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Chemical Structure| 22246-12-4
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Product Details of [ 22246-12-4 ]

CAS No. :22246-12-4 MDL No. :MFCD04114865
Formula : C10H11NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :WLQWIZAWNPYMBR-UHFFFAOYSA-N
M.W : 177.20 Pubchem ID :10607392
Synonyms :

Calculated chemistry of [ 22246-12-4 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.3
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 52.7
TPSA : 38.33 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.53 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.78
Log Po/w (XLOGP3) : 1.2
Log Po/w (WLOGP) : 0.6
Log Po/w (MLOGP) : 1.14
Log Po/w (SILICOS-IT) : 2.07
Consensus Log Po/w : 1.36

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.97
Solubility : 1.9 mg/ml ; 0.0107 mol/l
Class : Very soluble
Log S (Ali) : -1.6
Solubility : 4.44 mg/ml ; 0.025 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.29
Solubility : 0.0903 mg/ml ; 0.000509 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.55

Safety of [ 22246-12-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 22246-12-4 ]

* 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 [ 22246-12-4 ]
  • Downstream synthetic route of [ 22246-12-4 ]

[ 22246-12-4 ] Synthesis Path-Upstream   1~23

  • 1
  • [ 110192-21-7 ]
  • [ 22246-12-4 ]
YieldReaction ConditionsOperation in experiment
76% With polyphosphoric acid In ethyl acetate at 20 - 120℃; for 6 h; To a preheated polyphosphoric acid (184 mL, 183.99 mmol) at 120 °C was added 10 (35.0 g, 167.26 mmol) slowly at 120 °C.
The reaction mixture was stirred at rt for 6 h, quenched with ice water, basified with K2CO3, and extracted with DCM.
The combined organic layers were dried with Na2SO4, filtered, and concentrated.
The crude mixture was purified by silica gel column chromatography using EtOAc/hexanes (1/1) as an eluent to afford the title compound 11 (38.5 g, 218 mmol, 76percent) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.86 (dd, J = 8.7, 2.4 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 3.85 (s, 3H), 3.56 (td, J = 6.6, 2.8 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H); EI/MS m/z 177.1 [M+].
65% at 20 - 120℃; for 6 h; Polyphosphoric acid (184 mL, 184 mmol) was added to the reaction vessel and the temperature was raised to 120° C. The methyl 3-methoxyphenethylcarbamate (35.0 g, 167 mmol) obtained in step 1 was slowly added thereto, and stirred at room temperature for 6 hours.
The reaction mixture was poured into ice water, diluted with water, neutralized with potassium carbonate, extracted with dichloromethane, and washed with brine.
The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (22.0 g, 65percent).
1H NMR (300 MHz, CDCl3) δ 2.91-2.99 (m, 2H), 3.53-3.58 (m, 2H), 3.85 (s, 3H), 6.71 (m, 1H), 6.79-6.91 (m, 1H), 8.00-8.03 (m, 1H);
EI/MS 177.1 [M+].
64% at 145℃; for 0.166667 h; General procedure: To the compound 21a (2.5 g, 12.9 mmol) was added poly-phosphoric acid (30 g). The reaction mixture was heated at 145 °C for 10 min and cooled down at 0 °C. Water was added and the organic phase was extracted with CH2Cl2. The combinded organic fractions were dried over Na2SO4 and the solvent was evaporated in vacuo. The resulting residue was purified by a column chromatography (EtOAc:hexane = 1:1) to give compound 23a (674 mg, 32percent) as an ivory crystal.
Reference: [1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 2, p. 207 - 219
[2] Patent: US2017/145007, 2017, A1, . Location in patent: Paragraph 0322-0325
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 4, p. 789 - 801
[4] Patent: WO2012/97682, 2012, A1, . Location in patent: Page/Page column 134
[5] Patent: WO2012/97684, 2012, A1, . Location in patent: Page/Page column 108
  • 2
  • [ 5111-70-6 ]
  • [ 22246-12-4 ]
YieldReaction ConditionsOperation in experiment
49% With sodium azide; sulfuric acid In benzene at 0 - 60℃; for 24 h;
Sulfuric acid (82.6 mL) was carefully added, at 0° C., to 5-methoxy-1-indanone (25 g, 154 mmol) in benzene (400 mL) followed by sodium azide (18 g, 277.4 mmol).
The resulting mixture was heated at 60° C. for 24 h.
After cooling at room temperature, the benzene was evaporated and the resulting mixture was diluted with water and extracted with dichloromethane.
After drying of the organic layer with MgSO4, filtration and evaporation the product was obtained as a white solid after purification by chromatography (SiO2, ethyl acetate/n-hexane 1:1 to 4:1 v:v gradient) (13.2 g, 49percent). MS: m/e=177.2 (M+)
Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1993, vol. 32, # 12, p. 1209 - 1213
[2] Patent: US2003/225122, 2003, A1, . Location in patent: Page 18
[3] Patent: US2002/72518, 2002, A1,
[4] Patent: US5707994, 1998, A,
[5] Journal of Medicinal Chemistry, 2012, vol. 55, # 5, p. 2452 - 2468
[6] European Journal of Medicinal Chemistry, 2013, vol. 69, p. 920 - 930
  • 3
  • [ 33543-63-4 ]
  • [ 22246-12-4 ]
YieldReaction ConditionsOperation in experiment
68% at 120℃; for 3 h; REFERENCE EXAMPLE 9; 6-Methoxy-1 ,2,3,4-tetrahydroisoquinolin-1 -one; A mixture of ethyl Λ/-[2-(3-methoxyphenyl)ethyl]carbamate (18.98 g, 85.0 mmol, obtained in reference example 8) and polyphosphoric acid (60 g) was heated at 120 0C for 3 h and then allowed to cool to 60 0C. Water and EtOAc were added and the mixture was allowed to cool to room temperature. The phases were separated and the aqueous phase was reextracted several times with CHCI3. The combined organic phases were dried over Na2SO4 and the solvent was evaporated. The crude product obtained was purified by chromatography on silica gel using EtOAc-MeOH mixtures of increasing polarity as eluent, to afford 10.24 g of the desired compound (yield: 68percent).1H NMR (300 MHz, CDCI3) δ (TMS): 2.97 (m, 2 H), 3.55 (m, 2 H), 3.85 (s, 3 H)1 6.31 (broad s, 1 H)1 6.70 (d, J = 2.1 Hz, 1 H), 6.85 (dd, J = 8.7 Hz, J1 = 2.4 Hz, 1 H), 8.01 (d, J = 8.4 Hz, 1 H).
68% at 120℃; for 3 h; Reference Example 9; 6-Methoxy-1,2,3,4-tetrahydroisoquinolin-1-oneA mixture of ethyl N-[2-(3-methoxyphenyl)ethyl]carbamate (18.98 g, 85.0 mmol, obtained in reference example 8) and polyphosphoric acid (60 g) was heated at 120° C. for 3 h and then allowed to cool to 60° C. Water and EtOAc were added and the mixture was allowed to cool to room temperature. The phases were separated and the aqueous phase was reextracted several times with CHCl3. The combined organic phases were dried over Na2SO4 and the solvent was evaporated. The crude product obtained was purified by chromatography on silica gel using EtOAc-MeOH mixtures of increasing polarity as eluent, to afford 10.24 g of the desired compound (yield: 68percent).1H NMR (300 MHz, CDCl3) 8 (TMS): 2.97 (m, 2H), 3.55 (m, 2H), 3.85 (s, 3H), 6.31 (broad s, 1H), 6.70 (d, J=2.1 Hz, 1H), 6.85 (dd, J=8.7 Hz, J'=2.4 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H).
68% at 120℃; for 3 h; REFERENCE EXAMPLE 9; 6-Methoxy-1 ,2,3,4-tetrahydroisoquinolin-1 -one; A mixture of ethyl Λ/-[2-(3-methoxyphenyl)ethyl]carbamate (18.98 g, 85.0 mmol, obtained in reference example 8) and polyphosphoric acid (60 g) was heated at 120 0C for 3h and then allowed to cool to 60 0C. Water and EtOAc were added and the mixture was allowed to cool to room temperature. The phases were separated and the aqueous phase was reextracted several times with CHCI3. The combined organic phases were dried over Na2SO4 and the solvent was evaporated. The crude product obtained was purified by chromatography on silica gel using EtOAc-MeOH mixtures of increasing polarity as eluent, to afford 10.24 g of the desired compound (yield: 68percent). 1H NMR (300 MHz, CDCI3) δ (TMS): 2.97 (m, 2 H), 3.55 (m, 2 H), 3.85 (s, 3 H), 6.31 (broad s, 1 H), 6.70 (d, J = 2.1 Hz, 1 H), 6.85 (dd, J = 8.7 Hz, J1 = 2.4 Hz, 1 H), 8.01 (d, J = 8.4 Hz, 1 H).
64% at 120℃; for 1.5 h; Inert atmosphere 6.1.17
6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one (34)
A mixture of 33 (2.82 g, 12.6 mmol) in polyphosphoric acid (12 g, 35.5 mmol) was stirred at 120 °C under N2 for 1.5 h.
After cooling to room temperature, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL * 3).
The combined organic layer was dried over Na2SO4 and concentrated.
The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100:1) to give 34 (1.4 g, 64percent) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.70 (s, 1H), 6.38 (s, 1H), 3.84 (s, 3H), 3.55 (t, J = 5.2 Hz, 2H), 2.96 (t, J = 6.4 Hz, 2H).
7.6% at 120℃; for 1 h; Step 4:
Preparation of Intermediate 6-Methoxy-3,4-dihydro-2H-isoquinolin-1-one (I-11d)
Using an analogous procedure and workup as described in Example 1, step 4, [2-(3-methoxy-phenyl)-ethyl]-carbamic acid ethyl ester (I-11c: 6.2 g, 29.5238 mmol) in POCl3 (62 mL) was reacted with P2O5 (8.38 g, 59.047 mmol).
The resulting mixture was stirred at 120° C. for 1 hour to afford the crude product.
Purification by column chromatography on silica gel (2percent methanol in DCM) afforded 0.400 g of the product (7.6percent yield).
LCMS purity: 100percent, m/z=178.0 (M+1)

Reference: [1] Journal of Medicinal Chemistry, 2000, vol. 43, # 21, p. 3878 - 3894
[2] European Journal of Medicinal Chemistry, 2008, vol. 43, # 10, p. 2211 - 2219
[3] Patent: WO2007/339, 2007, A1, . Location in patent: Page/Page column 42
[4] Patent: US2010/222363, 2010, A1, . Location in patent: Page/Page column 15
[5] Patent: WO2007/337, 2007, A1, . Location in patent: Page/Page column 35
[6] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 6855 - 6868
[7] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 814 - 819
[8] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 16, p. 4727 - 4730
[9] Patent: US2014/45872, 2014, A1, . Location in patent: Paragraph 0319; 0320
[10] Archiv der Pharmazie, 1991, vol. 324, # 8, p. 509 - 518
[11] Patent: WO2006/71940, 2006, A2, . Location in patent: Page/Page column 419
[12] Patent: WO2009/5998, 2009, A1, . Location in patent: Page/Page column 276-277
[13] Patent: WO2013/80222, 2013, A1, . Location in patent: Page/Page column 39
[14] Patent: US2016/24063, 2016, A1, . Location in patent: Paragraph 0265-0267
[15] Patent: EP3207928, 2017, A2, . Location in patent: Paragraph 0159-0161
[16] Patent: WO2007/84451, 2007, A1, . Location in patent: Page/Page column 180
  • 4
  • [ 62334-10-5 ]
  • [ 22246-12-4 ]
Reference: [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2097 - 2102
[2] European Journal of Organic Chemistry, 2013, # 5, p. 965 - 971
  • 5
  • [ 2039-67-0 ]
  • [ 22246-12-4 ]
Reference: [1] Yakugaku Zasshi, 1959, vol. 79, p. 329,334[2] Chem.Abstr., 1959, p. 16177
[3] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 14, p. 1885 - 1888
[4] Journal of Medicinal Chemistry, 2000, vol. 43, # 21, p. 3878 - 3894
[5] Journal of Medicinal Chemistry, 1987, vol. 30, # 12, p. 2208 - 2216
[6] Archiv der Pharmazie, 1991, vol. 324, # 8, p. 509 - 518
[7] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 814 - 819
[8] Patent: WO2012/97682, 2012, A1,
[9] Patent: WO2012/97684, 2012, A1,
[10] Patent: WO2013/80222, 2013, A1,
[11] Patent: US2014/45872, 2014, A1,
[12] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 6855 - 6868
[13] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 2, p. 207 - 219
[14] Patent: US2016/24063, 2016, A1,
[15] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 4, p. 789 - 801
[16] Patent: EP3207928, 2017, A2,
[17] Patent: US2017/145007, 2017, A1,
[18] Patent: WO2007/84451, 2007, A1,
  • 6
  • [ 337913-25-4 ]
  • [ 5111-70-6 ]
  • [ 22246-12-4 ]
Reference: [1] Patent: US5334600, 1994, A,
[2] Patent: US5260316, 1993, A,
  • 7
  • [ 5111-70-6 ]
  • [ 75-09-2 ]
  • [ 22246-12-4 ]
Reference: [1] Patent: US5334600, 1994, A,
  • 8
  • [ 110192-21-7 ]
  • [ 74904-29-3 ]
  • [ 22246-12-4 ]
Reference: [1] Journal of Medicinal Chemistry, 1987, vol. 30, # 12, p. 2208 - 2216
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 14, p. 1885 - 1888
  • 9
  • [ 10516-71-9 ]
  • [ 22246-12-4 ]
Reference: [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2097 - 2102
[2] Chemical and Pharmaceutical Bulletin, 1980, vol. 28, # 3, p. 1003 - 1005
  • 10
  • [ 40478-49-7 ]
  • [ 22246-12-4 ]
Reference: [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2097 - 2102
[2] Chemical and Pharmaceutical Bulletin, 1980, vol. 28, # 3, p. 1003 - 1005
  • 11
  • [ 19924-43-7 ]
  • [ 22246-12-4 ]
Reference: [1] Archiv der Pharmazie, 1991, vol. 324, # 8, p. 509 - 518
  • 12
  • [ 1190890-94-8 ]
  • [ 22246-12-4 ]
Reference: [1] European Journal of Organic Chemistry, 2013, # 5, p. 965 - 971
  • 13
  • [ 163713-49-3 ]
  • [ 22246-12-4 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1980, vol. 28, # 3, p. 1003 - 1005
  • 14
  • [ 62334-10-5 ]
  • [ 74904-29-3 ]
  • [ 22246-12-4 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1980, vol. 28, # 3, p. 1003 - 1005
  • 15
  • [ 2039-67-0 ]
  • [ 74904-29-3 ]
  • [ 22246-12-4 ]
Reference: [1] Heterocycles, 2016, vol. 93, # 2, p. 705 - 713
  • 16
  • [ 22246-12-4 ]
  • [ 52986-70-6 ]
Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1993, vol. 32, # 12, p. 1209 - 1213
  • 17
  • [ 22246-12-4 ]
  • [ 42923-77-3 ]
YieldReaction ConditionsOperation in experiment
86% With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 70℃; for 12 h; To a solution of LiAlH4 (8.17 g, 215 mmol) in THF (250 mL) was added a solution of 11 (38.0 g, 214 mmol) in THF (250 mL) at 0 °C.
The reaction mixture was stirred at 70 °C for 12 h, cooled down to rt, quenched with water and 15percent NaOH (aq), and extracted with EtOAc.
The combined organic layers were dried with Na2SO4, filtered, and concentrated.
The crude mixture was purified by silica gel column chromatography using EtOAc/hexanes (2/1) as an eluent to afford the title compound 12 (30.0 g, 184 mmol, 86percent) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.92 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 6.62 (s, 1H), 3.95 (s, 2H), 3.77 (s, 3H), 3.11 (t, J = 5.6 Hz, 2H), 2.78 (t, J = 5.4 Hz, 2H), 2.20 (br s, 1H); EI/MS m/z 163.1 [M+].
84% With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 2 h; Reflux General procedure: A solution of 23a (1.02 g, 6.3 mmol) in 25 mL of dry THF was slowly added into the suspension of LiAlH4 (504 mg, 12.6 mmol) in dry THF (67 mL) at 0 °C. The mixture was refluxed for 2 h and was quenched by the sequential addition of THF and 30percent NaOH solution in the ice bath. The reaction mixture was filtered through celite and was washed by EtOAc. The residue was evaporated in vacuo and purified by a column chromatography (EtOAc:MeOH = 20:1) to give compound 7a (693 mg, 74percent) as a white crystal.
77% With lithium aluminium tetrahydride In tetrahydrofuran at 60℃; Inert atmosphere 6.1.18
6-Methoxy-1,2,3,4-tetrahydroisoquinoline (35)
To a solution of 34 (1.4 g, 7.9 mmol) in dry THF (20 mL) was added LiAlH4 (601 mg, 15.8 mmol) slowly under N2, and the mixture was stirred at 60 °C overnight.
After cooling to room temperature, the mixture was diluted with water (0.6 mL) and 15percent NaOH solution (0.6 mL), then stirred for 30 min.
The mixture was filtered and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (dichloromethane/methanol = 20:1) to give 35 (1.06 g, 77percent) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 6.94 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.63 (s, 1H), 4.00 (s, 2H), 3.78 (s, 3H), 3.16 (t, J = 5.6 Hz, 2H), 2.83 (t, J = 5.2 Hz, 2H).
Reference: [1] Journal of Medicinal Chemistry, 1987, vol. 30, # 12, p. 2208 - 2216
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1993, vol. 32, # 12, p. 1209 - 1213
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 2, p. 207 - 219
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 4, p. 789 - 801
[5] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 6855 - 6868
[6] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 14, p. 1885 - 1888
[7] Patent: WO2012/97682, 2012, A1, . Location in patent: Page/Page column 134
[8] Patent: WO2012/97684, 2012, A1, . Location in patent: Page/Page column 108-109
[9] Patent: WO2013/80222, 2013, A1, . Location in patent: Page/Page column 39
[10] Patent: US2016/24063, 2016, A1, . Location in patent: Paragraph 0268-0270
[11] Patent: EP3207928, 2017, A2, . Location in patent: Paragraph 0162-0164
  • 18
  • [ 22246-12-4 ]
  • [ 22245-98-3 ]
YieldReaction ConditionsOperation in experiment
75% With boron tribromide In dichloromethane at -78 - 20℃; Step 1:
6-Hydroxy-3,4-dihydroisoquinolin-1(2H)-one
A solution of 6-methoxy-3,4-dihydroisoquinolin-1(2H)-one (2.58 g, 14 mmol) in dichloromethane at -78° C. was treated with boron tribromide (2.7 mL, 28 mmol), allowed to warm to room temperature overnight, quenched with cold water and extracted with ethyl acetate.
The combined extracts were concentrated in vacuo.
The residue was purified by ISCO CombiFlash.(R). chromatography (silica, 0-15percent methanol in dichloromethane) to afford the title compound as a light brown solid, 1.8 g (75percent), mp 204-206° C.; MS (ES) m/z 162.1 [M+H]+.
65% With hydrogen bromide In water at 95℃; for 72 h; Heating / reflux
The 6-methoxy-3,4-dihydro-2H-isoquinolin-1-one (10 g, 56.4 mmol) was dissolved in hydrobromic acid 48percent in water (126 mL) and refluxed for 72 h at 95° C.
After cooling to 0° C. a saturated solution of ammonium hydroxide was added and the mixture extracted with ethyl acetate.
After drying of the organic layer with MgSO4, filtration and evaporation, the residue was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0 to 9:1 v:v gradient) to give the title alcohol as a brown solid (6 g, 65percent). MS: m/e=162.2 (M-H+).
27% at 100℃; for 72 h; Intermediate 9: Methyl 2-(l,2,3,4-tetrahydro-l-oxoisoquinolin-6-yloxy)-2- methylpropanoate.[0067] Step A: 3,4-dihydro-6-methoxyisoquinolin-l(2H)-one (760 mg, 4.3 mmol) is dissolved in 48percent aqueous HBr (5 mL) and heated at 100 0C for 72 h. The mixture is cooled and poured into a saturated solution of NaHCU3 (50 mL) and extracted with ethyl acetate (2 x 20 mL). The organic fractions are combined, washed with brine (20 mL), dried (MgSO4), filtered and evaporated to give crude 3,4-dihydro-6-hydroxyisoquinolin- l(2H)-one 8 (193 mg, 27percent), which is used in Step B without further purification.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 814 - 819
[2] Patent: US2009/69300, 2009, A1, . Location in patent: Page/Page column 23
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 5, p. 2452 - 2468
[4] Patent: US2003/225122, 2003, A1, . Location in patent: Page 18-19
[5] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 16, p. 4727 - 4730
[6] Patent: WO2007/89557, 2007, A2, . Location in patent: Page/Page column 23
[7] Patent: US5334600, 1994, A,
[8] Patent: US5260316, 1993, A,
[9] Patent: WO2006/71940, 2006, A2, . Location in patent: Page/Page column 420
[10] Patent: WO2015/92634, 2015, A1, . Location in patent: Paragraph 00327
  • 19
  • [ 541-41-3 ]
  • [ 22246-12-4 ]
  • [ 59839-23-5 ]
Reference: [1] Patent: US2010/113512, 2010, A1,
[2] Patent: US2011/124559, 2011, A1,
  • 20
  • [ 22246-12-4 ]
  • [ 59839-23-5 ]
Reference: [1] Journal of Medicinal Chemistry, 1987, vol. 30, # 12, p. 2208 - 2216
[2] Patent: WO2013/80222, 2013, A1,
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 4, p. 789 - 801
  • 21
  • [ 24424-99-5 ]
  • [ 22246-12-4 ]
  • [ 158984-83-9 ]
Reference: [1] Patent: CN102516115, 2016, B, . Location in patent: Paragraph 0488; 0489
  • 22
  • [ 22246-12-4 ]
  • [ 158984-83-9 ]
Reference: [1] Patent: US2011/124559, 2011, A1,
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 4, p. 789 - 801
  • 23
  • [ 22246-12-4 ]
  • [ 860436-57-3 ]
Reference: [1] Patent: WO2012/97682, 2012, A1,
[2] Patent: WO2012/97684, 2012, A1,
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