[ CAS No. 121660-37-5 ] {[proInfo.proName]}

Name: 121660-37-5|2-Cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde|95%
Brand: Ambeed
SKU: A137854
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2D 3D

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Quality Control of [ 121660-37-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 121660-37-5 ]

SDS Specification

Alternatived Products of [ 121660-37-5 ]

Product Details of [ 121660-37-5 ]

CAS No. :	121660-37-5	MDL No. :	MFCD09032925
Formula :	C₁₉H₁₄FNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	291.32	Pubchem ID :	-
Synonyms :

Calculated chemistry of [ 121660-37-5 ]

Physicochemical Properties

Num. heavy atoms :	22
Num. arom. heavy atoms :	16
Fraction Csp3 :	0.16
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	84.99
TPSA :	29.96 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.27 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.8
Log Po/w (XLOGP3) :	3.96
Log Po/w (WLOGP) :	5.09
Log Po/w (MLOGP) :	3.62
Log Po/w (SILICOS-IT) :	5.55
Consensus Log Po/w :	4.2

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.48
Solubility :	0.00962 mg/ml ; 0.000033 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.29
Solubility :	0.015 mg/ml ; 0.0000513 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-7.04
Solubility :	0.0000267 mg/ml ; 0.0000000916 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.31

Safety of [ 121660-37-5 ]

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 [ 121660-37-5 ]

* 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 [ 121660-37-5 ]
Downstream synthetic route of [ 121660-37-5 ]

[ 121660-37-5 ] Synthesis Path-Upstream 1~9

1
[ 121660-37-5 ]
[ 154057-56-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	With Dichloromethylsilane; iron(III) chloride; phosphorus tribromide In acetonitrile at 75 - 85℃; Inert atmosphere	In a 100 ml three-necked flask, 29.1 g of compound I, 17.2 g of methyl dichlorosilane, 8 g of ferric chloride, 40.2 g of phosphorus tribromide, 60 ml of acetonitrile and 75 to 85 ° C under nitrogen atmosphere were stirred and refluxed to TLC The reaction was complete, the reaction was quenched by adding dilute hydrochloric acid to the reaction system, the layers were separated, the organic layer was separated, washed with sodium bicarbonate and saturated brine, and the washing liquid was separated from the organic layer. To the organic layer was added anhydrous magnesium sulfate, Dried and filtered, and the filtrate was concentrated under reduced pressure to give 30.5 g of the compound. The compound II was confirmed to be Compound II, as compared with the standard compound II melting point data. The melting point of Compound II was 138-140° C and the yield of Compound II was 86percent.

Reference： [1] Patent: CN103508946, 2016, B, . Location in patent: Paragraph 0043-0048
[2] Patent: WO2012/63254, 2012, A1,
[3] Organic Letters, 2018, vol. 20, # 11, p. 3286 - 3290

2
[ 121660-37-5 ]
[ 146578-99-6 ]

Reference： [1] Organic Letters, 2018, vol. 20, # 11, p. 3286 - 3290

3
[ 113832-57-8 ]
[ 121660-37-5 ]
[ 148901-68-2 ]

Yield	Reaction Conditions	Operation in experiment
78.3%	With sodium hydride In tetrahydrofuran at 63℃; for 11 h;	Example 2; The same operation as in Example 1 was performed except that ethylidenecyclohexylamine (1.7 g, 13.8 mmol) was used instead of ethylidene tert-butylamine (1.4 g, 14.1 mmol). A part of the obtained reaction mixture was poured into the 10 mass percent aqueous acetic acid solution, and an analysis by internal standard methods was performed using high performance liquid chromatography. As a result, (E) -3- (4'-(4"-fluorophenyl)-2'-cyclopropylquinolin-3'-yl)propenaldehyde (1.7 g, 5.4 mmol, yield 78.3percent) was found to have been produced.

Reference： [1] Patent: EP1614682, 2006, A1, . Location in patent: Page/Page column 6

4
[ 7020-80-6 ]
[ 121660-37-5 ]
[ 148901-68-2 ]

Yield	Reaction Conditions	Operation in experiment
68%	With sodium hydride In tetrahydrofuran at 63℃; for 11 h;	Example 1; 4-(4'-Fluorophenyl)-2-cyclopropylquinoline-3-carbaldehyde (2.0 g, 6.9mmol), ethylidene tert-butylamine (1.4 g, 14.1 mmol) and tetrahydrofuran (10 ml) were charged in a 50 ml three-neck flask equipped with a thermometer, a magnetic stirrer and a nitrogen balloon and the mixture was heated to 63°C. Sodium hydride (60 mass percent, 0.44 g, 11.0 mmol) was added over 3 hrs. After completion of the addition, the mixture was further stirred for 8 hrs. A part of the obtained reaction mixture was poured into the 10 mass percent aqueous acetic acid solution, and an analysis by internal standard methods was performed using high performance liquid chromatography. As a result, (E)-3-(4'-(4"-fluorophenyl)-2'-cyclopropylquinolin-3'-yl)propenaldehyde (1.5 g, 4.7 mmol, yield 68.0percent) was found to have been produced. melting point: 124-132°C ¹H-NMR (600 MHz, CDCl₃, TMS, ppm) .δ: 1.08-1.13(2H,m), 1.41-1.45(2H,m), 2.32-2.38(1H,m), 6.45(1H,dd,J=8,16Hz), 7.22-7.25 (4H,m), 7.35-7.39 (2H,m), 7.56(1H,d,J=16Hz), 7.67(1H,ddd,J=3,6,8Hz), 7.98(1H,d,J=8Hz), 9.51(1H,d,J=8Hz)

Reference： [1] Patent: EP1614682, 2006, A1, . Location in patent: Page/Page column 6

5
[ 6898-74-4 ]
[ 121660-37-5 ]
[ 148901-68-2 ]

Yield	Reaction Conditions	Operation in experiment
60.3%	With sodium hydride In tetrahydrofuran at 63℃; for 11 h;	Example 3; The same operation as in Example 1 was performed except that ethylidene n-butylamine (1.4 g, 14.1 mmol) was used instead of ethylidene tert-butylamine (1.4 g, 14.1 mmol). A part of the obtained reaction mixture was poured into the 10 mass percent aqueous acetic acid solution, and an analysis by internal standard methods was performed using high performance liquid chromatography. As a result, (E)-3-(4'-(4"-fluorophenyl)-2'-cyclopropylquinolin-3'-yl)propenaldehyde (1.3 g, 4.2 mmol, yield 60.3percent) was found to have been produced.

Reference： [1] Patent: EP1614682, 2006, A1, . Location in patent: Page/Page column 6-7

6
[ 121660-37-5 ]
[ 148901-68-2 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 10, p. 2727 - 2743
[2] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 20, p. 2977 - 2982
[3] Patent: WO2012/140490, 2012, A2,

7
[ 2537-48-6 ]
[ 121660-37-5 ]
[ 256431-72-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 20, p. 2977 - 2982

8
[ 121660-37-5 ]
[ 148901-69-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 10, p. 2727 - 2743
[2] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 20, p. 2977 - 2982

9
[ 121660-37-5 ]
[ 586966-54-3 ]

Reference： [1] Patent: WO2012/63254, 2012, A1,

[ 121660-37-5 ] Synthesis Path-Downstream 1~88

1
[ 124931-12-0 ]
[ 121660-37-5 ]
[ 141750-56-3 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1995,vol. 68,p. 350 - 363

2
[ 78191-00-1 ]
[ 121660-37-5 ]
[ 155849-96-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	REFERENTIAL EXAMPLE 11 STR40 Butyllithium (1.64M hexane solution, 7.54 ml, 12.4 mmol) was added to a THF (40 ml) solution of diisopropylamine (1.25 g, 12.4 mmol) at -78 C., and the mixture was stirred for 15 minutes. Thereto was added a THF (20 ml) solution of N-methoxy-N-methylacetamide (1.27 g, 12.3 mmol) at -78 C., and the resulting mixture was stirred at -78 C. for 15 minutes. To this mixture was added a THF (40 ml) solution of <strong>[121660-37-5]2-cyclopropyl-4-(4-fluorophenyl)-3-formylquinoline</strong> (3.00 g, 10.3 mmol). The reaction mixture was stirred at -78 C. to room temperature over a period of 3 hours before quenching with water and extraction with diethyl ether. The ethereal organic layer was washed with saturated sodium chloride aq solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (hexane:ethyl acetate=2:1) to give N-methoxy-N-methyl-3 -{2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl}-3-hydroxypropanamide (3.70 g, 91% yield). Rf=0.30 (hexane:ethyl acetate=2:1) IR (CHCl3): 3450, 3000, 1640, 1515, 1490, 1420, 1230, 1070, 780 cm-1. 1 H NMR (CDCl3): delta=1.02-1.16 (m, 3H), 1.74 1.79 (m, 1H), 2.66 (d, J=17.2 Hz, 1H), 3.17 (s, 3H), 3.16-3.24 (m, 1H), 3.52 (dd, J=17.2, 11.3 Hz, 1H), 3.62 (s, 3H), 4.14 (d, J=2.4 Hz, 1H), 5.35 (dt, J=11.3, 2.4 Hz, 1H), 7.12-7.35 (m, 6H), 7.58 (dd, J=6.8, 1.4 Hz, 1H), 7.92 (dq, J=8.4, 0.6 Hz, 1H). MS: m/z (rel. intensity) 394 (M+, 11), 363, (M+ -OMe, 46), 334 (58), 292 (100), 274 (38), 263 (37).

Reference： [1]Patent: US5276154,1994,A
[2]Bulletin of the Chemical Society of Japan,1995,vol. 68,p. 350 - 363

3
[(4R)-4-[(tert-butyl)dimethylsilyl]oxy}-2,6-dioxo-6-[(1S)-1-phenylethyl]amino}hexyl]phosphonic acid dimethyl ester [ No CAS ]
[ 121660-37-5 ]
(3R,6E)-3-[(tert-butyl)dimethylsilyl]oxy}-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-5-oxo-[(1S)-1-phenylethyl]hept-6-enamide [ No CAS ]

Reference： [1]Helvetica Chimica Acta,2007,vol. 90,p. 1069 - 1081

4
[ 3800-06-4 ]
[ 121660-37-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 2727 - 2743
[2]Journal of the American Chemical Society,2015,vol. 137,p. 14043 - 14046

5
[ 32249-35-7 ]
[ 121660-37-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 2727 - 2743

6
[ 121660-37-5 ]
[ 148901-68-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 2727 - 2743
[2]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982
[3]Patent: WO2012/140490,2012,A2

7
[ 121660-37-5 ]
[ 148901-69-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 2727 - 2743
[2]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982

8
[ 121660-37-5 ]
(±)-E-3,5-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-heptenoic acid ethyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 2727 - 2743
[2]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 2727 - 2743
[3]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982

9
[ 121660-37-5 ]
ethyl (E)-3,5-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]hept-6-enoate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 2727 - 2743

10
[ 121660-37-5 ]
sodium (E)-3,5-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]hept-6-enoate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 2727 - 2743
[2]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 2727 - 2743

11
[ 121659-86-7 ]
[ 121660-37-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 2727 - 2743
[2]Journal of the American Chemical Society,2015,vol. 137,p. 14043 - 14046

12
[ 121660-37-5 ]
[ 254452-86-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982

13
[ 121660-37-5 ]
[ 147526-32-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982
[2]Patent: WO2014/154845,2014,A1
[3]Patent: WO2014/154845,2014,A1

14
[ 121660-37-5 ]
[ 254452-94-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982

15
[ 121660-37-5 ]
[ 254452-90-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982

16
[ 121660-37-5 ]
(E)-(3R,5R)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982
[2]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982

17
[ 121660-37-5 ]
(E)-(3S,5S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982
[2]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982

18
[ 121660-37-5 ]
[ 380848-32-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982
[2]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982

19
[ 121660-37-5 ]
[ 380848-30-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982
[2]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982

20
[ 121660-37-5 ]
[ 254452-95-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982
[2]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982

21
[ 121660-37-5 ]
[ 254452-91-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982
[2]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982
[3]Patent: WO2012/140490,2012,A2

22
[ 121660-37-5 ]
[ 254452-93-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982

23
[ 121660-37-5 ]
[ 254452-89-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 2977 - 2982

24
[ 121660-37-5 ]
3-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)acrylonitrile [ No CAS ]

Reference： [1]Patent: US6335449,2002,B1 .Location in patent: Page column 4

25
[ 477950-34-8 ]
[ 121660-37-5 ]

Yield	Reaction Conditions	Operation in experiment
86.7%		A methanol (50 g) solution containing 5.0 g (11.1 mmol) of ethyl (6E)3,5-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-hept-6-enoate was cooled to 0C, ozone gas (1 gO3/hr) was introduced over a period of one hour at from 0C to 5C, and then, excess ozone gas was removed by nitrogen gas. To this solution, an aqueous (14.1 g) solution of thiourea (0.85 g) was dropwise added over a period of 10 minutes at from 0C to 5C, followed by stirring at the same temperature for one hour to have crystals precipitated. Further, 26 g of water was dropwise added to let crystals precipitate, followed by stirring at 5C for one hour, whereupon crystals were collected by filtration, washed with 6 g of 50% water-containing methanol and dried to obtain 2.81 g (yield: 86. 7%) of crystals of 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde having a purity of 99.2%.1H-NMR (CDCl3) ?: 1.08-1.13 (2H, m), 1.36-1.41 (2H, m), 3.18-3.26 (1H, m), 7.23-7.47 (6H, m), 7.72-7.77 (1H, m), 7.98 (1H, d, J=8.4 Hz), 10.05 (1H, S). ???(Melting point: 144.0-144.3C).
86.2%		A methanol (50 g) solution containing 5.0 g (11.1 mmol) of ethyl (6E)3,5-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-hept-6-enoate was cooled to 0C, ozone gas (1 gO3/hr) was introduced over a period of one hour at from 0C to 5C, and then, excess ozone gas was removed by nitrogen gas. To this solution, an aqueous (19.3 g) solution of sodium thiosulfate pentahydrate (4.0 g) was dropwise added. The reaction solution was heated to 12C and stirred for one hour to have crystals precipitated. Further, water (20 g) was dropwise added to let crystals precipitate, followed by cooling to 5C and stirring for one hour, whereupon crystals were collected by filtration, washed with 6 g of 50% water-containing methanol and dried. To a THF (100 ml) solution of the crystals, a 1N HCl aqueous solution (100 ml) was dropwise added and stirred at an internal temperature of 12C for one hour and at an internal temperature of 50C for two hours and then extracted with toluene (100 g) to obtain an organic layer. The aqueous layer was again extracted with toluene (50 ml), and the joined organic layer was washed with water (100 g), and then dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. To the residue, methanol (50 g) was added, and then, water (40 g) was dropwise added to let crystals precipitate, followed by stirring at 5C for one hour, whereupon the crystals were collected by filtration, washed with 6 g of 50% water-containing methanol and dried to obtain 2.79 g (yield: 86.2%) of crystals of 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde having a purity of 98.6%. The 1H-NMR spectrum of this product agreed with that of the standard product (melting point: 145.6-145.9C).
82.4%		A methanol (50 g) solution containing 5.0 g (11.1 mmol) of ethyl (6E)3,5-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-hept-6-enoate was cooled to 0C, ozone gas (1 gO3/hr) was introduced over a period of one hour at from 0C to 5C, and then, excess ozone gas was removed by nitrogen gas. This solution was dropwise added over a period of 30 minutes to a methanol (10 g) suspension of a Lindlar catalyst first grade, manufactured by Wako Junyaku K.K.) (0.051 g) in a hydrogen atmosphere, followed by stirring for 30 minutes at the same temperature. Then, it was heated to 20C and, after adding a Lindlar catalyst (0.1 g), stirred for two hours. The reaction solution was filtered through cerite, and washed with methanol (50 g). Then, 80 g of water was dropwise added to have crystals precipitated. After cooling to 5C, stirring was carried out for one hour, whereupon the crystals were collected by filtration, washed with 6 g of 50% water-containing methanol and dried to obtain 2.67 g (yield: 82.4%) of crystals of 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde having a purity of 97.6%. The 1H-NMR spectrum of this product agreed with that of the standard product (melting point: 147-148C).

62.7 - 87.3%

A methanol (50 g) solution containing 5.0 g (11.1 mmol) of ethyl (6E)3,5-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-hept-6-enoate was cooled to 0C, ozone gas (1 gO3/hr) was introduced over a period of one hour at from 0C to 5C, and then, excess ozone gas was removed by nitrogen gas. This solution was dropwise added over a period of 10 minutes to a methanol (10 g) suspension of 10% Pd-C (0.026 g) in a hydrogen atmosphere, followed by stirring for one hour at the same temperature. The reaction solution was filtered through cerite, and the filtered product was washed with methanol (20 g). To the filtrate, 56 g of water was added to have crystals precipitated. After cooling to 5C, stirring was carried out for one hour, whereupon the crystals were collected by filtration, washed with 6 g of 50% water-containing methanol and dried to obtain 2.83 g (yield: 87.3%) of crystals of 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde having a purity of 98.6%. 1H-NMR (CDCl3) ?: 1.08-1.13 (2H, m), 1.36-1.41 (2H, m), 3.18-3.26 (1H, m), 7.23-7.47 (6H, m), 7.72-7.77 (1H, m), 7.98 (1H, d, J=8.4 Hz), 10.06 (1H, S). ???(Melting point: 147-148C). A methanol (50 g) solution containing 5.0 g (11.1 mmol) of ethyl (6E)3,5-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-hept-6-enoate was cooled to 0C, ozone gas (1 gO3/hr) was introduced over a period of one hour at from 0C to 5C, and then, excess ozone gas was removed by nitrogen gas. This solution was dropwise added over a period of 40 minutes to a methanol (10 g) suspension of 10% Pd-C (0.15 g) in a hydrogen atmosphere. The reaction solution was heated to 20C, stirred for 1.5 hours, then filtered through cerite, and washed with methanol (200 g). This solution was distilled under reduced pressure until the residue became 105 g. Then, 80 g of water was dropwise added to have crystals precipitated. After cooling to 5C, stirring was carried out for one hour, whereupon the crystals were collected by filtration, washed with 6 g of 50% water-containing methanol and dried to obtain 2.03 g (yield: 62.7%) of crystals of 2-cyclopropyl-4-(4-.fluorophenyl)-quinoline-3-carbaldehyde having a purity of 96.9%. The 1H-NMR spectrum of this product agreed with that of the standard product (melting point: 143-144C).

Reference： [1]Patent: EP1391455,2004,A1 .Location in patent: Page 4-5
[2]Patent: EP1391455,2004,A1 .Location in patent: Page 5
[3]Patent: EP1391455,2004,A1 .Location in patent: Page 5-6
[4]Patent: EP1391455,2004,A1 .Location in patent: Page 5

26
2-[2'-cyclopropyl-4'-(4''-fluorophenyl)quinolin-3'-yl]-1,3-dioxane [ No CAS ]
[ 121660-37-5 ]

Yield	Reaction Conditions	Operation in experiment
93%	With hydrogenchloride; In water; toluene; at 40℃; for 10h;	(b) To the organic layer obtained in the above-mentioned (a) was added 2 mass % of hydrochloric acid (20 g), and the mixture was stirred at 40C for 10 hr. To the obtained reaction mixture was added 5 mass % of aqueous sodium carbonate solution (41.2 g, 51.5 mmol) to partition the mixture between the organic layer and the aqueous layer. The obtained organic layer was analyzed by gas chromatography. As a result, 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-carbaldehyde was contained (1.96 g, yield 93.%).

Reference： [1]Patent: EP1568693,2005,A1 .Location in patent: Page/Page column 10

27
[ 113832-57-8 ]
[ 121660-37-5 ]
[ 148901-68-2 ]

Yield	Reaction Conditions	Operation in experiment
78.3%	With sodium hydride; In tetrahydrofuran; at 63℃; for 11h;Product distribution / selectivity;	Example 2; The same operation as in Example 1 was performed except that ethylidenecyclohexylamine (1.7 g, 13.8 mmol) was used instead of ethylidene tert-butylamine (1.4 g, 14.1 mmol). A part of the obtained reaction mixture was poured into the 10 mass % aqueous acetic acid solution, and an analysis by internal standard methods was performed using high performance liquid chromatography. As a result, (E) -3- (4'-(4"-fluorophenyl)-2'-cyclopropylquinolin-3'-yl)propenaldehyde (1.7 g, 5.4 mmol, yield 78.3%) was found to have been produced.

Reference： [1]Patent: EP1614682,2006,A1 .Location in patent: Page/Page column 6

28
[ 7020-80-6 ]
[ 121660-37-5 ]
[ 148901-68-2 ]

Yield	Reaction Conditions	Operation in experiment
68.0%	With sodium hydride; In tetrahydrofuran; at 63℃; for 11h;Product distribution / selectivity;	Example 1; 4-(4'-Fluorophenyl)-2-cyclopropylquinoline-3-carbaldehyde (2.0 g, 6.9mmol), ethylidene tert-butylamine (1.4 g, 14.1 mmol) and tetrahydrofuran (10 ml) were charged in a 50 ml three-neck flask equipped with a thermometer, a magnetic stirrer and a nitrogen balloon and the mixture was heated to 63C. Sodium hydride (60 mass %, 0.44 g, 11.0 mmol) was added over 3 hrs. After completion of the addition, the mixture was further stirred for 8 hrs. A part of the obtained reaction mixture was poured into the 10 mass % aqueous acetic acid solution, and an analysis by internal standard methods was performed using high performance liquid chromatography. As a result, (E)-3-(4'-(4"-fluorophenyl)-2'-cyclopropylquinolin-3'-yl)propenaldehyde (1.5 g, 4.7 mmol, yield 68.0%) was found to have been produced. melting point: 124-132C 1H-NMR (600 MHz, CDCl3, TMS, ppm) .delta: 1.08-1.13(2H,m), 1.41-1.45(2H,m), 2.32-2.38(1H,m), 6.45(1H,dd,J=8,16Hz), 7.22-7.25 (4H,m), 7.35-7.39 (2H,m), 7.56(1H,d,J=16Hz), 7.67(1H,ddd,J=3,6,8Hz), 7.98(1H,d,J=8Hz), 9.51(1H,d,J=8Hz)

Reference： [1]Patent: EP1614682,2006,A1 .Location in patent: Page/Page column 6

29
[ 6898-74-4 ]
[ 121660-37-5 ]
[ 148901-68-2 ]

Yield	Reaction Conditions	Operation in experiment
60.3%	With sodium hydride; In tetrahydrofuran; at 63℃; for 11h;Product distribution / selectivity;	Example 3; The same operation as in Example 1 was performed except that ethylidene n-butylamine (1.4 g, 14.1 mmol) was used instead of ethylidene tert-butylamine (1.4 g, 14.1 mmol). A part of the obtained reaction mixture was poured into the 10 mass % aqueous acetic acid solution, and an analysis by internal standard methods was performed using high performance liquid chromatography. As a result, (E)-3-(4'-(4"-fluorophenyl)-2'-cyclopropylquinolin-3'-yl)propenaldehyde (1.3 g, 4.2 mmol, yield 60.3%) was found to have been produced.

Reference： [1]Patent: EP1614682,2006,A1 .Location in patent: Page/Page column 6-7

30
[ 109-87-5 ]
[ 121660-37-5 ]
3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrite [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With hydrogenchloride; sodium methylate; In toluene; acetonitrile;	EXAMPLE 6 Preparation of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrite In a 50 mL-volume glass flask equipped with a stirrer and a thermometer were placed under argon atmosphere 1.75 g (6.01 mmol) of <strong>[121660-37-5]2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde</strong>, 2.5 mL (47.5 mmol) of acetonitrile, 13.5 mL of methylal (dielectric constant at 20 C.: 2.7), and 0.56 g (10.3 mmol) of sodium methoxide. The content was reacted at 41 C. for 9 hours. The resulting mixture was chilled in an ice bath. To the chilled mixture were slowly added under stirring 30 mL of toluene and 7.0 mL (7.00 mmol) of hydrochloric acid (1 mol/L), successively. The separated organic portion was taken out. After washing with two portions of saturated aqueous sodium chloride solution (10 mL), the organic portion was dried over anhydrous magnesium sulfate. The organic portion was then filtered and analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 1.79 g (yield: 96%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrite was produced.

Reference： [1]Patent: US2003/13885,2003,A1

31
[ 124-63-0 ]
[ 121660-37-5 ]
3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrite [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With triethylamine; In acetonitrile;	EXAMPLE 3 Preparation of 3-[2-cyclopropyl-4-(4-fluorophenyl)- 3-quinolyl]prop-2-enenitrite In a 50 mL-volume glass flask equipped with a stirrer and a thermometer were placed under argon atmosphere 200 mg (0.69 mmol) of <strong>[121660-37-5]2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde</strong>, 2 mL of acetonitrile and 41.5 mg (1.04 mmol) of sodium hydride (purity: 60%). The content was stirred at room temperature for 2 hours. The resulting mixture was chilled to 0 C. To the chilled mixture were added 0.08 mL (1.03 mmol) of methanesulfonyl chloride and 0.15 mL (1.08 mmol) of triethylamine, and the mixture was stirred for 3 hours at the same temperature. Subsequently, to the mixture was added 5 mL of chilled water, and the mixture was extracted with three portions of ethyl acetate (15 mL) which were previously chilled in an ice bath. The mixture was dried over anhydrous magnesium sulfate. The organic portion was then filtered, and the filtrate was analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 180 mg (yield: 83%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrite was produced.

Reference： [1]Patent: US2003/13885,2003,A1

32
[ 121660-37-5 ]
[ 109-94-4 ]
3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrite [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydrogenchloride; In acetonitrile;	EXAMPLE 1 Preparation of 3-[2-cyclopropyl-4-(4-fluorophenyl)- 3-quinolyl]prop-2-enenitrite In a 100 mL-volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed under argon atmosphere 1.94 g (6.66 mmol) of <strong>[121660-37-5]2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde</strong>, 10 mL of acetonitrile and 0.422 g (10.6 mmol) of sodium hydride (purity: 60%). The content was stirred at room temperature for 2 hours. The resulting mixture was chilled to -10 C. To the chilled mixture was added 20 mL (248 mmol) of ethyl formate, and the mixture was stirred for 4 hours at the same temperature. Subsequently, to the mixture was slowly added 11 mL of hydrochloric acid (1 mol/L) which was previously chilled in an ice bath. In the mixture, an organic portion separated from an aqueous portion. The organic portion was taken out, washed with two 10 mL portions of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The organic portion was filtered and analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 1.71 g (yield: 85%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrite was produced. The organic portion was concentrated under reduced pressure to leave a yellow solid residue. The solid residue was recrystallized from toluene/hexane (1/8, vol. ratio) to obtain 1.79 g of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl] prop-2-enenitrite as a yellow crystalline product (purity: 97%). The obtained 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrite had the following characteristics: m.p.: 174.5-175.0 C. EI-MS(m/e): 314(M), CI-MS(m/e): 315(M+1) IR (Kbr, cm-1): 2223, 1513, 1490, 1224, 1161, 846, 768.

Reference： [1]Patent: US2003/13885,2003,A1

33
[ 121660-37-5 ]
3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrite [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With hydrogenchloride; sodium methylate; In toluene; acetonitrile;	EXAMPLE 5 Preparation of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrite In a 200 mL-volume glass flask equipped with a stirrer and a thermometer were placed under argon atmosphere 9.2 g (31.6 mmol) of <strong>[121660-37-5]2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde</strong>, 7.5 mL (143 mmol) of acetonitrile, 45 mL of toluene (dielectric constant at 25 C.: 2.38), and 1.99 g (36.8 mmol) of sodium methoxide. The content was reacted at 50 C. for 8 hours. The resulting mixture was chilled in an ice bath. To the chilled mixture were slowly added under stirring 40 mL of toluene and 34.0 mL (34.0 mmol) of hydrochloric acid (1 mol/L), successively. The separated organic portion was taken out. After washing with 30 mL of saturated aqueous sodium chloride solution, the organic portion was dried over anhydrous magnesium sulfate. The organic portion was then filtered and analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 9.52 g (yield: 96%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrite was produced. The organic portion was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane (15/85, vol. ratio) to obtain 9.29 g (yield 88%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrite as a yellow crystalline product (purity: 94%, measured by high performance liquid chromatography).

Reference： [1]Patent: US2003/13885,2003,A1

34
[ 110-91-8 ]
[ 121659-86-7 ]
[ 121660-37-5 ]

Yield	Reaction Conditions	Operation in experiment
77%	With sulfuric acid; In tetrahydrofuran; toluene;	EXAMPLE 1 Lithium aluminum hydride (0.569 g, 15 mmol) was placed in a 50 ml volume three-necked flask equipped with a thermometer, a magnetic stirrer and a dropping funnel, and tetrahydrofuran (10 ml) was added as a solvent, followed by replacement of the system with nitrogen. To this solution was added dropwise morpholine (4.18 g, 48 mmol) gradually at room temperature, and after completion of the addition, the mixture was stirred at room temperature for 1 hr. This solution was cooled to 0 C. and a solution obtained by dissolving methyl 4-(4'-fluorophenyl)-2-cyclopropylquinoline-3-carboxylate (3.21 g, 10 mmol) in tetrahydrofuran (9.63 g) was added dropwise to this solution while maintaining the inner temperature to not higher than 0 C. After the completion of the addition, the mixture was stirred for 2 more hours at 10 to 20 C. This reaction mixture was added dropwise to a 15% aqueous sulfuric acid solution (50 ml) while maintaining the inner temperature to not higher than 10 C., and then, toluene (50 ml) was added to the mixture. The organic layer was separated from the mixture and the aqueous layer was extracted with toluene (10 ml). The extract was combined with the organic layer obtained earlier and the mixture was washed with water (30 ml), dried over anhydrous sodium sulfate, then low boiling point components, such as the solvent and the like, were removed under reduced pressure. The obtained residue was purified by column chromatography (eluent: hexane-ethyl acetate mixture) to give 4-(4'-fluorophenyl)-2-cyclopropylquinoline-3-carbaldehyde (2.27 g, yield 77%) as a pale-yellow solid having the following properties. 1H-NMR (300 MHz, CDCl3, TMS, ppm) delta: 1.08-1.14 (2H, m), 1.37-1.40 (2H, m), 3.20-3.26 (1H, m), 7.24-7.48 (6H, m), 7.76 (1H, ddd, J=1.8, 6.5, 8.4 Hz), 7.97-8.00 (1H, m), 10.06 (1H, s)
76%	With sodium bis(2-methoxyethoxy)aluminum dihydride; sulfuric acid; In toluene;	EXAMPLE 4 70% Toluene solution (57.8 g, 200 mmol) of sodium bis(2-methoxyethoxy)aluminum hydride was placed in a 200 ml three-necked flask equipped with a thermometer, a magnetic stirrer and a dropping funnel, and toluene (100 ml) was added as a solvent, which was followed by replacement of the system with nitrogen. To this solution was added dropwise morpholine (13.9 g, 160 mmol) gradually at room temperature, and after completion of the dropwise addition, the mixture was stirred at room temperature for 1 hr. Methyl 4-(4'-fluorophenyl)-2-cyclopropylquinoline-3-carboxylate (32.1 g, 100 mmol) and toluene (300 ml) were placed in a different 1000 ml three-necked flask, and the system was replaced by nitrogen and cooled to -5 C. To this solution was added dropwise the entire amount of a toluene solution prepared earlier by mixing sodium bis(2-methoxyethoxy)aluminum hydride and morpholine, while maintaining the. inner temperature to not higher than 0 C., and after completion of the addition, the mixture was heated to room temperature and stirred for 3 hr. This reaction mixture was added dropwise to a 15% aqueous sulfuric acid solution (200 ml) while maintaining the inner temperature to not higher than 10 C. The organic layer was separated from the mixture and the aqueous layer was extracted with toluene (30 ml). The extract was combined with the organic layer obtained earlier. The mixture was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated. The obtained residue was recrystallized from diisopropyl ether to give 4-(4'-fluorophenyl)-2-cyclopropylquinoline-3-carbaldehyde (22.4 g, yield 76%).

Reference： [1]Patent: US2003/125355,2003,A1
[2]Patent: US2003/125355,2003,A1

35
[ 19841-57-7 ]
[ 121660-37-5 ]
[ 166803-31-2 ]

Yield	Reaction Conditions	Operation in experiment
82%		In a mixture solution of 1.37 g of an oily 60% sodium hydride and 10 ml of tetrahydrofuran, a mixture solution of 2.36 g of 3,5-dioxohexanoic acid ethyl ester and 10 ml of tetrahydrofuran was dropped in 5 minutes while keeping an inner temperature of 20 C. After stirring the mixture for 1 hour at that temperature, a mixture of 2.01 g of 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-carbaldehyde and 20 ml of tetrahydrofuran was dropped for 20 minutes. After stirring the mixture for 4 hours, a reaction solution was added in 3.09 g of acetic acid and 20 ml of water to terminate the reaction. An organic phase was extracted with 40 ml of ethyl acetate and was then washed with 20 ml of saturated brine, followed by being dried with 2 g of anhydrous sodium sulfate. As a result of analysis on the resulting organic phase, 2.52 g of (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dioxohept-6-enic acid ethyl ester (DOXE) (yield 82%) was obtained. [0131] After distilling the solvent off, 1.7 ml of 4 mol/L hydrochloric acid/ethyl acetate solution was added in the resulting residue at a room temperature. After the generation of a crystal, the temperature was lowered to 5 C. Then, the crystal was obtained through a filtration and was then dried, resulting in 2.49 g of hydrochloride (yield 75%) of (E)-7-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-3,5-dioxohept-6-enic acid ethyl ester.

Reference： [1]Patent: US2004/30139,2004,A1 .Location in patent: Page 12

36
[ 19841-57-7 ]
[ 121660-37-5 ]
7-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-7-hydroxy-3,5-dioxoheptanoic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%		In a mixture solution of 2.40 g of an oily 60% sodium hydride and 200 ml of tetrahydrofuran, a mixture solution of 10.3 g of 3,5-dioxohexanoic acid ethyl ester and 40 ml of tetrahydrofuran was dropped in 20 minutes while keeping an inner temperature at 2 C. or less. After allowing a reaction for 50 minutes at -10 C., 75 ml of a hexane solution of 1.6 M n-butyl lithium was dropped in 40 minutes with the inner temperature kept at -20 to -15 C., while allowing a reaction for 40 minutes at an inner temperature of 2 C. or less. In this case, furthermore, while keeping an inner temperature of -15 C. or less, a mixture of 11.7 g of 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-carbaldehyde and 80 ml of tetrahydrofuran was dropped in 40 minutes and was then reacted at 10 C. or less for 1 hour. Furthermore, while keeping an inner temperature of 5 C. or less, 14.4 ml of acetic acid and 40 ml of toluene were added in a reaction system, followed by washing with 100 ml of water and 100 ml of saturated brine in that order. After the solvent is distilled off, the residue thus obtained was added with 100 ml of hexane and 5 ml of ethyl acetate so as to be crystallized, followed by filtrating and drying it to obtain 16.6 g (yield: 89%) of 7-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-7-hydroxy-3,5-dioxoheptanoic acid ethyl ester was obtained. [0119] NMR of the compound is as follows. [0120] 1H-NMR (CDCl3): 1.11 (2H, m), 1.13 (1H, m), 1.27 (3H, t, J=10), 1.76 (1H, m), 2.40 (1H, m), 2.48 (2H, ABq, J=66,14), 2.69 (2H, ABq, J=52,16), 2.78 (1H, m), 3.30 (1H, m), 4.18 (2H, m), 5.25 (1H, d, J=3), 5.58 (1H, dd, J=12,4), 7.16-7.26 (5H, m), 7.33 (1H, dd, J=7,7), 7.61 (1H, dd, J=7,7), 7.93 (1H, d, J=7)

Reference： [1]Patent: US2004/30139,2004,A1 .Location in patent: Page 10

37
[ 1343494-44-9 ]
[ 121660-37-5 ]
(R,E)-methyl 3-(tert-butyldimethylsilyloxy)-7-(2-cyclopropyl-4-(-4-fluorophenyl)-quinolin-3-yl)-5-oxohept-6-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With piperidine; In N,N-dimethyl-formamide; at 20 - 40℃; for 10.25h;Inert atmosphere;Product distribution / selectivity;	Example 5 Synthesis of a compound of formula (II): (R,E)-methyl 3-(tert-butyldimethylsilyloxy)-7-(2-cyclopropyl-4-(-4-fluorophenyl)-quinolin-3-yl)-5-oxohept-6-enoate The compound (IV) obtained as in Example 4 (885 mg, 2.78 mmol) is solubilized in DMF (4 mL) under N2 atmosphere and added with <strong>[121660-37-5]2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde</strong> (271 mg, 0.93 mmol) and piperidine (46 muL, 0.46 mmol). The mixture is left under magnetic stirring at room temperature for 15 minutes, then heated at 40 C. for 10 hours. The solution is diluted with AcOEt and washed with 1 N HCl and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The reaction crude is purified by flash silica gel chromatography (eluent: EtPet/AcOEt 9:1). 280 mg of a pale yellow oil are obtained in 55% yield. 1H NMR (400 MHz, CDCl3) delta: 7.93 (d, J=8, 1H); 7.63-7.57 (m, 2H); 7.36-7.29 (m, 2H); 7.19-7.16 (m, 4H); 6.31 (d, J=16, 1H); 4.57-4.54 (m, 1H); 3.63 (s, 3H); 2.74-2.62 (m, 2H); 2.50-2.38 (m, 2H); 2.34-2.30 (m, 1H); 1.38-1.36 (m, 2H); 1.05-1.03 (m, 2H); 0.79 (s, 9H); 0.03 (s, 3H); -0.02 (s, 3H). 13C NMR (100 MHz, CDCl3) delta: 196.80; 170.89; 163.40; 160.93; 159.51; 146.96; 145.57; 139.70; 133.72; 131.86; 131.27; 131.21; 129.35; 128.57; 126.63; 125.80; 125.46; 125.25; 115.39; 115.18; 65.47; 51.03; 47.61; 41.95; 25.23; 17.43; 15.89; 10.23; 10.16; -5.20; -5.42. MS (ES+): m/z 570 [M+Na]+.

Reference： [1]Patent: US2011/269962,2011,A1 .Location in patent: Page/Page column 6

38
[ 1343494-44-9 ]
[ 121660-37-5 ]
[ 182075-76-9 ]

Yield	Reaction Conditions	Operation in experiment
	With piperidine; In N,N-dimethyl-formamide; at 40℃; for 10h;Inert atmosphere;Product distribution / selectivity;	The compound (IV) obtained as in Example 4 (885 mg, 2.78 mmol) is solubilized in DMF (4 mL) under N2 atmosphere and added with <strong>[121660-37-5]2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde</strong> (271 mg, 0.93 mmol) and piperidine (46 muL, 0.46 mmol). The mixture is left under magnetic stirring at room temperature for 15 minutes, then heated at 40C for 10 hours. The solution is diluted with AcOEt and washed with 1 N HCl and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The reaction crude is purified by flash silica gel chromatography (eluent: EtPet/AcOEt 9:1). 280 mg of a pale yellow oil are obtained in 55% yield. 1H NMR (400 MHz, CDCl3) delta: 7.93 (d, J = 8, 1H); 7.63-7.57 (m, 2H); 7.36-7.29 (m, 2H); 7.19-7.16 (m, 4H); 6.31 (d, J = 16, 1H); 4.57-4.54 (m, 1H); 3.63 (s, 3H); 2.74-2.62 (m, 2H); 2.50-2.38 (m, 2H); 2.34-2.30 (m, 1H); 1.38-1.36 (m, 2H); 1.05-1.03 (m, 2H); 0.79 (s, 9H); 0.03 (s, 3H); -0.02 (s, 3H). 13C NMR (100 MHz, CDCl3) delta: 196.80; 170.89; 163.40; 160.93; 159.51; 146.96; 145.57; 139.70; 133.72; 131.86; 131.27; 131.21; 129.35; 128.57; 126.63; 125.80; 125.46; 125.25; 115.39; 115.18; 65.47; 51.03; 47.61; 41.95; 25.23; 17.43; 15.89; 10.23; 10.16; -5.20; -5.42. MS(ES+): m/z 570 [M+Na]+.

Reference： [1]Patent: EP2383260,2011,A2 .Location in patent: Page/Page column 8

39
[ 1353637-12-3 ]
[ 121660-37-5 ]
[ 1353637-17-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With lithium hexamethyldisilazane; In tetrahydrofuran; at -20 - -10℃; for 1h;	Example 21. [317] E-(6-{2-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]vinyl}-[(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl])-N-methoxy-N-methyl-acetamide [318] 2-[(4R,6S)-2,2-dimethyl-6-(1-phenyl-1H-tetrazole-5-sulfonylmethyl)-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide (16.6 g), 2-cyclopropyl-3-formyl-4-(4-fluorophenyl)quinoline (10.0 g), and tetrahydrofuran (400.0 mL) were added to a reactor and then the reaction mixture was cooled to -70C. A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 36.0 mL) was slowly added to the reaction mixture, the temperature of which was adjusted to -20?-10C. The reaction mixture was stirred at the same temperature for 1 hour and then 8% sodium bicarbonate solution (80.0 mL) was added thereto under stirring. The separated organic layer was washed with water (60.0 mL) and then concentrated under reduced pressure to obtain E-(6-{2-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]vinyl}-[(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl])-N-methoxy-N-methyl-acetamide as a solid (15.6 g, yield 90%).[319] 1H-NMR, 400 MHz, CDCl3, ppm : 1.05(d, 2H), 1.35(m, 2H), 1.43~1.51(m, 2H), 2.41(m, 1H), 2.43~2.50(m, 2H), 3.19(s, 3H), 3.71(s, 3H), 4.13(t, 1H), 4.31(s, 1H), 4.42(s, 1H), 5.57(dd, 1H), 6.62(d, 1H), 7.14~7.28(m, 4H), 7.30(m, 1H), 7.62(m, 1H), 7.94(d, 1H)

Reference： [1]Patent: WO2012/2741,2012,A2 .Location in patent: Page/Page column 34

40
[ 6704-19-4 ]
[ 121660-37-5 ]

Reference： [1]Patent: WO2012/13325,2012,A1

41
[ 1356998-79-2 ]
[ 121660-37-5 ]

Reference： [1]Patent: WO2012/13325,2012,A1

42
[ 121660-37-5 ]
[ 121660-11-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With borohydride anion exchange resin (BER); In ethanol; at 20℃; for 3h;	To a solution of 19 (0.5 g, 1.7 mmol) in EtOH (10 mL) was addedborohydride anion exchange resin (BER). The reaction mixture wasstirred at room temperature for 3 h. The mixture was filteredthrough Celite and concentrated in vacuo to afford 20 (0.5 g, quant.)as a white solid. The material was carried on without further purification.Mp 129e130 C, lit.5e mp 133.3e134.7 C; 1H NMR(400 MHz, CDCl3) d 7.96 (d, J8.4 Hz, 2H), 7.60e7.64 (m, 1H),7.29e7.38 (m, 4H), 7.21 (t, J8.8 Hz, 2H), 4.75 (s, 2H), 2.56e2.62 (m,1H), 1.63 (br s, 1H), 1.36e1.40 (m, 2H), 1.08e1.12 (m, 2H); MS (ESI):m/z 294 (MH).
	With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 0 - 5℃; for 2h;	2-Cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde (30 gm) was added methanol (30 ml) and tetrahydrofuran (270 ml) at room temperature. The reaction mixture was then cooled to 0C and then added sodium borohydride (5.8 gm) for 30 minutes at 0 to 5C. The reaction mass was stirred for 1 hour 30 minutes and then added water (150 ml) and ethyl acetate (150 ml). The reaction mass was stirred for 10 minutes, and then the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate and then concentrated to obtain a residual solid. To the residual solid was added n-hexane (150 ml) and stirred for 30 minutes. The separated solid was filtered and dried to obtain 29 gm of (2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)methanol.

Reference： [1]Tetrahedron,2015,vol. 71,p. 4730 - 4737
[2]Patent: WO2012/63254,2012,A1 .Location in patent: Page/Page column 9
[3]Organic Letters,2018,vol. 20,p. 3286 - 3290

43
[ 121660-37-5 ]
[ 147526-32-7 ]

Reference： [1]Patent: WO2012/63254,2012,A1
[2]Patent: WO2012/140490,2012,A2
[3]Patent: WO2012/140490,2012,A2
[4]Patent: WO2014/154845,2014,A1
[5]Patent: WO2014/154845,2014,A1
[6]Patent: WO2014/154857,2014,A1
[7]Patent: WO2014/154857,2014,A1
[8]Patent: WO2014/154856,2014,A1
[9]Patent: WO2014/154856,2014,A1
[10]Patent: CN103508946,2016,B
[11]Organic Letters,2018,vol. 20,p. 3286 - 3290

44
[ 121660-37-5 ]
<2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide [ No CAS ]

Reference： [1]Patent: WO2012/63254,2012,A1

45
[ 121660-37-5 ]
[ 586966-54-3 ]

Reference： [1]Patent: WO2012/63254,2012,A1

46
[ 121660-37-5 ]
tert-butyl (3R,5S,6Z)-7-{2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl}-3,5-isopropylidenedioxy-6-heptenoate [ No CAS ]

Reference： [1]Patent: WO2012/63254,2012,A1

47
[ 121660-37-5 ]
[ 147511-70-4 ]

Reference： [1]Patent: WO2012/63254,2012,A1

48
[ 21204-67-1 ]
[ 121660-37-5 ]
[ 1403338-19-1 ]

Yield	Reaction Conditions	Operation in experiment
97%	In isopropyl alcohol; at 25 - 82℃;	EXAMPLE 1PREPARATION OF METHYL (2£ 3-[2-CYCLOPROPYL-4-(4- FLUOROPHENYL)QUINOLIN-3YLJACRYLATEMixture of 2-Cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxaldehyde (50 g, 0.171 mole) and methyl(triphenylphosphoranylidene)acetate (68.86 g, 0.205 mole) was suspended in isopropyl alcohol (250 ml) at 25-30C. The contents were heated to 78- 82C during which a clear solution was obtained. The completion of the reaction was confirmed by TLC. After completion of the reaction, the temperature was subsequently lowered to 25-30C during which product was precipitated out. The product was cooled to 0-5C, filtered, washed with precooled isopropyl alcohol and dried at 40-45C under reduced pressure (-20 mm Hg) till water content is < 0.3%. Yield: 58.0 g (97%).1H NMR (CDCb, 300 MHz): delta 1.06-1.09 (m, 2H), 1.38-1.40 (m, 2H), 2.37-2.39 (m, 1H), 3.73 (s, 3H), 6.04 (d, J = 16.2 Hz, 1H), 7.19-7.25 (m, 4H), 7.33-7.36 (m,2H), 7.63-7.66 (m, lH), 7.78 (d, J = 16.2 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H).

Reference： [1]Patent: WO2012/140490,2012,A2 .Location in patent: Page/Page column 18

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[ 167073-19-0 ]