[ CAS No. 94952-46-2 ] {[proInfo.proName]}

Name: 94952-46-2|1-(5-Chloropyridin-2-yl)ethanone|98%
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Quality Control of [ 94952-46-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 94952-46-2 ]

Product Details of [ 94952-46-2 ]

CAS No. :	94952-46-2	MDL No. :	MFCD07375071
Formula :	C₇H₆ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VVYMEQBXUFPILB-UHFFFAOYSA-N
M.W :	155.58	Pubchem ID :	10154166
Synonyms :

Calculated chemistry of [ 94952-46-2 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	39.44
TPSA :	29.96 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.18 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.84
Log Po/w (XLOGP3) :	1.5
Log Po/w (WLOGP) :	1.94
Log Po/w (MLOGP) :	0.73
Log Po/w (SILICOS-IT) :	2.29
Consensus Log Po/w :	1.66

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.13
Solubility :	1.16 mg/ml ; 0.00745 mol/l
Class :	Soluble
Log S (Ali) :	-1.74
Solubility :	2.85 mg/ml ; 0.0183 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.96
Solubility :	0.17 mg/ml ; 0.00109 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.39

Safety of [ 94952-46-2 ]

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 [ 94952-46-2 ]

* 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 [ 94952-46-2 ]
Downstream synthetic route of [ 94952-46-2 ]

[ 94952-46-2 ] Synthesis Path-Upstream 1~7

1
[ 40473-01-6 ]
[ 127-19-5 ]
[ 94952-46-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: With sec.-butyllithium In diethyl ether; hexane at -60℃; for 2 h; Stage #2: for 3 h; Stage #3: With hydrogenchloride; water In diethyl ether; hexane	2-Bromo-5-chloropyridine (5.8g, 30mmol) was added to dry diethyl ether (100ml). The mixture was cooled to-60°C and a solution of sec-BuLi (1.4M solution in hexanes, 22mL) was added dropwise and the mixture was stirred for 2hrs. A solution of N, N- dimethylacetamide (3. 1ml, 33mmol) in diethyl ether (20ml) was added slowly dropwise and the solution left to stir for 3hrs. The reaction was brought to room temperature, hydrolysed with 2N HC1 and extracted with DCM. The organic phase was washed with water, dried over MgS04 and evaporated to give 1- (5-Chloro-pyridin-2-yl)-ethanone (4. 0g, 85percent).
59%	Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; Stage #2: for 0.5 h;	2) 1-(5-chloro-2-pyridyl)ethanone; A 1.56M solution of n-butyllithium in hexane (27 ml) was added dropwise to a solution of the 2-bromo-5-chloropyridine (6.8 g) in diethylether (45 ml) at-78°C, and thereafter, N,N-dimethyl acetamide (5 ml) was added dropwise to the solution. The mixture was stirred for 30 minutes. To the reaction liquid was added saturated aqueous ammonium chloride and ethyl acetate, and the phases were separated. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give 1-(5-chloro-2-pyridyl)ethanone (3.26 g, 59percent) as a solid. ¹H-NMR (400 MHz, CDCl₃)δ: 2.70 (3H, s), 7.80 (1H, dd, J = 8.42, 2.32 Hz), 8.00 (1H, d, J = 8.42 Hz), 8.62 (1H, d, J = 2.32 Hz).
59%	With n-butyllithium In diethyl ether; hexane at -78℃; for 0.5 h;	2) 1-(5-Chloro-2-pyridyl)ethanone At -78°C, n-butyllithium (1.56M hexane solution, 27 mL) was added dropwise to 2-bromo-5-chloropyridine (6.8 g) in diethyl ether (45 mL), and then N,N-dimethylacetamide (5 mL) was added dropwise to the resultant mixture, followed by stirring for 30 minutes. Subsequently, a saturated aqueous solution of ammonium chloride was added to the reaction mixture. Ethyl acetate was added for partitioning the resultant mixture. The organic layer was dried over sodium sulfate anhydrate. After a filtration step, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane - ethyl acetate), to thereby give 1-(5-chloro-2-pyridyl)ethanone as a solid product (3.26 g, 59percent). ¹H-NMR(400MHz,CDCl₃)δ:2.70(3H,s), 7.80(1H,dd,J=8.42,2.32Hz), 8.00(1H,d,J=8.42Hz), 8.62(1H,d,J=2.32Hz).

Reference： [1] Patent: WO2005/92304, 2005, A2, . Location in patent: Page/Page column 43
[2] Patent: EP1698626, 2006, A1, . Location in patent: Page/Page column 41
[3] Patent: EP1762568, 2007, A1, . Location in patent: Page/Page column 25
[4] Patent: US2009/253708, 2009, A1, . Location in patent: Page/Page column 12

2
[ 89809-64-3 ]
[ 75-16-1 ]
[ 94952-46-2 ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: at -63 - 20℃; for 2.25 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran; diethyl ether for 4 h; Stage #3: With sodium hydrogencarbonate In tetrahydrofuran; diethyl ether	a) l-(5-Chloropyridin-2-yl)ethanone5-Chloropyridine-2-carbonitxile (10.7 g, 77 mmol) was dissolved in diethyl ether (65 mL) and THF (35 mL) under a nitrogen atmosphere. The mixture was cooled until the internal temperature was -63 ⁰C. Methylmagnesium bromide (3M in THF, 35 mL, 105 mmol) was added over 30 min. The reaction mixture was then left stirring at -60 °C for 45 min and was then warmed to room temperature. THF (50 mL) was added to dissolve any precipitated material and the reaction mixture was stirred for 1 h. 2M HCl aq. (100 mL) was added and the reaction mixture was stirred for 4 h. The pH was then adjusted to 7 with sodium bicarbonate. The phases were separated and the product extracted from the aqueous phase with DCM. The combined organic extracts were dried over sodium sulphate and concentrated in vacuo. The product was purified by flash column chromatography (eluent heptane:EtoAc gradient) to yield 7.9 g (64percent yield) of the title compound.¹R NMR (300 MHz, CDCl₃) δ ppm 8.62 (m, IH); 8.00 (m, IH); 7.80 (m, IH); 2.70 (s, 3H).
64%	Stage #1: at -63 - 20℃; for 2.25 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran; diethyl ether for 4 h; Stage #3: With sodium hydrogencarbonate In tetrahydrofuran; diethyl ether	a) 1 - (5- Chloropyridin-2-yl)ethanone5-Chloropyridine-2-carbonitrile (10.71 g, 77 mmol) was dissolved in diethylether (65 mL) and THF (35 mL) under a nitrogen atmosphere. The mixture was cooled until the internal temperature was -63 °C. Methyl magnesium bromide (3M in THF, 35 mL, 105 mmol) was added over 30 min. The reaction mixture was then left stirring at -60 ⁰C for 45 min and was then warmed to room temperature. 50 mL of THF was added to dissolve any precipitated material. After 1 h at room temperature the reaction was judged complete by HPLC. 2M hydrochloric acid (aq., 100 mL) was added and the reaction mixture was stirred for 4 h. pH was adjusted to 7 with sodium bicarbonate. The phases were separated and the product extracted from the aqueous phase twice with DCM. The combined organise extracts were dried over sodium sulphate and concentrated in vacuo. The product was purified by column chromatography (eluent heptane: ethyl acetate gradient) to yield 7.9 g (64percent yield) of the title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.62 (m, IH); 8.00 (m, IH); 7.80 (m, IH); 2.70 (s, 3H).

Reference： [1] Patent: WO2008/39139, 2008, A1, . Location in patent: Page/Page column 26
[2] Patent: WO2008/39138, 2008, A1, . Location in patent: Page/Page column 28

3
[ 342601-76-7 ]
[ 75-16-1 ]
[ 94952-46-2 ]

Yield	Reaction Conditions	Operation in experiment
93%	at 20℃; for 4 h;	To 5-chloro-N-methoxy-N-methylpicolinamide (8.3 g, 41.5 mmol) in THF (100 mL) was added methyl magnesium bromide (3M in THF, 16.6 mL, 49.8 mmol) at room temperature. After the addition, the mixture was stirred at room temperature for 4 h. Water (200 mL) was added and the mixture extracted with ethyl acetate (200 mL x 3). The combined organicphases were dried over magnesium sulphate and the solvent evaporated in vacuo. The residue was purified by column chromatography (silica:200-300 mesh, 50 g, petroleum ether I ethyl acetate 9:1) to give 1-(5-chloropyridin-2-yl)ethanone as white solid (6 g, 93percent).LCMS: Rt 1.45 mi MH 156.

Reference： [1] Patent: WO2016/188828, 2016, A1, . Location in patent: Page/Page column 22
[2] Patent: US6642237, 2003, B1, . Location in patent: Page/Page column 224

4
[ 40473-01-6 ]
[ 94952-46-2 ]

Reference： [1] Patent: US5622982, 1997, A,

5
[ 1174280-80-8 ]
[ 94952-46-2 ]

Reference： [1] Chemistry - A European Journal, 2009, vol. 15, # 24, p. 5950 - 5955

6
[ 86873-60-1 ]
[ 94952-46-2 ]

Reference： [1] Patent: WO2016/188828, 2016, A1,

7
[ 1072-98-6 ]
[ 94952-46-2 ]

Reference： [1] Patent: US2009/253708, 2009, A1,

[ 94952-46-2 ] Synthesis Path-Downstream 1~46

1
[ 89809-64-3 ]
[ 75-16-1 ]
[ 94952-46-2 ]

Yield	Reaction Conditions	Operation in experiment
64%		a) l-(5-Chloropyridin-2-yl)ethanone5-Chloropyridine-2-carbonitxile (10.7 g, 77 mmol) was dissolved in diethyl ether (65 mL) and THF (35 mL) under a nitrogen atmosphere. The mixture was cooled until the internal temperature was -63 0C. Methylmagnesium bromide (3M in THF, 35 mL, 105 mmol) was added over 30 min. The reaction mixture was then left stirring at -60 C for 45 min and was then warmed to room temperature. THF (50 mL) was added to dissolve any precipitated material and the reaction mixture was stirred for 1 h. 2M HCl aq. (100 mL) was added and the reaction mixture was stirred for 4 h. The pH was then adjusted to 7 with sodium bicarbonate. The phases were separated and the product extracted from the aqueous phase with DCM. The combined organic extracts were dried over sodium sulphate and concentrated in vacuo. The product was purified by flash column chromatography (eluent heptane:EtoAc gradient) to yield 7.9 g (64% yield) of the title compound.1R NMR (300 MHz, CDCl3) delta ppm 8.62 (m, IH); 8.00 (m, IH); 7.80 (m, IH); 2.70 (s, 3H).
64%		a) 1 - (5- Chloropyridin-2-yl)ethanone5-Chloropyridine-2-carbonitrile (10.71 g, 77 mmol) was dissolved in diethylether (65 mL) and THF (35 mL) under a nitrogen atmosphere. The mixture was cooled until the internal temperature was -63 C. Methyl magnesium bromide (3M in THF, 35 mL, 105 mmol) was added over 30 min. The reaction mixture was then left stirring at -60 0C for 45 min and was then warmed to room temperature. 50 mL of THF was added to dissolve any precipitated material. After 1 h at room temperature the reaction was judged complete by HPLC. 2M hydrochloric acid (aq., 100 mL) was added and the reaction mixture was stirred for 4 h. pH was adjusted to 7 with sodium bicarbonate. The phases were separated and the product extracted from the aqueous phase twice with DCM. The combined organise extracts were dried over sodium sulphate and concentrated in vacuo. The product was purified by column chromatography (eluent heptane: ethyl acetate gradient) to yield 7.9 g (64% yield) of the title compound. 1H NMR (300 MHz, CDCl3) delta ppm 8.62 (m, IH); 8.00 (m, IH); 7.80 (m, IH); 2.70 (s, 3H).

Reference： [1]Patent: WO2008/39139,2008,A1 .Location in patent: Page/Page column 26
[2]Patent: WO2008/39138,2008,A1 .Location in patent: Page/Page column 28

2
[ 94952-46-2 ]
[ 1016227-95-4 ]

Yield	Reaction Conditions	Operation in experiment
88%		b) (lS)-l-(5-Chloropyridin~2-yl)ethanolThe title compound was prepared by General method B2 starting from l-(5-chloropyridin- 2-yl)ethanone (780 mg, 5mmol). Purification by flash column chromatography yielded 695 mg (88% yield) of the title compound with 92% ee.1HNMR (300 MHz, CDCl3): 8.47 (s, IH); 7.65 (d, IH); 7.26 (d, IH); 4.87 (q, IH); 3.87 (br s, IH); 1.47 (d, 3H); MS (ESI) m/z 140 and 142 [MH]+.
88%		b) (lS)-l-(5-Chloropyridin-2-yl)ethanol <n="30"/>The title compound was prepared by General method E2 starting from l-(5-chloropyridin- 2-yl)ethanone (780 mg, 5mmol). Purification by flash column chromatography yielded 695 mg (88% yield) of the title compound with 92% ee. 1H NMR (300 MHz, CDCl3): 8.47 (s, IH); 7.65 (d, IH); 7.26 (d, IH); 4.87 (q, IH); 3.87 (br s, IH); 1.47 (d, 3H); MS (ESI) m/z 140 and 142 [M+l]+.

Reference： [1]Patent: WO2008/39139,2008,A1 .Location in patent: Page/Page column 27
[2]Patent: WO2008/39138,2008,A1 .Location in patent: Page/Page column 28; 29

3
[ 342601-76-7 ]
[ 75-16-1 ]
[ 94952-46-2 ]

Yield	Reaction Conditions	Operation in experiment
93%	In tetrahydrofuran; at 20℃; for 4h;	To 5-chloro-N-methoxy-N-methylpicolinamide (8.3 g, 41.5 mmol) in THF (100 mL) was added methyl magnesium bromide (3M in THF, 16.6 mL, 49.8 mmol) at room temperature. After the addition, the mixture was stirred at room temperature for 4 h. Water (200 mL) was added and the mixture extracted with ethyl acetate (200 mL x 3). The combined organicphases were dried over magnesium sulphate and the solvent evaporated in vacuo. The residue was purified by column chromatography (silica:200-300 mesh, 50 g, petroleum ether I ethyl acetate 9:1) to give 1-(5-chloropyridin-2-yl)ethanone as white solid (6 g, 93%).LCMS: Rt 1.45 mi MH 156.
		To a solution of the amide from the previous step (33.1 g, 165 mmol) in anhydrous THF (300 mL), at 0 C., was added methylmagnesium bromide (1.4M solution, 355 mL, 497 mmol). The reaction solution was stirred at 0 C. for 3 hours and poured into 800 mL of ice-water. Ethyl acetate was used to extract it (3 times, 500 mL each time). The combined organic layers was dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography on silica gel with hexanes/ethyl acetate=3/1 as eluant to give the title compound as a white solid.

Reference： [1]Patent: WO2016/188828,2016,A1 .Location in patent: Page/Page column 22
[2]Patent: US6642237,2003,B1 .Location in patent: Page/Page column 224

4
[ 94952-46-2 ]
[ 342601-77-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; hydroxylamine hydrochloride; In ethanol; for 8h;Heating / reflux;	To a suspension of the acetylpyridine obtained as from the previous step (30 g, 193 mmol) and hydroxyamine hydrochloride (16.1 g, 231 mmol) in ethyl alcohol (200 mL) was added sodium hydroxide powder (10 g, 250 mmol). The reaction mixture was refluxed for 8 hours to see that the starting material was consumed by LCMS. The solvent was vacuum removed. The residue was washed with cooled water for several times to give the title compound as a white solid.

Reference： [1]Patent: US6642237,2003,B1 .Location in patent: Page/Page column 224

Yield	Reaction Conditions	Operation in experiment
65%		The product was recrystallized from hexane to give 29.35 g of 2-acetyl-5-chloropyridine (65% yield based on sec-butyllithium, the limiting reagent).
65%		The product was recrystallized from hexane to give 29.35 g of 2-acetyl-5-chloropyridine (65% yield based on sec-butyllithium, the limiting reagent).
		In a comparative run using similar amounts of reagents and procedures, but with the substitution of n-butyllithium for sec-butyllithium, the yield of 2-acetyl-5-chloropyridine amounted to 30%.

In a comparative run using similar amounts of reagents and procedures, but with the substitution of n-butyllithium for sec-butyllithium, the yield of 2-acetyl-5-chloropyridine amounted to 30%.

6
[ 94952-46-2 ]
[ 145905-09-5 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; In hydrogen bromide;	b 2-Bromoacetyl-5-chloropyridine hydrobromide To a solution of 10 g of <strong>[94952-46-2]2-acetyl-5-chloropyridine</strong> in 150 ml of 48% aqueous hydrobromic acid are added 4 ml of bromine dissolved in 40 ml of hydrobromic acid, with stirring, drop by drop, at 80. The mixture is stirred for additionally 3 hours at 80. Afterwards the solution is evaporated in vacuo. The residue is triturated with acetone, filtered by suction, washed with acetone and dried in vacuo to yield yellow crystals of the compound, which is used for the next step without purification.

Reference： [1]Patent: US5622982,1997,A

7
[ 40473-01-6 ]
[ 94952-46-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; n-butyllithium; In tetrahydrofuran; diethyl ether; hexane; N,N-dimethyl acetamide; water;	a 2-Acetyl-5-chloropyridine To a suspension of 56 g of 2-bromo-5-chloropyridine in 560 ml of dry diethylether is added a solution of 179 ml of n-butyllithium (15% solution in hexane) at -78 and under argon at such a rate that the temperature never exceeds -72. Immediately thereafter the solution of 25.7 ml of N,N-dimethylacetamide in dry THF is added. The mixture is stirred for one hour at the same temperature and thereafter decomposed by careful addition of 100 ml of 3N hydrochloric acid, followed by 100 ml of water with vigorous cooling. Working up by process A (see Example 1) and purification by chromatogrphy over silica gel (toluene/ethyl acetate=20/1) yields the compound as white needles; m.p.: 58-65.

Reference： [1]Patent: US5622982,1997,A

8
[ 40473-01-6 ]
[ 127-19-5 ]
[ 94952-46-2 ]

Yield	Reaction Conditions	Operation in experiment
85%		2-Bromo-5-chloropyridine (5.8g, 30mmol) was added to dry diethyl ether (100ml). The mixture was cooled to-60C and a solution of sec-BuLi (1.4M solution in hexanes, 22mL) was added dropwise and the mixture was stirred for 2hrs. A solution of N, N- dimethylacetamide (3. 1ml, 33mmol) in diethyl ether (20ml) was added slowly dropwise and the solution left to stir for 3hrs. The reaction was brought to room temperature, hydrolysed with 2N HC1 and extracted with DCM. The organic phase was washed with water, dried over MgS04 and evaporated to give 1- (5-Chloro-pyridin-2-yl)-ethanone (4. 0g, 85%).
59%		2) 1-(5-chloro-2-pyridyl)ethanone; A 1.56M solution of n-butyllithium in hexane (27 ml) was added dropwise to a solution of the 2-bromo-5-chloropyridine (6.8 g) in diethylether (45 ml) at-78C, and thereafter, N,N-dimethyl acetamide (5 ml) was added dropwise to the solution. The mixture was stirred for 30 minutes. To the reaction liquid was added saturated aqueous ammonium chloride and ethyl acetate, and the phases were separated. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give 1-(5-chloro-2-pyridyl)ethanone (3.26 g, 59%) as a solid. 1H-NMR (400 MHz, CDCl3)delta: 2.70 (3H, s), 7.80 (1H, dd, J = 8.42, 2.32 Hz), 8.00 (1H, d, J = 8.42 Hz), 8.62 (1H, d, J = 2.32 Hz).
59%	With n-butyllithium; In diethyl ether; hexane; at -78℃; for 0.5h;	2) 1-(5-Chloro-2-pyridyl)ethanone At -78C, n-butyllithium (1.56M hexane solution, 27 mL) was added dropwise to 2-bromo-5-chloropyridine (6.8 g) in diethyl ether (45 mL), and then N,N-dimethylacetamide (5 mL) was added dropwise to the resultant mixture, followed by stirring for 30 minutes. Subsequently, a saturated aqueous solution of ammonium chloride was added to the reaction mixture. Ethyl acetate was added for partitioning the resultant mixture. The organic layer was dried over sodium sulfate anhydrate. After a filtration step, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane - ethyl acetate), to thereby give 1-(5-chloro-2-pyridyl)ethanone as a solid product (3.26 g, 59%). 1H-NMR(400MHz,CDCl3)delta:2.70(3H,s), 7.80(1H,dd,J=8.42,2.32Hz), 8.00(1H,d,J=8.42Hz), 8.62(1H,d,J=2.32Hz).

B. 2-Acetyl-5-chloropyridine A two liter 4 neck flask was equipped with an overhead air-driven stirrer, a low temperature thermometer and a 250 mL addition funnel. The reaction setup was flushed with nitrogen overnight. A 1.3 M cyclohexane solution of s-butyllithium (222 ml, 0.289 mol) was charged to the addition funnel with a cannula. 2-Bromo-4-chloropyridine (57.72 g; 0.30 mol) and 600 mL of anhydrous ether were charged to the flask and then cooled in an acetone/dry ice bath. The temperature of the resultant slurry was -76 C. The s-butyllithium was added dropwise at a rate to maintain the temperature at -74 C. or lower. The addition took 1.5 hours. When the addition was complete the addition funnel was rinsed with 20 mL of anhydrous ether, then charged with 30.7 mL of dimethylacetamide (0.330 mol) and 30 mL of anhydrous ether. Ten minutes after the completion of the s-butyllithium addition, the dimethylacetamide solution was added dropwise to the reaction mixture, again maintaining the temperature at -74 C. or less. This addition took about 40 minutes. The reaction mixture was held at -76 C. for one hour after the dimethylacetamide addition was complete, then the bath was removed and the temperature allowed to warm to -30 C. At this temperature the cold bath was replaced and the reaction was quenched with 200 mL of 3 N HCl. The reaction mixture was allowed to warm to room temperature. The ether layer was separated, washed with water and saturated brine, dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in methylene chloride, slurried with one weight equivalent of silica gel, filtered through celite and concentrated under reduced pressure. The resultant solid was an orange color. The product was recrystallized from hexane to give 29.35 g of product as an orange/tan solid. The NMR data is as follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 2.70 (s, 3H); 7.85 (d, 1H); 7.95 (d, 1H); 8.63 (s, 1H).

Reference： [1]Patent: WO2005/92304,2005,A2 .Location in patent: Page/Page column 43
[2]Patent: EP1698626,2006,A1 .Location in patent: Page/Page column 41
[3]Patent: EP1762568,2007,A1 .Location in patent: Page/Page column 25
[4]Patent: US2009/253708,2009,A1 .Location in patent: Page/Page column 12

9
[ 94952-46-2 ]
[ 1122705-36-5 ]

Yield	Reaction Conditions	Operation in experiment
		Reference Production Example 3. In 50 mL of methanol, 243 mg of sodium borohydride was suspended and 1.00 g of <strong>[94952-46-2]2-acetyl-5-chloropyridine</strong> was added thereto at room temperature. After stirring at the same temperature for 2 hours, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and then the resulting residue was dissolved in 50 mL of tetrahydrofuran. To the solution were added dropwise 0.5 mL of methanesulfonyl chloride and 0.9 mL of triethylamine at room temperature. After stirring at the same temperature for 2 hours, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and then the resulting residue was dissolved in 50 mL of N, N-dimethylformamide . To the solution was added 1.12 g of lithium bromide at room temperature. After stirring at the same temperature for 6 hours, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and then the resulting residue was subjected to column chromatography to obtain 368 mg of 2- ( 1-bromoethyl) -5-chloropyridine .1H-NMR (CDCl3, TMS) : delta (ppm) 8.25 (IH, s), 7.66 (IH, d) , 7.42 (IH, d) , 5.12 (IH, q) , 1,87 (3H, d).

Reference： [1]Patent: WO2009/25397,2009,A1 .Location in patent: Page/Page column 162-163

10
[ 94952-46-2 ]
[ 298-12-4 ]
C₉H₇ClNO₄^(1-)*K⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In methanol; water; at 20℃;Inert atmosphere;	To a slurry of 5.05 g of <strong>[94952-46-2]2-acetyl-5-chloropyridine</strong> (32.4 mmol) in 36 mL of methanol at room temperature was added 60 mL of water and 4.8 g of 50% glyoxylic acid (32.4 mmol). Potassium carbonate (8.96 g, 2 equivalents) was added carefully (foaming), and the reaction mixture was stirred overnight at room temperature under nitrogen. The next day, the slurry was partially stripped on the rotovap to remove methanol (maximum bath temperature 30 C.). The slurry was transferred to a separatory funnel and extracted twice with methylene chloride. The aqueous phase was transferred back to a round bottom flask and treated carefully with 13.7 mL of acetic acid (foaming) followed by 1.9 g of hydrazine hydrate (38 mmol). The reaction mixture was refluxed for 2 hours. It became very dark. While cooling, potassium carbonate was carefully added until the pH was 7. The reaction mixture was cooled to room temperature, then filtered and washed with water. The solids were dried in a vacuum oven at 50 C. The product was 4.13 g of a fine black solid. The NMR data is as follows: 300 MHz 1H NMR (DMSO d-6, TMS=0 ppm) 7.10 (d, 1H); 7.75 (d, 1H); 8.11 (d, 1H) 8.70 (d, 1H); 13.4 (bs, 1H). The yield of pyridazinone was 61%.

Reference： [1]Patent: US2009/253708,2009,A1 .Location in patent: Page/Page column 12

11
[ 1174280-80-8 ]
[ 94952-46-2 ]

Reference： [1]Chemistry - A European Journal,2009,vol. 15,p. 5950 - 5955

12
[ 553-90-2 ]
[ 94952-46-2 ]
[ 741288-10-8 ]

Yield	Reaction Conditions	Operation in experiment
77%		3) Ethyl 4-(5-chloro-2-pyridyl)-2,4-dioxobutanoate; Dimethyl oxalate (5 g) was added to a solution of sodium methoxide (2.26 g) in ethanol (100 ml), and the mixture was stirred for 5 minutes. 1- (5-Chloro-2-pyridyl) ethanone (3.26 g) was then added to the solution and the mixture was stirred at room temperature for 45 minutes. After water and diethylether were added to the reaction liquid, the aqueous layer was separated. The aqueous layer was acidified with 1N aqueous hydrochloric acid, and chloroform was added to the solution and the phases were separated. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give ethyl 4-(5-chloro-2-pyridyl)-2,4-dioxobutanoate (4.12 g, 77%) as a solid. 1H-NMR (400 MHz, CDCl3)delta: 1.42 (3H, t, J = 7.08 Hz), 4.41 (2H, q, J = 7.08 Hz), 7.64 (1H, s), 7.87 (1H, dd, J = 8.42, 2.44 Hz), 8.11 (1H, d, J = 8.42 Hz), 8.67 (1H, d, J = 2.44 Hz). ESI-MSm/z: 256 (M+H)+.

Reference： [1]Patent: EP1698626,2006,A1 .Location in patent: Page/Page column 41

13
[ 94952-46-2 ]
[ 95-92-1 ]
[ 741288-10-8 ]

Yield	Reaction Conditions	Operation in experiment
100%		3) 4-(5-Chloro-2-pyridyl)-2,4-dioxobutanoic acid ethyl ester Diethyl oxalate (1.75 mL) was added to sodium ethoxide (0.88 g) in ethanol (30 mL), followed by stirring for 5 minutes. Subsequently, <strong>[94952-46-2]1-(5-chloro-2-pyridyl)ethanone</strong> (1.00 g) was added to the resultant mixture, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, and then the resultant mixture was washed with diethyl ether. The aqueous layer was acidified with 1N aqueous solution of hydrochloric acid. Subsequently, chloroform was added for partitioning the resultant mixture. The organic layer was dried over magnesium sulfate anhydrate. After a filtration step, the solvent was evaporated under reduced pressure, to thereby give 4-(5-chloro-2-pyridyl)-2,4-dioxobutanoic acid ethyl ester as a solid product (2.59 g, quantitative amount). 1H-NMR(400MHz,CDCl3)delta:1.42(3H,t,J=7.08Hz), 4.41(2H,q,J=7.08Hz), 7.27(1H,s), 7.86(1H,dd,J=8.42,2.44Hz), 8.11(1H,d,J=8.42Hz), 8.67(1H,d,J=2.44Hz). ESI-MS m/z:256(M+H)+.

Reference： [1]Patent: EP1762568,2007,A1 .Location in patent: Page/Page column 25

14
[ 94952-46-2 ]
[ 1016227-95-4 ]
(1R)-1-(5-chloropyridin-2-yl)ethanol [ No CAS ]