[ CAS No. 1093880-37-5 ] {[proInfo.proName]}

Name: 1093880-37-5|6-Chloro-2-fluoronicotinaldehyde|97%
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Quality Control of [ 1093880-37-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1093880-37-5 ]

Product Details of [ 1093880-37-5 ]

CAS No. :	1093880-37-5	MDL No. :	MFCD16556251
Formula :	C₆H₃ClFNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JOIFMKYYVLAEGT-UHFFFAOYSA-N
M.W :	159.55	Pubchem ID :	51040786
Synonyms :

Calculated chemistry of [ 1093880-37-5 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	34.59
TPSA :	29.96 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.39
Log Po/w (XLOGP3) :	1.71
Log Po/w (WLOGP) :	2.11
Log Po/w (MLOGP) :	0.83
Log Po/w (SILICOS-IT) :	2.57
Consensus Log Po/w :	1.72

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.28
Solubility :	0.829 mg/ml ; 0.00519 mol/l
Class :	Soluble
Log S (Ali) :	-1.95
Solubility :	1.77 mg/ml ; 0.0111 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.86
Solubility :	0.222 mg/ml ; 0.00139 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.66

Safety of [ 1093880-37-5 ]

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 [ 1093880-37-5 ]

* 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 [ 1093880-37-5 ]
Downstream synthetic route of [ 1093880-37-5 ]

[ 1093880-37-5 ] Synthesis Path-Upstream 1~2

1
[ 1093880-37-5 ]
[ 63725-51-9 ]

Yield	Reaction Conditions	Operation in experiment
92%	With hydrazine hydrate In tetrahydrofuran at 60℃; for 5 h;	To the solution of 6-chloro-2-fluoropyridine-3-carboxaldehyde (4gm, 25.lmmol) in THF (30mL), was added hydrazine hydrate (2.5 15gm, 56.3mmol) and the reaction mixture was heated60°C for 5h. The reaction mixture was concentrated and quenched with ice water. The solid was filtered and dried under vacuum to obtain the title compound (3.5gm, 92percent).‘HNMR (DMSO-d6, 300MHz): ö 13.8 (s, 1H), 8.32-8.29 (d, 1H), 8.20 (s, 1H), 7.27-7.24 (d,1H). LCMS: 89.96percent, mlz = 153.9 (M+1).

Reference： [1] Patent: WO2017/9798, 2017, A1, . Location in patent: Page/Page column 66

2
[ 20885-12-5 ]
[ 68-12-2 ]
[ 1093880-37-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexanes at -78℃; for 1 h; Inert atmosphere Stage #2: at -78℃; for 1 h; Inert atmosphere	Example 3 - Synthesis of Phantasmidine (Figure 3) 6-Chloro-2-fluoropyridine-3-carboxaldehyde (8b). A solution of diisopropylamine (5.80 mL, 41.5 mmol) in anhydrous THF (100 mL) was treated with n- BuLi (2.1 M in hexanes, 18.0 mL, 37.8 mmol) at -78 °C. The cold bath was removed and the resulting solution was stirred at 0 °C for 30 min. The light yellow solution was re- cooled to -78 °C and 2-chloro-6-fluoropyridine (15, 3.80 g, 29.0 mmol) in anhydrous THF (20 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 1 h. Dimethylformamide (4.49 mL, 58.0 mmol) was added dropwise and the mixture was stirred an additional 1 h and saturated HCl in ether was added at -78 °C slowly to the mixture until pH 1 was reached. The reaction was warmed to 25 °C and H₂0 (50 mL) was added. The layers were separated. The aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with H₂0 (50 mL) and brine (50 mL), dried (MgS0₄), and concentrated to give crystalline crude 8b. The crude needles were recrystallized from hexanes to give 4.14 g (90percent) of 8b: R_f = 0.27 (10: 1 hexanes/EtOAc); mp 49-50 °C; 1H NMR 10.27 (s, 1), 8.27 (dd, 1, J = 8.8, 8.0), 7.41 (d, J = 8.0); ¹³C NMR 185.0, 162.6 (d, J = 254), 154.8 (d, J = 15), 141.3, 123.0 (d, J = 5.3), 116.9 (d, J1697, 1595, 1562. The 1H NMR spectrum is identical to that previously reported.

Reference： [1] Organic Letters, 2011, vol. 13, # 3, p. 526 - 529
[2] Patent: WO2012/78608, 2012, A1, . Location in patent: Page/Page column 30-31
[3] Heterocycles, 2014, vol. 88, # 1, p. 779 - 787
[4] Patent: WO2015/75023, 2015, A1, . Location in patent: Page/Page column 112-113
[5] Patent: WO2016/177690, 2016, A1, . Location in patent: Page/Page column 75-76

[ 1093880-37-5 ] Synthesis Path-Downstream 1~49

1
[ 1093880-37-5 ]
(2aS,4aR,9aR)-7-chloro-1,2,2a,3,4,4a-hexahydrobenzofuro[2,3-c]cyclobuta[b]pyrrole [ No CAS ]
(2aR,4aS,9aS)-7-chloro-1,2,2a,3,4,4a-hexahydrobenzofuro[2,3-c]cyclobuta[b]pyrrole [ No CAS ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529

2
[ 1093880-37-5 ]
[ 1227509-94-5 ]

Yield	Reaction Conditions	Operation in experiment
91%		6-Chloro-2-fluoro-3-pyridinemethanol (9b). A solution of 8b (2.00 g, 12.6 mmol) in MeOH (20 mL) was treated with NaBH4 (479 mg, 12.6 mmol) in portions over 5 min at - -10 C. The reaction was stirred at -10 C for 30 min. 10% aqueous hydrochloric acid was added dropwise to the reaction until pH 1 was reached and MeOH was removed under vacuum. The residue was extracted with CH2CI2 (50 mL x 3). The combined CH2CI2 layers were washed with H20 (50 mL) and brine (50 mL), dried (Na2S04), and concentrated to give 1.99 g of 9b as a white solid. Recrystallization from hexanes/EtOAc gave 1.84 g(91%) of pure 9b: Rf = 0.24 (3:1 hexanes/EtOAc); mp 60-61 C; 1H NMR 7.91 (dd, 1, J = 8.8, 8.0), 7.26 (d, 1, J = 8.0), 4.75 (d, 2, J = 4.8), 2.80 (t, 1, J = 4.8, OH); 13C NMR 159.1 (d, J = 244), 147.1 (d, J = 14), 141.6 (d, J = 6), 121.8 (d, J = 5.3), 121.4 (d, J = 27), 57.7; IR 3230; HRMS (EI) calcd for C6H5NC1F0 (M+) 161.0044, found 161.0052.

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1 .Location in patent: Page/Page column 31

3
[ 1093880-37-5 ]
[ 1227577-88-9 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1

4
[ 1093880-37-5 ]
[ 1227598-89-1 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1

5
[ 1093880-37-5 ]
[ 1261593-73-0 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1

6
[ 1093880-37-5 ]
[ 1261593-74-1 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529

7
[ 1093880-37-5 ]
(2aS,4aS,9aR)-rac-7-chloro-1,2,2a,3,4,4a-hexahydrobenzofuro[2,3-c]cyclobuta[b]pyrrol-4-one [ No CAS ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1

8
[ 1093880-37-5 ]
(2aS,4aR,9aR)-rac-7-chloro-1,2,2a,3,4,4a-hexahydrobenzofuro[2,3-c]cyclobuta[b]pyrrole [ No CAS ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1

9
[ 1093880-37-5 ]
phantasmidine trifluoroacetate [ No CAS ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1

10
[ 1093880-37-5 ]
1-[(2aS,4aR,9aR)-rac-7-chloro-2,2a,4,4a-tetrahydrobenzofuro[2,3-c]cyclobuta[b]pyrrol-3(1H)-yl]-ethanone [ No CAS ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1

11
[ 20885-12-5 ]
[ 68-12-2 ]
[ 1093880-37-5 ]

Yield	Reaction Conditions	Operation in experiment
90%		Example 3 - Synthesis of Phantasmidine (Figure 3) 6-Chloro-2-fluoropyridine-3-carboxaldehyde (8b). A solution of diisopropylamine (5.80 mL, 41.5 mmol) in anhydrous THF (100 mL) was treated with n- BuLi (2.1 M in hexanes, 18.0 mL, 37.8 mmol) at -78 C. The cold bath was removed and the resulting solution was stirred at 0 C for 30 min. The light yellow solution was re- cooled to -78 C and <strong>[20885-12-5]2-chloro-6-fluoropyridine</strong> (15, 3.80 g, 29.0 mmol) in anhydrous THF (20 mL) was added dropwise. The reaction mixture was stirred at -78 C for 1 h. Dimethylformamide (4.49 mL, 58.0 mmol) was added dropwise and the mixture was stirred an additional 1 h and saturated HCl in ether was added at -78 C slowly to the mixture until pH 1 was reached. The reaction was warmed to 25 C and H20 (50 mL) was added. The layers were separated. The aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with H20 (50 mL) and brine (50 mL), dried (MgS04), and concentrated to give crystalline crude 8b. The crude needles were recrystallized from hexanes to give 4.14 g (90%) of 8b: Rf = 0.27 (10: 1 hexanes/EtOAc); mp 49-50 C; 1H NMR 10.27 (s, 1), 8.27 (dd, 1, J = 8.8, 8.0), 7.41 (d, J = 8.0); 13C NMR 185.0, 162.6 (d, J = 254), 154.8 (d, J = 15), 141.3, 123.0 (d, J = 5.3), 116.9 (d, J1697, 1595, 1562. The 1H NMR spectrum is identical to that previously reported.
		To a solution of diisopropylamine (5.26 mL) in THF (70 mL) was added at -78C nBuLi 1.6M in hexanes (21.6 mL). The mixture was stirred at 0C for 45 min. 2-Chloro-6-fluoropyridine (3.5g) in THF (36 mL) was added dropwise at -78C over 1 h under nitrogen to the previous mixture and the reaction mixture was stirred at -78C for 1.5h. DMF (4.12 mL) was added dropwise over 1 h and the reaction mixture was stirred an additional 1 .5h. HCI 2M in diethylether (45 mL) was added slowly at -78C, water (30 mL) was added and the layers were separated. The aq. phase was extracted with EA and the combined org. layers were washed with sat. aq. NaCI, dried over Na2S04, filtrated off and evaporated in vacuo. The crude (4.4g of an orange solid) was used without purification in the next step. GC-MS (A): tR = 1 .55 min; [M+H]+: 159.80.
		To a solution of diisopropylamine (5.26ml) in THF (70ml) was added at -78C nBuLi 1.6M in hexanes (21.6ml). The mixture was stirred at 0C for 45min. <strong>[20885-12-5]2-chloro-6-fluoropyridine</strong> (3.5g) in THF (36ml) was added dropwise at -78C over 1 h under nitrogen to the previous mixture and the reaction mixture was stirred at -78C for 1.5h. DMF (4.12ml) was added dropwise over 1 h and the reaction mixture was stirred an additional 1.5h. HCI 2M in diethylether (45ml) was added slowly at -78C, water (30ml) was added and the layers were separated. The aq. phase was extracted with EA and the combined org. layers were washed with sat. aq. NaCI, dried over Na2S04, filtrated off and evaporated in vacuo. The crude (4.4g of an orange solid) was used without purification in the next step. GC-MS (A): tR = 1.55min; [M+H]+: 159.80.

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1 .Location in patent: Page/Page column 30-31
[3]Heterocycles,2014,vol. 88,p. 779 - 787
[4]Patent: WO2015/75023,2015,A1 .Location in patent: Page/Page column 112-113
[5]Patent: WO2016/177690,2016,A1 .Location in patent: Page/Page column 75-76

12
[ 1093880-37-5 ]
(2aS,4aR,9aR)-7-chloro-1,2,2a,3,4,4a-hexahydrobenzofuro[2,3-c]cyclobuta[b]pyrrole [ No CAS ]

Reference： [1]Patent: WO2012/78608,2012,A1

13
[ 1093880-37-5 ]
[ 1261593-74-1 ]
[ 1227598-64-2 ]

Reference： [1]Patent: WO2012/78608,2012,A1

14
[ 1093880-37-5 ]
(2aR,4aS,9aS)-7-chloro-1,2,2a,3,4,4a-hexahydrobenzofuro[2,3-c]cyclobuta[b]pyrrole [ No CAS ]

Reference： [1]Patent: WO2012/78608,2012,A1

15
[ 1093880-37-5 ]
[ 1380601-17-1 ]

Reference： [1]Patent: WO2012/78608,2012,A1

16
[ 1093880-37-5 ]
[ 1380584-11-1 ]

Reference： [1]Patent: WO2012/78608,2012,A1

17
[ 1093880-37-5 ]
[ 21860-07-1 ]
methyl 3-(3-(6-chloro-2-fluoropyridin-3-yl)-3-hydroxypropanoyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71.2%		Example 112A methyl 3 -(3 -(6-chloro-2-fluoropyridin-3 -yl)-3 -hydroxypropanoyl)benzoate A solution of methyl 3-acetylbenzoate (1 g, 5.61 mmol) in tetrahydrofuran (25 mL) was cooled to - 78 C, treated dropwise with 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (7.30 ml, 7.30 mmol), stirred at - 78 C for 15 minutes, treated dropwise with a solution of 6- chloro-2-fluoronicotinaldehyde (0.895 g, 5.61 mmol) in tetrahydrofuran (10 mL), stirred at -78 C for 15 minutes, treated with saturated NH4C1 solution (30 mL) and the mixture was allowed to warm to near room temperature. The mixture was extracted with ethyl acetate (30 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine, dried (MgS04), filtered, and concentrated. The residue was chromatographed on silica gel and eluted with a gradient of 20 % - 100 % ethyl acetate in heptanes to provide the title compound (1.35 g, 4.00 mmol, 71.2 % yield). 1H NMR (400 MHz, CDCl3) 5 ppm 8.56 (t, J = 1.8 Hz, 1H), 8.28 (dt, J= 7.7, 1.5 Hz, 1H), 8.15 (dt, J = 7.9, 1.6 Hz, 1H), 8.10 - 8.05 (m, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.30 (dd, J= 7.8, 1.0 Hz, 1H), 5.53 (dt, J= 9.4, 2.9 Hz, 1H), 3.96 (s, 3H), 3.89 (d, J= 3.9 Hz, 1H), 3.55 (dd, J= 18.0, 2.4 Hz, 1H), 3.29 (dd, J= 18.0, 9.3 Hz, 1H); MS (ESI) m/z 338 (M+H)+.

Reference： [1]Patent: WO2016/69757,2016,A1 .Location in patent: Page/Page column 212

18
[ 1093880-37-5 ]
C₁₆H₁₅ClFNO₄ [ No CAS ]

Reference： [1]Patent: WO2016/69757,2016,A1

19
[ 1093880-37-5 ]
methyl rac-3-((2R,4R)-7-chloro-4-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)benzoate [ No CAS ]

Reference： [1]Patent: WO2016/69757,2016,A1

20
[ 1093880-37-5 ]
methyl rac-3-((2R,4S)-7-chloro-4-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)benzoate [ No CAS ]

Reference： [1]Patent: WO2016/69757,2016,A1

21
[ 1093880-37-5 ]
methyl rac-3-((2R,4R)-4-azido-7-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)benzoate [ No CAS ]

Reference： [1]Patent: WO2016/69757,2016,A1

22
[ 1093880-37-5 ]
methyl rac-3-((2R,4R)-4-amino-7-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)benzoate [ No CAS ]

Reference： [1]Patent: WO2016/69757,2016,A1

23
[ 1065010-87-8 ]
[ 1093880-37-5 ]
6-cyclopropyl-2-fluoronicotinaldehyde [ No CAS ]