[ CAS No. 654655-68-2 ] {[proInfo.proName]}

Name: 654655-68-2|3-Benzyl-6-bromo-2-chloroquinoline|97%
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SKU: A376628
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Quality Control of [ 654655-68-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 654655-68-2 ]

Product Details of [ 654655-68-2 ]

CAS No. :	654655-68-2	MDL No. :	MFCD22493487
Formula :	C₁₆H₁₁BrClN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UGXUDVNBDYIJHJ-UHFFFAOYSA-N
M.W :	332.62	Pubchem ID :	57471585
Synonyms :

Calculated chemistry of [ 654655-68-2 ]

Physicochemical Properties

Num. heavy atoms :	19
Num. arom. heavy atoms :	16
Fraction Csp3 :	0.06
Num. rotatable bonds :	2
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	83.91
TPSA :	12.89 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-4.24 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.31
Log Po/w (XLOGP3) :	5.76
Log Po/w (WLOGP) :	5.24
Log Po/w (MLOGP) :	4.66
Log Po/w (SILICOS-IT) :	5.66
Consensus Log Po/w :	4.93

Druglikeness

Lipinski :	1.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-6.02
Solubility :	0.000316 mg/ml ; 0.00000095 mol/l
Class :	Poorly soluble
Log S (Ali) :	-5.8
Solubility :	0.000528 mg/ml ; 0.00000159 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-8.06
Solubility :	0.00000288 mg/ml ; 0.0000000087 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.13

Safety of [ 654655-68-2 ]

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

Application In Synthesis of [ 654655-68-2 ]

* 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 [ 654655-68-2 ]
Downstream synthetic route of [ 654655-68-2 ]

[ 654655-68-2 ] Synthesis Path-Upstream 1~12

1
[ 68-12-2 ]
[ 316146-27-7 ]
[ 654655-68-2 ]

Yield	Reaction Conditions	Operation in experiment
67%	at 10 - 80℃;	Phosphoric trichloride (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 1 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with DCM. The organic layer was dried (MgS04), filtered, and the solvent was evaporated. The product was used without further purification, yielding 77.62 g of intermediate 2 (67percent).
67%	at 20 - 80℃;	Example A2; Preparation of intermediate 2; The reaction was carried out twice. POC13 (1.225 mol) was added dropwise at 10 °C to DMF (0.525 mol). Then intermediate 1 (0.175 mol) was added at room temperature . The mixture was stirred overnight at 80 °C, poured out on ice and extracted with CH2CI2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated, yielding 77.62 g (67percent) of intermediate 2. The product was used without further purification.
67%	at 10 - 80℃;	b) Preparation of intermediate 11; The reaction was carried out twice. POCl₃ (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 10 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 8O⁰C, poured out on ice and extracted with CH2CI2. The organic layer was dried (MgSO₄), filtered, and the solvent was evaporated. Yield: 77.62 g of intermediate 11 (67percent).

67%	Stage #1: at 10 - 20℃; Stage #2: at 20 - 80℃;	b. Preparation of intermediate 10; The reaction was carried out twice . POCl₃ (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol) . Then intermediate 9 (0.175 mol) was added at room temperature . The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH₂Cl₂ . The organic layer was dried (MgSO₄), filtered, and the solvent was evaporated . Yield: 77.62 g of intermediate 10 (67 percent).
67%	at 10 - 80℃;	b) Preparation of intermediate 5; The reaction was carried out twice. POCl₃ (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 4 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH₂Cl₂. The organic layer was dried (MgSO₄), filtered, and the solvent was evaporated. The product was used without further purification. Yield: 77.62 g of intermediate 5 (67 percent).
67%	Stage #1: at 10℃; Stage #2: at 20 - 80℃;	Intermediate 2 The reaction was carried out twice . POCI3 (1.225 mol) was added dropwise at 10 ⁰C to DMF (0.525 mol) . Then intermediate 1 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80 ⁰C, poured out on ice and extracted with CH₂CI₂ . The organic layer was dried (MgSO/t), filtered, and the solvent was evaporated, yielding 77.62 g (67percent) of intermediate 2. The product was used without further purification.

Reference： [1] Patent: WO2005/70430, 2005, A1, . Location in patent: Page/Page column 34
[2] Patent: WO2005/70924, 2005, A1, . Location in patent: Page/Page column 27
[3] Patent: WO2007/435, 2007, A1, . Location in patent: Page/Page column 44
[4] Patent: WO2007/436, 2007, A1, . Location in patent: Page/Page column 33
[5] Patent: WO2007/14885, 2007, A1, . Location in patent: Page/Page column 31
[6] Patent: WO2007/14934, 2007, A2, . Location in patent: Page/Page column 33
[7] ChemMedChem, 2017, vol. 12, # 2, p. 106 - 119
[8] Patent: EP2371819, 2011, A1, . Location in patent: Page/Page column 7

2
[ 75-05-8 ]
[ 316146-27-7 ]
[ 654655-68-2 ]

Yield	Reaction Conditions	Operation in experiment
71%	With trichlorophosphate In N,N-dimethyl-formamide at 80℃; Inert atmosphere	POCl3 (129 g, 0.840 mol) was added dropwise into DMF (32.6 ml, 0.420 mol) at 0°C. After 1h of vigorous agitation under room temperature, compound 1 (32 g, 0.105 mol) and CH3CN (50mL) was added into the mixture, followed by being stirred overnight at 80°C. After solvent was partially removed, the residue was poured out into ice water (300mL) with rapid stirring and crude compound 2 precipitates gradually. Then the solid was filtrated and washed with portions of cold CH3OH. Finally, compound 2 (25g, 71percent) can be recrystallized from CH2Cl2 and CH3OH.

Reference： [1] Chinese Chemical Letters, 2015, vol. 26, # 6, p. 790 - 792

3
[ 316146-27-7 ]
[ 654655-68-2 ]

Yield	Reaction Conditions	Operation in experiment
67%	Stage #1: at 10℃; Stage #2: at 20 - 80℃;	The reaction was carried out twice . POCl₃ (1.225 mol) was added dropwise at 10°C to iV,iV-dimethylformamide (DMF) (0.525 mol) . Then intermediate compound 1 (prepared according Al) (0.175 mol) was added at room temperature . The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH2CI2 . The organic layer was dried (MgSO₄), filtered, and the solvent was evaporated . The product was used without further purification. Yield : 77.62g of intermediate compound 2 (67percent).
67%	With trichlorophosphate In DMF (N,N-dimethyl-formamide) at 80℃;	The reaction was carried out twice. POC13 (1.225 mol) was added dropwise at [10C] to DMF (0.525 mol). Then intermediate compound 1 (prepared according [A1)] (0.175 mol) was added at room temperature. The mixture was stirred overnight at [80C,] poured out on ice and extracted with CH2C12. The organic layer was dried [(MgS04),] filtered, and the solvent was evaporated. The product was used without further purification. Yielding : (77.62g ; Yield=67percent).
67%	at 10 - 80℃;	b) Preparation of intermediate compound 4b; The reaction was carried out twice. POCl₃ (1.225 mol) was added dropwise at 10°C to iV,iV-dimethylformamide (0.525 mol). Then intermediate compound 4a (0.175 mol) was EPO <DP n="39"/>added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH2CI2. The organic layer was dried (MgSO₄), filtered, and the solvent was evaporated. The product was used without further purification. Yield: 77.62 g (67 percent) of intermediate compound 4b.

67%	at 20 - 80℃;	Example A2; Preparation of intermediate 2. Phosphoric trichloride (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 1 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with DCM. The organic layer was dried (MgSO₄), filtered, and the solvent was evaporated. The product was used without iurther purification, yielding 77.62 g of intermediate 2 (67percent).
64%	With cetyltrimethylammonim bromide; N,N-dimethyl-formamide; trichlorophosphate In acetonitrile at 5 - 80℃; for 8 h;	Preparation of3-Benzyl-6-bromo-2-chloro-quinoline; Phosphorus oxychloπde (30.0 g, 196 9 mmol) was added dropwise to JV, JV-Dimethylformamide (14 34 g, 196.18 mmol) at 5 ⁰C, the mixture was allowed to warm up to room temperature and stirred for 20 mm. The above reagent was added to a suspension of7V-(4-Bromo phenyl)-3-phenyl propionamide (3.0 g, 9.86 mmol) and cetyltrimethylammomum bromide (CTAB, 0.04 g, 0.10 mmol) m acetomtπle at 5 ⁰C. The reaction mixture was heated at 80 ⁰C for 8 h, cooled to room temperature, poured into 100 ml of 3percent hypo solution at 0 ⁰C, extracted with dichloromethane, the organic layer was washed with water until the water extracts became neutral to pH paper followed by brme, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (100-200) eluted with hexane - ethyl acetate (97:3) to afford the title compound (2.0 g, 64percent yield) as a white crystalline solid, Mp 102°C-104°C. ¹H NMR (400 MHz, CDCL₃). δ 4.22 (s, 2 H), 7.20-7.24 (m, 2 <n="24"/>H), 7 26-7 31 (m, 1 H), 7 32-7 38 (m, 2 H), 7 65 (s, 1 H), 7 72 (dd, /= 12 0, 4 0 Hz, 1 H), 7 84-7 88 (m, 2H). [M+H]⁺ = 332, 335.

Reference： [1] Patent: WO2006/67048, 2006, A1, . Location in patent: Page/Page column 27
[2] Patent: WO2004/11436, 2004, A1, . Location in patent: Page 17
[3] Patent: WO2007/434, 2007, A1, . Location in patent: Page/Page column 36-37
[4] Patent: WO2007/14940, 2007, A2, . Location in patent: Page/Page column 41
[5] Patent: WO2009/91324, 2009, A1, . Location in patent: Page/Page column 22-23

4
[ 924633-09-0 ]
[ 654655-68-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: for 0.5 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In watercooling with ice	Preparation of 3-benzyl-6-bromo-2-chloroquinoline; 3-Benzyl-6-bromo-lH-qumoline-2-one (0 87 g, 2.8 mmol) and freshly distilled phosphorous oxychloπde (5 mL) were refluxed togethei for 30 mm The reaction was poured into ice-water mixture, basified with saturated sodium bicarbonate solution to pH 8-8 5 and extracted with ethyl acetate (3 * 50 mL). The organic fractions were combined, washed with brme (50 mL), dried over anhydrous sodium sulfate, filtered and the solvents were evaporated under reduced pressure to obtain the crude product as a gum, <n="22"/>which on purification by column chromatography (silica gel 100-200 mesh, eluent 3percent ethyl acetate in n- hexane) gave pure 3-Benzyl-6-bromo-2-chloro-qumolm (0.85 g, 92percent), Mp 102-104 ⁰C. ¹H NMR (400 MHz, CDCl₃): δ 4.22 (s, 2 H), 7.20-7.24 (m, 2 H), 7.26-7.31 (m, 1 H), 7.32-7.38 (m, 2 H), 7.65 (s, 1 H), 7 72 (dd, J = 12.0, 4 0 Hz, 1 H), 7 84-7.88 (m, 2 H). [M+H]⁺ = 332, 335

Reference： [1] Tetrahedron, 2007, vol. 63, # 2, p. 451 - 460
[2] Patent: WO2009/91324, 2009, A1, . Location in patent: Page/Page column 20-21

5
[ 106-40-1 ]
[ 654655-68-2 ]

Reference： [1] Patent: EP2371819, 2011, A1,
[2] Chinese Chemical Letters, 2015, vol. 26, # 6, p. 790 - 792
[3] ChemMedChem, 2017, vol. 12, # 2, p. 106 - 119

6
[ 924658-20-8 ]
[ 654655-68-2 ]

Reference： [1] Tetrahedron, 2007, vol. 63, # 2, p. 451 - 460

7
[ 37442-45-8 ]
[ 654655-68-2 ]

Reference： [1] Tetrahedron, 2007, vol. 63, # 2, p. 451 - 460

8
[ 105479-98-9 ]
[ 654655-68-2 ]

Reference： [1] Tetrahedron, 2007, vol. 63, # 2, p. 451 - 460

9
[ 501-52-0 ]
[ 654655-68-2 ]

Reference： [1] Patent: EP2371819, 2011, A1,

10
[ 645-45-4 ]
[ 654655-68-2 ]

Reference： [1] ChemMedChem, 2017, vol. 12, # 2, p. 106 - 119

11
[ 654655-68-2 ]
[ 124-41-4 ]
[ 654655-69-3 ]

Yield	Reaction Conditions	Operation in experiment
96%	Reflux; Inert atmosphere	Compound 2 (20g, 0.06mol) was dissolved into anhydrous CH3OH (100mL), and 108g solution of CH3ONa (15percent) in CH3OH was added. The mixture was stirred and refluxed overnight. Then the mixture was cooled to room temperature and stored in refrigerator at -20°C overnight. Crude compound 3 precipitates in the form of white needles. The solid was separated with filtration, washed with water, and air dried to give 19g (96percent) of compound 3 as white solid.
33%	Heating / reflux	A mixture of intermediate 2 (0.233 mol) in a 30percent MeONa in MeOH solution (222.32 ml) and MeOH (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with DCM. The organic layer was separated, dried (MgS04), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/cyclohexane 20/80 and then 100/0; 20-45um). The pure fractions were collected and the solvent was evaporated, yielding 25g of intermediate 3 (33percent).
33%	Heating / reflux	A mixture of intermediate compound 2 (prepared according to A2) (0.233 mol) in CH₃ONa (30percent) in methanol (222.32 ml) and methanol (776ml) was stirred and refluxed overnight, then poured out on ice and extracted with CH2CI2 . The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated . The residue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/cyclohexane 20/80 and then 100/0; 20-45μm). The pure fractions were collected and the solvent was evaporated . Yield : 25g of intermediate compound 3 (Yield=33percent; mρ.84°C) as a white powder

33%	Heating / reflux	Preparation of intermediate compound 3 A mixture of intermediate compound 2 (prepared according to A2) (0.233 mol) in [CH30NA] (30percent) in methanol (222.32 ml) and methanol [(776ML)] was stirred and refluxed overnight, then poured out on ice and extracted with [CH2CL2.] The organic layer was separated, dried [(MGSO4),] filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: [CH2CL2/CYCLOHEXANE] 20/80 and then [100/0 ; 20-45 UM). THE] pure fractions were collected and the solvent was evaporated. Yielding: 25g of intermediate compound 3 (Yield=33percent; mp. [84C)] as a white powder.
33%	Heating / reflux	Example A3; Preparation of intermediate 3 Intermediate 3; A mixture of intermediate 2 (0.233 mol) in CH30Na (30percent) in MeOH (222.32 ml) and MeOH (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl21cyclohexane 20/80 and then 100/0; 20-45um). The pure fractions were collected and the solvent was evaporated. Yield: 25 g (33percent) of intermediate 3 (M. P.: 84 °C).
33%	Heating / reflux	c-3) Preparation of intermediate 19; A mixture of intermediate 11 (0.233 mol) in CH₃ONa (30percent) in methanol (222.32 ml) and methanol (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with CH2CI2 . The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated . The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/cyclohexane 20/80 and then 100/0; 20-45 μm). The pure fractions were collected and the solvent was evaporated . Yield: 25 g of intermediate 19 (33percent) (melting point: 84°C).
33%	Heating / reflux	A mixture of intermediate 2 (0.233 mol) in CH₃ONa (30percent) in MeOH (222.32 ml) and MeOH (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with CH₂CI₂ . The organic layer was separated, dried (MgSO/t), filtered and the solvent was evaporated . The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/cyclohexane 20/80 and then 100/0; 20-45 μm). The pure fractions were collected and the solvent was evaporated . Yield: 25 g (33percent) of intermediate 3 (M.P.: 84 ⁰C).
33%	Heating / reflux	a) Preparation of intermediate 3: A mixture of intermediate 2 (0.233 mol) in a 30percent MeONa in MeOH solution (222.32 ml) and MeOH (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with DCM. The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/cyclohexane 20/80 and then 100/0; 20-45 μm). The pure fractions were collected and the solvent was evaporated, yielding 25g of intermediate 3 (33percent).
33%	Heating / reflux	Example A3; a. Preparation of intermediate 9; A mixture of 6-bromo-2-chloro-3-(phenylmethyl)-quinoline (prepared according to the teachings in WO2005/070924 of which the content is incorporated herein by reference) (0.233 mol) in CH₃ONa 30percent in CH₃OH (222.32 ml) and CH₃OH (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl2/cyclohexane 20/80 and then 100/0; 20-45 μm). The pure fractions were collected and the solvent was evaporated. Yield: 25 g of intermediate 9 (33 percent) .

Reference： [1] ChemMedChem, 2017, vol. 12, # 2, p. 106 - 119
[2] Tetrahedron, 2007, vol. 63, # 2, p. 451 - 460
[3] Chinese Chemical Letters, 2015, vol. 26, # 6, p. 790 - 792
[4] Patent: WO2005/70430, 2005, A1, . Location in patent: Page/Page column 34-35
[5] Patent: WO2006/67048, 2006, A1, . Location in patent: Page/Page column 27
[6] Patent: WO2004/11436, 2004, A1, . Location in patent: Page 18
[7] Patent: WO2005/70924, 2005, A1, . Location in patent: Page/Page column 27
[8] Patent: WO2007/435, 2007, A1, . Location in patent: Page/Page column 46
[9] Patent: WO2007/14934, 2007, A2, . Location in patent: Page/Page column 33
[10] Patent: WO2007/14940, 2007, A2, . Location in patent: Page/Page column 41
[11] Patent: WO2008/68266, 2008, A1, . Location in patent: Page/Page column 57

12
[ 654655-68-2 ]
[ 67-56-1 ]
[ 124-41-4 ]
[ 654655-69-3 ]

Yield	Reaction Conditions	Operation in experiment
89%	for 8 h; Heating / reflux	Preparation of 3 -Benzyl- 6-bromo-2-m ethoxy-q u m olin e; To a stirred solution of compound 3-Benzyl-6-bromo-2-chloro-qumolme (5 O g, 15 0 mmol) m dry methanol (50 ml) was added sodium methoxide (30percent w/v m methanol, 15.0 ml, 84 0 mmol) and the contents were heated under reflux for 8 h The volatiles were removed under reduced pressure, poured into ice-water mixture, the solid separated out was filtered, washed with water and dried to furnish the compound (4 4 g, 89percent) as an off-white solid, Mp 83-85⁰C ¹H NMR (400 MHz, CDCl₃). δ 4.02 (s, 2 H), 4 07 (s, 3 H), 7 20-7 26 (m, 3 H), 7 29-7 34 (m, 2 H), 7 47 (s, 1 H), 7 60 (dd, J = 8 0, 4 0 Hz, 1 H), 7 60 (dd, J = 8 8, 2 2 Hz, 1 H), 7.73 (d, J= 2.0 Hz, 1 H) (M+H)⁺= 328, 330
33%	Heating / reflux	c. Preparation of intermediate 11; A mixture of intermediate 10 (0.233 mol) in CH₃ONa(30 percent) in methanol (222.32 ml) and methanol (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with CH₂Cl₂ . The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated . The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/cyclohexane 20/80 and then 100/0; 20-45 μm). The pure fractions were collected and the solvent was evaporated . Yield: 25 g of intermediate 11 (33 percent) (melting point: 84°C).
33%	Heating / reflux	c) Preparation of intermediate 6; A mixture of intermediate 5 (0.233 mol) in CH₃ONa 30 percent in CH₃OH (222.32 ml) and CH₃OH (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/cyclohexane 20/80 and then 100/0; 20-45 μm). The pure fractions were collected and the solvent was evaporated. Yield: 25 g of intermediate 6 (33 percent).

Reference： [1] Patent: WO2009/91324, 2009, A1, . Location in patent: Page/Page column 23
[2] Patent: WO2007/436, 2007, A1, . Location in patent: Page/Page column 33
[3] Patent: WO2007/14885, 2007, A1, . Location in patent: Page/Page column 31

[ 654655-68-2 ] Synthesis Path-Downstream 1~55

1
[ 924633-09-0 ]
[ 654655-68-2 ]

Yield	Reaction Conditions	Operation in experiment
92%		Preparation of 3-benzyl-6-bromo-2-chloroquinoline; 3-Benzyl-6-bromo-lH-qumoline-2-one (0 87 g, 2.8 mmol) and freshly distilled phosphorous oxychlo?de (5 mL) were refluxed togethei for 30 mm The reaction was poured into ice-water mixture, basified with saturated sodium bicarbonate solution to pH 8-8 5 and extracted with ethyl acetate (3 * 50 mL). The organic fractions were combined, washed with brme (50 mL), dried over anhydrous sodium sulfate, filtered and the solvents were evaporated under reduced pressure to obtain the crude product as a gum, <n="22"/>which on purification by column chromatography (silica gel 100-200 mesh, eluent 3% ethyl acetate in n- hexane) gave pure 3-Benzyl-6-bromo-2-chloro-qumolm (0.85 g, 92%), Mp 102-104 0C. 1H NMR (400 MHz, CDCl3): delta 4.22 (s, 2 H), 7.20-7.24 (m, 2 H), 7.26-7.31 (m, 1 H), 7.32-7.38 (m, 2 H), 7.65 (s, 1 H), 7 72 (dd, J = 12.0, 4 0 Hz, 1 H), 7 84-7.88 (m, 2 H). [M+H]+ = 332, 335

Reference： [1]Tetrahedron,2007,vol. 63,p. 451 - 460
[2]Patent: WO2009/91324,2009,A1 .Location in patent: Page/Page column 20-21

2
[ 654655-68-2 ]
[ 124-41-4 ]
[ 654655-69-3 ]

Yield	Reaction Conditions	Operation in experiment
96%	In methanol;Reflux; Inert atmosphere;	Compound 2 (20g, 0.06mol) was dissolved into anhydrous CH3OH (100mL), and 108g solution of CH3ONa (15%) in CH3OH was added. The mixture was stirred and refluxed overnight. Then the mixture was cooled to room temperature and stored in refrigerator at -20C overnight. Crude compound 3 precipitates in the form of white needles. The solid was separated with filtration, washed with water, and air dried to give 19g (96%) of compound 3 as white solid.
33%	In methanol;Heating / reflux;	A mixture of intermediate 2 (0.233 mol) in a 30% MeONa in MeOH solution (222.32 ml) and MeOH (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with DCM. The organic layer was separated, dried (MgS04), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/cyclohexane 20/80 and then 100/0; 20-45um). The pure fractions were collected and the solvent was evaporated, yielding 25g of intermediate 3 (33%).
33%	With methanol;Heating / reflux;	A mixture of <strong>[654655-68-2]intermediate compound 2</strong> (prepared according to A2) (0.233 mol) in CH3ONa (30%) in methanol (222.32 ml) and methanol (776ml) was stirred and refluxed overnight, then poured out on ice and extracted with CH2CI2 . The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated . The residue was purified by column chromatography over silica gel (eluent:CH2Cl2/cyclohexane 20/80 and then 100/0; 20-45mum). The pure fractions were collected and the solvent was evaporated . Yield : 25g of intermediate compound 3 (Yield=33%; mrho.84C) as a white powder

33%	In methanol;Heating / reflux;	Preparation of intermediate compound 3 A mixture of <strong>[654655-68-2]intermediate compound 2</strong> (prepared according to A2) (0.233 mol) in [CH30NA] (30%) in methanol (222.32 ml) and methanol [(776ML)] was stirred and refluxed overnight, then poured out on ice and extracted with [CH2CL2.] The organic layer was separated, dried [(MGSO4),] filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: [CH2CL2/CYCLOHEXANE] 20/80 and then [100/0 ; 20-45 UM). THE] pure fractions were collected and the solvent was evaporated. Yielding: 25g of intermediate compound 3 (Yield=33%; mp. [84C)] as a white powder.
33%	In methanol;Heating / reflux;	Example A3; Preparation of intermediate 3 Intermediate 3; A mixture of intermediate 2 (0.233 mol) in CH30Na (30%) in MeOH (222.32 ml) and MeOH (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl21cyclohexane 20/80 and then 100/0; 20-45um). The pure fractions were collected and the solvent was evaporated. Yield: 25 g (33%) of intermediate 3 (M. P.: 84 C).
33%	In methanol;Heating / reflux;	c-3) Preparation of intermediate 19; A mixture of intermediate 11 (0.233 mol) in CH3ONa (30%) in methanol (222.32 ml) and methanol (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with CH2CI2 . The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated . The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/cyclohexane 20/80 and then 100/0; 20-45 mum). The pure fractions were collected and the solvent was evaporated . Yield: 25 g of intermediate 19 (33%) (melting point: 84C).
33%	In methanol;Heating / reflux;	A mixture of intermediate 2 (0.233 mol) in CH3ONa (30%) in MeOH (222.32 ml) and MeOH (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with CH2CI2 . The organic layer was separated, dried (MgSO/t), filtered and the solvent was evaporated . The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/cyclohexane 20/80 and then 100/0; 20-45 mum). The pure fractions were collected and the solvent was evaporated . Yield: 25 g (33%) of intermediate 3 (M.P.: 84 0C).
33%	In methanol;Heating / reflux;	a) Preparation of intermediate 3: A mixture of intermediate 2 (0.233 mol) in a 30% MeONa in MeOH solution (222.32 ml) and MeOH (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/cyclohexane 20/80 and then 100/0; 20-45 mum). The pure fractions were collected and the solvent was evaporated, yielding 25g of intermediate 3 (33%).
33%	In methanol;Heating / reflux;	Example A3; a. Preparation of intermediate 9; A mixture of <strong>[654655-68-2]6-bromo-2-chloro-3-(phenylmethyl)-quinoline</strong> (prepared according to the teachings in WO2005/070924 of which the content is incorporated herein by reference) (0.233 mol) in CH3ONa 30% in CH3OH (222.32 ml) and CH3OH (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/cyclohexane 20/80 and then 100/0; 20-45 mum). The pure fractions were collected and the solvent was evaporated. Yield: 25 g of intermediate 9 (33 %) .

Reference： [1]ChemMedChem,2017,vol. 12,p. 106 - 119
[2]Tetrahedron,2007,vol. 63,p. 451 - 460
[3]Chinese Chemical Letters,2015,vol. 26,p. 790 - 792
[4]Patent: WO2005/70430,2005,A1 .Location in patent: Page/Page column 34-35
[5]Patent: WO2006/67048,2006,A1 .Location in patent: Page/Page column 27
[6]Patent: WO2004/11436,2004,A1 .Location in patent: Page 18
[7]Patent: WO2005/70924,2005,A1 .Location in patent: Page/Page column 27
[8]Patent: WO2007/435,2007,A1 .Location in patent: Page/Page column 46
[9]Patent: WO2007/14934,2007,A2 .Location in patent: Page/Page column 33
[10]Patent: WO2007/14940,2007,A2 .Location in patent: Page/Page column 41
[11]Patent: WO2008/68266,2008,A1 .Location in patent: Page/Page column 57
[12]Russian Chemical Bulletin,2019,vol. 68,p. 1908 - 1918
Izv. Akad. Nauk, Ser. Khim.,2019,vol. 68,p. 1908 - 1918,11

3
3-benzylidene-6-bromo-3,4-dihydro-1H-quinolin-2-one [ No CAS ]
[ 654655-68-2 ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 451 - 460

4
[ 924658-20-8 ]
[ 654655-68-2 ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 451 - 460

5
[ 37442-45-8 ]
[ 654655-68-2 ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 451 - 460

6
[ 105479-98-9 ]
[ 654655-68-2 ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 451 - 460

7
[ 654655-68-2 ]
[ 654655-70-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium ethanolate; In ethanol; for 12h;Heating / reflux;	Preparation of intermediate compound 4 A mixture of <strong>[654655-68-2]intermediate compound 2</strong> (prepared according to A2) (0.045 mol) in NaOEt 21% in ethanol (50ml) and ethanol (150ml) was stirred and refluxed for 12 hours. The mixture was poured out on ice and extracted with [CH2CK.] The organic layer was separated, dried [(MGS04),] filtered and the solvent was evaporated. Yielding: 15.2g of intermediate compound 4 (98%).

Reference： [1]Patent: WO2004/11436,2004,A1 .Location in patent: Page 18

8
[ 316146-27-7 ]
[ 654655-68-2 ]

Yield	Reaction Conditions	Operation in experiment
67%		The reaction was carried out twice . POCl3 (1.225 mol) was added dropwise at 10°C to iV,iV-dimethylformamide (DMF) (0.525 mol) . Then intermediate compound 1 (prepared according Al) (0.175 mol) was added at room temperature . The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH2CI2 . The organic layer was dried (MgSO4), filtered, and the solvent was evaporated . The product was used without further purification. Yield : 77.62g of intermediate compound 2 (67percent).
67%	With trichlorophosphate; In DMF (N,N-dimethyl-formamide); at 80℃;	The reaction was carried out twice. POC13 (1.225 mol) was added dropwise at [10C] to DMF (0.525 mol). Then intermediate compound 1 (prepared according [A1)] (0.175 mol) was added at room temperature. The mixture was stirred overnight at [80C,] poured out on ice and extracted with CH2C12. The organic layer was dried [(MgS04),] filtered, and the solvent was evaporated. The product was used without further purification. Yielding : (77.62g ; Yield=67percent).
67%	With N,N-dimethyl-formamide; trichlorophosphate; at 10 - 80℃;	b) Preparation of intermediate compound 4b; The reaction was carried out twice. POCl3 (1.225 mol) was added dropwise at 10°C to iV,iV-dimethylformamide (0.525 mol). Then intermediate compound 4a (0.175 mol) was EPO <DP n="39"/>added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH2CI2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The product was used without further purification. Yield: 77.62 g (67 percent) of intermediate compound 4b.

67%	With N,N-dimethyl-formamide; trichlorophosphate; at 20 - 80℃;	Example A2; Preparation of intermediate 2. Phosphoric trichloride (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 1 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with DCM. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The product was used without iurther purification, yielding 77.62 g of intermediate 2 (67percent).
64%	With cetyltrimethylammonim bromide; N,N-dimethyl-formamide; trichlorophosphate; In acetonitrile; at 5 - 80℃; for 8h;Product distribution / selectivity;	Preparation of3-Benzyl-6-bromo-2-chloro-quinoline; Phosphorus oxychlopide (30.0 g, 196 9 mmol) was added dropwise to JV, JV-Dimethylformamide (14 34 g, 196.18 mmol) at 5 0C, the mixture was allowed to warm up to room temperature and stirred for 20 mm. The above reagent was added to a suspension of7V-(4-Bromo phenyl)-3-phenyl propionamide (3.0 g, 9.86 mmol) and cetyltrimethylammomum bromide (CTAB, 0.04 g, 0.10 mmol) m acetomtpile at 5 0C. The reaction mixture was heated at 80 0C for 8 h, cooled to room temperature, poured into 100 ml of 3percent hypo solution at 0 0C, extracted with dichloromethane, the organic layer was washed with water until the water extracts became neutral to pH paper followed by brme, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (100-200) eluted with hexane - ethyl acetate (97:3) to afford the title compound (2.0 g, 64percent yield) as a white crystalline solid, Mp 102°C-104°C. 1H NMR (400 MHz, CDCL3). delta 4.22 (s, 2 H), 7.20-7.24 (m, 2 <n="24"/>H), 7 26-7 31 (m, 1 H), 7 32-7 38 (m, 2 H), 7 65 (s, 1 H), 7 72 (dd, /= 12 0, 4 0 Hz, 1 H), 7 84-7 88 (m, 2H). [M+H]+ = 332, 335.

Reference： [1]Patent: WO2006/67048,2006,A1 .Location in patent: Page/Page column 27
[2]Patent: WO2004/11436,2004,A1 .Location in patent: Page 17
[3]Patent: WO2007/434,2007,A1 .Location in patent: Page/Page column 36-37
[4]Patent: WO2007/14940,2007,A2 .Location in patent: Page/Page column 41
[5]Patent: WO2009/91324,2009,A1 .Location in patent: Page/Page column 22-23

9
[ 68-12-2 ]
[ 316146-27-7 ]
[ 654655-68-2 ]

Yield	Reaction Conditions	Operation in experiment
67%	With trichlorophosphate; at 10 - 80℃;	Phosphoric trichloride (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 1 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with DCM. The organic layer was dried (MgS04), filtered, and the solvent was evaporated. The product was used without further purification, yielding 77.62 g of intermediate 2 (67percent).
67%	With trichlorophosphate; at 20 - 80℃;	Example A2; Preparation of intermediate 2; The reaction was carried out twice. POC13 (1.225 mol) was added dropwise at 10 °C to DMF (0.525 mol). Then intermediate 1 (0.175 mol) was added at room temperature . The mixture was stirred overnight at 80 °C, poured out on ice and extracted with CH2CI2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated, yielding 77.62 g (67percent) of intermediate 2. The product was used without further purification.
67%	With trichlorophosphate; at 10 - 80℃;	b) Preparation of intermediate 11; The reaction was carried out twice. POCl3 (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 10 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 8O0C, poured out on ice and extracted with CH2CI2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. Yield: 77.62 g of intermediate 11 (67percent).

67%		b. Preparation of intermediate 10; The reaction was carried out twice . POCl3 (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol) . Then intermediate 9 (0.175 mol) was added at room temperature . The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH2Cl2 . The organic layer was dried (MgSO4), filtered, and the solvent was evaporated . Yield: 77.62 g of intermediate 10 (67 percent).
67%	With trichlorophosphate; at 10 - 80℃;	b) Preparation of intermediate 5; The reaction was carried out twice. POCl3 (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 4 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The product was used without further purification. Yield: 77.62 g of intermediate 5 (67 percent).
67%		Intermediate 2 The reaction was carried out twice . POCI3 (1.225 mol) was added dropwise at 10 0C to DMF (0.525 mol) . Then intermediate 1 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80 0C, poured out on ice and extracted with CH2CI2 . The organic layer was dried (MgSO/t), filtered, and the solvent was evaporated, yielding 77.62 g (67percent) of intermediate 2. The product was used without further purification.
	With trichlorophosphate; In chloroform; at 10℃;Reflux;	Case 2 Obtaining intermediate compound IIIa; [Show Image] To the cooled down to 10°C mixture of the 84 grams of the dimethyl formamide and 200 grams of the intermediate compound Va in 600 ml of chloroform, 400 ml of the phosphorous oxychloride are added by drops; then the mixture is boiled during the night. The mixture is then cooled and poured out into 2 kgs of ice; the organic layer is flushed with water, dried above MgSO4, and filtered; the solvent is vacuum distilled. The residue is crystallized from the methanol. Yield: 163 grams of the intermediate compound IIIa.

Reference： [1]Patent: WO2005/70430,2005,A1 .Location in patent: Page/Page column 34
[2]Patent: WO2005/70924,2005,A1 .Location in patent: Page/Page column 27
[3]Patent: WO2007/435,2007,A1 .Location in patent: Page/Page column 44
[4]Patent: WO2007/436,2007,A1 .Location in patent: Page/Page column 33
[5]Patent: WO2007/14885,2007,A1 .Location in patent: Page/Page column 31
[6]Patent: WO2007/14934,2007,A2 .Location in patent: Page/Page column 33
[7]ChemMedChem,2017,vol. 12,p. 106 - 119
[8]Patent: EP2371819,2011,A1 .Location in patent: Page/Page column 7

10
[ 654655-68-2 ]
[ 141-52-6 ]
[ 654655-70-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	In ethanol; for 12h;Heating / reflux;	A mixture of intermediate 2 (0.045 mol) in a 21% EtONa in EtOH solution (50 ml) and EtOH (150 ml) was stirred and refluxed for 12 hours. The mixture was poured out on ice and extracted with DCM. The organic layer was separated, dried (MgS04), filtered and the solvent was evaporated, yielding 15.2 g of intermediate 4 (98%).
98%	In ethanol; for 12h;Heating / reflux;	b) Preparation of intermediate 4: A mixture of intermediate 2 (0.045 mol) in a 21% EtONa in EtOH solution (50 ml) and EtOH (150 ml) was stirred and refluxed for 12 hours. The mixture was poured out on EPO <DP n="44"/>ice and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 15.2 g of intermediate 4 (98%).

Reference： [1]Patent: WO2005/70430,2005,A1 .Location in patent: Page/Page column 35
[2]Patent: WO2007/14940,2007,A2 .Location in patent: Page/Page column 41-42

11
[ 654655-68-2 ]
[ 67-56-1 ]
[ 124-41-4 ]
[ 654655-69-3 ]

Yield	Reaction Conditions	Operation in experiment
89%	for 8h;Heating / reflux;	Preparation of 3 -Benzyl- 6-bromo-2-m ethoxy-q u m olin e; To a stirred solution of compound 3-Benzyl-6-bromo-2-chloro-qumolme (5 O g, 15 0 mmol) m dry methanol (50 ml) was added sodium methoxide (30% w/v m methanol, 15.0 ml, 84 0 mmol) and the contents were heated under reflux for 8 h The volatiles were removed under reduced pressure, poured into ice-water mixture, the solid separated out was filtered, washed with water and dried to furnish the compound (4 4 g, 89%) as an off-white solid, Mp 83-850C 1H NMR (400 MHz, CDCl3). delta 4.02 (s, 2 H), 4 07 (s, 3 H), 7 20-7 26 (m, 3 H), 7 29-7 34 (m, 2 H), 7 47 (s, 1 H), 7 60 (dd, J = 8 0, 4 0 Hz, 1 H), 7 60 (dd, J = 8 8, 2 2 Hz, 1 H), 7.73 (d, J= 2.0 Hz, 1 H) (M+H)+= 328, 330
33%	Heating / reflux;	c. Preparation of intermediate 11; A mixture of intermediate 10 (0.233 mol) in CH3ONa(30 %) in methanol (222.32 ml) and methanol (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with CH2Cl2 . The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated . The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/cyclohexane 20/80 and then 100/0; 20-45 mum). The pure fractions were collected and the solvent was evaporated . Yield: 25 g of intermediate 11 (33 %) (melting point: 84C).
33%	Heating / reflux;	c) Preparation of intermediate 6; A mixture of intermediate 5 (0.233 mol) in CH3ONa 30 % in CH3OH (222.32 ml) and CH3OH (776 ml) was stirred and refluxed overnight, then poured out on ice and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/cyclohexane 20/80 and then 100/0; 20-45 mum). The pure fractions were collected and the solvent was evaporated. Yield: 25 g of intermediate 6 (33 %).

Reference： [1]Patent: WO2009/91324,2009,A1 .Location in patent: Page/Page column 23
[2]Patent: WO2007/436,2007,A1 .Location in patent: Page/Page column 33
[3]Patent: WO2007/14885,2007,A1 .Location in patent: Page/Page column 31

12
[ 654655-68-2 ]
[ 918439-70-0 ]

Yield	Reaction Conditions	Operation in experiment
74%		) Preparation of intermediate compound 4c; A mixture of intermediate compound 4b (0.045 mol) and thiourea (0.05 mol) in ethanol (150 ml) was stirred and refluxed for 8 hours and then brought to room temperature. A solution of KOH (0.068 mol) in water (15 ml) was added. The mixture was stirred and refluxed for 1 hour and poured out on ice. The precipitate was filtered off, washed with H2O and dried. Yield: H g (74 %) of intermediate compound4c.
74%		c) Preparation of intermediate 12; A mixture of intermediate 11 (0.045 mol) and thiourea (0.05 mol) in ethanol (150 ml) was stirred and refluxed for 8 hours and then brought to room temperature. A solution of KOH (0.068 mol) in water (15 ml) was added. The mixture was stirred and refluxed for 1 hour and poured out on ice. The precipitate was filtered off, washed with H2O and dried. Yield: 11 g of intermediate 12 (74%).
74%		Example A6A; a. Preparation of intermediate 15; A mixture of intermediate 10 (prepared according to A4.b) (0.045 mol) and thiourea (0.05 mol) in ethanol (150 ml) was stirred and refluxed for 8 hours and then brought to EPO <DP n="37"/>room temperature. A solution of KOH (0.068 mol) in H2O (15 ml) was added. The mixture was stirred and refluxed for 1 hour and poured out on ice. The precipitate was filtered off, washed with H2O and dried. Yield: H g of intermediate 15 (74 %).

74%

Example A2; a. Preparation of intermediate 5; A mixture of <strong>[654655-68-2]6-bromo-2-chloro-3-(phenylmethyl)-quinoline</strong> (prepared according to the teachings in WO2005/070924 of which the content is incorporated herein by reference) (0.045 mol) and thiourea (0.05 mol) in ethanol (150 ml) was stirred and refluxed for 8 hours and then brought to room temperature. A solution of KOH (0.068 mol) in H2O <n="58"/>(15 ml) was added. The mixture was stirred and re fluxed for 1 hour and poured out on ice. The precipitate was filtered off, washed with H2O and dried. Yield: 11 g of intermediate 5 (74 %).

Reference： [1]Patent: WO2007/434,2007,A1 .Location in patent: Page/Page column 37
[2]Patent: WO2007/435,2007,A1 .Location in patent: Page/Page column 44
[3]Patent: WO2007/436,2007,A1 .Location in patent: Page/Page column 34-35
[4]Patent: WO2008/68266,2008,A1 .Location in patent: Page/Page column 55-56

13
[ 654655-68-2 ]
[ 108-95-2 ]
[ 924633-12-5 ]

Yield	Reaction Conditions	Operation in experiment
57%	With sodium hydride; In 1,4-dioxane; N,N-dimethyl-formamide; for 20h;Heating / reflux;	Example A11; a) Preparation of intermediate 28; Phenol (0.066 mol) was added portion wise to a mixture of NaH 60 % (0.069 mol) in 1,4-dioxane (200 ml) and DMF (80 ml) then intermediate 5 (prepared according to A2.b) (0.033 mol) was added and the suspension was heated under reflux for 20 hours. The mixture was cooled and poured into K2CO3 10% and extracted with CH2Cl2. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/CH2Cl2: 70/30). The pure fractions were collected and the solvent was evaporated. Yield: 7.3 g of intermediate 28 (57%) (melting point: H l0C).

Reference： [1]Patent: WO2007/14885,2007,A1 .Location in patent: Page/Page column 41

14
[ 654655-68-2 ]
[ 924633-09-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; water;Heating / reflux;	Example A10; a) Preparation of intermediate 24; A mixture of intermediate 5 (prepared according to A2.b) (0.009 mol) in HCl (6N) (50 ml) was stirred and refluxed overnight. The precipitate was filtered, washed with H2O, then with DIPE and dried. Yield: 2.8 g of intermediate 24.

Reference： [1]Patent: WO2007/14885,2007,A1 .Location in patent: Page/Page column 40

15
[ 288-32-4 ]
[ 654655-68-2 ]
[ 1173292-03-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	With pyridine; for 12h;Heating / reflux;	Preparation of 3-benzyl-6-bromo-2- (lH-imidazol-1-yl) quinoline; 3-Benzyl-6-bromo-2-chloro qumolm (0.2 g, 0.6 mmol) and imidazole (0.2 g, 3 0 mmol) were dissolved in anhydrous pyridine (5 mL) and the mixture was heated under reflux for 12 hrs. The reaction mixture was poured into ice-water, extracted with ethyl acetate (2 x 10 mL), the combined organic layer was washed with water (2 x 10 mL) followed by brine (1 x 10 mL), dried over anhydrous sodium sulfate, filtered and the solvents were evaporated to obtain a sticky mass, which on purification by column chromatography (silica gel 100-200 mesh, ehited with 3-7 % ethyl acetate in n-hyxane) gave pure 3-benzyl-6-bromo-2- (ltf-imidazol-1-yl) quinoline (0.186 g, 85%) as a sticky mass. 1H NMR (400 MHz, CDCl3). delta 4.13 (s, 2 <n="23"/>H), 7.01 (d, J = 6 8 Hz, 2 H), 7.20 (s, 1 H), 7.25-7.34 (m, 4 H), 7.80 (dd, J= 9.0, 2 1 Hz, 1 H), 7.89 (s, 2H), 7.91 -7.99 (m, 2 H). [M+H]+ = 366, 368.

Reference： [1]Patent: WO2009/91324,2009,A1 .Location in patent: Page/Page column 21-22

16
[ 654655-68-2 ]
[ 1481-27-2 ]
1-[2-(3-benzyl-6-bromo-quinolin-2-yloxy)-5-fluoro-phenyl]-ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51.5%	With potassium carbonate; In dimethyl sulfoxide; at 130℃; for 12h;	Preparation ofl-[2-(3-Benzyl-6-bromo-quinolin-2-yloxy)-5-fluoro-phenyl]-ethanone; A mixture of l-(2-Hydroxy-phenyl)-ethanone] (023 g, 1 51 mmol) and potassium carbonate (0 23 g, 1 70 mmol) m anhydrous dimethylsulfoxide (6 mL) was heated to 130 0C for 12 h under inert atmosphere The mixture was poured into ice-water mixture, extracted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (silica gel 100-200 mesh, elutmg with 8% ethyl acetate in n-hexane) gave pure l-[2-(3- Benzyl-6-bromo-qumolm-2-yloxy)-5-fluoro-phenyl]-ethanone (0.28 g, 51 5%) as a pale yellow solid, Mp 115-117 0C. 1H NMR (400 MHz, CDCl3): delta 2.23 (s, 3 H), 4.22 (s, 2 H), 6 98 (dd, J = 9.2, 4.4 Hz, 1 H), 7.18-7 23 (m, 1 H), 726-7.37 (m, 5 H), 7 48 (d, /= 8 8 Hz, 1 H), 7.52 (dd, J= 8 8, 3 2 Hz, 1 H), 7.59 (dd, J= 8.8, 2.0 Hz, I H), 7.75 (s, 1 H), 7.84 (J = 2 0 Hz, 1 H). [M+H]+ = 450, 452.

Reference： [1]Patent: WO2009/91324,2009,A1 .Location in patent: Page/Page column 21

17
[ 654655-68-2 ]
[ 111-90-0 ]
[ 918519-43-4 ]

Yield	Reaction Conditions	Operation in experiment
97%		Example Al 4; a. Preparation of intermediate 38; NaH (60 % in oil; 0.0072 mol) was added portionwise at 0 C to a solution of 2-(2- ethoxyethoxy)-ethanol (0.0072 mol) in THF (12.5 ml) under N2 flow. The mixture was stirred at 0C for 1 hour. A solution of intermediate 10 (0.006 mol) in THF (12.5 ml) was added dropwise. The mixture was stirred and refluxed for 18 hours and was then cooled to room temperature. EtOAc and H2O were added. The organic layer was washed with H2O and then with saturated NaCl. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. Yield: 2.5 g intermediate 38 (97 %). EPO <DP n="45"/>

Reference： [1]Patent: WO2007/436,2007,A1 .Location in patent: Page/Page column 42

18
[ 654655-68-2 ]
[ 13196-35-5 ]
C₂₅H₂₄BrClN₂OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		c) Preparation of intermediate 28: 1.6M Butyllithium (0.029 mol) was added at -10C to a solution of iV-propyl-1- propanamine (0.029 mol) in THF (50 ml) under N2 flow. The mixture was stirred for 20 minutes, then cooled to -70C. A solution of intermediate 2 (0.024 mol) in THF (30 ml) was added. The mixture was stirred at -70C for 1 hour. A solution of 3- (dimethylamino)-l-(2-thienyl)-l-propanone (0.029 mol) in THF (20 ml) was added. The mixture was stirred at -70C for 1 hour, then brought to -20C and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/MeOH/NH4OH 96/4/0.1; 20-45mum). The pure fractions were collected and the solvent was evaporated. The residue (4.65 g) was crystallized from DIPE. The precipitate was filtered off and dried, yielding 2.7 g of intermediate 28 (M.P.: 168C). The mother layer was evaporated, yielding another 1.7g of intermediate 28.

Reference： [1]Patent: WO2007/14940,2007,A2 .Location in patent: Page/Page column 49

19
[ 654655-68-2 ]
[ 3506-36-3 ]
[ 861872-59-5 ]
[ 861872-58-4 ]

Yield	Reaction Conditions	Operation in experiment
8%		a) Preparation of intermediate 22 and intermediate 23: 1.6M Butyllithium (0.12 mol) was added dropwise at -10C under N2 flow to a solution of 2,2,6,6-tetramethylpiperidine (0.12 mol) in THF (200 ml). The mixture was stirred at -10C for 20 minutes and then cooled to -70C. A mixture of intermediate 2 (0.1 mol) in THF (100 ml) was added. The mixture was stirred at -70C for 45 minutes. A solution of 3 -(dimethylamino)-l -phenyl- 1-propanone (0.1 mol) in THF (100 ml) was added. The mixture was stirred at -70C for 1 hour, brought to -50C and hydro lysed. H2O (100 ml) was added at -50C. The mixture was stirred at room temperature for 30 minutes and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was taken up in EtOAc. The precipitate was filtered off, washed with EtOAc and diethyl ether and dried in vacuo, yielding 4 g of intermediate 23 (8%). The mother layer was evaporated. The residue (26g) was purified by column chromatography over silica gel (eluent: DCM/MeOH/NH4OH 97/3/0.1; 15-40mum). The desired fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding Ig of intermediate 22.

Reference： [1]Patent: WO2007/14940,2007,A2 .Location in patent: Page/Page column 47-48

20
[ 106-40-1 ]
[ 654655-68-2 ]

Reference： [1]Patent: EP2371819,2011,A1
[2]Chinese Chemical Letters,2015,vol. 26,p. 790 - 792
[3]ChemMedChem,2017,vol. 12,p. 106 - 119
[4]Russian Chemical Bulletin,2019,vol. 68,p. 1908 - 1918
Izv. Akad. Nauk, Ser. Khim.,2019,vol. 68,p. 1908 - 1918,11

21
[ 501-52-0 ]
[ 654655-68-2 ]

Reference： [1]Patent: EP2371819,2011,A1
[2]Russian Chemical Bulletin,2019,vol. 68,p. 1908 - 1918
Izv. Akad. Nauk, Ser. Khim.,2019,vol. 68,p. 1908 - 1918,11

22
[ 654655-68-2 ]
[ 10320-49-7 ]
[ 1228594-68-0 ]
[ 1228594-69-1 ]

Yield	Reaction Conditions	Operation in experiment
		B. Obtaining claimed compounds Case 4 4-dimethylamino-2-(1-naphthyl)-1-phenyl-1-quinoline-3-ilbutane-2-ol (IIa) ; [Show Image] To the cooled down to -50C solution of the 190 grams of the intermediate naphthylketone IVa in 2 liters of the dry tetrahydrofuran 50 grams of the diethylamide of lithium are added in an argon flow. The mixture is agitated during 1 hour, cooled down to -70C; then 150 grams of the intermediate compound IIIa in 500 ml of the tetrahydrofuran are added inside; the mixture is then cured during 2 hours at -70C; then 50 ml of the methanol are added inside. The mixture is warmed up to the room temperature, then 150 ml of the 5 M solution of the hydrogen chloride in the isopropyl alcohol are added. The sediment is filtered and recrystallized from the isopropyl alcohol. Yield: 67 grams. The compound IIa is obtained in the form of mixture of the optical isomers with the diastereoisomerous ratio (dr) close to 1:1. The diastereoselectivity of the process may be changed by using the appropriate ligands, solvents, and metalizing agents. Further on, the pairs (RR+SS) and (RS+SR) can be separated into enantiomerously clean products using the traditional methods, such as crystallization of the relevant diastereoisomerous salts from an appropriate solvent, or the chromatography. We illustrate the possibilities to separate the claimed compounds into individual stereoisomers by the case of the data of the X-ray crystallographic analysis of the two stereoisomers (1S,2R) and (1R,2S) of the compound IIa, obtained by separating the mixture of the isomers by one of the known methods (see Fig. 1).

Reference： [1]Patent: EP2371819,2011,A1 .Location in patent: Page/Page column 7-8

23
[ 75-05-8 ]
[ 316146-27-7 ]
[ 654655-68-2 ]

Yield	Reaction Conditions	Operation in experiment
71%	With trichlorophosphate; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere;	POCl3 (129 g, 0.840 mol) was added dropwise into DMF (32.6 ml, 0.420 mol) at 0°C. After 1h of vigorous agitation under room temperature, compound 1 (32 g, 0.105 mol) and CH3CN (50mL) was added into the mixture, followed by being stirred overnight at 80°C. After solvent was partially removed, the residue was poured out into ice water (300mL) with rapid stirring and crude compound 2 precipitates gradually. Then the solid was filtrated and washed with portions of cold CH3OH. Finally, compound 2 (25g, 71percent) can be recrystallized from CH2Cl2 and CH3OH.

Reference： [1]Chinese Chemical Letters,2015,vol. 26,p. 790 - 792

24
[ 654655-68-2 ]
(6-bromo-2-memoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol [ No CAS ]

Reference： [1]Chinese Chemical Letters,2015,vol. 26,p. 790 - 792

25
[ 654655-68-2 ]
rac-(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenylbutan-2-ol [ No CAS ]

Reference： [1]Chinese Chemical Letters,2015,vol. 26,p. 790 - 792

26
[ 654655-68-2 ]
[ 843663-66-1 ]
[ 654655-80-8 ]

Reference： [1]Chinese Chemical Letters,2015,vol. 26,p. 790 - 792

27
[ 645-45-4 ]
[ 654655-68-2 ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 106 - 119

28
[ 654655-68-2 ]
[ 924632-90-6 ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 106 - 119

29
[ 654655-68-2 ]
N-((6-bromo-2-methoxyquinolin-3-yl) (phenyl)methyl)-2-(2-(dimethylamino)ethoxy)aniline [ No CAS ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 106 - 119

30
[ 654655-68-2 ]
1-((6-bromo-2-methoxyquinolin-3-yl) (phenyl)methyl)-4-methyl-1, 2, 3,4-tetrahydroquinoxaline [ No CAS ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 106 - 119

31
[ 654655-68-2 ]
1-(1-((6-bromo-2-methoxyquinolin-3-yl)(phenyl)methyl)indolin-3-yl)-N,N-dimethylmethanamine [ No CAS ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 106 - 119

32
[ 654655-68-2 ]
1-(1-((6-bromo-2-methoxyquinolin-3-yl) (phenyl)methyl)-1H-indol-3-yl)-N,N-dimethylmethanamine [ No CAS ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 106 - 119

33
[ 654655-68-2 ]
C₃₀H₃₃BrN₂O₂ [ No CAS ]