33400-49-6|N2-(4-Fluorobenzyl)-5-nitropyridine-2,6-diamine| Ambeed

Structure of 33400-49-6

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Quality Control of [ 33400-49-6 ] Purity: 97% SDS Specification

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Product Details of [ 33400-49-6 ]

CAS No. :	33400-49-6
Formula :	C₁₂H₁₁FN₄O₂
M.W :	262.24
SMILES Code :	NC1=C([N+]([O-])=O)C=CC(NCC2=CC=C(F)C=C2)=N1
MDL No. :	MFCD08282317
InChI Key :	ZVCIIRBNNSUNCH-UHFFFAOYSA-N
Pubchem ID :	118472

Safety of [ 33400-49-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 33400-49-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	19
Num. arom. heavy atoms	12
Fraction Csp3	0.08
Num. rotatable bonds	4
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	71.21
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	96.76 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.63
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.8
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.41
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.34
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.03
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.64

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.43
Solubility	0.0967 mg/ml ; 0.000369 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-4.49
Solubility	0.00851 mg/ml ; 0.0000325 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-4.3
Solubility	0.0131 mg/ml ; 0.0000499 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.91 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	2.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.4

Application In Synthesis of [ 33400-49-6 ]

* 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.

Downstream synthetic route of [ 33400-49-6 ]

[ 33400-49-6 ] Synthesis Path-Downstream 1~35

1
[ 27048-04-0 ]
[ 140-75-0 ]
[ 33400-49-6 ]

Yield	Reaction Conditions	Operation in experiment
97.2%	With triethylamine; In methanol; at 80℃; for 10h;	To a reaction flask, 200 mL of methanol, 52.08 g of compound 1, 37.54 g of p-fluorobenzylamine and 50.0 mL of triethylamine werea added. The reaction mixture was heated to 80 C for 10 hours, and the reaction solution was added with 10 times of water to give 76.47 g of compound 3 in a yield of 97.2% and a purity of 99.62% (HPLC).
96.8%	With triethylamine; In isopropyl alcohol; for 14h;Inert atmosphere; Reflux; Industry scale;	2-Amino-6-chloro-3-nitropyridine (ACNP, 10.0 kg) was suspended in isopropanol (49 L) under stirring and a nitrogen blanket. 4-Fluorobenzylamine (7.7 kg) and triethylamine (8.4 kg) were added and the mixture was heated to reflux. Stirring at reflux was maintained for 14 h. The reaction mixture was cooled to 50C and samples were taken for checking completion of the reaction by HPLC (amount of residual ACNP: 0.02%). Water (163 kg) was added and the mixture was stirred for 5 min, then cooled to 5C and stirred for 30 minutes. The precipitate was filtered off, washed with water (41 L) and dried under reduced pressure at 50C. Yield: 14.6 kg (96.8% of theory).
96.6%	With triethylamine; In isopropyl alcohol; at 70 - 80℃; for 12h;Large scale;	Was added to the reaction kettle 3.04kg and 10kg of isopropanol fluorobenzylamine, with stirring, was added 4kg2- amino-3-nitro-6-chloropyridine and 8.67kg of triethylamine, and heated at reflux temperature for 12h 70-80 , cooled to 60 , reaction was monitored sampling is complete, add 4% sodium hydroxide aqueous solution prepared 1.07kg, 55 concentrated under reduced pressure until no solvent flows, centrifuged solids, temperature 50-60 , dried 10-12 hours to give flupirtine maleate intermediate (2-amino-3-nitro-6- (p-fluoro-benzylamino) pyridine) 5.86kg, a yield of 96.6%

88%	With triethylamine; In isopropyl alcohol; at 90℃; for 0.666667h;Microwave irradiation;	To a solution of Intermediate 5 (500 mg, 2.9 mmol) in isopropanol was added 4- fluorobenzylamine (463 iil, 4.06 mmol) and triethylamine (805 iil, 5.8 mmol). This mixture was stirred at 90C for 40 minutes in the microwave. Water was added to the mixture and the resulting precipitate was filtered off, washed with water and then driedover vacuum for an hour. Intermediate 6 was isolated as a bright yellow solid (661 mg,88%).LCMS (m/z): [IVIH] calcd. for C12H11FN4O2, 262.24; found 263.00.
79.4%	With triethylamine; In isopropyl alcohol; at 5℃; for 0.5h;	2-Amino-3-nitro-6-chloropyridine (Compound 1) (50.0 g, 288 mmol, 1.00 eq) was dissolved in isopropyl alcohol (500 mL).p-Fluorobenzylamine (39.7 g, 317 mmol, 1.10 eq) and TEA (32.0 g, 317 mmol, 1.10 eq.Thereafter, the reaction solution was poured into water (1.5 L), and slowly cooled to 5 C and stirred for 30 minutes.Filter and filter cake was washed with water (500 mL).The filter cake was collected and dried to give a yellow solid (Compound 2) 60 g, yield 79.4%.
150 g	With triethylamine; In water; at 20 - 85℃;	100 gm of 2-amino-3-nitro-6-chloro-pyridine is taken in 800 ml of water. 90 gm of p-fluorobenzylamine is added dropwise into the reaction mixture at 20-25C. Then 87 gm triethylamine is also added dropwise into the reaction mixture at 20-25C. After complete addition, the reaction mass is stirred at 40-45C for half an hour again the reaction mass is heated to 80-85C and stirred at this temperature for 3-4 hours. After completion of the reaction, the reaction mass is cooled to 20-25C and stirred at this temperature for 2-3 hours and then stirred at 15-20C for 3-4 hours. The solid mass is filtered and then washed with 200 ml of water and 100 ml isopropyl alcohol and then dried in air oven till constant weight to get 140-150 gm. of 2-amino-3-nitro-6-p- fluorobenzylamino-py ridine.
	With potassium carbonate; In butan-1-ol; for 2h;Reflux;	Step-2: Synthesis of Compound 4: 2-Amino-6-chloro-3-nitropyridine 2 (17.35 g, 0.10 mol), 4-fluoro benzyl amine (0.10 mol) and powdered potassium carbonate (10.4 g, 0.035 mol) in n-butanol (100 mL) were heated under reflux for 2 hours. The suspension was filtered and after cooling to room temperature the solid 4 was collected by filtration, washed with butanol, and dried.
	at 60 - 65℃; for 6h;Large scale;	2,6-dichloro-3-nitropyridine (5 kg, 25.9 mol) was added to a reaction vessel containing 20 kg of ethanol, and 25% aqueous ammonia (9.07 kg, 64.8 mol) was added at room temperature to control the internal temperature. 30~35 C, heat preservation reaction for about 6h, TLC monitoring the raw material reaction completely stop the reaction, adding p-fluorobenzylamine (3.8kg, 31.1mol), heating to 60~65 C reaction for about 6h, TLC monitoring the raw material reaction is complete The reaction was stopped, and the temperature was lowered to 5 to 10 C for crystallization for 1 to 2 hours and then filtered. The obtained wet product was added to 60 kg of isopropyl alcohol, heated to reflux, and cooled to room temperature for 2 hours, filtered, and the wet product was kept in the reaction vessel. 75 kg of isopropanol, 5% Pd/C 0.3 kg and ethyl chloroformate (3 kg, 27.6 mol) were added to the reaction vessel, and hydrogen pressure was maintained at 1.2 to 1.5 MPa, and the temperature was controlled at 60 to 70 C for 5 hours. Filtration, the filtrate was cooled to 0~5 C and stirred for 2 h, and dried under reduced pressure at 60 C for 4 h to obtain white flupirtine hydrochloride 6.48 kg, the yield was 73.4%, and the chromatographic purity was 99.62%. The nuclear magnetic data is basically consistent with the data of Example 1.

References: [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9739 - 9756.
[2]Zeitschrift fur Naturforschung, B: Chemical Sciences,2012,vol. 67,p. 1297 - 1304.
[3]Patent: CN105541705,2016,A .Location in patent: Paragraph 0013; 0027; 0028.
[4]Patent: WO2012/4391,2012,A1 .Location in patent: Page/Page column 39.
[5]Patent: CN104086481,2016,B .Location in patent: Paragraph 0033 - 0037.
[6]Organic and Biomolecular Chemistry,2019,vol. 17,p. 4512 - 4522.
[7]Patent: WO2016/27089,2016,A1 .Location in patent: Page/Page column 27.
[8]Patent: CN110317167,2019,A .Location in patent: Paragraph 0052-0056; 0065-0067; 0076-0078.
[9]Arzneimittel-Forschung/Drug Research,1993,vol. 43,p. 627 - 631.
[10]Journal of Medicinal Chemistry,1994,vol. 37,p. 3016 - 3022.
[11]Patent: WO2013/80215,2013,A1 .Location in patent: Page/Page column 32.
[12]Patent: US2015/152057,2015,A1 .Location in patent: Paragraph 0111; 0114; 0115.
[13]Patent: CN109053563,2018,A .Location in patent: Paragraph 0015; 0033; 0038; 0042; 0043; 0044; 0046.

2
[ 33400-49-6 ]
[ 112523-78-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium tetrahydroborate; tin(II) chloride dihdyrate; In ethanol; for 1.5h;Reflux;	To a solution of Intermediate 6 (300 mg, 1.15 mmol) in ethanol was added tin (II) chloride dihydrate (1.29 g, 5.72 mmol). This mixture was heated to reflux before the dropwise addition of a solution of sodium borohydride (216 mg, 5.72 mmol) in ethanol. The resulting mixture was refluxed for 90 minutes and allowed to cool before filtrationthrough celite and concentration under reduced pressure. Intermediate 7 was isolated as an orange residue (230 mg, 86%).LCMS (m/z): [IVIH] calcd. for C12H13FN4, 232.26; found 233.10.
55.5%	With palladium on activated charcoal; hydrogen; In methanol; at 20℃; under 1551.49 Torr; for 5h;	Compound 2 (60 g, 229 mmol, 1.00 eq) was dissolved in methanol (600 mL) and Pd / C (6.0 g).The reactor was replaced with hydrogen three times, and then the reaction was stirred at room temperature under a hydrogen (30 psi) atmosphere for 5 h.After that, the reaction solution was filtered through Celite, and then filtered and washed with methanol (300mL).The filtrate was combined, and the solvent was evaporated under reduced pressure.29.5 g of a brownish yellow solid (Compound 3) was obtained in a yield of 55.5%.
	With hydrogen; In 1,4-dioxane; at 60℃; under 4125.41 Torr; for 2h;	Step-3: Synthesis of Compound 5: 0.10 mol of compound 4 was hydrogenated under 5.5 bar of H2 in the presence of 10 g of Raney-Ni in 400 mL of dioxane at 60 C. After 2 hours the reaction mixture was cooled to room temperature, filtrated and evaporated to get the compound 5.

With hydrogen; In isopropyl alcohol; at 70℃; under 22502.3 - 30003 Torr;Autoclave; Inert atmosphere; Large scale;Catalytic behavior;

24.7kg adding isopropanol in an autoclave, intermediate 5.86kg, Raney nickel 0.826kg, sealed autoclave, after nitrogen gas was hydrogen, the temperature controlled at ?70 , hydrogen pressure control 3.0 ~ 4.0Mpa hydrogenation.After the hydrogenation, under nitrogen, was added dropwise temperature ?40 ethyl 2596ml, stirred for 0.3 hours, triethylamine was added rapidly dropwise 3972ml.0.5Mpa nitrogen under 40 ~ 50 stirred overnight incubation with nitrogen filtered and the filtrate was added rapidly stirred aqueous solution of maleic acid state, the above crystallization five hours, centrifuged solid, temperature controlled at 60 ~ 70 , dried 5 to 8 hours to give flupirtine maleate crude

References: [1]Patent: WO2016/27089,2016,A1 .Location in patent: Page/Page column 27; 28.
[2]Patent: CN110317167,2019,A .Location in patent: Paragraph 0052-0054; 0057-0058; 0065; 0068-0069; 0076.
[3]Arzneimittel-Forschung/Drug Research,1993,vol. 43,p. 627 - 631.
[4]Journal of Medicinal Chemistry,1994,vol. 37,p. 3016 - 3022.
[5]Patent: US2015/152057,2015,A1 .Location in patent: Paragraph 0111; 0116; 0117.
[6]Patent: CN104086481,2016,B .Location in patent: Paragraph 0119; 0121.
[7]Journal of Medicinal Chemistry,2017,vol. 60,p. 9739 - 9756.
[8]Patent: CN109053563,2018,A .Location in patent: Paragraph 0015.

3
[ 16013-85-7 ]
[ 33400-49-6 ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3016 - 3022.
[2]Patent: WO2013/80215,2013,A1 .
[3]Patent: US2015/152057,2015,A1 .
[4]Patent: WO2016/27089,2016,A1 .
[5]Journal of Medicinal Chemistry,2017,vol. 60,p. 9739 - 9756.
[6]Patent: CN109053563,2018,A .
[7]Organic and Biomolecular Chemistry,2019,vol. 17,p. 4512 - 4522.

4
[ 33400-49-6 ]
allyl 6-(4-fluorobenzylamino)-2-aminopyridin-3-ylcarbamate [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3016 - 3022.
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 9739 - 9756.

5
[ 33400-49-6 ]
flupirtine hydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3016 - 3022.
[2]Patent: CN105541705,2016,A .

6
[ 33400-49-6 ]
D-13223 [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3016 - 3022.

7
[ 33400-49-6 ]
[2-Amino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-carbamic acid methyl ester; hydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3016 - 3022.

8
[ 33400-49-6 ]
[2-Amino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-carbamic acid 2-chloro-ethyl ester; hydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3016 - 3022.

9
[ 33400-49-6 ]
[2-Amino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-carbamic acid phenyl ester; hydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3016 - 3022.

10
[ 33400-49-6 ]
3,5-Dimethyl-isoxazole-4-carboxylic acid [2-amino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-amide; hydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3016 - 3022.

11
[ 33400-49-6 ]
2-Amino-3-(allyloxycarbonylamino)-6-(4-fluorobenzylamino)pyridine hydrochloride [ No CAS ]

References: [1]Arzneimittel-Forschung/Drug Research,1993,vol. 43,p. 627 - 631.

12
[ 33400-49-6 ]
2-Amino-3-(prop-1-in-3-yloxycarbonylamino)-6-(4-fluorobenzylamino)pyridine hydrochloride [ No CAS ]

References: [1]Arzneimittel-Forschung/Drug Research,1993,vol. 43,p. 627 - 631.

13
[ 33400-49-6 ]
2-Amino-3-(but-2-en-1-yloxycarbonylamino)-6-(4-fluorobenzylamino)pyridine hydrochloride [ No CAS ]

References: [1]Arzneimittel-Forschung/Drug Research,1993,vol. 43,p. 627 - 631.

14
[ 33400-49-6 ]
2-Amino-3-(benzyloxycarbonylamino)-6-(4-fluorobenzylamino)pyridine hydrochloride [ No CAS ]

References: [1]Arzneimittel-Forschung/Drug Research,1993,vol. 43,p. 627 - 631.

15
[ 7440-02-0 ]
[ 1885-14-9 ]
[ 33400-49-6 ]
phenyl (2-amino-6-((4-fluorobenzyl)amino)pyridin-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With magnesium sulfate; In 1,4-dioxane;	EXAMPLE 11 2-amino-3-phenoxycarbonylamino-6-(4-fluorobenzylamino)-pyridine 24.3 grams of 2-amino-3-nitro-6-(4-fluorobenzylamino)-pyridine were hydrogenated with 18 grams of Raney-nickel and 18 grams of magnesium sulfate in 250 ml of dioxane at 65 C. under a pressure of 7.5 bar. Subsequently the product was filtered with suction from the catalyst under nitrogen, washed with a little dioxane and the filtrate treated under nitrogen with 17.1 grams of phenyl chloroformate. The reaction product crystallized out after a short time and was filtered off with suction. The compound was recrystallized from methanol under addition of carbon and dried in a vacuum.

References: [1]Patent: US4554281,1985,A .

16
[ 541-41-3 ]
[ 110-16-7 ]
[ 33400-49-6 ]
flupirtine maleate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.1%		The processes described in Examples 2 to 4 were repeated under slightly different reaction conditions (such as varying the redox catalyst (e.g., Pt/C), the reducing system (e.g., a formate salt with redox catalyst or a dithionite salt without redox catalyst; cf. also Example 5), the ester solvent, the reaction temperatures and times, the amounts of reactants, and washing/purification reagents) and flupirtine maleate was obtained with yield and purity values similar to those presented above in Examples 2 to 4. For example, the following procedure has been used to prepare flupirtine maleate. A round bottom flask (1 L) was charged with acetonitrile (200 niL), followed by ANFP (20.0 g, 76 mmol), sodium dithionite (55.0 g, 315 mmol) and 29% aqueous ammonia (250 mL). The reaction mixture was stirred and gently heated at 36 to 37C for 60 min. The mixture was heated up to 44C over 35 min and then gradually cooled. The colour turned from yellow (starting material) to white. Acetonitrile, ammonia and water were removed by distillation at reduced pressure on a rotary evaporator. After distillation the mixture was diluted with water (100 mL) and ethyl acetate (310 mL) under a nitrogen stream. The water layer was separated and discarded. The air sensitive ethyl acetate layer was treated with ethyl chloroformate (14.5 mL, 151 mmol), while stirring and slowly flushing with nitrogen for 30 min. Triethylamine (25 mL, 179 mmol) was added and stirred for 30 min. An aqueous solution of maleic acid prepared from maleic acid (14.0 g, 120 mmol) and water (160 mL) was added to the reaction mixture. The mixture was maintained at 40C for 1 h, then cooled to 20C. The precipitate was collected by filtration, the vessel and the precipitate were washed with an additional portion of ethyl acetate (55 mL). The obtained wet product was dried in a vacuum drying oven at 50C, until the loss on drying was less than 1.0%. Yield: 29.5 g (94.3%> assay, 66.2 mmol; 87.1%> of theory); purity: 99.84%.
		In an autoclave, 100 gm. 2-amino-3-nitro-6-p-fluorobenzylamino- pyridine is taken in 500 ml. 1, 4-dioxane and 20 ml aqueous ammonia solution. 10 gm of raney nickel is added under nitrogen atmosphere and hydrogenated at 75-80C for 2-3 hours under 4-5 kg pressure. After completion of the reaction, the reaction mass is cooled and filtered at 40- 45Cthen in filtrate 45 ml of ethyl chloroformate is added slowly at 5- 10C. The temperature is raised to 25-30C and 80 ml triethyl amine is added under nitrogen atmosphere. The reaction mass, is heated at 55- 60C under stirring for 3-4 hours. After completion of the reaction, the reaction mass is distilled up to 70-80% under vacuum. This concentrated reaction mass is added into aqueous solution of maleic acid (72 gm in 2000 ml DM water at 65-70C and maintained at 65-70C for 2 hours under nitrogen to get crude Flupirtine Maleate as a solid. The reaction mass is cooled to 25-30C in 5-6 hours and maintained at this temperature for next 2-3 hours then filtered. The wet cake is washed with 200 ml water and dried to get 145 gm of flupirtine maleate.

References: [1]Patent: WO2012/4391,2012,A1 .Location in patent: Page/Page column 39.
[2]Patent: WO2013/80215,2013,A1 .Location in patent: Page/Page column 32-33.

17
[ 33400-49-6 ]
[ 1422275-80-6 ]
[ 1422275-81-7 ]

References: [1]Zeitschrift fur Naturforschung, B: Chemical Sciences,2012,vol. 67,p. 1297 - 1304.

18
[ 33400-49-6 ]
[ 1422275-79-3 ]

References: [1]Zeitschrift fur Naturforschung, B: Chemical Sciences,2012,vol. 67,p. 1297 - 1304.

19
[ 33400-49-6 ]
[ 1417916-52-9 ]

References: [1]Zeitschrift fur Naturforschung, B: Chemical Sciences,2012,vol. 67,p. 1297 - 1304.

20
[ 33400-49-6 ]
[ 1422275-78-2 ]

References: [1]Zeitschrift fur Naturforschung, B: Chemical Sciences,2012,vol. 67,p. 1297 - 1304.

21
[ 33400-49-6 ]
[ 1482053-40-6 ]

References: [1]Patent: WO2014/68459,2014,A2 .

22
[ 33400-49-6 ]
[ 1609102-48-8 ]

References: [1]Patent: WO2014/68459,2014,A2 .

23
[ 33400-49-6 ]
[ 1609102-49-9 ]

References: [1]Patent: WO2014/68459,2014,A2 .

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[ 24424-99-5 ]
[ 33400-49-6 ]
[ 1609102-47-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium hydroxide; In N,N-dimethyl-formamide; at 40℃;	26.22 g of compound 3 (100 mmol) was suspended in 50 ml of dry DMF and 12.0 g of sodium hydroxide was added at room temperature to give a brown solution. 34.50 ml of Boc2O (150 mmol) was added. After stirring for 10 minutes, the mixture was heated to 40C. The reaction mixture was poured into water and extracted with ethyl acetate (2 x 100 mL). The aqueous phase was adjusted to pH 4-5 with 2M aqueous HCl and extracted with dichloromethane (3 x 100 mL). The combined organic phases were concentrated under reduced pressure to give 24.27 g of compound 4 in 97.0% yield, 99.7% pure (HPLC).
80%	With potassium carbonate; In dichloromethane; at 20℃;	To a stirred solution of compound- 1 (N2-(4-fluorobenzyl)-6-nitropyridine-2,5- diamine) in 10 Vol of DCM were added BOC anhydride equivalently (1.0 eq) and 1.5 eq potassium carbonate. The mixture was magnetically stirred at room temperature and reaction was monitored by TLC. After completion of the reaction, the solution was diluted with water and the layers were separated. The aqueous layer was extracted with DCM 20V ol. The organic layer was washed with water and dried over sodium sulphate, later the evaporation of the solvent yielded the corresponding BOC derivative (yield: 80%).

References: [1]Patent: CN105541705,2016,A .Location in patent: Paragraph 0013; 0029; 0030.
[2]Patent: WO2014/68459,2014,A2 .Location in patent: Paragraph 0097-0099.

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[ 33400-49-6 ]
N-(2-amino-6-((4-fluorobenzyl)amino)pyridin-3-yl)pent-4-enamide [ No CAS ]

References: [1]Patent: WO2016/27089,2016,A1 .

26
[ 33400-49-6 ]
flupirtine maleate [ No CAS ]

References: [1]Patent: CN105541705,2016,A .

27
[ 33400-49-6 ]
prop-2-yn-1-yl (2-amino-6-((4-fluorobenzyl)amino)pyridin-3-yl)carbamate [ No CAS ]