[ CAS No. 26163-03-1 ] {[proInfo.proName]}

Name: 26163-03-1|3-Bromo-5-chloropyridin-2-amine|98%
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SKU: A177197
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Quality Control of [ 26163-03-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 26163-03-1 ]

Product Details of [ 26163-03-1 ]

CAS No. :	26163-03-1	MDL No. :	MFCD00955627
Formula :	C₅H₄BrClN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UWGGGYYCKDCTGN-UHFFFAOYSA-N
M.W :	207.46	Pubchem ID :	2763971
Synonyms :

Calculated chemistry of [ 26163-03-1 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	41.35
TPSA :	38.91 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) :	-6.27 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.7
Log Po/w (XLOGP3) :	1.82
Log Po/w (WLOGP) :	2.09
Log Po/w (MLOGP) :	1.6
Log Po/w (SILICOS-IT) :	2.03
Consensus Log Po/w :	1.85

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.77
Solubility :	0.355 mg/ml ; 0.00171 mol/l
Class :	Soluble
Log S (Ali) :	-2.26
Solubility :	1.15 mg/ml ; 0.00553 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.14
Solubility :	0.15 mg/ml ; 0.000724 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.62

Safety of [ 26163-03-1 ]

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

Application In Synthesis of [ 26163-03-1 ]

* 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 [ 26163-03-1 ]
Downstream synthetic route of [ 26163-03-1 ]

[ 26163-03-1 ] Synthesis Path-Upstream 1~12

1
[ 12775-96-1 ]
[ 26163-03-1 ]
[ 40966-87-8 ]

Reference： [1] Patent: US4033975, 1977, A,

2
[ 1072-98-6 ]
[ 26163-03-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With bromine In chloroform at 20℃; for 1 h;	5-Chloropyridin-2-amine (5000.0 mg, 38.90 mmol) was dissolved in CHCl₃(78.0 mL), and then Br₂(2.0 mL, 38.90 mmol) was added thereto. The reaction mixture was stirred at room temperature for one hour and solvent was removed therefrom under reduced pressure. The residue was dissolved in EtOAc, and it was then washed with saturated NaHCO₃aqueous solution and brine, dried over anhydrous Na₂SO₄, filtered and then distilled under reduced pressure. The residue was purified by column chromatography (EtOAc:n-Hex=1:9) on silica. The fractions containing the product were collected and evaporated to obtain yellow solid compound of 3-bromo-5-chloropyridin-2-amine (7500.0 mg, 93percent). [0621] LCMS ESI(+): 207 (M+1), 209 (M+3) [0622] ¹H-NMR (300 MHz, CDCl₃); δ: 7.98 (d, 1H, J=2.1 Hz), 7.66 (d, 1H, J=2.1 Hz), 4.93 (bs, 2H)
88.1%	Stage #1: With bromine In chloroform at 20℃; for 0.5 h; Stage #2: With sodium hydrogensulfite In chloroform; water	Step A: 3-bromo-5-chloropyridin-2-amine A 250 mLround-bottomed flask was charged with 5-chloropyridin-2-amine (80 g, 622.3 mmol) and CHCl₃ (100 mL). Added bromine (31.98 mL, 622.3 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was poured into saturated bicarbonate and NaHSO₃ and extracted with CH₂Cl₂. The organic layer was dried with sodium sulfate, filtered and concentrated to afford the title compound (113.8 g, 88.1percent yield) as a tan solid. ¹H NMR (d₆-DMSO) δ 7.97 (d, 1H), 7.90 (d, 1H), 6.44 (bs, 2H).
74%	at 10 - 20℃; for 2 h;	To 5-chloro-2-pyridineamine (3 g, 23.3 mmol) dissolved in acetic acid (40 ml) a solution of bromine (1.29 ml, 25 mmol) in acetic acid was added dropwise at 10°C. The mixture was stirred for 2 h at room temperature and then concentrated. Work-up and purification on a column packed with silica gel using 40percent ethyl acetate in heptane as an eluent yielded the title compound as a colourless powder (3.58 g, 74percent).

71%	With N-Bromosuccinimide In acetonitrile at 80℃; for 1 h;	To a solution of 9 5-chloropyridin-2-amine (10g, 77.8mmol, 1 equiv.) in 31 acetonitrile (150mL), 10 N-bromosuccinimide (13.8g, 77.8mmol, 1 equiv.) was added. The reaction mixture was stirred and refluxed for 1h. Then the solvent was evaporated in vacuo. Compound 11 1 was obtained, after purification by chromatography on silica gel (eluent: dichloromethane–ethyl acetate 9:1) and recrystallization from propan-2-ol as a pale beige solid in 71percent yield. mp: 82°C, Lit.: 83–84°C; ¹H NMR (400MHz, [D₆]DMSO) δ: 6.43 (2H, s), 7.88 (1H, d, J=2.2Hz), 7.96 (1H, d, J=2.2Hz), ¹³C NMR (100MHz, [D₆]DMSO) δ: 103.0 (C), 117.1 (C), 139.0 (CH), 145.0 (CH), 155.3 (C); MS ESI⁺ (m/z): 207.27/209.32 [M+H]⁺.
70.4%	With N-Bromosuccinimide In ethanol; N,N-dimethyl-formamide at 85℃; for 3.5 h;	DMF and ethanol was added in a 50L round-bottomed three-necked flask volume ratio of 1: mixed solvent 18.7L 1.8, insert the thermometer and reflux condenser installation means, start with a magnetic stirrer, and adding 4986.6g of 2-amino-5- chloro pyridine, N- bromosuccinimide 17336.3g, at 85 reaction was stirred 3.5 hours, GC and TLC determined the completion of the reaction, the solvent was removed by rotary evaporation to give the crude product from n-hexane to give the pure product recrystallized from 2- amino-3-bromo-5-chloropyridine, after drying, the yield was calculated 70.4percent, a purity of 99.15percent.
48%	With sodium hydroxide; bromine; sodium acetate In water; acetic acid	Example 2 A suspension of 2-amino-5-chloropyridine (5.14 g, 40 mmol) and anhydrous sodium acetate (3.29 g, 40 mmol) in acetic acid (25 mL) was mechanically stirred and warmed to a bath temperature of 45° C. A solution of bromine (2.1 mL, 40 mmol) in acetic acid (2 mL) was added over 1 hour. The resulting orange mixture was cooled to 15° C. and filtered. The solids were taken up in 400 mL of water, the suspension made basic by addition of 1 N NaOH and the suspension extracted with ethyl acetate (5100 mL). The combined extracts were washed with 10percent NaHSO₃(1100 mL) and were dried over MgSO₄. Concentration afforded 2-amino-3-bromo-5-chloropyridine (4 g, 48percent), mp 82-84° C.
70.7%	With bromine; sodium acetate In water; acetic acid	EXAMPLE 1 2-Amino-3-bromo-5-chloropyridine An acetic acid (400 mL) suspension of sodium acetate (57.1 g, 0.696 mol) and 2-amino-5-chloropyridine (89.5 g, 0.696 mol) was treated with a solution of bromine (35.9 mL, 0.696 mol) in acetic acid (15 mL) over a period of 1.25 hours with gentle warming to 43° C. The resulting orange slurry was then cooled to 15° C. and filtered to provide a solid which was subsequently dissolved in water, basified (pH 8.5) with 1N NaOH, and extracted with ethyl acetate (5150 mL). The combined organic layers were washed with 10percent sodium bisulfite (2150 mL), dried over magnesium sulfate, and condensed to give 102.1 g (70.7percent) of a yellow solid, m.p. 83-85° C.: IR(CHCl₃) 3683, 3504, 3401, 2987, 2482, 2392, 1608, 1571, 1544, 1455, 1389, 1316, 1207, 1127, 1057, 1026, 895, 881, 650, 607, 249, 236 cm^-1; ¹ H NMR (300 MHz, CDCl₃) δ 5.20 (br s, 2H), 7.70 (d, 1H), J=2.2 Hz), 8.0 (d, 1H, J=2.2 Hz); ¹³ C NMR (CDCl₃) δ 104.08, 120.33, 139.62, 145.24, 154.10; exact mass calculated for C₅ H₄ N₂ BrCl=205.9246. High resolution mass spec. 205.9246.
2.75 g	Stage #1: at 10 - 35℃; for 2 h; Stage #2: at 0℃; for 0.5 h;	10716] To a solution of 5-chloropyridin-2-amine (5.0 g) in acetic acid (90 mE) was added dropwise a solution ofbromine (12.4 g) in acetic acid (4 mE) at 10° C. The reaction solution was stirred at room temperature for 2 hr, and saturated aqueous sodium thiosulfate solution was added thereto at 0° C. The mixture was stirred for 30 mm, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.75 g).10717] ‘H NMR (300 MHz, CDC13) ö 4.92 (2H, brs), 7.66 (1H, d, J=2.3 Hz), 7.98 (1H, d, J=2.3 Hz).

Reference： [1] Patent: US2014/315888, 2014, A1, . Location in patent: Paragraph 0620-0622
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 7, p. 2949 - 2961
[3] Patent: US2009/156603, 2009, A1, . Location in patent: Page/Page column 46
[4] Patent: EP1202994, 2004, B1, . Location in patent: Page 18
[5] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 115 - 126
[6] Patent: CN104016909, 2016, B, . Location in patent: Paragraph 0029; 0030
[7] Patent: US6388084, 2002, B1,
[8] Journal of Organic Chemistry, 1992, vol. 57, # 6, p. 1930 - 1933
[9] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 19, p. 2777 - 2782
[10] Patent: US2003/83311, 2003, A1,
[11] Patent: US5861419, 1999, A,
[12] Patent: US6004950, 1999, A,
[13] Patent: US6046217, 2000, A,
[14] Patent: US5068333, 1991, A,
[15] Patent: US4847263, 1989, A,
[16] Patent: EP1012142, 2004, B1, . Location in patent: Page 28
[17] Patent: EP1015431, 2005, B1, . Location in patent: Page/Page column 24
[18] Patent: US2015/266872, 2015, A1, . Location in patent: Paragraph 0716; 0717

3
[ 171774-38-2 ]
[ 26163-03-1 ]

Reference： [1] Tetrahedron, 1995, vol. 51, # 31, p. 8649 - 8654

4
[ 504-29-0 ]
[ 26163-03-1 ]

Reference： [1] Patent: US4033975, 1977, A,

5
[ 26163-03-1 ]
[ 137628-16-1 ]

Reference： [1] Journal of Organic Chemistry, 1992, vol. 57, # 6, p. 1930 - 1933

6
[ 26163-03-1 ]
[ 73583-39-8 ]

Reference： [1] Tetrahedron, 2004, vol. 60, # 51, p. 11869 - 11874

7
[ 26163-03-1 ]
[ 137628-17-2 ]

Reference： [1] Tetrahedron, 2004, vol. 60, # 51, p. 11869 - 11874
[2] Journal of Organic Chemistry, 2016, vol. 81, # 11, p. 4576 - 4587

8
[ 26163-03-1 ]
[ 138006-41-4 ]

Reference： [1] Journal of Organic Chemistry, 2016, vol. 81, # 11, p. 4576 - 4587
[2] Journal of Organic Chemistry, 1992, vol. 57, # 6, p. 1930 - 1933

9
[ 26163-03-1 ]
[ 823221-97-2 ]

Yield	Reaction Conditions	Operation in experiment
71.2%	With copper(l) iodide; tert.-butylnitrite; iodine In acetonitrile at 60℃; for 2 h; Inert atmosphere; Cooling with ice	Under nitrogen protection,Acetonitrile (100 mL) was added sequentially to a 500 mL three-necked flask,Elemental iodine (48.9 g, 192.8 mmol)Cuprous iodide (23.9 g, 125.3 mmol) andTert-butyl nitrite (14.9 g, 144.6 mmol)2-Amino-3-bromo-5-chloropyridine (20.0 g, 96.4 mmol) was slowly added under ice-cooling to react at 60 ° C for 2 h.After completion of the reaction, water (45 mL) was added,The filter cake was extracted with ethyl acetate (45 mL x 1) and the filtrate was extracted with ethyl acetate (200 mL x 2)The phases were washed with saturated aqueous sodium thiosulfate solution (110 mL x 2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.A small amount of methanol beating, filter, filter cake after drying 2 - iodo-3-bromo-5-chloropyridine white solid 21.9g, the yield of 71.2percent.

Reference： [1] Patent: CN106467488, 2017, A, . Location in patent: Paragraph 0011; 0012; 0013; 0014; 0015; 0016-0037
[2] Tetrahedron, 2004, vol. 60, # 51, p. 11869 - 11874

10
[ 557-21-1 ]
[ 26163-03-1 ]
[ 869557-28-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In 1-methyl-pyrrolidin-2-one at 110℃; for 5 h;	3-Bromo-5-chloropyridin-2-amine (2700.0 mg, 13.00 mmol) was dissolved in NMP (60.0 mL), and then Zn(CN)₂(2300.0 mg, 19.50 mmol) and Pd(PPh₃)₄(1500.0 mg, 1.30 mmol) were added thereto. The reaction mixture was stirred at 110° C. for 5 hours and then cooled to room temperature. Water and EtOAc were added to the reaction mixture, and it was stirred for 10 minutes and then filtered through celite. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and then distilled under reduced pressure. The residue was purified by column chromatography (EtOAc:n-Hex=1:9) on silica. The fractions containing the product were collected and evaporated to obtain white solid compound of 2-amino-5-chloronicotinonitrile (1900.0 mg, 100percent). [0624] LCMS ESI(+): 154 (M+1), 156 (M+3) [0625] ¹H-NMR (300 MHz, DMSO-d₆); δ: 8.22 (d, 1H, J=2.7 Hz), 8.07 (d, 1H, J=2.7 Hz), 7.14 (s, 2H)

Reference： [1] Patent: US2014/315888, 2014, A1, . Location in patent: Paragraph 0623-0625
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 7, p. 2949 - 2961

11
[ 557-21-1 ]
[ 26163-03-1 ]
[ 869557-28-8 ]

Reference： [1] Patent: WO2005/111001, 2005, A1, . Location in patent: Page/Page column 56; 57

12
[ 107-20-0 ]
[ 26163-03-1 ]
[ 957187-27-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	at 50℃;	A mixture of 3-bromo-5-chloropyridin-2-amine (10 g, 49 mmol) and chloroacetaldehyde (50percent in H₂O, 12 mL, 98 mmol) in ethanol (100 mL) was heated at 50° C. overnight. It was then cooled to room temperature and concentrated. Acetone (30 mL) was added to the residue and the resulting mixture was stirred rapidly for 2 h. The resulting solid was collected through filtration and dried to afford 101a as a yellow solid (10.0 g, 89percent). MS: [M+H]⁺231. ¹H NMR (500 MHz, DMSO) δ 9.20 (s, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 8.09 (s, 1H)
55.2%	for 3 h; Reflux	Example 39 2'-amino-6-(6-chloroimidazo[ 1 ,2-a]pyridin-8-yl)- 1 ',2,2-trimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-oneStep A: 3-Bromo-5-chloro-2-pyridinamine (487 mg, 2.35 mmol) was diluted with ethanol (4 mL), followed by the addition of 2-chloroacetaldehyde (614 , 4.69 mmol). The reaction was heated at reflux for 3 hours. The reaction was cooled and loaded onto silica gel eluting with 10-50percent ethyl acetate/hexanes to yield 8-bromo-6-chloroimidazo[l,2-a]pyridine (300 mg, 1.30 mmol, 55.2percent yield).Step B: 2'-Amino-r,2,2-trimethyl-6-(4,4,5,5-tetramethyl

Reference： [1] Patent: US2013/116262, 2013, A1, . Location in patent: Paragraph 0195; 0196; 0197
[2] Patent: WO2011/72064, 2011, A1, . Location in patent: Page/Page column 74

[ 26163-03-1 ] Synthesis Path-Downstream 1~88

1
[ 1072-98-6 ]
[ 26163-03-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With bromine; In chloroform; at 20℃; for 1h;	5-Chloropyridin-2-amine (5000.0 mg, 38.90 mmol) was dissolved in CHCl3 (78.0 mL), and then Br2 (2.0 mL, 38.90 mmol) was added thereto. The reaction mixture was stirred at room temperature for one hour and solvent was removed therefrom under reduced pressure. The residue was dissolved in EtOAc, and it was then washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and then distilled under reduced pressure. The residue was purified by column chromatography (EtOAc:n-Hex=1:9) on silica. The fractions containing the product were collected and evaporated to obtain yellow solid compound of 3-bromo-5-chloropyridin-2-amine (7500.0 mg, 93percent). [0621] LCMS ESI(+): 207 (M+1), 209 (M+3) [0622] 1H-NMR (300 MHz, CDCl3); delta: 7.98 (d, 1H, J=2.1 Hz), 7.66 (d, 1H, J=2.1 Hz), 4.93 (bs, 2H)
88.1%		Step A: 3-bromo-5-chloropyridin-2-amine A 250 mLround-bottomed flask was charged with 5-chloropyridin-2-amine (80 g, 622.3 mmol) and CHCl3 (100 mL). Added bromine (31.98 mL, 622.3 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was poured into saturated bicarbonate and NaHSO3 and extracted with CH2Cl2. The organic layer was dried with sodium sulfate, filtered and concentrated to afford the title compound (113.8 g, 88.1percent yield) as a tan solid. 1H NMR (d6-DMSO) delta 7.97 (d, 1H), 7.90 (d, 1H), 6.44 (bs, 2H).
74%	With bromine; acetic acid; at 10 - 20℃; for 2h;	To 5-chloro-2-pyridineamine (3 g, 23.3 mmol) dissolved in acetic acid (40 ml) a solution of bromine (1.29 ml, 25 mmol) in acetic acid was added dropwise at 10°C. The mixture was stirred for 2 h at room temperature and then concentrated. Work-up and purification on a column packed with silica gel using 40percent ethyl acetate in heptane as an eluent yielded the title compound as a colourless powder (3.58 g, 74percent).

71%	With N-Bromosuccinimide; In acetonitrile; at 80℃; for 1h;	To a solution of 9 5-chloropyridin-2-amine (10g, 77.8mmol, 1 equiv.) in 31 acetonitrile (150mL), 10 N-bromosuccinimide (13.8g, 77.8mmol, 1 equiv.) was added. The reaction mixture was stirred and refluxed for 1h. Then the solvent was evaporated in vacuo. Compound 11 1 was obtained, after purification by chromatography on silica gel (eluent: dichloromethane?ethyl acetate 9:1) and recrystallization from propan-2-ol as a pale beige solid in 71percent yield. mp: 82°C, Lit.: 83?84°C; 1H NMR (400MHz, [D6]DMSO) delta: 6.43 (2H, s), 7.88 (1H, d, J=2.2Hz), 7.96 (1H, d, J=2.2Hz), 13C NMR (100MHz, [D6]DMSO) delta: 103.0 (C), 117.1 (C), 139.0 (CH), 145.0 (CH), 155.3 (C); MS ESI+ (m/z): 207.27/209.32 [M+H]+.
70.4%	With N-Bromosuccinimide; In ethanol; N,N-dimethyl-formamide; at 85℃; for 3.5h;	DMF and ethanol was added in a 50L round-bottomed three-necked flask volume ratio of 1: mixed solvent 18.7L 1.8, insert the thermometer and reflux condenser installation means, start with a magnetic stirrer, and adding 4986.6g of 2-amino-5- chloro pyridine, N- bromosuccinimide 17336.3g, at 85 reaction was stirred 3.5 hours, GC and TLC determined the completion of the reaction, the solvent was removed by rotary evaporation to give the crude product from n-hexane to give the pure product recrystallized from 2- amino-3-bromo-5-chloropyridine, after drying, the yield was calculated 70.4percent, a purity of 99.15percent.
48%	With sodium hydroxide; bromine; sodium acetate; In water; acetic acid;	Example 2 A suspension of 2-amino-5-chloropyridine (5.14 g, 40 mmol) and anhydrous sodium acetate (3.29 g, 40 mmol) in acetic acid (25 mL) was mechanically stirred and warmed to a bath temperature of 45° C. A solution of bromine (2.1 mL, 40 mmol) in acetic acid (2 mL) was added over 1 hour. The resulting orange mixture was cooled to 15° C. and filtered. The solids were taken up in 400 mL of water, the suspension made basic by addition of 1 N NaOH and the suspension extracted with ethyl acetate (5100 mL). The combined extracts were washed with 10percent NaHSO3(1100 mL) and were dried over MgSO4. Concentration afforded 2-amino-3-bromo-5-chloropyridine (4 g, 48percent), mp 82-84° C.
	With sodium hydroxide; bromine; In water; acetic acid; ethyl acetate;	1.1 2-Amino-3-bromo-5-chloropyridine A solution of 257 g (1.61 mol) of bromine in 380 ml of acetic acid was added dropwise over a period of one hour to a solution of 187 g (1.45 mol) of 2-amino-5-chloropyridine in 1.5 of acetic acid. The reaction mixture was refluxed for 3 h and then allowed to cool to ambient temperature. 1-9 l of demineralized water were added and the mixture was concentrated in vacuo. The residue was partitioned between 4 l of ethyl acetate and 1.8 l of water. The mixture was basified with 3 l of a 10percent by weight aqueous sodium hydroxide solution. The organic layer was separated and washed with brine (21.5 l), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was filtered, washed with hexane (2100 ml) and dried in vacuo to give 192 g of 2-amino-3-bromo-5-chloropyridine. The mother liquor was concentrated in vacuo, filtered, washed with hexane and dried to give further 75 g of the same product.
	With sodium hydroxide; bromine; In acetic acid; ethyl acetate;	Step 1: 2-Amino-3-bromo-5-chloropyridine To a solution of 2-amino-5-chloropyridine (10 g) in acetic acid (75 mL) at r.t. was added bromine (2.6 mL) slowly. After 30 min, the acid was neutralized by the careful addition of sodium hydroxide (10N) at 0° C. The resulting orange precipitate was dissolved in ethyl acetate and washed successively with saturated potassium carbonate, saturated Na2 S2 O3 and brine, dried and concentrated. Flash chromatography (eluding with hexane/ethyl acetate, 3:1 v/v) of the residual solid provided the title compound as a pale yellow solid (14.8 g).
	With sodium hydroxide; bromine; In acetic acid; ethyl acetate;	Step 1 2-Amino-3-bromo-5-chloropyridine To a solution of 2-amino-5-chloropyridine (10 g) in acetic acid (75 mL) at r.t. was added bromine (2.6 mL) slowly. After 30 min, the acid was neutralized by the careful addition of sodium hydroxide (10 N) at 0° C. The resulting orange precipitate was dissolved in ethyl acetate and washed successively with saturated potassium carbonate, saturated Na2 S2 O3 and brine, dried and concentrated. Flash chromatography (eluding with hexane/ethyl acetate, 3:1 v/v) of the residual solid provided the title compound as a pale yellow solid (14.8 g).
	With sodium hydroxide; bromine; In acetic acid; ethyl acetate;	Step 1 2-Amino-3-bromo-5-chloropyridine To a solution of 2-amino-5-chloropyridine (10 g) in acetic acid (75 mL) at r.t. was added bromine (2.6 mL) slowly. After 30 min, the acid was neutralized by the careful addition of sodium hydroxide (10 N) at 0° C. The resulting orange precipitate was dissolved in ethyl acetate and washed successively with saturated potassium carbonate, saturated Na2 S2 O3 and brine, dried and concentrated. Flash chromatography (eluding with hexane/ethyl acetate, 3:1 v/v) of the residual solid provided the title compound as a pale yellow solid (14.8 g).
102.1 g (70.7%)	With bromine; sodium acetate; In water; acetic acid;	EXAMPLE 1 2-Amino-3-bromo-5-chloropyridine An acetic acid (400 mL) suspension of sodium acetate (57.1 g, 0.696 mol) and 2-amino-5-chloropyridine (89.5 g, 0.696 mol) was treated with a solution of bromine (35.9 mL, 0.696 mol) in acetic acid (15 mL) over a period of 1.25 hours with gentle warming to 43° C. The resulting orange slurry was then cooled to 15° C. and filtered to provide a solid which was subsequently dissolved in water, basified (pH 8.5) with 1N NaOH, and extracted with ethyl acetate (5150 mL). The combined organic layers were washed with 10percent sodium bisulfite (2150 mL), dried over magnesium sulfate, and condensed to give 102.1 g (70.7percent) of a yellow solid, m.p. 83-85° C.: IR(CHCl3) 3683, 3504, 3401, 2987, 2482, 2392, 1608, 1571, 1544, 1455, 1389, 1316, 1207, 1127, 1057, 1026, 895, 881, 650, 607, 249, 236 cm-1; 1 H NMR (300 MHz, CDCl3) delta 5.20 (br s, 2H), 7.70 (d, 1H), J=2.2 Hz), 8.0 (d, 1H, J=2.2 Hz); 13 C NMR (CDCl3) delta 104.08, 120.33, 139.62, 145.24, 154.10; exact mass calculated for C5 H4 N2 BrCl=205.9246. High resolution mass spec. 205.9246.
	With bromine; In dichloromethane;	1.1. 2-Amino-3-bromo-5-chloropyridine 20 g (77.8 mmol) of 2-amino-5-chloropyridine dissolved in 160 ml of CH2 Cl2 are reacted with 8 ml of bromine, which is added dropwise at 0° C. After the addition is complete, the mixture is left to react at 25° C. for 2 h. The suspension is washed with 10percent strength sodium hydroxide solution, and the organic phase is washed with water and then dried over MgSO4, filtered and evaporated. The compound obtained is recrystallized in isopropanol. M.p. 82° C.
	With bromine; In acetic acid; at 20℃; for 0.5h;	To a solution of 2-amino-5-chloropyridine (10 g) in acetic acid (75 mL) at r.t. was added bromine (2.6 mL) slowly. After 30 min, the acid was neutralized by the careful addition of sodium hydroxide (10 N) at 0°C. The resulting orange precipitate was dissolved in ethyl acetate and washed successively with saturated potassium carbonate, saturated Na2S2O3 and brine, dried and concentrated. Flash chromatography (eluting with hexane/ethyl acetate, 3:1 v/v) of the residual solid provided the title compound as a pale yellow solid (14.8 g).
	With bromine; acetic acid; at 18 - 25℃; for 0.5h;	EXAMPLE 35-Chloro-3-(4-methylsulfonyl)phenyl-2-piperidin-1-ylpyridineStep 1: 2-Amino-3-bromo-5-chloropyridine To a solution of 2-amino-5-chloropyridine (10 g) in acetic acid (75 mL) at r.t. was added bromine (2.6 mL) slowly. After 30 min, the acid was neutralized by the careful addition of sodium hydroxide (10 N) at 0°C. The resulting orange precipitate was dissolved in ethyl acetate and washed successively with saturated potassium carbonate, saturated Na2S2O3 and brine, dried and concentrated. Flash chromatography (eluting with hexane/ethyl acetate, 3:1 v/v) of the residual solid provided the title compound as a pale yellow solid (14.8 g).
2.75 g		10716] To a solution of 5-chloropyridin-2-amine (5.0 g) in acetic acid (90 mE) was added dropwise a solution ofbromine (12.4 g) in acetic acid (4 mE) at 10° C. The reaction solution was stirred at room temperature for 2 hr, and saturated aqueous sodium thiosulfate solution was added thereto at 0° C. The mixture was stirred for 30 mm, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.75 g).10717] ?H NMR (300 MHz, CDC13) oe 4.92 (2H, brs), 7.66 (1H, d, J=2.3 Hz), 7.98 (1H, d, J=2.3 Hz).

Reference： [1]Patent: US2014/315888,2014,A1 .Location in patent: Paragraph 0620-0622
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 2949 - 2961
[3]Patent: US2009/156603,2009,A1 .Location in patent: Page/Page column 46
[4]Patent: EP1202994,2004,B1 .Location in patent: Page 18
[5]European Journal of Medicinal Chemistry,2018,vol. 157,p. 115 - 126
[6]Patent: CN104016909,2016,B .Location in patent: Paragraph 0029; 0030
[7]Patent: US6388084,2002,B1
[8]Journal of Organic Chemistry,1992,vol. 57,p. 1930 - 1933
[9]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 2777 - 2782
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[16]Patent: EP1012142,2004,B1 .Location in patent: Page 28
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[18]Patent: US2015/266872,2015,A1 .Location in patent: Paragraph 0716; 0717

2
[ 504-02-9 ]
[ 26163-03-1 ]
[ 1005499-39-7 ]

Yield	Reaction Conditions	Operation in experiment
62%		In a 200-ml flask connected to a Dean-Stark trap, 2- amino-3-bromo-5-chloropyridine (48.7 mmol, 10.1 g) , 1,3- cyclohexanedione (73.1 mmol, 1.5 eq, 8.20 g), p- toluenesulfonic acid monohydrate (4.87 mmol, 0.1 eq, 926 mg) and toluene (101 ml) were mixed, and the mixture was heated to reflux for 7 hours. After completion of the reaction, the reaction solution was cooled, a 3percent aqueous sodium bicarbonate solution (100 ml) was added, and the mixture was extracted three times with ethyl acetate (100 ml) . The organic layers were combined, washed three times with a 3percent aqueous sodium bicarbonate solution (100 ml) and once with water (100 ml), and then concentrated under reduced pressure. Ethyl acetate (25 ml) was added to the residue, and the mixture was stirred with heating for 1 hour, and then stood to cool and ice-cooled. Precipitated crystals were collected by filtration, washed with cold ethyl acetate, and dried under reduced pressure at 5O0C, to yield the title compound (9.11 g, yield 62percent) .1H-NMR (DMSOd6, TMS, 300 MHz): delta (ppm) : 1.8-2.0 (2H, m) , 2.2-2.3 (2H, m) , 2.6-2.7 (2H, m) , 6.20 (IH, s) , 8.33 (IH, d, J = 4.5 Hz) , 8.41 (IH, d, J = 4.5 Hz), 8.49 (IH, br) .

Reference： [1]Patent: WO2008/16184,2008,A1 .Location in patent: Page/Page column 207

3
[ 26163-03-1 ]
[ 73583-39-8 ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 11869 - 11874

4
[ 26163-03-1 ]
[ 823222-22-6 ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 11869 - 11874

5
[ 26163-03-1 ]
5-chloro-2-(trifluoromethyl)pyridine-3-carboxylic acid [ No CAS ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 11869 - 11874

6
[ 26163-03-1 ]
[ 301542-41-6 ]