[ CAS No. 103041-38-9 ] {[proInfo.proName]}

Name: 103041-38-9|Ethyl 3-(pyridin-2-ylamino)propanoate|95%
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Quality Control of [ 103041-38-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 103041-38-9 ]

CAS No. :	103041-38-9	MDL No. :	MFCD09833621
Formula :	C₁₀H₁₄N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UITNIDFEANEWPC-UHFFFAOYSA-N
M.W :	194.23	Pubchem ID :	11984503
Synonyms :

Calculated chemistry of [ 103041-38-9 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.4
Num. rotatable bonds :	6
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	54.06
TPSA :	51.22 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.13 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.1
Log Po/w (XLOGP3) :	1.91
Log Po/w (WLOGP) :	1.26
Log Po/w (MLOGP) :	0.84
Log Po/w (SILICOS-IT) :	1.45
Consensus Log Po/w :	1.51

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.17
Solubility :	1.32 mg/ml ; 0.00678 mol/l
Class :	Soluble
Log S (Ali) :	-2.61
Solubility :	0.478 mg/ml ; 0.00246 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.37
Solubility :	0.0827 mg/ml ; 0.000426 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.76

Safety of [ 103041-38-9 ]

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 [ 103041-38-9 ]

* 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 [ 103041-38-9 ]
Downstream synthetic route of [ 103041-38-9 ]

[ 103041-38-9 ] Synthesis Path-Upstream 1~4

1
[ 504-29-0 ]
[ 140-88-5 ]
[ 103041-38-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With trifluorormethanesulfonic acid In ethanol at 120℃; for 12 h; Inert atmosphere; Green chemistry	General procedure: 2-Aminopyridine (1a) (0.2 mol) and ethyl acrylate (2)(0.4 mol) were mixed in a 250 mL dry round bottom flaskand then TfOH (30 mmol) and some drops of ethanol wereadded. The mixture was heated to 120 °C and stirred for 12 hunder a nitrogen atmosphere. The reaction was monitored byTLC. After the completion of the reaction, the unreactedethyl acrylate (2) was removed under vacuum. The residuewas extracted with and recrystallized in petroleum ether toobtain 36.5 g (0.188mol) of ethyl 3-[(pyridine-2-yl)amino]propionate (3a) as a pale solid, with a yield of 94molpercent. Reactions of other 2-aminopyridines 1 with ethylacrylate (2) were carried out following the procedure describedhere and gave the products 3b(96 molpercent), 3c(5molpercent), 3d(41 molpercent), 3e(59 molpercent), 3g(44 molpercent), 3h(16molpercent).
86.7%	With acetic acid In acetic acid at 88℃;	b) Ethyl 3-(2-pyridylamino)propanoate 200 g (2.12 mol) of 2-aminopyridine and 346 mL (3.19 mol) of ethyl acrylate were dissolved in 53 mL of acetic acid. The mixture was heated to 88°C and stirred overnight at this temperature. Solvent was removed under vacuum, and the title compound was purified by column chromatography, eluting with ethyl acetate, to obtain 360 g of ethyl 3-(2-pyridylamino)propionate as a white solid. Yield: 86.7 percent.
86.7%	at 88℃;	b) Ethyl 3-(2-pyridylamino)propanoate200 g (2.12 mol) of 2-aminopyridine and 346 mL (3.19 mol) of ethyl acrylate were dissolved in 53 mL of acetic acid. The mixture was heated to 88°C and stirred overnight at this temperature. Solvent was removed under vacuum, and the title compound was purified by column chromatography, eluting with ethyl acetate, to obtain 360 g of ethyl 3 -(2 -pyridylamino propionate as a white solid. Yield: 86.7 percent.

72%	at 100℃; for 24 h; Inert atmosphere	Under nitrogen, ethyl acrylate (27.58, 0.275 mol) was added to 2-aminopyridine (22.58, 0.251111), stirred at reflux for more than 100 ° C for 24 h, and the precipitate was filtered off and the residue was concentrated. Purification of the column gave ethyl 3- (N-2-pyridylamino) -propionate (34.9 g, 72percent yield) as a white solid. Mass spectrum (ESI-MS): 195.1 (M + H) +, 217.3 (M + Na) +; Ci O Hi 4 N2 020 (194)
49.67%	at 80℃; for 24 h;	75.2 g (0.80 mol) Of 2-aminopyridine was dissolved in 88.0 g (0.88 mol) of ethyl acrylate and 20 mL of acetic acid. The mixture was heated to 80°C and stirred for 24 hours at the same temperature. -Solvent was removed under vacuum, and the title compound was isolated by vacuum distillation to obtain 77.0 g of ethyl 3-(2- pyridylamino)propionate as a white solid.Yield: 77.Og (49.67percent); Purity by HPLC: 98.5percent.
295 g	at 90 - 100℃; for 50 h;	A mixture of 2-aminopyridine (200 g) and ethyl acrylate (468 g) was heated to 90-100° C. and then stirred for 50 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-35° C. Ethyl acetate was added to the reaction mixture and treating the reaction mixture with hydrochloric acid, followed by ammonia. Both the organic and aqueous layers were separated, the organic layer was washed with sodium chloride solution and then distilled off the solvent completely from the organic layer to get title compound as a residue. Yield: 295 grams.

Reference： [1] Letters in Organic Chemistry, 2015, vol. 12, # 2, p. 146 - 152
[2] Patent: EP2522662, 2012, A1, . Location in patent: Page/Page column 19
[3] Patent: WO2012/152855, 2012, A1, . Location in patent: Page/Page column 34; 35
[4] Patent: CN103524559, 2016, B, . Location in patent: Paragraph 0096; 0099-0101
[5] Patent: WO2015/128875, 2015, A2, . Location in patent: Page/Page column 41
[6] Patent: US2015/87842, 2015, A1, . Location in patent: Paragraph 0215
[7] Archiv der Pharmazie, 2015, vol. 348, # 5, p. 353 - 365

2
[ 504-29-0 ]
[ 140-88-5 ]
[ 103041-38-9 ]
[ 5439-14-5 ]

Reference： [1] Journal of Organic Chemistry, 1958, vol. 23, p. 1358

3
[ 504-29-0 ]
[ 98-29-3 ]
[ 140-88-5 ]
[ 103041-38-9 ]
[ 5439-14-5 ]

Reference： [1] Journal of Organic Chemistry, 1958, vol. 23, p. 1358

4
[ 103041-38-9 ]
[ 212322-56-0 ]

Reference： [1] Patent: US2015/87842, 2015, A1,
[2] Patent: WO2015/128875, 2015, A2,
[3] Patent: CN105669651, 2016, A,
[4] Patent: CN103524559, 2016, B,

[ 103041-38-9 ] Synthesis Path-Downstream 1~53

1
[ 504-29-0 ]
[ 98-29-3 ]
[ 140-88-5 ]
[ 103041-38-9 ]
[ 5439-14-5 ]

Reference： [1]Journal of Organic Chemistry,1958,vol. 23,p. 1358

2
[ 504-29-0 ]
[ 140-88-5 ]
[ 103041-38-9 ]
[ 5439-14-5 ]

Reference： [1]Journal of Organic Chemistry,1958,vol. 23,p. 1358

3
[ 103041-38-9 ]
[ 82357-48-0 ]
[ 429659-01-8 ]

Yield	Reaction Conditions	Operation in experiment
180 g		100 g (0.SOmol) of 4-(methylamino)-3-nitrobenzoic acid as obtained in step (a) was suspended in 800 ml dichioromethane. To the obtained suspension was added of 200 ml of thionyl chloride diluted with 200 ml dichioromethane. Finally to the reaction mixture was added 2 ml of N,N-dimethylformamide. The mixture was stirred at reflux temperature for 4-5 hr. completion of reaction was monitored by TLC. Excess thionyl chloride was removed by vacuum distillation. The residue was dissolved in 100 ml of dichioromethane which was distilled under vacuum. Finally to the obtained residue was charged 700 ml of dichioromethane and solution was cooled to 0-5C. To the cooled solution was added mixture of2l3 ml triethylamine and 100 ml ?0dichloromethane at 0-10C temperature and stirred fQr 10-15 mm. Finally to thereaction mixture was added 93 gm (0.48 mol) Ethyl 3-(2-pyridylamino)propanoate dissolved in 200 ml dichloromethane at 0-10C. temperature and stirred for 10-15 mm. Reaction mixture was then warmed to 25-30C and stirred for 4-5 hr and ?completion of reaction was monitored by TLC. Upon completion of reaction, reaction mixture was quenched with 1.0 Lit purified water at 0-10C and stirred for 30 mm. Layers were then allowed to separate for 30 mm. Organic layer was separated and was washed with purified water 1.0 Lit at 0-10C. Finally organic layer was washed with 2% HC1 solution 1.0 Lit X 3 times. The obtained organic layer was then washed with 10% sodium bicarbonate solution 1.0 lit X 2 times. Dichloromethane layer was then distilled under vacuum to obtain crude Ethyl3 - { [{ 1-(methylamino)-2-nitrophen-4-yl } carbonyl] (pyridyn-2-yl)aminol propanoate. Yield: 180 g (94.82%); Purity by HPLC: 97.6 %.
	With triethylamine; In dichloromethane; at 20℃; for 12h;	Ethyl 3- (N-2-pyridinylamino) -propionate (9.7 g, 0.05 mol) was dissolved in 30 ml CH 2 Cl 2 and 30 ml triethylamine and 4-methylamino-3-nitro- Acid chloride in CH2C12 solution. The mixture was allowed to react at room temperature for 12 h. The precipitate was filtered off and the filtrate was concentrated and purified on a silica gel column to give 3- (2-nitro-1 -methylamino-phenyl-4-yl) N-2-pyridyl) amido-propionic acid ethyl ester (15.4 g, yield 83%). Mass spectrometry (ESI-MS): 373.1 (M + H)% 39 5.2 (M + Na) +; C18H2QN4O5 (372)
	With triethylamine; In dichloromethane; at 0 - 5℃;Inert atmosphere;	10 g of compound 2 was dissolved in 1 L ofdichloromethane under the nitrogen atmosphere and cooled to 0-5 C. Thionyl chloride was added to the reaction mixture for1 h and the reaction mixture was heated to reflux for 5-6 h. Acid chloride compound 3 was obtained by removing excessthionyl chloride under vacuum and it was used at the next step.Compound 3 (7.91 g, 0.0369 mol) was then dissolved in dichloromethane (100 mL) under an inert atmosphere andtriethyl amine (7.47 g, 0.0738 mol) was added. To the reaction mixture a solution of ethyl-3-(pyridine-2-ylamino)propanoate(8.60 g, 0.0443 mol) in dichloromethane (20 mL) was added slowly at 0-5 C. After the completion of the reaction, thereaction mass was diluted with water (150 mL) and the product was extracted with dichloromethane (200 mL). Compound 4was obtained by distilling off the solvent under vacuum and purified by hexane. 1H NMR (DMSO-d6, 400 MHz): delta 1.11 (t,3H, -CH2CH3), 2.65 (t, 2H, -COCH2), 2.89 (d, 3H, -NHCH3), 3.95 (q, 2H, -NCH2), 4.17 (t, 2H, -CO2CH2), 6.82 (s, 1H,NH), 7.08 (d, 1H, Ar-H), 7.21 (m, 1H, Py-H), 7.30 (d, 1H, Py-H), 7.69 (s, 1H, Ar-H), 7.93 (s, 1H, Ar-H), 8.43 (m, 2H,Py-H). IR: numax (cm-1): 3306 (s), 1632 (s), 1532 (s), 1406 (s), 1322 (m), 1187 (m), 1027 (s), 950 (w), 860 (w), 786 (w).10 g of compound 4 was dissolved in 100 mL of a mixture of dioxane and water and heated to 50 C. Sodiumdithionate (24.90 g, 0.1208 mol) and potassium carbonate (1.11 g, 0.0081 mol) was added to the reaction mixture andmaintained at 50 C for 6 h. Title compound 1 was obtained by removing the solvent under vacuum and purified byrecrystallization from ethylacetate. 1H NMR (DMSO-d6, 400 MHz): delta 1.11 (t, 3H, -CH2CH3), 2.65 (t, 2H, -COCH2), 2.89 (d,3H, -NHCH3), 3.95 (q, 2H, -NCH2), 4.17 (t, 2H, -CO2CH2), 4.53 (s, 2H, -NH2), 5.06 (s, 1H, -NH), 6.67 (s, 1H, Ar-H), 6.75(d, 1H, Ar-H), 7.10 (s, 1H, Ar-H), 7.56 (d, 1H, Py-H), 7.76 (t, 1H, Py-H), 8.38 (d, 1H, Py-H). IR: numax (cm-1): 1607 (s),1555 (s), 1397 (s), 1321 (m), 1193 (m), 1028 (w), 948 (w), 861 (w), 797 (w), 704 (w). HRMS (ESI+), m/z: calc. forC18H22N4O3: 365.1590 [M+Na+], found 365.1546.

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 1757 - 1766
[2]Patent: WO2015/128875,2015,A2 .Location in patent: Page/Page column 41; 42
[3]Patent: CN103524559,2016,B .Location in patent: Paragraph 0096; 0111-0113
[4]Journal of Structural Chemistry,2019,vol. 60,p. 2009 - 2014
Zh. Strukt. Kim.,2019,vol. 60,p. 2097 - 2102,6

4
[ 103041-38-9 ]
[ 82357-48-0 ]
[ 1187067-68-0 ]

Yield	Reaction Conditions	Operation in experiment
		After cooling of the solution of acid chloride I to the temperature of 40 C dry triethylamine was added. To this solution a solution of substance II in dry THF (50 ml) was added dropwise. The time of dripping was 15 minutes. During the adding of substance II the reaction mixture was cooled in a water bath. This was accompanied by the temperature drop to 30 C. Then, the reaction mixture was stirred without heating for 2 hours. After sucking off triethylamine hydrochloride THF was evaporated. The evaporation residue was dissolved in 500 ml of chloroform and shaken with water. The separated organic layer was shaken with 2 M HCl and then with water.The organic layer was dried with sodium sulphate and chloroform was evaporated.Yield:Crude product: 20Og (96%); HPLC: 88.2%; brown honey The hydrochloride was prepared from this substance. Preparation of the hydrochloride:EtAc: 850 mlHCl/Et2O The crude product was dissolved in 850 ml of ETAC at the laboratory temperature. 95 ml of a solution of HCl in Et2O were added slowly to the solution dropwise under intensive stirring. During the stirring a yellow precipitate separates. After cooling in a fridge it was filtered off <n="12"/>and dried (at the laboratory temperature overnight, then in vacuum at 55 - 75 C, then in vacuum without heating over the weekend (the weight remained already the same).Yield:Crude hydrochloride: 161.3 g (77.4%); HPLC: 93.3%Crystallization of the hydrochloride:The crude hydrochloride was crystallized from a mixture of denatured non-dried ethanol with acetonitrile 9:1.Yield:Crystallized hydrochloride: 120.2 g (61.6%); HPLC: 99.3%

Reference： [1]Patent: WO2009/111997,2009,A1 .Location in patent: Page/Page column 9-10

5
[ 103041-38-9 ]
[ 82357-48-0 ]
ethyl N-(4-methylamine-3-nitrobenzoyl)-N-(2-pyridyl)-3-aminopropionate hydrobromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		4-(Methylamine)-3-nitrobenzoic acid hydrochloride (13.52 g, 58.1 mmol) was suspended in SOCI2 (105 mL, 1 .44 mol), anhydrous N,N-dimethylformamide (DMF) (0.55 mL) was added and refluxed for 45 minutes. After leaving the orange solution to cool down, the SOCI2 was distilled at low pressure. Next, the yellow solid residue obtained was suspended in toluene (40 mL) and the solvent was distilled at low pressure. This operation was performed three times.The solid obtained was suspended under Ar in anhydrous THF (80 mL) and Et3N (20.2 mL, 144.9 mmol) was slowly added. Next, it was chilled down to 0 C, an ethyl N-(2-pyridyl)-3-aminopropionate (VIII) solution (1 1 .3 g, 58.1 mmol) was slowly added in anhydrous THF (42 mL) and stirred at r.t.overnight. The solvent was distilled at low pressure, the residue was redissolved in CH2CI2 (140 mL) and washed with H2O (85 mL). The orange aqueous phase was extracted with CH2CI2 (2 x 28 mL). The organic phases were mixed, washed with NaOH 1 N (24 mL) and dried over anhydrous MgSO4, and the solvent was distilled at low pressure.The brown oil obtained was dissolved in THF (120 mL) and 48% HBr (7.60 mL, 67.2 mmol) was added dropwise. After a short time an abundant yellow solid appeared. The suspension was stirred at r.t for 30 min, and after at 0 C for 1 h. The solid was filtered out, washed with THF (10 mL) and dried under vacuum, obtaining the crude compound (VII-HBr) corresponding to crystalline form I (22.16 g, 84% yield, 91 .2% a/a purity according toHPLC/MS).1H RMN (400 MHz, d6-DMSO) : delta (ppm) = 8.42 (ddd, J = 4.8, 1 .6, 0.8, 1 H), 8.34 (bs, 1 H), 7.91 (d, J = 2.4, 1 H), 7.69 (ddd, J = 8.0, 7.6, 1 .6, 1 H), 7.31 (dd, J = 8.8, 2.0, 1 H), 7.20 (ddd, J = 7.6, 4.8, 0.8, 1 H), 7.07 (d, J = 8.0, 1 H), 6.82 (d, J = 8.8, 1 H), 4.16 (t, J = 7.2, 2H), 3.95 (q, J = 7.2, 2H), 2.89 (s, 3H), 2.64 (t, J = 6.8, 2H), 1 .10 (t, J = 7.2, 3H).Melting point (Tme,t): 165-166 CPXRD: FIG. 1 , 2theta angle values (): 8.0, 1 1 .8, 12.1 , 12.8, 14.6, 16.1 , 17.6, 18.3, 20.3, 21 .4, 23.8, 24.7, 25.0 and 27.3.The crystalline form I was recrystallized from EtOH (95 mL), filtered out, washed with EtOH (10 mL) and dried under vacuum, obtaining crystalline form II of compound (VII-HBr) (18.61 g, 71 % global yield, 100% a/a purity according to HPLC/MS).Melting point (Tme,t): 169-170 CPXRD: FIG. 2, 2theta angle values (): 9.2, 1 1 .8, 18.0, 19.3, 20.2, 23.5, 24.7, 26.0, 28.4, 28.8, 29.6 and 30.4.

Reference： [1]Patent: WO2012/4397,2012,A1 .Location in patent: Page/Page column 16-17

6
[ 504-29-0 ]
[ 140-88-5 ]
[ 103041-38-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With trifluorormethanesulfonic acid; In ethanol; at 120℃; for 12h;Inert atmosphere; Green chemistry;	General procedure: 2-Aminopyridine (1a) (0.2 mol) and ethyl acrylate (2)(0.4 mol) were mixed in a 250 mL dry round bottom flaskand then TfOH (30 mmol) and some drops of ethanol wereadded. The mixture was heated to 120 C and stirred for 12 hunder a nitrogen atmosphere. The reaction was monitored byTLC. After the completion of the reaction, the unreactedethyl acrylate (2) was removed under vacuum. The residuewas extracted with and recrystallized in petroleum ether toobtain 36.5 g (0.188mol) of ethyl 3-[(pyridine-2-yl)amino]propionate (3a) as a pale solid, with a yield of 94mol%. Reactions of other 2-aminopyridines 1 with ethylacrylate (2) were carried out following the procedure describedhere and gave the products 3b(96 mol%), 3c(5mol%), 3d(41 mol%), 3e(59 mol%), 3g(44 mol%), 3h(16mol%).
86.7%	With acetic acid; In acetic acid; at 88℃;Product distribution / selectivity;	b) Ethyl 3-(2-pyridylamino)propanoate 200 g (2.12 mol) of 2-aminopyridine and 346 mL (3.19 mol) of ethyl acrylate were dissolved in 53 mL of acetic acid. The mixture was heated to 88C and stirred overnight at this temperature. Solvent was removed under vacuum, and the title compound was purified by column chromatography, eluting with ethyl acetate, to obtain 360 g of ethyl 3-(2-pyridylamino)propionate as a white solid. Yield: 86.7 %.
86.7%	In acetic acid; at 88℃;Product distribution / selectivity;	b) Ethyl 3-(2-pyridylamino)propanoate200 g (2.12 mol) of 2-aminopyridine and 346 mL (3.19 mol) of ethyl acrylate were dissolved in 53 mL of acetic acid. The mixture was heated to 88C and stirred overnight at this temperature. Solvent was removed under vacuum, and the title compound was purified by column chromatography, eluting with ethyl acetate, to obtain 360 g of ethyl 3 -(2 -pyridylamino propionate as a white solid. Yield: 86.7 %.

72%	at 100℃; for 24h;Inert atmosphere;	Under nitrogen, ethyl acrylate (27.58, 0.275 mol) was added to 2-aminopyridine (22.58, 0.251111), stirred at reflux for more than 100 C for 24 h, and the precipitate was filtered off and the residue was concentrated. Purification of the column gave ethyl 3- (N-2-pyridylamino) -propionate (34.9 g, 72% yield) as a white solid. Mass spectrum (ESI-MS): 195.1 (M + H) +, 217.3 (M + Na) +; Ci O Hi 4 N2 020 (194)
49.67%	With acetic acid; at 80℃; for 24h;	75.2 g (0.80 mol) Of 2-aminopyridine was dissolved in 88.0 g (0.88 mol) of ethyl acrylate and 20 mL of acetic acid. The mixture was heated to 80C and stirred for 24 hours at the same temperature. -Solvent was removed under vacuum, and the title compound was isolated by vacuum distillation to obtain 77.0 g of ethyl 3-(2- pyridylamino)propionate as a white solid.Yield: 77.Og (49.67%); Purity by HPLC: 98.5%.
33%	With Imidazole hydrochloride; In neat (no solvent); at 100℃; for 5h;Green chemistry;	General procedure: The 1 (5.0 mmol) and 2 (6.5 mmol) in a molar ratio of 1:1.3 reacted with stirring in the presenceof imidazolium hydrochloride (1.5 mmol, 0.3 eq). Heating was performed using an oil bath and thereaction was followed up by TLC until completion. After completion of the reaction, the system wascooled. The organic layer was extracted using water (15 mL) and ethyl acetate (20 mL) and driedusing anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue wassubjected to column chromatography eluting with petroleum ether: ethyl acetate (7:1) mixtures.
295 g	at 90 - 100℃; for 50h;	A mixture of 2-aminopyridine (200 g) and ethyl acrylate (468 g) was heated to 90-100 C. and then stirred for 50 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-35 C. Ethyl acetate was added to the reaction mixture and treating the reaction mixture with hydrochloric acid, followed by ammonia. Both the organic and aqueous layers were separated, the organic layer was washed with sodium chloride solution and then distilled off the solvent completely from the organic layer to get title compound as a residue. Yield: 295 grams.

Reference： [1]Letters in Organic Chemistry,2015,vol. 12,p. 146 - 152
[2]Patent: EP2522662,2012,A1 .Location in patent: Page/Page column 19
[3]Patent: WO2012/152855,2012,A1 .Location in patent: Page/Page column 34; 35
[4]Patent: CN103524559,2016,B .Location in patent: Paragraph 0096; 0099-0101
[5]Patent: WO2015/128875,2015,A2 .Location in patent: Page/Page column 41
[6]Molecules,2019,vol. 24
[7]Patent: US2015/87842,2015,A1 .Location in patent: Paragraph 0215
[8]Archiv der Pharmazie,2015,vol. 348,p. 353 - 365

7
[ 103041-38-9 ]
3-({2-[(4-carbamimidoylphenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-yl-amino)propionic acid ethyl ester [ No CAS ]

Reference： [1]Patent: EP2522662,2012,A1
[2]Patent: WO2015/128875,2015,A2
[3]Patent: CN103524559,2016,B

8
[ 103041-38-9 ]
[ 211915-06-9 ]

Reference： [1]Patent: EP2522662,2012,A1
[2]Patent: US2015/87842,2015,A1
[3]Patent: WO2015/128875,2015,A2
[4]Patent: CN105669651,2016,A
[5]Patent: CN105669651,2016,A

9
[ 103041-38-9 ]
[ 1223061-77-5 ]

Reference： [1]Patent: EP2522662,2012,A1

10
[ 103041-38-9 ]
[ 872728-81-9 ]

Reference： [1]Patent: EP2522662,2012,A1
[2]Patent: EP2522662,2012,A1
[3]Patent: US2015/87842,2015,A1
[4]Patent: CN105669651,2016,A
[5]Patent: CN105669651,2016,A

11
[ 103041-38-9 ]
ethyl 3-[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate [ No CAS ]

Reference： [1]Patent: EP2522662,2012,A1

12
[ 103041-38-9 ]
[ 41263-74-5 ]
ethyl 3-[{1-(methylamino)-2-nitrophen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.2%		c) Ethyl 3-[{1-(methylamino)-2-nitrophen-4-yl}carbonyl](pyridyn-2-yl)aminolpropanoate hydrochloride [Show Image] 50 g (0.25 mol) of 4-(methylamino)-3-nitrobenzoic acid as obtained in step (a) were suspended in a mixture of 459.2 g of thionyl chloride and 3 mL of N,N-dimethylformamide. The mixture was stirred at reflux temperature for 45 minutes. Excess thionyl chloride was removed by vacuum distillation. The residue was dissolved in 300 mL of toluene, which was subsequently removed by vacuum distillation to remove completely any residual thionyl chloride. The brownish crystalline residue obtained was dissolved in 280 mL of tetrahydrofuran at 60°C. At this point, 35.1 g of triethylamine were added to the solution. Then, a solution of 45 g (0.23 mol) of ethyl 3-(2-pyridylamino)propanoate as obtained in step (b) in 95 mL of tetrahydrofuran was added dropwise over the reaction mixture, keeping the temperature at about 30°C. The resulting mixture was stirred overnight at room temperature. Solvent was removed by vacuum distillation, and the residue was dissolved in 1 L of dichloromethane. The resulting solution was washed with 500 mL of water, 500 mL of 2M hydrochloric acid, 500 mL of saturated sodium bicarbonate and 500 mL of water. The organic phase was dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved with 600 mL of ethyl acetate, and dry hydrogen chloride was bubbled into the solution until precipitation was completed. The solid was isolated by filtration and dried to obtain 63 g of the title compound, which was recrystallized in a mixture of 450 mL of ethanol and 50 mL of acetonitrile at reflux temperature. After cooling to 10°C, solid was isolated by filtration and dried to yield 44.7 g of ethyl 3-[{1-(methylamino)-2-nitrophen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate hydrochloride as a yellow solid. Yield: 47.2 percent. Purity (HPLC, method 1): 97.6 percent.

Reference： [1]Patent: EP2522662,2012,A1 .Location in patent: Page/Page column 16

13
[ 103041-38-9 ]
[ 41263-74-5 ]
ethyl 3-[{1-(methylamino)-2-nitrophen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.2%		c) E t h y l 3-([(l-(methylamino)-2-nitrophen-4-yl\|carbonyll(pyridyn-2- yl)amino\|propanoate hydrochloride50 g (0.25 mol) of 4-(methylamino)-3-nitrobenzoic acid as obtained in step (a) were suspended in a mixture of 459.2 g of thionyl chloride and 3 mL of N,N- dimethylformamide. The mixture was stirred at reflux temperature for 45 minutes. Excess thionyl chloride was removed by vacuum distillation. The residue was dissolved in 300 mL of toluene, which was subsequently removed by vacuum distillation to remove completely any residual thionyl chloride. The brownish crystalline residue obtained was dissolved in 280 mL of tetrahydrofuran at 60°C. At this point, 35.1 g of triethylamine were added to the solution. Then, a solution of 45 g (0.23 mol) of ethyl 3- (2-pyridylamino)propanoate as obtained in step (b) in 95 mL of tetrahydrofuran was added dropwise over the reaction mixture, keeping the temperature at about 30°C. The resulting mixture was stirred overnight at room temperature. Solvent was removed by vacuum distillation, and the residue was dissolved in 1 L of dichloromethane. The resulting solution was washed with 500 mL of water, 500 mL of 2M hydrochloric acid, 500 mL of saturated sodium bicarbonate and 500 mL of water. The organic phase was dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved with 600 mL of ethyl acetate, and dry hydrogen chloride was bubbled into the solution until precipitation was completed. The solid was isolated by filtration and dried to obtain 63 g of the title compound, which was recrystallized in a mixture of 450 mL of ethanol and 50 mL of acetonitrile at reflux temperature. After cooling to 10°C, solid was isolated by filtration and dried to yield 44.7 g of ethyl 3-[{l-(methylamino)-2- nitrophen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate hydrochloride as a yellow solid. Yield: 47.2 percent. Purity (HPLC, method 1): 97.6 percent.

Reference： [1]Patent: WO2012/152855,2012,A1 .Location in patent: Page/Page column 28; 29-30

14
[ 103041-38-9 ]
[ 82357-48-0 ]
ethyl 3-[[4-(methylamino)-3-nitrobenzoyl](pyridin-2-yl)amino]propanoate hydrochloride hemisulfate [ No CAS ]

Reference： [1]Patent: WO2013/24384,2013,A1 .Location in patent: Paragraph 61; 62; 63

15
[ 103041-38-9 ]
[ 41263-74-5 ]
[ 429659-01-8 ]

Yield	Reaction Conditions	Operation in experiment
		Exampler2: Preparation of crystalline ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2- vDbenzamido) propanoate of Formula (2A) 113.6 g of 4-(methylamino)-3-nitrobenzoic acid of Formula (A), 1.2 mL dimethylformamide and thionyl chloride (170.5 mL) were stirred for 15 minutes at 25°C to 35°C. The reaction mixture was heated to 75°C to 80°C for one hour. Excess of thionyl chloride was distilled out. 75 g of ethyl 3-(pyridin-2-ylamino)\propanoate of Formula (B) and ethyl acetate (100 mL) were added to' the reaction mixture. 121 mL of triethylamine was added and the reaction mixture was stirred for 1 hour. The reaction mixture was washed with mixture of water and ethyl acetate and charcoalized. The reaction mixture was filtered to obtain of ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-2- yl)benzamido)propanoate of Formula (C).
		113.6 g of 4-(methylamino)-3-nitrobenzoic acid of Formula (A), 1.2 mL dimethylformamide and thionyl chloride (170.5 mL) were stirred for 15 minutes at 25° C. to 35° C. The reaction mixture was heated to 75° C. to 80° C. for one hour. Excess of thionyl chloride was distilled out. 75 g of ethyl 3-(pyridin-2-ylamino)\propanoate of Formula (B) and ethyl acetate (100 mL) were added to the reaction mixture. 121 mL of triethylamine to was added and the reaction mixture was stirred for 1 hour. The reaction mixture was washed with mixture of water and ethyl acetate and charcoalized. The reaction mixture was filtered to obtain of ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-2-yl)benzamido)propanoate of Formula (C). The compound (C) in-situ in ethyl acetate layer was added 3.75 g Pd/C at 25° C. to 35° C. and stirred for 20 min. The reaction mixture was maintained under 5 Kg pressure at 50° C. to 55° C. The reaction mixture was filtered and washed with ethyl acetate and distilled to obtain residue. 150 mL isopropanol was added and heated for 5-10 minutes at 70° C. to 75° C. The reaction mixture was cooled to 0° C. to 5° C. and filtered. The wet-cake was washed with isopropanol and dried to afforded 75percent ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate of Formula (2A) with 98percent purity. The compound of Formula (2A) is characterized by x-ray powder diffraction as depicted in . FIG.1.
162 g		A mixture of 4-(methylamino)-3-nitrobenzoic acid compound of formula-5 (151.4 g), thionyl chloride (64 ml), dimethyl formamide (5 ml) and toluene (400 ml) was heated to 65-75° C. and stirred for 2 hours. After completion of the reaction, the solvent from the reaction mixture was completely distilled off under reduced pressure and followed by co-distillation with toluene to get the corresponding acid chloride compound as a residue. Toluene (300 ml) was added to the obtained residue. Triethyl amine (157.5 ml), followed by a solution of ethyl 3-(pyridin-2-ylamino)propanoate compound of formula-4 (50 g) and toluene (200 ml) was added to the reaction mixture and stirred for 3 hours at 20-30° C. Filtered the unwanted solid, the filtrate was washed with sodium bicarbonate solution followed by water and sodium chloride solution. The organic layer was concentrated to get title compound. Yield: 162 g.

Reference： [1]Patent: WO2013/111163,2013,A2 .Location in patent: Page/Page column 18
[2]Patent: US2015/11589,2015,A1 .Location in patent: Paragraph 0119-0120
[3]Patent: US2015/87842,2015,A1 .Location in patent: Paragraph 0220

16
[ 103041-38-9 ]
[ 38818-50-7 ]
[ 1620205-04-0 ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; In dichloromethane; at 20℃; for 1h;	A mixture of ethyl 3_ (pyridine-2-yl-amino) propionate (9.6 g, 49.6 mmol), triethylamine (13. 8 ml, 99 mmol)And dichloromethane (20 ml) were added to the reaction vessel, and a solution of the compound 2 obtained in Example 1 in dichloromethane was added dropwise.Add room temperature stirring lh. The reaction solution was washed with water, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated to dryness,The remaining solid was purified by column chromatography,Compound 3 (16.3 g, yield 87.0%) was obtained.
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -5 - 0℃; for 1h;	To a solution of 4-chloro-3-nitrobenzoic acid (1, 80 g, 0.40 mol) in a mixture of toluene(650 ml) and N,N-dimethylformamide (2 ml) at 70C, thionyl chloride (34 ml, 0.47 mol)was added dropwise and the mixture was stirred for 2 h. After the volatiles were removedin vacuo at 55C, the remaining liquid was dissolved in anhydrous dichloro- methane(400 ml). A solution of <strong>[103041-38-9]3-(pyridin-2-ylamino)propionic acid ethyl ester</strong> 4 (77 g, 0.40 mol)in anhydrous dichloromethane (400 ml), and N,N-diisopropylethylamine (131 ml) wereadded, and the reaction temperature was maintained between 0 and -5C. The mixture wasstirred for 1 h at 0C, and then the solvents were removed in vacuo at 30C to give anoff-white powder. HPLC analysis of an aliquot of the powder indicated a purity of 93%(determined by peak areas).N,N-dimethylformamide (DMF, 740 ml) was added and the mixture was stirred at70C for 15 min. Then a solution of 27?30% methylamine in ethanol (140 ml) was added dropwise. The mixture was cooled to 25C. After 30 min, ananlysis by HPLC indicatedthat it was the complete consumption of 8.To the above solution, 10% Pd/C (11.1 g) and ammonium formate (65.1 g, 1.03 mol)were then added. The mixture was stirred for 12 h at room temperature. The resultingmixture was filtered through Celite by gravity and the filtrate was evaporated to yield anoil which was dissolved in ethyl acetate (500 ml), and the solution was washed with water(300 ml × 3) and brine (300 ml), respectively. The organic layer was dried over anhydrousNa2SO4, evaporated in vacuo at 35C. The residual solid was recrystallized from toluene(350 ml) to give 6 (116.1 g, 85% overall yield from 1) as a white powder, mp. 103-104C.
16.3 g	With triethylamine; In dichloromethane; at 20℃; for 1h;	Example 2 Synthesis of ethyl 3-[(3-nitro-4-chlorobenzoyl)(pyridin-2-yl)amino]propionate (compound 3) Ethyl 3-(pyridin-2-yl-amino)propionate (9.6 g, 49.6 mmol), thiethylamine (13.8 ml, 99.2 mmol), and dichloromethane (20 ml) were added to a reactor, and the dichloromethane solution of the compound 2 obtained in Example 1 was added dropwise, and then stirred at room temperature for 1 hr. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness, and the remaining solid was purified by column chromatography, to obtain the compound 3(16.3 g, yield 87.0%).

Reference： [1]Patent: CN103922999,2016,B .Location in patent: Paragraph 0058-0061; 0070-0073; 0078-0081
[2]Organic Preparations and Procedures International,2014,vol. 46,p. 376 - 380
[3]Patent: US2017/190666,2017,A1 .Location in patent: Paragraph 0050-0051

17
[ 103041-38-9 ]
[ 212322-56-0 ]

Reference： [1]Patent: US2015/87842,2015,A1
[2]Patent: WO2015/128875,2015,A2
[3]Patent: CN105669651,2016,A
[4]Patent: CN103524559,2016,B

18
[ 103041-38-9 ]
ethyl 3-(2-((4-cyanophenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate mesylate [ No CAS ]

Reference： [1]Patent: US2015/87842,2015,A1

19
[ 103041-38-9 ]
3-(2-(((4-methylamidinophenyl)amino)methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzo[d]imidazole-5-carbonylamino)ethyl propionate methanesulfonate [ No CAS ]

Reference： [1]Patent: US2015/87842,2015,A1

20
[ 103041-38-9 ]
dabigatran etexilate (-)-camphor sulfonate salt [ No CAS ]

Reference： [1]Patent: US2015/87842,2015,A1

21
[ 103041-38-9 ]
[ 1019206-79-1 ]

Reference： [1]Patent: US2015/87842,2015,A1

22
[ 103041-38-9 ]
[ 1019206-70-2 ]

Reference： [1]Patent: US2015/87842,2015,A1

23
[ 103041-38-9 ]
3-[(3-amino-4-ethylamino-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester [ No CAS ]