[ CAS No. 321601-48-3 ]

Name: 321601-48-3|Methyl 6-bromo-3-hydroxypicolinate|98%
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Product Details of [ 321601-48-3 ]

CAS No. :	321601-48-3	MDL No. :	MFCD12828055
Formula :	C₇H₆BrNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	232.03 g/mol	Pubchem ID :	-
Synonyms :

Calculated chemistry of of [ 321601-48-3 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	45.24
TPSA :	59.42 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) :	-6.11 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.16
Log Po/w (XLOGP3) :	2.26
Log Po/w (WLOGP) :	1.34
Log Po/w (MLOGP) :	0.51
Log Po/w (SILICOS-IT) :	1.41
Consensus Log Po/w :	1.53

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.94
Solubility :	0.266 mg/ml ; 0.00115 mol/l
Class :	Soluble
Log S (Ali) :	-3.14
Solubility :	0.166 mg/ml ; 0.000717 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.39
Solubility :	0.954 mg/ml ; 0.00411 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.97

Safety of [ 321601-48-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 321601-48-3 ]

* 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 [ 321601-48-3 ]
Downstream synthetic route of [ 321601-48-3 ]

[ 321601-48-3 ] Synthesis Path-Upstream 1~4

1
[ 62733-99-7 ]
[ 321601-48-3 ]
[ 321596-58-1 ]

Reference： [1] Patent: EP1516874, 2015, B1,

2
[ 321601-48-3 ]
[ 1256810-26-0 ]

Reference： [1] Patent: WO2014/121418, 2014, A1,
[2] Patent: WO2014/209727, 2014, A1,
[3] Patent: WO2014/205593, 2014, A1,

3
[ 321601-48-3 ]
[ 74-88-4 ]
[ 945954-94-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 3 h;	A mixture of methyl 6-bromo-3-hydroxypicolinate (4 g, 17.2 mmol), CH₃I (7.15 g, 34.5 mmol) and K₂C0₃ (4.76 g, 34.5 mmol) in DMF (50 mL) was stirred at RT for 3 hours. After concentrated, the mixture was diluted with H₂0 and extracted with EtOAc (50 mL * 3). The organic layer was dried over Na₂S0₄ and concentrated to give crude methyl 6-bromo-3- methoxypicolinate (4 g, yield: 90percent). 1H- MR (CDC1₃ , 400 MHz) δ 7.56 (d, J= 8.0 Hz, 1H), 7.25 (d, J= 8.0 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H). MS (M+H)⁺: 256 / 258.
78%	With potassium carbonate In acetone for 3 h; Reflux	[0183] Methyl 6-bromo-3-hydroxypicolinate (5.07 g, 21.85 mmol) was dissolved in acetone (75 mL). To the resulting solution were added dropwise potassium carbonate (K₂CO₃) (4.83 g, 34.96 mmol) and iodomethane (CH₃I) (1.77 mL, 28.41 mmol) and the solution was refluxed with heat for 3 hrs. The solution was evaporated under reduced pressure to concentrate, diluted with EtOAc, and washed with water. The washed organic solvent was dried over anhydrous magnesium sulfate (MgSO₄) to concentrate. The resulting residue was isolated and purified by silica gel column chromatography (hexane/ethylacetate = 3/1) to give the white title compound (4.18 g, 78 percent). ¹H NMR (600 MHz, CDCl₃) δ 7.57 (d, J = 9.0 Hz, 1H), 7.26 (d, J = 9.0 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H).
76%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4 h;	(step 3 ); A solution of the compound obtained in step 2 (9.42 g) , methyl iodide (2.78 mL) and potassium carbonate (7.29 g) in DMF (80 mL) was stirred at room temperature for 4 hrs, and poured into cold water. The mixture was extracted twice with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 20-25percent ethyl acetate/hexane) and <n="86"/>crystallized from ethyl acetate/hexane to give methyl 6-bromo-3-methoxypyridine-2-carboxylate (7.57 g, 76percent) as white crystals,

42%	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	A mixture of methyl 6-bromo-3-hydroxypicolinate (10.0 g, 43.10 mmol), Mel (12.3 g, 86.66 mmol) and K₂C0₃ (12.0 g, 86.83 mmol) in DMF (100 mL) was stirred at RT overnight. Then the reaction mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was dried over a₂S0₄ and concentrated to give methyl 6-bromo-3- methoxypicolinate (4.5 g, yield 42percent). ^XH-NMR (CDC1₃, 400 MHz) δ 7.55 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H). MS (M+H)⁺: 246 / 248.
42%	With potassium carbonate In N,N-dimethyl-formamide at 25℃;	A mixture of methyl 6-bromo-3-hydroxypicolinate (10.0 g, 43.10 mmol), Mel (12.3 g, 86.66 mmol) and K2C03 (12.0 g, 86.83 mmol) in DMF (100 mL) was stirred at RT overnight. Then the reaction mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give methyl 6-bromo-3-methoxypicolinate (4.5 g,yield 42percent). ‘H-NMR (CDC13, 400 MHz) 7.55 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 3.94(s, 3H), 3.90 (s, 3H). MS (M+H): 246 / 248.

Reference： [1] Patent: WO2014/121418, 2014, A1, . Location in patent: Page/Page column 45
[2] Patent: EP3255042, 2017, A2, . Location in patent: Paragraph 0180; 0183
[3] Patent: WO2007/89031, 2007, A1, . Location in patent: Page/Page column 84-85
[4] Patent: WO2014/209727, 2014, A1, . Location in patent: Page/Page column 39
[5] Patent: WO2014/205593, 2014, A1, . Location in patent: Page/Page column 41; 42

4
[ 186581-53-3 ]
[ 321601-48-3 ]
[ 945954-94-9 ]

Reference： [1] Patent: WO2007/31558, 2007, A1, . Location in patent: Page/Page column 33

[ 321601-48-3 ] Synthesis Path-Downstream 1~32

1
[ 37441-50-2 ]
[ 321601-48-3 ]
[ 835594-64-4 ]

Yield	Reaction Conditions	Operation in experiment
		A stirred mixture of methyl 6-BROMO-3-HYDROXYPYRIDINE-2-CARBOXYLATE (6.15 g, 26.5 mmol), 8-sultam (described in WO 02/30931-A2, Merck & Co. , Inc. , 2002) (3. 98 g, 29.4 mmol) and copper (I) oxide (5.75 g, 40.2 mmol) in anhydrous pyridine (100 mL) was heated at 130 C, under argon, for 6 h. The mixture was cooled, and the pyridine removed under reduced pressure. The residue was treated with CH2C12 (400 mL) and EDTA (0.35 M in H20, 300 ML, 105 mmol) and air was bubbled into the mixture for 18 h. The mixture was filtered through a pad of celite and the aqueous layer was saturated with solid NACI and extracted with CH2CLZ (4 x 250 mL). The combined organic extracts were dried (NA2S04), filtered, and concentrated in vacuo to afford a crude oil. The oil was dissolved in MEOH (400 mL) and conc. H2S04 (2 ML) and heated to reflux for 18 h, then allowed to cool to ambient temperature. Most of the solvent was removed in vacuo and the residual mixture was partitioned between CHZCLX (400 mL) and saturated NAHCO3 (400 mL). The aqueous layer was extracted further with CH2Cl2 (2 x 250 mL) and the combined organic extracts were dried (NA2S04), filtered, and concentrated in vacuo to afford a crude sample of the product. This crude product was partially purified by silica gel chromatography, eluting with a gradient of CH2C12 : MEOH-100 : 0 to 95: 5 to give a yellow solid that was crystallized from MEOH to afford the title compound as a pale yellow solid of sufficient purity for use in the next step. MS: FALZ = 287 (M + 1).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6705 - 6708
[2]Patent: WO2005/9962,2005,A1 .Location in patent: Page 25; 26

2
[ 62733-99-7 ]
[ 321601-48-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With bromine In water at 0℃; regioselective reaction;	2.2.2. Synthesis of methyl 3-hydroxy-6-bromopicolinate (Compound 3) To a solution of methyl 3-hydroxypicolinate 2 (10 g, 65.36 mmol) inosmosed water (0.1 M) with crushed ice at 0 °C, was added portionwisebromine (4×1.02 mL every 30 min, 78.4 mmol, 1.2 equiv) under vigorousstirring. The mixture was vigorously stirred at 0 °C for 1-2 h. Thesolution was extracted by dichloromethane and the combined organiclayers were washed with brine, dried over MgSO4 and concentratedunder reduced pressure to give 3 as a white-off solid (15.1 g, 99%).Rf=0.3 (Petroleum ether/EtOAc 3/2, v/v). 1H NMR (300 MHz, CDCl3)δ (ppm)=4.07 (s, 3H), 7.29 (d, J=8.7 Hz, 1H), 7.58 (dd, J=0.3,8.7 Hz, 1H), 10.72 (br s, 1H). 13C NMR (75 MHz, CDCl3) δ(ppm)=53.5, 129.5, 130.0, 130.7, 134.5, 158.5, 169.1. MS (ESI+): m/z (%): 234 (85) and 232 (100) [M+H]+ .
99%	With bromine In water at 0℃;	1 Methyl 6-bromo-3-hydroxypicolinate - 9a To a solution of methyl 3-hydroxypicolinate 8 (10 g, 65.36 mmol) in osmosed water (0.1 M) with crushed ice at 0 °C, was added portionwise bromine (4 x 1.02 mL every 30 min, 78.4 mmol, 1.2 equiv.) under vigorous stirring. The mixture was vigorously stirred at 0 °C for 1-2 h. The solution was extracted by dichloromethane and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 9a as a white-off solid (15.08 g, 99%). Rf = 0.3 (Petroleum ether/EtOAc 6/4, v/v). 1H NMR (300 MHz, CDCl3) δ (ppm) 4.07 (s, 3H), 7.29 (d, J = 8.7 Hz, 1H), 7.58 (dd, J = 0.3, 8.7 Hz, 1H), 10.72 (br s, 1H). 13C NMR (75 MHz, CDCl3): δ (ppm) 53.5, 129.5, 130.0, 130.7, 134.5, 158.5, 169.1. MS (ESI+): m/z (%): 234 (85) and 232 (100) [M+H]+.
99%	With bromine In water at 0℃;	1 Methyl 6-bromo-3-hydroxypicolinate - 9a To a solution of methyl 3-hydroxypicolinate 8 (10 g, 65.36 mmol) in osmosed water (0.1 M) with crushed ice at 0 °C, was added portionwise bromine (4 x 1.02 mL every 30 min, 78.4 mmol, 1.2 equiv.) under vigorous stirring. The mixture was vigorously stirred at 0 °C for 1-2 h. The solution was extracted by dichloromethane and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 9a as a white-off solid (15.08 g, 99%). Rf = 0.3 (Petroleum ether/EtOAc 6/4, v/v). 1H NMR (300 MHz, CDCl3) δ (ppm) 4.07 (s, 3H), 7.29 (d, J = 8.7 Hz, 1H), 7.58 (dd, J = 0.3, 8.7 Hz, 1H), 10.72 (br s, 1H). 13C NMR (75 MHz, CDCl3): δ (ppm) 53.5, 129.5, 130.0, 130.7, 134.5, 158.5, 169.1. MS (ESI+): m/z (%): 234 (85) and 232 (100) [M+H]+.

82%	With bromine In water at 20℃; for 3h;	135.2 Methyl 3-[(1-[(1-methylethyl)oxy]carbonyl}-4-piperidinyl)methyl]oxy}-6-[4-(methylsulfonyl)phenyl]-2-pyridinecarboxylate A stirred solution of methyl 3-hydroxy-2-pyridinecarboxylate (1.69 g, 11.0 mmol) in water (75 mL) at ambient temperature was treated dropwise with bromine (2.39 g, 15.0 mmol). The reaction mixture was stirred at ambient temperature for 3 h, during which time a fine white precipitate formed. The mixture was extracted with CH2Cl2 (100 mL×2). The combined organic extracts were washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give 2.11 g (82%) of methyl 6-bromo-3-hydroxy-2-pyridinecarboxylate as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 10.69 (s, 1H), 7.55 (d, 1H, J=8.8 Hz), 7.27 (d, 1H, J=8.8 Hz), 4.04 (s, 3H); LRMS (APCI), m/z 232/234 (M+H).
80.7%	With bromine In water at 25℃;	19.2; 20.2 Synthesis of methyl 6-bromo-3-hydroxypicolinate A solution of methyl 3-hydroxypicolinate (5 g, 32.65 mmol) in 60 mL of H20 was stirred at RT and Br2 (5.22 g, 32.65 mmol) was added dropwise. The mixture was stirred at RT overnight, and the resulting solid was collected and washed with water to afford methyl 6- bromo-3-hydroxypicolinate. Then the filtrate was basified with Na2C03 until pH reached 7, and after extracted with EtOAc, the organic layer was concentrated to give the 2nd part of methyl 6- bromo-3-hydroxypicolinate (6.1 g total, yield: 80.7%). 1H- MR (CDC13 , 400 MHz) δ 10.67 (s, 1H), 7.54 (t, J= 8.0 Hz, 1H), 7.24 (d, J= 4.0 Hz, 1H), 4.02 (s, 3H). MS (M+H)+: 232 / 234.
80.7%	With bromine In water at 20℃;	1.1 Step 1 - Synthesis of methyl 6-bromo-3-hydroxypicolinate A mixture of methyl 3-hydroxypicolinate (5.0 g, 32.65 mmol) in H2O was stirred at RT and then Br2 (5.2 g, 32.65 mmol) was added dropwise. After the mixture was stirred at RT overnight, the mixture was filtered and the precipitate was washed with water and dried to give methyl 6-bromo-3-hydroxypicolinate (6.1 g, yield 80.7%). XH-NMR (DMSO, 400 MHz) δ 10.71 (s, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 3.87 (s, 3H). MS (M+H)+: 232 / 234.
80.7%	With bromine In water at 25℃;	1.1 Synthesis of methyl 6-bromo-3-hydroxypicolinate A mixture of methyl 3-hydroxypicolinate (5.0 g, 32.65 mmol) in H20 was stirred at RT and then Br2 (5.2 g, 32.65 mmol) was added dropwise. After the mixture was stirred at RT overnight, the mixture was filtered and the precipitate was washed with water and dried to give methyl 6-bromo-3-hydroxypicolinate (6.1 g, yield 80.7%). ‘H-NMR (DMSO, 400 MHz) 10.71 (s, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 3.87 (s, 3H). MS (M+H): 232 / 234.
80%	With bromine In water at 20℃; for 3h;
79%	With bromine In water
74%	With bromine In water at 20℃; for 4h;	3.2 (step 2); To a solution of the compound obtained in step 1(9.19 g) in water (150 mL) was added bromine (3.23 mL) at room temperature and the mixture was stirred for 4 hrs . The reaction mixture was extracted with a mixture of ethyl acetate/THF, and the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from ethyl acetate/hexane to give methyl 6-bromo-3- hydroxypyridine-2-carboxylate (10.3 g, 74%) as brown crystals,
72%	With bromine In water at 20℃; for 4h;	3-2 Preparation Example 3-2 : Preparation of methyl 6-bromo-3-hydroxypicolinate (LXVI) [0182] Methyl 3-hydroxypicolinate (4.62 g, 30.17 mmol) was dissolved in distilled water (200 mL). To the resulting solution was slowly added dropwise bromine water (1.7 mL, 33.18 mmol) and the solution was stirred at room temperature for 4 hrs. The solution was diluted with ethylacetate and washed with water. The washed organic solvent was dried over anhydrous magnesium sulfate (MgSO4) to concentrate. The resulting residue was isolated and purified by silica gel column chromatography (hexane/ethylacetate = 3/1) to give the white title compound (5.07 g, 72 %). 1H NMR (600 MHz, CDCl3) δ 7.55 (d, J = 9.0 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 4.04 (s, 3H).
66%	With bromine In water at 20℃; for 2h;	22 Intermediate 65: methyl 6-bromo-3-hydroxypicolinate A solution of methyl 3-hydroxypicolinate (21 g, 137 mmol) in Water (500 mL) was stired at rt for 2 h. The precipitate was filtered, washed with water and dried in vacuo to provide the desired product methyl 6-bromo-3-hydroxypicolinate (21 g, 91 mmol, 66.0 % yield), m/z: [M + H]+ Calcd for C7H6BrN03 232.0; Found 232
53%	With bromine In water at 0 - 20℃; for 17h;
53%	With bromine In water at 0 - 20℃; for 17h;
52.8%	With bromine In water at 0℃; for 2h;	Step-2 synthesis of methyl 6-bromo-3-hydroxypicolinate (Intermediate AA198-4) To a solution of Intermediate AA198-3 (5.0 g, 32.67 mmol) in water (50 mL) at 0° C. was added slowly dropwise bromine (2.0 mL, 39.20 mmol, 1.2 eq). After stirring for 2 h, the reaction mixture was extracted with DCM (3×80 mL). The combined organic extracts were washed with brine (250 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford Intermediate AA198-4 (4.0 g, 52.80%), MS (ES): m/z 232.9 [M+H]+
	With bromine In water	6-BROMO-3-HYDROXYPICOLINIC ACID (17). 6-BROMO-3-HYDROXYPICOLINIC ACID (17). To a mechanically stirred solution of methyl 3-hydroxypicolinate (30.6 g) in water (800 mL) was slowly added bromine (32 g) over a 30 minute period. After the addition was complete, stirring was continued for an additional hour. Ether (300 mL) was added and stirring continued until all the solids had dissolved. The organic layer was separated and the aqueous phase extracted with ether (200 mL). The organic phases were combined, dried (MgSO4) and the solvent evaporated to give 32.8 g of methyl 6-bromo-3-hydroxypicolinate as an off-white solid. Recrystallization from methanol/water gave an analytical sample, m.p. 115-117° C.
	With bromine In water at 20℃;	45 To a stirred solution of methyl 3-hydroxy-2-pyridinecarboxylate D44 (0.100 g) in water (5 ml), Br2 (0.045 ml, 0.882 mmol) was added dropwise and the solution was left stirring at room temperature. A precipitate occurred. The mixture was left stirring for 30 minutes, then DCM was added and the two phases were separated. The aqueous one was extracted with DCM. The organic layers were filtered through a phase separator and evaporated. The crude was purified by flash chromatography on silica gel (Flash Master Personal, 1O g cartridge eluting with Cy 90% EtOAc 10%). The fractions were collected and the solvent removed in vacuo obtaining the title compound D45 (0.100 g). MS: (ES/+) m/z: 233 (M+l). C7H6BrNO3 requires 232. 1H-NMR (400 MHz, CDCl3) δ ppm: 10.69 (s, 1 H), 7.61-7.51 (d, 1 H), 7.32-7.25 (d, 1 H), 4.06 (s, 3 H).
	With bromine In water for 0.5h;	10.A Step A: methyl 6-bromo-3-hydroxypicolinate To a water (20 mL) solution of methyl 3-hydroxypicolinate (500 mg, 3.27 mmol) was added dropwise bromine (225 μ, 4.37 mmol). A precipitate formed. After 30 min, the reaction was extracted with DCM (2 x 20 mL). The combined organic layers were dried (Na2SC"4), filtered and concentrated to give the title compound. 1H NMR (500 MHz, CDC13): δ 10.71 (s, 1H), 7.59 (d, 1H), 7.25 (d, 1H), 4.04 (s, 3H).
	With bromine In water at 20℃; for 3h;	B Step B. Methyl 6-BROMO-3-HYDRYPYRIDINE-2-CARBOXYLATE To a stirred solution of methyl 3-hydroxypyridine-2-carboxylate (9.03 g, 59.0 mmol) in H20 (400 mL), at ambient temperature, was added dropwise bromine (12.8 g, 4.10 ML, 80.0 mmol). The mixture was stirred for 3 h, during which time a fine white precipitate formed. The aqueous mixture was extracted with CH2C12 (2 x 500 mL) and the combined organic extracts were dried (NA2SO4), filtered, and concentrated IN VACUO TO afford the title compound as a white solid of sufficient purity for use in the next step. MS: m/z = 232 (M + 1).
3.5 g	With bromine In water at 20℃; for 6h;	39.39.2 39.2 Methyl 6-bromo-3-hydroxy-2-picolinate A 250 mL single-necked flask was charged with methyl 3-hydroxy-2-picolinate (3.00 g), bromine (4.70 g) and 80 mL of water, which were reacted at room temperature for 6 h. A sample was taken, and TLC detection showed that the spots of the raw materials disappeared. The mixture was extracted with ethyl acetate (50 mL × 3), washed with 100 mL of saturated saline, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE : EA = 7 : 1), so as to obtain 3.5 g of methyl 6-bromo-3-hydroxy-2-picolinate.

Reference： [1]Pashirova, Tatiana N.; Braïki, Anissa; Zueva, Irina V.; Petrov, Konstantin A.; Babaev, Vasily M.; Burilova, Evgenia A.; Samarkina, Darya A.; Rizvanov, Ildar Kh.; Souto, Eliana B.; Jean, Ludovic; Renard, Pierre-Yves; Masson, Patrick; Zakharova, Lucia Ya.; Sinyashin, Oleg G. [Journal of Controlled Release, 2018, vol. 290, p. 102 - 111]
[2]Current Patent Assignee: NATIONAL INSTITUTE OF APPLIED SCIENCES; UNIVERSITY OF ROUEN NORMANDIE; ETAT FRANCAIS REPRESENTE PAR LA DIRECTION CENTRALE DU SERVICE DE SANTE DES ARMEES; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - EP3945092, 2022, A1 Location in patent: Paragraph 0086; 0101-0102
[3]Current Patent Assignee: NATIONAL INSTITUTE OF APPLIED SCIENCES; UNIVERSITY OF ROUEN NORMANDIE; ETAT FRANCAIS REPRESENTE PAR LA DIRECTION CENTRALE DU SERVICE DE SANTE DES ARMEES; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - EP3945092, 2022, A1 Location in patent: Paragraph 0086; 0101-0102
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2010/29650, 2010, A1 Location in patent: Page/Page column 65
[5]Current Patent Assignee: MERCK & CO INC; WUXI APPTEC CO., LTD. - WO2014/121418, 2014, A1 Location in patent: Page/Page column 44; 45
[6]Current Patent Assignee: WUXI APPTEC CO., LTD. - WO2014/209727, 2014, A1 Location in patent: Page/Page column 32
[7]Current Patent Assignee: WUXI APPTEC CO., LTD. - WO2014/205593, 2014, A1 Location in patent: Page/Page column 33; 34
[8]Nguyen, William; Lee, Erinna F.; Evangelista, Marco; Lee, Mihwa; Harris, Tiffany J.; Colman, Peter M.; Smith, Nicholas A.; Williams, Luke B.; Jarman, Kate E.; Lowes, Kym N.; Haeberli, Cécile; Keiser, Jennifer; Smith, Brian J.; Fairlie, W. Douglas; Sleebs, Brad E. [ACS Infectious Diseases, 2021, vol. 7, # 5, p. 1143 - 1163]
[9]Location in patent: scheme or table Zartman, C. Blair; Bell, Ian M.; Gallicchio, Steven N.; Graham, Samuel L.; Kane, Stefanie A.; Mallee, John J.; Rutledge, Ruth Z.; Salvatore, Christopher A.; Vacca, Joseph P.; Williams, Theresa M. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 22, p. 6705 - 6708]
[10]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2007/89031, 2007, A1 Location in patent: Page/Page column 84
[11]Current Patent Assignee: BEYONDBIO INC - EP3255042, 2017, A2 Location in patent: Paragraph 0180; 0182
[12]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2019/63748, 2019, A1 Location in patent: Page/Page column 263
[13]Mercey, Guillaume; Verdelet, Tristan; Saint-Andre, Geraldine; Gillon, Emilie; Wagner, Alain; Baati, Rachid; Jean, Ludovic; Nachon, Florian; Renard, Pierre-Yves [Chemical Communications, 2011, vol. 47, # 18, p. 5295 - 5297]
[14]Renou, Julien; Loiodice, Mélanie; Arboléas, Mélanie; Baati, Rachid; Jean, Ludovic; Nachon, Florian; Renard, Pierre-Yves [Chemical Communications, 2014, vol. 50, # 30, p. 3947 - 3950]
[15]Current Patent Assignee: NIMBUS THERAPEUTICS INC; CHARLES RIVER LABORATORIES INTERNATIONAL INC; NIMBUS SATURN - US2021/78996, 2021, A1 Location in patent: Paragraph 1014; 1016
[16]Current Patent Assignee: VINCENT YUVAL R D - US6355660, 2002, B1
[17]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2010/72722, 2010, A1 Location in patent: Page/Page column 39-40
[18]Current Patent Assignee: MERCK & CO INC - WO2014/130608, 2014, A1 Location in patent: Page/Page column 142-143
[19]Current Patent Assignee: MERCK & CO INC - WO2005/9962, 2005, A1 Location in patent: Page 25
[20]Current Patent Assignee: NANJING GEAR PHARMA TECH; SINO BIOPHARMACEUTICAL LIMITED - EP3689860, 2020, A1 Location in patent: Paragraph 0434; 0436

3
[ 908094-01-9 ]
[ 321601-48-3 ]
[ 945954-94-9 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; diethyl ether at 0℃; for 2h;	c A solution of diazomethane in diethyl ether (about 0.4 M) is added in excess to a solution of 2.3 mmol of methyl 6-bromo-3-hydroxypyridine-2-carboxylate [321601-48-3] in 30 ml of methanol at 0°C. The mixture is stirred at 0°C for 2 hours, then quenched with magnesium sulphate, filtered and evaporated. The crude title compound is identified by means of the Rf.

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2007/31558, 2007, A1 Location in patent: Page/Page column 33

4
[ 321601-48-3 ]
[ 74-88-4 ]
[ 945954-94-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 3h;	19.3; 20.3 Synthesis of methyl 6-bromo-3-methox icolinate A mixture of methyl 6-bromo-3-hydroxypicolinate (4 g, 17.2 mmol), CH3I (7.15 g, 34.5 mmol) and K2C03 (4.76 g, 34.5 mmol) in DMF (50 mL) was stirred at RT for 3 hours. After concentrated, the mixture was diluted with H20 and extracted with EtOAc (50 mL * 3). The organic layer was dried over Na2S04 and concentrated to give crude methyl 6-bromo-3- methoxypicolinate (4 g, yield: 90%). 1H- MR (CDC13 , 400 MHz) δ 7.56 (d, J= 8.0 Hz, 1H), 7.25 (d, J= 8.0 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H). MS (M+H)+: 256 / 258.
81%	With potassium carbonate In acetone at 38℃; for 2h;	22 Intermediate 66: methyl 6-bromo-3-methoxypicolinate To a solution of methyl 6-bromo-3-hydroxypicolinate (21 g, 91 mmol) in Acetone (400 mL) was added iodomethane (38.5 g, 272 mmol) at rt. The mixture was stired for 2 h at 38 °C. The precipitate was filtered, washed with water and dried in vacuo to provide the desired product methyl 6-bromo-3-methoxypicolinate (18g, 73.2 mmol, 81 % yield), m/z: [M + H]+ Calcd for C8H8BrN03 246.0; Found 246.0
78%	With potassium carbonate In acetone for 3h; Reflux;	3-3 Preparation Example 3-3 : Preparation of methyl 6-bromo-3-methoxypicolinate (LXVII) [0183] Methyl 6-bromo-3-hydroxypicolinate (5.07 g, 21.85 mmol) was dissolved in acetone (75 mL). To the resulting solution were added dropwise potassium carbonate (K2CO3) (4.83 g, 34.96 mmol) and iodomethane (CH3I) (1.77 mL, 28.41 mmol) and the solution was refluxed with heat for 3 hrs. The solution was evaporated under reduced pressure to concentrate, diluted with EtOAc, and washed with water. The washed organic solvent was dried over anhydrous magnesium sulfate (MgSO4) to concentrate. The resulting residue was isolated and purified by silica gel column chromatography (hexane/ethylacetate = 3/1) to give the white title compound (4.18 g, 78 %). 1H NMR (600 MHz, CDCl3) δ 7.57 (d, J = 9.0 Hz, 1H), 7.26 (d, J = 9.0 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H).

76%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4h;	3.3 (step 3 ); A solution of the compound obtained in step 2 (9.42 g) , methyl iodide (2.78 mL) and potassium carbonate (7.29 g) in DMF (80 mL) was stirred at room temperature for 4 hrs, and poured into cold water. The mixture was extracted twice with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 20-»25% ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give methyl 6-bromo-3-methoxypyridine-2-carboxylate (7.57 g, 76%) as white crystals,
42%	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	10.1 Step 1 - Synthesis of methyl 6-bromo-3-methoxypicolinate A mixture of methyl 6-bromo-3-hydroxypicolinate (10.0 g, 43.10 mmol), Mel (12.3 g, 86.66 mmol) and K2C03 (12.0 g, 86.83 mmol) in DMF (100 mL) was stirred at RT overnight. Then the reaction mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was dried over a2S04 and concentrated to give methyl 6-bromo-3- methoxypicolinate (4.5 g, yield 42%). XH-NMR (CDC13, 400 MHz) δ 7.55 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H). MS (M+H)+: 246 / 248.
42%	With potassium carbonate In N,N-dimethyl-formamide at 25℃;	10.1 Synthesis of methyl 6-bromo-3-methoxypicolinate A mixture of methyl 6-bromo-3-hydroxypicolinate (10.0 g, 43.10 mmol), Mel (12.3 g, 86.66 mmol) and K2C03 (12.0 g, 86.83 mmol) in DMF (100 mL) was stirred at RT overnight. Then the reaction mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give methyl 6-bromo-3-methoxypicolinate (4.5 g,yield 42%). ‘H-NMR (CDC13, 400 MHz) 7.55 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 3.94(s, 3H), 3.90 (s, 3H). MS (M+H): 246 / 248.

Reference： [1]Current Patent Assignee: MERCK & CO INC; WUXI APPTEC CO., LTD. - WO2014/121418, 2014, A1 Location in patent: Page/Page column 45
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2019/63748, 2019, A1 Location in patent: Page/Page column 263
[3]Current Patent Assignee: BEYONDBIO INC - EP3255042, 2017, A2 Location in patent: Paragraph 0180; 0183
[4]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2007/89031, 2007, A1 Location in patent: Page/Page column 84-85
[5]Current Patent Assignee: WUXI APPTEC CO., LTD. - WO2014/209727, 2014, A1 Location in patent: Page/Page column 39
[6]Current Patent Assignee: WUXI APPTEC CO., LTD. - WO2014/205593, 2014, A1 Location in patent: Page/Page column 41; 42

5
[ 321601-48-3 ]
[ 588-63-6 ]
[ 1135872-25-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium hydride In ISOPROPYLAMIDE at 90℃; for 3h;	67.a a) 6-Bromo-3-(3-phenoxy-propoxy)-pyridine-2-carboxylic acid methyl esterA mixture of -bromo-3-hydroxypicolinic acid methyl ester (lOOmg, 0.43 mmol), sodium hydride (60% dispersion in mineral oil) (17.3mg, 0.43 mmol), 3-phenoxypropyl bromide(68 μL, 0.43 mmol), in dimethyl acetamide (1.5 mL) was heated at 9O0C for 3 hours. The reaction was allowed to cool, poured onto water and then extracted with ethyl acetate (2 x3mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by silica chromatography eluting with 100% petroleum ether to 30% ethyl acetate/petroleum ether to obtain a white solid (95mg, 60%). 1H NMR (300 MHz,CDCl3) δ: 7.48 (IH, d), 7.24-7.21 (3H, m), 6.91-6.86 (3H, m), 4.19 (2H, t), 4.15 (2H, t),3.88 (3H, s), 2.30-2.22 (2H, m).

Reference： [1]Current Patent Assignee: THE WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH - WO2009/39553, 2009, A1 Location in patent: Page/Page column 110

6
[ 321601-48-3 ]
[ 1135871-91-8 ]
[ 1135872-28-4 ]

Yield	Reaction Conditions	Operation in experiment
31%	With tetrabutylammomium bromide; caesium carbonate In 1,4-dioxane; water at 100℃; for 1.5h; Microwave irradiation;	68.a a) 3-Hydroxy-6-(8-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-pyridine-2-carboxylic acid methyl esterA mixture of methyl 6-bromo-3-hydroxypicolinate (lOOmg, 0.43 mmol), 7-pinacloatoborane-tetralone (129mg, 0.47 mmol), PdCl2(PPh3)2 (7.5mg, 2.5 mol%), tetrabutylammonium bromide (14mg, 0.043 mmol), caesium fluoride (145mg, 0.95 mmol) in dioxane:H2O (2:1, mL) was heated at 1000C under microwave irradiation for 90 minutes. The reaction was cooled, diluted with ethyl acetate and poured onto water. The aqueous phase was extracted with ethyl acetate (2 x 3mL), the organic layer was dried (MgSO4) and concentrated in vacuo. The residue was triturated with diethyl ether and the solid was filtered to afford an off-white solid (40mg, 31%). 1H NMR (d6-DMSO) δ: 10.55 (IH, bs), 8.42 (IH, d), 8.13 (IH, dd), 8.07 (IH, dd), 7.48 (IH, d), 7.43 (IH, d), 3.90 (3H, s), 2.96 (2H, t), 2.61 (2H, t), 2.07-2.01 (2H, m).

Reference： [1]Current Patent Assignee: THE WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH - WO2009/39553, 2009, A1 Location in patent: Page/Page column 111

7
[ 321601-48-3 ]
[ 1174728-40-5 ]

Yield	Reaction Conditions	Operation in experiment
56%	Stage #1: methyl 6-bromo-3-hydroxypyridine-2-carboxylate With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 2h; Stage #2: With sodium hydroxide; water In tetrahydrofuran for 1h;	133.17a To a solution of methyl 6-bromo-3-hydroxypyridine-2-carboxylate (2g, 8.6 mmol, prepared according to procedures in WO2005009962) in THF (30 mL), was added LAH (34 mL, 34.4 mmol, 1 M in TBDF). The solution was stirred at rt for 2 h. To the solution was then added water (1.3 mL), 10% aqueous NaOH (1.3 mL), and water (3.9 mL). After stirring for 1 h, the solution was filtered and the solids washed with EtOAc. The organics were then washed with IN HCl and brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield intermediate 17A (0.99g, 56%). 1H-NMR (CD3OD) δ 7.3 (d, J = 8.4 Hz, IH), 7.09 (d, J = 8.4 Hz, IH), 4.67 (s, 2 H); MS (ESI+): 204.1 (M+H).
	With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 0.5h;	10.B Step B: 6-bromo-2-(hvdroxymethyl)pyridin-3-ol To a THF (8 mL) solution of methyl 6-bromo-3-hydroxypicolinate (500 mg, 2.15 mmol) was added a LAH solution (1M in THF, 4 ml, 8.0 mmol. After 30 minutes at room temp, the reaction was quenched by the sequential addition of water (0.30 mL), 15% NaOH (0.30 mL), and water (0.90 mL). The mixture was then stirred vigorously as a white precipitate formed. The resulting mixture was filtered and concentrated to give the title compound. 1H NMR (500 MHz, CDCI3): δ 7.31 (d, 1H), 7.10 (d, 1H), 4.65 (s, 2H), 3.30 (br, 1H).

Reference： [1]Current Patent Assignee: LIGAND PHARMACEUTICALS INC; TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2009/97567, 2009, A1 Location in patent: Page/Page column 75-76
[2]Current Patent Assignee: MERCK & CO INC - WO2014/130608, 2014, A1 Location in patent: Page/Page column 142; 143

8
[ 321601-48-3 ]
[ 75-03-6 ]
[ 1233520-14-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	46 Methyl 6-bromo-3-hydroxy-2-pyridinecarboxylate D45 (0.200 g, 0.862 mmol), K2CO3 (0.596 g, 4.31 mmol) and iodoethane (0.139 ml, 1.724 mmol) were dissolved DMF (3 ml). The mixture was left stirring at room temperature overnight. To the solution were added H2O and DCM. The two layers were separated. The aqueous one was extracted several times with DCM. The organic layers were washed with brine/ice, filtered through a phase separator and evaporated. The crude was purified by flash chromatography on silica gel (Flash Master Personal, 20 g cartridge eluting from Cy 100 % to Cy 90 %: EtOAc 10 %). The fractions were collected obtaining the title compound D46 (0.200 g). MS: (ES/+) m/z: 260 (M+l). C9H10BrNO3 requires 259. 1H-NMR (400 MHz, CDCl3) δ ppm: 7.55-7.53 (d, 1 H), 7.25-7.23 (d, 1 H), 4.18-4.10 (m, 2 H), 3.96 (s, 3 H), 1.50-1.43 (m, 3 H).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2010/72722, 2010, A1 Location in patent: Page/Page column 40

9
[ 321601-48-3 ]
[ 1310031-62-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere

Reference： [1]Mercey, Guillaume; Verdelet, Tristan; Saint-Andre, Geraldine; Gillon, Emilie; Wagner, Alain; Baati, Rachid; Jean, Ludovic; Nachon, Florian; Renard, Pierre-Yves [Chemical Communications, 2011, vol. 47, # 18, p. 5295 - 5297]

10
[ 321601-48-3 ]
[ 1310031-64-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr

11
[ 321601-48-3 ]
[ 1310031-66-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr 4: 1H-imidazole / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere 5: diisobutylaluminium hydride / dichloromethane / 0.17 h / -78 °C 6: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 0 °C

12
[ 321601-48-3 ]
C₃₅H₄₈N₂O₅Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr 4: 1H-imidazole / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere

13
[ 321601-48-3 ]
[ 1310031-58-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr 4: 1H-imidazole / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere 5: diisobutylaluminium hydride / dichloromethane / 0.17 h / -78 °C 6: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 0 °C 7: hydroxylamine hydrochloride; sodium acetate / ethanol / 20 °C / Inert atmosphere

14
[ 321601-48-3 ]
[ 1310031-61-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere

15
[ 321601-48-3 ]
[ 1310031-63-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr

16
[ 321601-48-3 ]
C₃₄H₄₆N₂O₅Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr 4: 1H-imidazole; tert-butyldimethylsilyl chloride / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere

17
[ 321601-48-3 ]
[ 1310031-57-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr 4: diisobutylaluminium hydride / dichloromethane / 0.17 h / -78 °C 5: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 0 °C 6: hydroxylamine hydrochloride; sodium acetate / ethanol / 20 °C / Inert atmosphere

18
[ 321601-48-3 ]
[ 1310031-65-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr 4: diisobutylaluminium hydride / dichloromethane / 0.17 h / -78 °C 5: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 0 °C

19
[ 321601-48-3 ]
C₃₄H₄₆N₂O₄Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr 4: 1H-imidazole / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere 5: diisobutylaluminium hydride / dichloromethane / 0.17 h / -78 °C

20
[ 321601-48-3 ]
[ 100-39-0 ]
[ 1235142-25-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate In acetone Reflux;	2.2.3. Synthesis of methyl 3-(benzyloxy)-6-bromopicolinate (Compound 4) To a solution of methyl 3-hydroxy-6-bromopicolinate 3 (11.6 g,49.8 mmol), in acetone (200 mL, 0.25 M) was added successively K2CO3(21 g, 149 mmol, 3 equiv) and benzyl bromide (12 mL, 100 mmol, 2.0equiv). The heterogeneous reaction mixture was reflux overnight. Saltswere removed by filtration and the crude product was concentratedunder reduced pressure. Purification by flash chromatography (Petroleum ether/EtOAc 95/5 to 3/2, v/v) afforded the desired product4 as a white solid (15.2 g, 95%). Rf=0.4 (Petroleum ether/EtOAc 8/2,v/v). 1H NMR (300 MHz, CDCl3): δ (ppm)=3.97 (s, 3H), 5.21 (s, 2H),7.24 (d, J=8.7 Hz, 1H), 7.47-7.34 (m, 5H), 7.51 (d, J=8.7 Hz, 1H).13C NMR (75 MHz, CDCl3): δ (ppm)=52.9, 71.2, 125.0, 126.9, 128.4,128.8, 131.2, 131.4, 135.2, 139.8, 154.0, 164.0. MS (ESI+): m/z (%):324 (85) and 322 (100) [M+H]+.
95%	With potassium carbonate In acetone Reflux;	1 Methyl 3-(benzyloxy)-6-bromopicolinate - 4a To a solution of methyl 3-hydroxy-6-bromopicolinate 9a (11.6 g, 49.8 mmol), in acetone (200 mL, 0.25 M) was added successively potassium carbonate (21 g, 149 mmol, 3 equiv.) and benzyl bromide (12 mL, 100 mmol, 2.0 equiv.). The heterogeneous reaction mixture was reflux overnight. Salts were removed by filtration and the crude product was concentrated under reduced pressure. Purification by flash chromatography on silica gel (Petroleum ether/EtOAc 95/5 to 60/40, v/v) afforded the desired product 4a as a white solid (15.2 g, 95%). Rf = 0.4 (Petroleum ether/EtOAc 8/2, v/v). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.97 (s, 3H), 5.21 (s, 2H), 7.24 (d, J = 8.7 Hz, 1H), 7.47-7.34 (m, 5H), 7.51 (d, J = 8.7 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ (ppm) 52.9, 71.2, 125.0, 126.9, 128.4, 128.8, 131.2, 131.4, 135.2, 139.8, 154.0, 164.0. MS (ESI+): m/z (%): 324 (85) and 322 (100) [M+H] +.
95%	With potassium carbonate In acetone Reflux;	1 Methyl 3-(benzyloxy)-6-bromopicolinate - 4a To a solution of methyl 3-hydroxy-6-bromopicolinate 9a (11.6 g, 49.8 mmol), in acetone (200 mL, 0.25 M) was added successively potassium carbonate (21 g, 149 mmol, 3 equiv.) and benzyl bromide (12 mL, 100 mmol, 2.0 equiv.). The heterogeneous reaction mixture was reflux overnight. Salts were removed by filtration and the crude product was concentrated under reduced pressure. Purification by flash chromatography on silica gel (Petroleum ether/EtOAc 95/5 to 60/40, v/v) afforded the desired product 4a as a white solid (15.2 g, 95%). Rf = 0.4 (Petroleum ether/EtOAc 8/2, v/v). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.97 (s, 3H), 5.21 (s, 2H), 7.24 (d, J = 8.7 Hz, 1H), 7.47-7.34 (m, 5H), 7.51 (d, J = 8.7 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ (ppm) 52.9, 71.2, 125.0, 126.9, 128.4, 128.8, 131.2, 131.4, 135.2, 139.8, 154.0, 164.0. MS (ESI+): m/z (%): 324 (85) and 322 (100) [M+H] +.

93%	With potassium carbonate In acetone for 15h; Reflux;
93%	With potassium carbonate In acetone for 15h; Reflux;
	With potassium carbonate In tetrahydrofuran at 20℃; for 3h;	1.2 Step 2 - Synthesis of methyl 3-(benzyloxy)-6-bromopicolinate A mixture of methyl 6-bromo-3-hydroxypicolinate (500 mg, 2.15 mmol), BnBr (443 mg, 3.25 mmol) and K2C03 (595 mg, 4.31 mmol) in THF (5 mL) was stirred at RT for 3 h. Then water was added and the mixture was extracted with EtOAc (20 mL * 3). The organic layer was dried over Na2S04 and concentrated to give crude methyl 3-(benzyloxy)-6- bromopicolinate (500 mg, yield 72%), which was used for the next step without further purification. MS (M+H)+: 322 / 324.
	With potassium carbonate In tetrahydrofuran at 25℃; for 3h;	1.2 Synthesis of methyl 3-(benzyloxy)-6-bromopicolinate A mixture of methyl 6-bromo-3-hydroxypicolinate (500 mg, 2.15 mmol), BnBr (443 mg, 3.25 mmol) and K2C03 (595 mg, 4.31 mmol) in THF (5 mL) was stirred at RT for 3 h. Then water was added and the mixture was extracted with EtOAc (20 mL * 3). The organic layer was dried over Na2504 and concentrated to give crude methyl 3-(benzyloxy)-6-bromopicolinate (500 mg, yield 72%), which was used for the next step without further purification. MS (M+H): 322 / 324.

21
[ 321601-48-3 ]
4-bromo-N-(3,5-difluorobenzyl)-6-(1,1-dioxido-1,2-thiazinan-2-yl)-3-hydroxypyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: pyridine; copper(II) oxide / 130 °C 2: N-Bromosuccinimide; methylene chloride / 80 °C 3: toluene / Reflux
	Multi-step reaction with 4 steps 1.1: pyridine / copper(I) oxide / 6 h / 130 °C 1.2: 18 h / Heating / reflux 2.1: N-Bromosuccinimide / chloroform / 3 h / Heating / reflux 3.1: sodium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 3.2: pH 3 4.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / DMF (N,N-dimethyl-formamide) / 0.02 h / 20 °C 4.2: 2 h

Reference： [1]Zartman, C. Blair; Bell, Ian M.; Gallicchio, Steven N.; Graham, Samuel L.; Kane, Stefanie A.; Mallee, John J.; Rutledge, Ruth Z.; Salvatore, Christopher A.; Vacca, Joseph P.; Williams, Theresa M. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 22, p. 6705 - 6708]
[2]Current Patent Assignee: MERCK & CO INC - WO2005/9962, 2005, A1

22
[ 321601-48-3 ]
[ 835594-65-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: pyridine; copper(II) oxide / 130 °C 2: N-Bromosuccinimide; methylene chloride / 80 °C
	Multi-step reaction with 2 steps 1.1: pyridine / copper(I) oxide / 6 h / 130 °C 1.2: 18 h / Heating / reflux 2.1: N-Bromosuccinimide / chloroform / 3 h / Heating / reflux

23
[ 321601-48-3 ]
[ 107-30-2 ]
[ 1402603-50-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine In chloroform at 0 - 20℃; for 1.08333h; Inert atmosphere;	21.21.1 Reference Example 21(1) methyl 6-bromo-3-(methoxymethoxy)picolinate Diisopropylethylamine (1.46 mL) was added to a chloroform (20 mL) solution of methyl 6-bromo-3-hydroxypyridine-2-carboxylate (970 mg) and placed in a nitrogen atmosphere. Next, the reaction mixture was cooled to 0° C., and chloromethoxymethane (0.38 mL) was added thereto. The reaction mixture was stirred at 0° C. for 5 minutes, and then stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C., diluted with water, and extracted with chloroform. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give the desired product (1.22 g, yield: 100%) as a colorless oil. 1H-NMR (CDCl3) δ: 7.54 (1H, d, J=8.8 Hz), 7.51 (1H, d, J=8.8 Hz), 5.26 (2H, s), 3.96 (3H, s), 3.51 (3H, s). ESI-MS m/z 276,278 (MH+)
100%	With N-ethyl-N,N-diisopropylamine In chloroform at 0 - 20℃; for 1.08333h; Inert atmosphere;	21.1 Reference Example 21(1) methyl 6-bromo-3-(methoxymethoxy)picolinate Reference Example 21 Reference Example 21(1) methyl 6-bromo-3-(methoxymethoxy)picolinate Diisopropylethylamine (1.46 mL) was added to a chloroform (20 mL) solution of methyl 6-bromo-3-hydroxypyridine-2-carboxylate (970 mg) and placed in a nitrogen atmosphere. Next, the reaction mixture was cooled to 0°C, and chloromethoxymethane (0.38 mL) was added thereto. The reaction mixture was stirred at 0°C for 5 minutes, and then stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, diluted with water, and extracted with chloroform. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give the desired product (1.22 g, yield: 100%) as a colorless oil. 1H-NMR (CDCl3) δ: 7.54 (1H, d, J = 8.8 Hz), 7.51 (1H, d, J = 8.8 Hz), 5.26 (2H, s), 3.96 (3H, s), 3.51 (3H, s). ESI-MS m/z 276,278(MH+)
95%	Stage #1: methyl 6-bromo-3-hydroxypyridine-2-carboxylate; chloromethyl methyl ether With potassium carbonate at 0℃; Inert atmosphere; Reflux; Stage #2: With sodium hydride at 0℃; for 1h; Inert atmosphere;	1 Methyl 6-bromo-3-(methoxymethoxy)picolinate - 4b To a solution of 9a (4.84 g, 20.87 mmol) in acetone (100 mL) was slowly added potassium carbonate (5.8 g, 2 equiv.) and MOMCl (20 mL, 41.74 mmol, 2 equiv.) under argon at 0 °C. The mixture was stirred heated to reflux overnight. Salts were removed by filtration and the crude was concentrated under vacuum. The desired product was obtained after purification by flash chromatography on silica gel (Petroleum ether/EtOAc, 60/40, v/v) as a colourless oil (1.70 g, 94%). (0229) To a solution of 9a (1 g, 6.5 mmol) in DMF (65 mL) was slowly added NaH (230 mg, 9.75 mmol, 1.2 equiv.) and MOMCl (3 mL, 6.5 mmol, 1.0 equiv.) under argon at 0 °C. The mixture was stirred 1 h and quenched with aq. NH4Cl. The cooled reaction mixture was washed extracted with dichloromethane, washed with water, dried under magnesium sulfate and concentrated under reduced pressure. The desired product was obtained without further purification as a colourless oil (5.18 g, 95%). Rf = 0.25 (Petroleum ether/EtOAc 60/40, v/v). 1H NMR (300 MHz, CDCl3) δ (ppm) 7.53 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 5.25 (s, 2H), 3.95 (s, 3H), 3.50 (s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm) 52.7, 56.6, 95.1, 127.1, 131.3, 132.1, 140.1, 152.4, 163.9. MS (ESI+): m/z (%): 276 (85) [M+H]+ and 278 (100).

95%

Stage #1: methyl 6-bromo-3-hydroxypyridine-2-carboxylate; chloromethyl methyl ether With potassium carbonate at 0℃; Inert atmosphere; Reflux; Stage #2: With sodium hydride at 0℃; for 1h; Inert atmosphere;

1 Methyl 6-bromo-3-(methoxymethoxy)picolinate - 4b To a solution of 9a (4.84 g, 20.87 mmol) in acetone (100 mL) was slowly added potassium carbonate (5.8 g, 2 equiv.) and MOMCl (20 mL, 41.74 mmol, 2 equiv.) under argon at 0 °C. The mixture was stirred heated to reflux overnight. Salts were removed by filtration and the crude was concentrated under vacuum. The desired product was obtained after purification by flash chromatography on silica gel (Petroleum ether/EtOAc, 60/40, v/v) as a colourless oil (1.70 g, 94%). (0229) To a solution of 9a (1 g, 6.5 mmol) in DMF (65 mL) was slowly added NaH (230 mg, 9.75 mmol, 1.2 equiv.) and MOMCl (3 mL, 6.5 mmol, 1.0 equiv.) under argon at 0 °C. The mixture was stirred 1 h and quenched with aq. NH4Cl. The cooled reaction mixture was washed extracted with dichloromethane, washed with water, dried under magnesium sulfate and concentrated under reduced pressure. The desired product was obtained without further purification as a colourless oil (5.18 g, 95%). Rf = 0.25 (Petroleum ether/EtOAc 60/40, v/v). 1H NMR (300 MHz, CDCl3) δ (ppm) 7.53 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 5.25 (s, 2H), 3.95 (s, 3H), 3.50 (s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm) 52.7, 56.6, 95.1, 127.1, 131.3, 132.1, 140.1, 152.4, 163.9. MS (ESI+): m/z (%): 276 (85) [M+H]+ and 278 (100).

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - US2014/5185, 2014, A1 Location in patent: Paragraph 0199-0200
[2]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - EP2868660, 2015, A1 Location in patent: Paragraph 0149
[3]Current Patent Assignee: NATIONAL INSTITUTE OF APPLIED SCIENCES; UNIVERSITY OF ROUEN NORMANDIE; ETAT FRANCAIS REPRESENTE PAR LA DIRECTION CENTRALE DU SERVICE DE SANTE DES ARMEES; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - EP3945092, 2022, A1 Location in patent: Paragraph 0086; 0227-0229
[4]Current Patent Assignee: NATIONAL INSTITUTE OF APPLIED SCIENCES; UNIVERSITY OF ROUEN NORMANDIE; ETAT FRANCAIS REPRESENTE PAR LA DIRECTION CENTRALE DU SERVICE DE SANTE DES ARMEES; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - EP3945092, 2022, A1 Location in patent: Paragraph 0086; 0227-0229

24
[ 874-24-8 ]
[ 321601-48-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sulfuric acid / 24 h / Reflux 2: bromine / water / 17 h / 0 - 20 °C
	Multi-step reaction with 2 steps 1: sulfuric acid / 80 °C 2: bromine / water / 25 °C
	Multi-step reaction with 2 steps 1: sulfuric acid / 24 h / 0 °C / Reflux 2: bromine / water / 4 h / 20 °C

	Multi-step reaction with 2 steps 1: sulfuric acid / 6 h / 0 °C / Reflux 2: bromine / water / 0 °C
	Multi-step reaction with 2 steps 1: sulfuric acid / 72 h / 70 °C / Inert atmosphere 2: bromine / water / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: sulfuric acid / methanol / 16 h / 0 - 80 °C 2: bromine / water / 6 h / 20 °C
	Multi-step reaction with 2 steps 1: sulfuric acid / 72 h / 20 °C / Reflux 2: bromine / water / 3 h / 20 °C
	Multi-step reaction with 2 steps 1: sulfuric acid / 6 h / 0 °C / Reflux 2: bromine / water / 0 °C

Reference： [1]Renou, Julien; Loiodice, Mélanie; Arboléas, Mélanie; Baati, Rachid; Jean, Ludovic; Nachon, Florian; Renard, Pierre-Yves [Chemical Communications, 2014, vol. 50, # 30, p. 3947 - 3950]
[2]Current Patent Assignee: MERCK & CO INC; WUXI APPTEC CO., LTD. - WO2014/121418, 2014, A1
[3]Current Patent Assignee: BEYONDBIO INC - EP3255042, 2017, A2
[4]Pashirova, Tatiana N.; Braïki, Anissa; Zueva, Irina V.; Petrov, Konstantin A.; Babaev, Vasily M.; Burilova, Evgenia A.; Samarkina, Darya A.; Rizvanov, Ildar Kh.; Souto, Eliana B.; Jean, Ludovic; Renard, Pierre-Yves; Masson, Patrick; Zakharova, Lucia Ya.; Sinyashin, Oleg G. [Journal of Controlled Release, 2018, vol. 290, p. 102 - 111]
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2019/63748, 2019, A1
[6]Current Patent Assignee: NANJING GEAR PHARMA TECH; SINO BIOPHARMACEUTICAL LIMITED - EP3689860, 2020, A1
[7]Nguyen, William; Lee, Erinna F.; Evangelista, Marco; Lee, Mihwa; Harris, Tiffany J.; Colman, Peter M.; Smith, Nicholas A.; Williams, Luke B.; Jarman, Kate E.; Lowes, Kym N.; Haeberli, Cécile; Keiser, Jennifer; Smith, Brian J.; Fairlie, W. Douglas; Sleebs, Brad E. [ACS Infectious Diseases, 2021, vol. 7, # 5, p. 1143 - 1163]
[8]Current Patent Assignee: NATIONAL INSTITUTE OF APPLIED SCIENCES; UNIVERSITY OF ROUEN NORMANDIE; ETAT FRANCAIS REPRESENTE PAR LA DIRECTION CENTRALE DU SERVICE DE SANTE DES ARMEES; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - EP3945092, 2022, A1

25
[ 321601-48-3 ]
[ 1608149-63-8 ]
[ 1608149-64-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 50℃; for 22h; Inert atmosphere;	Methyl 3-hydroxy-6-[5-(1,2,3,4-tetrahydroacridin-9-ylsulfanyl)pent-1-yn-1-yl]pyridine-2-carboxylate(48) To the degazed solution of 47 (0.75 g, 3.2 mmol, 1 equiv) in 40 mL of THF/Et3N (1/1) catalysts Pd(PPh3)2Cl2 (0.124 g, 0.18mmol, 0.05 equiv) and CuI (0.034 g, 0.18mmol, 0.05equiv) were added. After degazation the mixture was stirred at the room temperature for 5 min, then 15 mL of degazed solution of alkyne 46(1.00 g, 3.55 mmol, 1.1 equiv) was added. The reaction mixture was degased with hydrogen, then stirred during 22 h at 50 °C in Ar/H2 atmosphere. After concentration at reduced pressure the residue was purified by flash chromatography (CH2Cl2/MeOH) to give 1.26g of 48 (90% yield). 1H NMR (400 MHz, CDCl3, δ): 8.42 (1H, dd, J = 8.4, 1.2 Hz), 7.97 (1H, d, J = 8.4 Hz), 7.59-7.55 (1H, m), 7.47-7.43 (1H, m), 7.27 (1H, d, J = 8.7 Hz), 7.21 (1H, d, J = 8.7 Hz), 3.95 (3H, s), 3.16 (2H, t, J = 6.3 Hz), 3.10 (2H, t, J = 6.3 Hz), 2.92 (2H, t, J = 7.3 Hz), 2.45 (2H, t, J = 6.9 Hz), 1.93-1.80 (4H, m), 1.76-1.69 (2H, m).13C NMR (100 MHz, CDCl3, δ): 169.61, 159.18, 158.00, 146.50, 141.94, 136.14, 135.41, 133.21, 129.89, 129.07, 129.00, 126.64, 126.54, 126.07, 88.54, 80.42, 53.62, 53.41, 35.08, 34.42, 29.38, 28.74, 23.19, 22.85, 18.71. HRMS (ESI) m/z: calculated for C25H25N2O3S [M+H]+ = 433.15858, found [M+H]+ = 433.15887.

Reference： [1]Kliachyna, Maria; Santoni, Gianluca; Nussbaum, Valentin; Renou, Julien; Sanson, Benoit; Colletier, Jacques-Philippe; Arboléas, Mélanie; Loiodice, Mélanie; Weik, Martin; Jean, Ludovic; Renard, Pierre-Yves; Nachon, Florian; Baati, Rachid [European Journal of Medicinal Chemistry, 2014, vol. 78, p. 455 - 467]

26
[ 321601-48-3 ]
[ 1256810-26-0 ]

Reference： [1]Patent: WO2014/121418,2014,A1
[2]Patent: WO2014/209727,2014,A1
[3]Patent: WO2014/205593,2014,A1

27
[ 62733-99-7 ]
[ 321601-48-3 ]
[ 321596-58-1 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; In tetrahydrofuran; water;	6-BROMO-3-HYDROXYPICOLINIC ACID (17). To a mechanically stirred solution of methyl 3-hydroxypicolinate (30.6 g) in water (800 mL) was slowly added bromine (32 g) over a 30 minute period. After the addition was complete, stirring was continued for an additional hour. Ether (300mL) was added and stirring continued until all the solids had dissolved. The organic layer was separated and the aqueous phase extracted with ether (200mL). The organic phases were combined, dried (MgSO4) and the solvent evaporated to give 32.8 g of methyl 6-bromo-3-hydroxypicolinate as an off-white solid. Recrystallization from methanol/water gave an analytical sample, m.p. 115-117 C. To a stirred solution of this ester (2.32 g) in THF (15 mL) was added all at once a solution of LiOH.H2O (1 g) in water (7 mL). The resulting mixture was stirred for 2 hours at room temperature then poured into water (100 mL). The pH was adjusted to approximately 3 with 1N HCl, then the mixture was extracted with CH2Cl2 (3 x 100 mL). The organic extract was dried (MgSO4), filtered and concentrated to give 2.0 g of a white solid, whose 1H-NMR and MS were consistent with the desired title acid 17.

Reference： [1]Patent: EP1516874,2015,B1

28
[ 321601-48-3 ]
[ 101691-65-0 ]
methyl 6-bromo-3-((tetrahydro-2H-pyran-4-yl)methoxy)-2-picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.30 g	With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere;	A 25 mL single-necked flask was charged with methyl 6-bromo-3-hydroxy-2-picolinate (1.50 g), p-toluenesulfonate-4-methyl pyran (1.92 g), potassium carbonate (2.68 g), tetrabutylammonium iodide (0.24 g) and 15 mL of dimethylformamide (DMF). The mixture was purged with nitrogen gas three times and then reacted in an oil bath at 80C for 16 h. A sample was taken, and TLC detection showed that the spots of the raw materials disappeared. 50 mL of water was added, and the resulting mixture was extracted with ethyl acetate (25 mL × 3), washed with 30 mL of saturated saline, dried over anhydrous sodium sulfate, and subjected to column chromatography (PE EA = 5 1), so as to obtain 1.30 g of methyl 6-bromo-3-((tetrahydro-2H-pyran-4-yl)methoxy)-2-picolinate.

Reference： [1]Patent: EP3689860,2020,A1 .Location in patent: Paragraph 0434; 0437

29
[ 321601-48-3 ]
[ 60-12-8 ]
methyl 6-bromo-3-(2-phenylethoxy)pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: methyl 6-bromo-3-hydroxypyridine-2-carboxylate With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 0.25h; Stage #2: 2-phenylethanol In tetrahydrofuran at 20℃; for 3h;

Reference： [1]Nguyen, William; Lee, Erinna F.; Evangelista, Marco; Lee, Mihwa; Harris, Tiffany J.; Colman, Peter M.; Smith, Nicholas A.; Williams, Luke B.; Jarman, Kate E.; Lowes, Kym N.; Haeberli, Cécile; Keiser, Jennifer; Smith, Brian J.; Fairlie, W. Douglas; Sleebs, Brad E. [ACS Infectious Diseases, 2021, vol. 7, # 5, p. 1143 - 1163]

30
[ 321601-48-3 ]
[ 135206-84-7 ]
methyl6-bromo-3-(2,2-difluoroethoxy)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate at 100℃; for 2h;	Step-2 Synthesis of methyl6-bromo-3-(2,2-difluoroethoxy)picolinate (Intermediate AA211-3) To a solution of Intermediate AA198-4 (1.5 g, 46.55 mmol) in DMF (15 mL) were added potassium carbonate (2.6 g, 39.65 mmol, 3 eq) and dropwise Intermediate-Intermediate AA211-2 (1.98 g, 40.55 mmol, 0.3 eq). After stirring at 100° C. and for 2 h, the reaction mixture was quenched with water (300 mL) and extracted by EtOAc (2×100). The combined organic layer was washed with brine (100 mL), passed through a Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (5-10% gradient with ethyl acetate in hexane) to afford Intermediate AA211-3 (1.2 g, 98%), MS (ES): m/z 295 [M+1]+.

Reference： [1]Current Patent Assignee: NIMBUS THERAPEUTICS INC; CHARLES RIVER LABORATORIES INTERNATIONAL INC; NIMBUS SATURN - US2021/78996, 2021, A1 Location in patent: Paragraph 1078; 1080

31
[ 321601-48-3 ]
[ 18162-48-6 ]
methyl 6-bromo-3-((tert-butyldimethylsilyl)oxy)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.21 g	With 1H-imidazole In dichloromethane at 20℃; for 18h;	Step 1: methyl 6-bromo-3-((tert-butyldimethylsilyl)oxy)picolinate (Intermediate AB84-2) A mixture of methyl-6-bromo-3-hydroxypyridine-2-carboxylate (Intermediate AB84-1) (2.50 g, 10 77 mmol), TBDMSCl (2.44 g, 16.16 mmol) and imidazole (1.10 g, 16.16 mmol) in DCM (30 mL) was stirred at RT for 18 h. The reaction was diluted with DCM and washed with water. The organic solution was washed with brine, dried over Na2SO4, and concentrated in vacuo to leave the title compound (Intermediate AB84-2) (3.21 g, 9.27 mmol) as a pale yellow oil which was used crude in subsequent reactions.

Reference： [1]Current Patent Assignee: NIMBUS THERAPEUTICS INC; CHARLES RIVER LABORATORIES INTERNATIONAL INC; NIMBUS SATURN - US2021/78996, 2021, A1 Location in patent: Paragraph 1176; 1177

32
[ 321601-48-3 ]
[ 112052-11-6 ]
methyl (R)-6-bromo-3-((tetrahydrofuran-3-yl)oxy)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67.2%	With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 16h;	Step-3 Synthesis of methyl (R)-6-bromo-3-((THF-3-yl)oxy)picolinate (Intermediate AA198-5) To a solution of Intermediate AA198-4 (4.0 g, 17.24 mmol) and Intermediate AA198-2 (5.4 g, 22.41 mmol, 1.5 eq) in DMF (20 mL) was added potassium carbonate (7.1 g, 51.72 mmol, 3.0 eq). After stirring at 90° C. for 16 h, the reaction was diluted with ice cold water (250 mL) and extracted into ethyl acetate (3×80 mL). The combined organic layer was washed with brine, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 17% ethyl acetate in hexane to afford Intermediate AA198-5 (3.5 g, 67.20%) as a yellow oil. MS (ES): m/z 302.9 [M+H]+.

Reference： [1]Current Patent Assignee: NIMBUS THERAPEUTICS INC; CHARLES RIVER LABORATORIES INTERNATIONAL INC; NIMBUS SATURN - US2021/78996, 2021, A1 Location in patent: Paragraph 1014; 1017

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P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 321601-48-3 ]

Quality Control of [ 321601-48-3 ]

Related Doc. of [ 321601-48-3 ]

Product Details of [ 321601-48-3 ]

Calculated chemistry of of [ 321601-48-3 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 321601-48-3 ]

Application In Synthesis of [ 321601-48-3 ]

[ 321601-48-3 ] Synthesis Path-Upstream 1~4

[ 321601-48-3 ] Synthesis Path-Downstream 1~32

Related Functional Groups of [ 321601-48-3 ]

Bromides

Esters

Alcohols

Related Parent Nucleus of [ 321601-48-3 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 321601-48-3 ]

Related Parent Nucleus of
[ 321601-48-3 ]