[ CAS No. 1458-18-0 ] {[proInfo.proName]}

Name: 1458-18-0|Methyl 3-amino-5,6-dichloropyrazine-2-carboxylate|97%
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SKU: A108171
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Quality Control of [ 1458-18-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1458-18-0 ]

SDS Specification

Alternatived Products of [ 1458-18-0 ]

Product Details of [ 1458-18-0 ]

CAS No. :	1458-18-0	MDL No. :	MFCD00010431
Formula :	C₆H₅Cl₂N₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	USYMCUGEGUFUBI-UHFFFAOYSA-N
M.W :	222.03	Pubchem ID :	73828
Synonyms :		Chemical Name :	Methyl 3-amino-5,6-dichloropyrazine-2-carboxylate

Calculated chemistry of [ 1458-18-0 ] Expand+

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	47.74
TPSA :	78.1 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.16 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.54
Log Po/w (XLOGP3) :	2.1
Log Po/w (WLOGP) :	1.16
Log Po/w (MLOGP) :	0.19
Log Po/w (SILICOS-IT) :	1.37
Consensus Log Po/w :	1.27

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.75
Solubility :	0.396 mg/ml ; 0.00178 mol/l
Class :	Soluble
Log S (Ali) :	-3.37
Solubility :	0.0946 mg/ml ; 0.000426 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.61
Solubility :	0.545 mg/ml ; 0.00245 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.33

Safety of [ 1458-18-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1458-18-0 ]

* 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 [ 1458-18-0 ]
Downstream synthetic route of [ 1458-18-0 ]

[ 1458-18-0 ] Synthesis Path-Upstream 1~1

1
[ 1458-18-0 ]
[ 4853-52-5 ]

Yield	Reaction Conditions	Operation in experiment
36%	Stage #1: for 0.25 h; Heating / reflux Stage #2: With hydrogenchloride In water at 20℃;	Preparative Example 72. Preparation of Table 1 Compound No. 207; A suspension of 100 (3.6 g, 16 mmol, Aldrich) and sodium hydroxide (1.6 g, 39 mmol) in water (30 ml_) was heated at reflux for 15 min. The solution was filtered, allowed to cool to room temperature, and was acidified with 1 N hydrochloric acid. The precipitated solid 101 (1.2 g, 36percent yield) was collected by filtration, air-dried, and dried further under vacuum.

Reference： [1] Patent: WO2006/88920, 2006, A1, . Location in patent: Page/Page column 147

[ 1458-18-0 ] Synthesis Path-Downstream 1~108

1
[ 109-01-3 ]
[ 1458-18-0 ]
[ 1151-35-5 ]

Yield	Reaction Conditions	Operation in experiment
90.2%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 2h;Reflux;	Example 68[0291] A suspension of <strong>[1458-18-0]methyl 3-amino-5,6-dichloro-2-pyrazinecarboxylate</strong> (5.0 gm, 2.25 X 10~2 moles) in 2-propanol (50 mL) was stirred asN-methylpiperazine (2.48 gm, 2.48 X 10~2 moles) was added. To this mixture was added diisopropyethylamine (3.2 gm, 2.48 X 10"2 moles) after which the reaction was heated to reflux. At reflux, a brown solution resulted. After 2 hours at reflux, TLC (silica, 10% methanol in methylene chloride) showed all of the starting material had been consumed with the formation of a single product. The reaction was cooled to room temperature overnight which caused the product to crystallize. The solid product was isolated by filtration and was washed with 2-propanol and then with diethyl ether. After drying there was obtained 5.8 gm (90.2%>) of the product as a pink solid.

Reference： [1]Patent: WO2012/167046,2012,A1 .Location in patent: Page/Page column 130
[2]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

2
[ 141-97-9 ]
[ 1458-18-0 ]
[ 113893-06-4 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 2052 - 2055

3
[ 124-40-3 ]
[ 1458-18-0 ]
[ 1458-21-5 ]

Reference： [1]Chemical Communications,2020,vol. 56,p. 3555 - 3558
[2]MedChemComm,2017,vol. 8,p. 1022 - 1036
[3]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

4
[ 1458-18-0 ]
3-Amino-5-((7R,9aS)-7-aminomethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl)-6-chloro-pyrazine-2-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 6218 - 6229

5
[ 1458-18-0 ]
3-Amino-5-((7S,9aS)-7-azidomethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl)-6-chloro-pyrazine-2-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 6218 - 6229

6
[ 1458-18-0 ]
3-Amino-6-chloro-5-((7S,9aS)-7-methanesulfonyloxymethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl)-pyrazine-2-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 6218 - 6229

7
[ 1458-18-0 ]
(7RS,9aRS)-3-amino-5-{7-[(7-amino-2-furan-2-yl[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)methyl]octahydropyrido[1,2-a]pyrazin-2-yl}-6-chloropyrazine-2-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 6218 - 6229

8
[ 1458-18-0 ]
[ 253192-41-5 ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4705 - 4713

9
[ 1458-18-0 ]
[ 253192-20-0 ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4705 - 4713

10
[ 1458-18-0 ]
[ 253191-88-7 ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4705 - 4713

11
[ 1458-18-0 ]
3-Amino-5-[1-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-ylamino]pyrazine-2-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4705 - 4713

12
[ 1458-18-0 ]
[ 253191-87-6 ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4705 - 4713

13
[ 1458-18-0 ]
3-Amino-5-[1-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-ylamino]-6-chloropyrazine-2-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4705 - 4713

14
[ 1458-18-0 ]
[ 21874-50-0 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

15
[ 1458-18-0 ]
[ 848187-36-0 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

16
[ 1458-18-0 ]
6-Chloro-5-dimethylamino-pyrazine-2-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

17
[ 1458-18-0 ]
methyl 5-(4-methylpiperazinyl)-6-chloro-2-pyrazinecarboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

18
[ 1458-18-0 ]
[ 150331-79-6 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

19
[ 1458-18-0 ]
C₁₉H₁₇ClN₃O₃P [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

20
[ 1458-18-0 ]
C₁₉H₁₈ClN₄O₃P [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

21
[ 1458-18-0 ]
N-tert-butyl-2-<2(R)-hydroxy-4-phenyl-3(S)-((N-((5-(dimethylamino)-6-chloro-2-pyrazinyl)carbonyl)-2(S)-(3(R)-tetrahydrofuranyl)glycinyl)amino)butyl>decahydro-(4aS,8aS) isoquinoline-3(S)-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

22
[ 1458-18-0 ]
N-tert-butyl-2-(2(R)-hydroxy-4-phenyl-3(S)-((N-((5-(dimethylamino)-6chloro-2-pyrazinyl)carbonyl)-2(S)-(3(R)-tetrahydrofuranyl)glycinyl)amino)butyl)decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

23
[ 1458-18-0 ]
5-(4-methylpiperazinyl)-6-chloro-2-pyrazinecarboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

24
[ 1458-18-0 ]
[ 27245-43-8 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

25
[ 1458-18-0 ]
[ 113892-80-1 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 2052 - 2055

26
[ 1458-18-0 ]
[ 113892-87-8 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 2052 - 2055

27
[ 1458-18-0 ]
[ 113892-98-1 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 2052 - 2055

28
[ 1458-18-0 ]
[ 113892-96-9 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 2052 - 2055

29
[ 1458-18-0 ]
[ 113892-95-8 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 2052 - 2055

30
[ 1458-18-0 ]
[ 113892-97-0 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 2052 - 2055

31
[ 1458-18-0 ]
[ 113892-99-2 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 2052 - 2055

32
[ 1458-18-0 ]
[ 207284-20-6 ]
[ 906810-37-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With caesium carbonate; In 1,4-dioxane; at 80℃; for 12h;	round bottomed flask was charged with methyl 6-amino 2,3-dichloro pyrazine 5-carboxylate (Aldrich, 25 g, 112.6 mmol), 2-S-ethyl piperazine (prepared as per Williams et al J. Med. Chem 1996, 39, 1345, 83% active, 15.7 g, 112.7 mmol), cesium carbonate (100 g, 300 mmol) and 1 ,4 dioxane (400 mL). The flask was equipped with a reflux condenser and heated to 8O0C. After 12hours the reaction was cooled, diluted with CH2CI2 (~ 200 mL), and filtered through celite. The filtrate was washed once with water and then concentrated to an oil. The crude product was purified by silica gel column chromatography (3% to 10% MeOH in CH2CI2) to afford compound A3 (30.8 g. 91 %). MS: M+H = 300
91%	With caesium carbonate; In 1,4-dioxane; at 80℃; for 12h;	PREPARATIVE EXAMPLES Preparative Exam ple1.A round bottomed flask was charged with methyl 6-amino 2,3-dichloro pyrazine 5-carboxylate (Aldrich, 25 g, 112.6 mmol), 2-S-ethyl piperazine (prepared as per Williams et al J. Med. Chem. 1996, 39, 1345, 83% active, 15.7 g, 112.7 mmol), cesium carbonate (100 g, 300 mmol) and 1 ,4 dioxane (400 ml). The flask was equipped with a reflux condenser and heated to8O0C. After 12 hours, the reaction was cooled, diluted with methylene chloride (~ 200 ml), and filtered through celite. The filtrate was washed once with water and then concentrated to an oil. The crude product was purified by silica gel chromatography using a methanol/ methylene chloride eluent (3% to 10% MeOH) to afford 30.8 g (91 %) of compound A3. MS, M+H = 300.
91%	With caesium carbonate; In 1,4-dioxane; at 80℃; for 12h;	A round bottomed flask was charged with methyl 6-amino 2,3-dichloro pyrazine 5-carboxylate (Aldrich, 25 g, 112.6 mmol), 2-S-ethyl piperazine (prepared as per Williams et al J. Med. Chem 1996, 39, 1345, 83% active, 15.7 g, 112.7 mmol), cesium carbonate (100 g, 300 mmol) and 1,4 dioxane (400 mL). The flask was equipped with a reflux condenser and heated to 80 C. After 12 hours the reaction was cooled, diluted with CH2Cl2 (200 mL), and filtered through celite. The filtrate was washed once with water and then concentrated to an oil. The crude product was purified by silica gel column chromatography (3% to 10% MeOH in CH2Cl2) to afford compound A3 (30.8 g, 91%). MS:M+H=300

Reference： [1]Patent: WO2006/88836,2006,A2 .Location in patent: Page/Page column 67
[2]Patent: WO2006/91428,2006,A2 .Location in patent: Page/Page column 112
[3]Patent: US2007/82913,2007,A1 .Location in patent: Page/Page column 29-30
[4]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6982 - 6986

33
[ 1458-18-0 ]
[ 4853-52-5 ]

Yield	Reaction Conditions	Operation in experiment
36%		Preparative Example 72. Preparation of Table 1 Compound No. 207; A suspension of 100 (3.6 g, 16 mmol, Aldrich) and sodium hydroxide (1.6 g, 39 mmol) in water (30 ml_) was heated at reflux for 15 min. The solution was filtered, allowed to cool to room temperature, and was acidified with 1 N hydrochloric acid. The precipitated solid 101 (1.2 g, 36% yield) was collected by filtration, air-dried, and dried further under vacuum.

Reference： [1]Patent: WO2006/88920,2006,A1 .Location in patent: Page/Page column 147

34
[ 1458-18-0 ]
[ 321596-59-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; sodium nitrite; In sulfuric acid;	5,6-DICHLORO-3-HYDROXYPYRAZINE-2-CARBOXYLIC ACID (21). Methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (5.0 g, 23 mmol) was stirred in conc. sulfuric acid (140 mL) and cooled to 0 C. Sodium nitrite was added slowly, maintaining the temperature close to 0 C. After an additional 30 minutes at 0 C. the mixture was allowed to warm to ambient temperature and stirred for 3 hours. The mixture was poured into 500 g of ice, resulting in bubbling and foaming. After 30 minutes, the mixture was extracted 3 times with EtOAc. The combined organic extract was dried (MgSO4), filtered and concentrated. The yellow solid which was left was washed with water and air-dried, to leave 5.0 g of a yellow solid, m.p. 114-116 C. whose 13C-NMR spectrum was consistent with the methyl ester of the title compound. This solid (5.0 g) was treated with 1N NaOH (20 mL) and the mixture heated at 90 C. for 1.5 hours. After allowing to cool, the mixture was acidified with conc. HCl, then extracted 3 times with EtOAc. Drying (MgSO4), filtration and concentration afforded 0.48 g of a dark yellow solid, whose 1H-NMR and MS spectra were consistent with the title acid 21.

Reference： [1]Patent: US6355660,2002,B1

35
[ 1458-18-0 ]
[ 321596-61-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; sodium methylate; sodium nitrite; In methanol; sulfuric acid; ethyl acetate;	6-CHLORO-3-HYDROXY-5-METHOXYPYRAZINE-2-CARBOXYLIC ACID (22). A stirred mixture of <strong>[1458-18-0]methyl 3-amino-5,6-dichloropyrazine-2-carboxylate</strong> (5.0 g, 23 mmol) and sodium methoxide (3.6 g, 67.5 mmol) in absolute MeOH (50 mL) was heated at reflux for 2 hours, then allowed to cool and acidified with conc. HCl. The precipitate was collected by filtration, washed with water and air-dried to afford 3.6 g of a brown solid. Recrystallization from hexane-EtOAc (1:1) afforded 2.6 g of a pale yellow solid whose spectra were consistent with methyl 3-amino-6-chloro-5-methoxypyrazine-2-carboxylate. This compound (1 g, 4.6 mmol) was taken up in conc. sulfuric acid, cooled to 0 C. and treated slowly with sodium nitrite (0.5 g, 6.9 mmol). After 30 minutes at 0 C. the mixture was poured into 300 g of ice/water, resulting in foaming. Stirring was continued for 30 minutes, then the solid was collected by filtration and washed with water. The wet solid was taken up in EtOAc, dried (MgSO4), filtered and concentrated. This gave 0.95 g of an off-white solid, m.p. 180-182 C.6 whose NMR spectra were consistent with methyl 6-chloro-3-hydroxy-5-methoxypyrazine-2-carboxylate. This solid (0.9 g, 4.1 mmol) was treated with 1N NaOH (60 mL), and the mixture was stirred for 1 hour, then acidified with conc. HCl. The precipitate was collected by filtration and washed with water, then was dissolved in EtOAc, dried (MgSO4), filtered and concentrated. This afforded 0.62 g of a pale yellow solid, m.p. 170-173 C. whose spectra were consistent with the desired title acid 22.

Reference： [1]Patent: US6355660,2002,B1

36
[ 443-69-6 ]
[ 1458-18-0 ]
2,3-dichloro-8-fluoroindolo[2,1-b]pteridine-6,12-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 69 2,3-Dichloro-8-fluoroindolo[2,1-b]pteridine-6,12-dione STR77 Using the procedure in Example 55 and substituting <strong>[1458-18-0]methyl 3-amino-5,6-dichloro-2-pyrazinecarboxylate</strong> for methyl 3-amino-2-thiophenecarboxylate and 5-fluoro-2-chloro-3H-indole-3-one (prepared from 5-fluoroisatin according to Grimshaw, J. et al, Synthesis 496, 1974) for 2-chloro-3H-indole-3-one gives the title compound.

Reference： [1]Patent: US5441955,1995,A

37
[ 878810-02-7 ]
[ 1458-18-0 ]
(R)-6'-amino-3'-chloro-4-[6-(4-fluoro-phenyl)-2-((R)-3-methyl-morpholin-4-yl)-pyrimidin-4-yl]-3-methyl-3,4,5,6-tetrahydro-2H-1,2'-bipyrazinyl-5'-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol; at 85℃; for 12h;	2. 6'-Amino-3'-chloro-4-[6-(4-fluoro-phenyl)-2-(3-(R)-methyl-morpholin-4-yl)-pyrimidin-4-yl]-3-methyl-3,4,5,6-tetrahydro-2H-[l, 2 ']bipyrazinyl-5 '-carboxylic acid methyl ester; FHeat a mixture of 4-[4-(4-fluoro-phenyl)-6-(2-methyl-piperazin-l-yl)-pyrimidin-2-yl]-3-(/?)-methyl-morpholine with 1.1 equivalents of 3-amin6-5,6-dichloro-pyrazine-2-carboxylic acid methyl ester (Cragoe et. al. J. Med. Chem., 1967, 10, 66-75) in isopropanol at 85C for 12 h. Concentrate the mixture under reduced pressure, and then partition between 10% NaOH and EtOAc. Dry the organic layer (Na2SC>4) and concentrate under reduced pressure to give the title compound.

Reference： [1]Patent: WO2006/26135,2006,A2 .Location in patent: Page/Page column 90

38
[ 1458-18-0 ]
2-amino-5,6-dichloro-3-(hydroxymethyl)-pyrazine [ No CAS ]
5,6-Dichloro-3-[(2-methoxyphenyl)imino]methylpyrazineamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Potassium borohydride; lithium chloride; In tetrahydrofuran;	A. 2-Amino-5,6-dichloro-3-(hydroxymethyl)pyrazine 88 grams of 2-amino-5,6-dichloro-3-(methoxycarbonyl)pyrazine, 27 grams of potassium borohydride, 21 grams of lithium chloride were added to 700 milliliters of tetrahydrofuran and the reaction mixture stirred for 18 hours to obtain 2-amino-5,6-dichloro-3-hydroxymethylaldehyde in the reaction mixture. The mixture was diluted with 2000 milliliters of water and chilled to obtain 2-amino-5,6-dichloro-3-(hydroxymethyl)pyrazine, m.p. 174-176 C.

Reference： [1]Patent: US4479953,1984,A

39
[ 1458-18-0 ]
2-amino-5,6-dichloro-3-(hydroxymethyl)-pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Potassium borohydride; lithium chloride; In tetrahydrofuran; water;	A. 2-Amino-5,6-dichloro-3-(hydroxymethyl)pyrazine To 70 ml of dry tetrahydrofuran there was added 2-amino-5,6-dichloro-3-(methoxycarbonyl)pyrazine (8.8 g; 0.04M), potassium borohydride (2.7 g; 0.05M), and lithium chloride (2.1 g; 0.05M), and the mixture was stirred at room temperature overnight (17 hours). The reaction mixture was then diluted with about 200 ml of water and chilled, after which the product crystallized, was filtered and dried (5.3 g).
	With Potassium borohydride; lithium chloride; In tetrahydrofuran; water;	Step A: 2-Amino-5,6-dichloro-3(hydroxymethyl)pyrazine To 70 ml of dry tetrahydrofuran there was added 2-amino-5,6-dichloro-3-(methoxycarbonyl)pyrazine (8.8 g; 0.04 M), potassium borohydride (2.7 g; 0.05 M), and lithium chloride (2.1 g; 0.05 M), and the mixture was stirred at room temperature overnight (17 hours). The reaction mixture was then diluted with about 200 ml of water and chilled, after which the product crystallized, was filtered and dried (5.3 g).

Reference： [1]Patent: US4507299,1985,A
[2]Patent: US4512991,1985,A

40
[ 67-56-1 ]
[ 1458-18-0 ]
[ 2038-34-8 ]

Yield	Reaction Conditions	Operation in experiment
83%		Sodium metal (0.31 g, 13.5 mmol, 1 equiv) was carefully added to anhydrous MeOH (300 mL) at 0 C and stirred at room temperature until full dissolution was observed. Methyl 3- amino-5,6-dichloropyrazine-2-carboxylate (3.00 g, 13.5 mmol, 1 equiv) was added and the mixture was stirred at reflux for 3 hours. The mixture was cooled to room temperature and product filtered to obtain methyl 3-amino-6-chloro-5-methoxypyrazine-2-carboxylate (2.45 g, 83%) used without further purification. 1H MR (400 MHz, DMSO-i) delta 7.63 (s 2H), 3.97 (s 3H), 3.80 (s 3H).
	With sodium;	S-Amino--chloro-S-methoxy-pyrazine-?-carboxylic acid methyl ester [00442]Methyl 3-amino-5,6-dichloropytauazinoate (1.1 g, 5 mmol) was dissolved in 200 mL of boiling anhydrous methanol containing metallic sodium (115 mg, 5 mmol). The product which separates on cooling, is filtered, washed with water and methanol and dried to give 1.Og (92%) of methyl S-amino-S-methoxy--chloro-pyrazinoate which was recrystallized from acetonitrile. MP. 255-257 C. [00443J 1H NMR (DMSO-rf«, 400MHz): delta 7.61 Qm, 2H, NH2, exchangeable with D2O), 3.97 (s, 3H), 3.80 (s, 3H).

Reference： [1]Patent: WO2018/13597,2018,A1 .Location in patent: Paragraph 0683
[2]Patent: WO2009/89263,2009,A2 .Location in patent: Page/Page column 126

41
[ 50-01-1 ]
[ 1458-18-0 ]
[ 76599-75-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2514 - 2518

42
[ 16419-60-6 ]
[ 1458-18-0 ]
methyl 3-amino-6-chloro-5-(2-methylphenyl)pyrazine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 110℃; for 48h;Inert atmosphere;	20.1. Methyl 3-amino-6-chloro-5-(2-methylphenyl)pyrazine-2-carboxylate; Put 5 g (22.5 mmol) of <strong>[1458-18-0]methyl 3-amino-5,6-dichloropyrazine-2-carboxylate</strong>, 3.2 g (23.65 mmol) of 2-methylphenyl boronic acid in 45 mL of anhydrous toluene in a screw-top bottle. After dissolution, add 34 mL (67.6 mmol) of a 2N aqueous solution of sodium carbonate and degas the two-phase mixture for 30 min by bubbling with argon. Then add 1.3 g (1.13 mmol) of Pd(PPh3)4 and stir the reaction mixture vigorously at 110 C. for 48 h. After cooling, distribute the solution in 500 mL of EtOAc/brine 1:1 mixture and extract the aqueous phase again with 4×50 mL of EtOAc. Combine the organic phases, dry over Na2SO4and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 20% of EtOAc. After concentration under reduced pressure, we obtain 2 g of methyl 3-amino-6-chloro-5-(2-methylphenyl)pyrazine-2-carboxylate in the form of yellow wax.Yield 50%

Reference： [1]Patent: US2009/318473,2009,A1 .Location in patent: Page/Page column 28

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[ 1458-18-0 ]
[ 149104-88-1 ]
[ 1251941-13-5 ]