reference: [1] Tetrahedron Asymmetry, 2001, vol. 12, # 10, p. 1399 - 1401
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Reference: [1] Bulletin of the Chemical Society of Japan, 1991, vol. 64, # 12, p. 3729 - 3731
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  • [ 100-51-6 ]
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Reference: [1] Heterocycles, 2014, vol. 89, # 8, p. 1844 - 1859
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  • [ 78183-55-8 ]
Reference: [1] Heterocycles, 2006, vol. 68, # 12, p. 2527 - 2547
[2] Patent: WO2006/117549, 2006, A1, . Location in patent: Page/Page column 86
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  • [ 79261-58-8 ]
YieldReaction ConditionsOperation in experiment
99% 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
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  • [ 13139-17-8 ]
  • [ 74163-81-8 ]
  • [ 79261-58-8 ]
Reference: [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 19, p. 3100 - 3108
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