[ CAS No. 50846-36-1 ] {[proInfo.proName]}

Name: 50846-36-1|2-Amino-2-methylpropanenitrile hydrochloride|95%
Brand: Ambeed
SKU: A252211
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Quality Control of [ 50846-36-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 50846-36-1 ]

SDS Specification

Alternatived Products of [ 50846-36-1 ]

Product Details of [ 50846-36-1 ]

CAS No. :	50846-36-1	MDL No. :	MFCD08456816
Formula :	C₄H₉ClN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RWPZHHGTDNTPFY-UHFFFAOYSA-N
M.W :	120.58	Pubchem ID :	12239465
Synonyms :

Calculated chemistry of [ 50846-36-1 ]

Physicochemical Properties

Num. heavy atoms :	7
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.75
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	30.8
TPSA :	49.81 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 :	Yes
Log Kp (skin permeation) :	-6.71 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.46
Log Po/w (WLOGP) :	1.05
Log Po/w (MLOGP) :	0.08
Log Po/w (SILICOS-IT) :	-0.46
Consensus Log Po/w :	0.23

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.88
Solubility :	16.0 mg/ml ; 0.133 mol/l
Class :	Very soluble
Log S (Ali) :	-1.07
Solubility :	10.2 mg/ml ; 0.0842 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.32
Solubility :	57.7 mg/ml ; 0.479 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.63

Safety of [ 50846-36-1 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P261-P264-P270-P271-P280-P302+P352-P304+P340-P310-P330-P361-P403+P233-P405-P501	UN#:	2811
Hazard Statements:	H301-H311-H331	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 50846-36-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 50846-36-1 ]
Downstream synthetic route of [ 50846-36-1 ]

[ 50846-36-1 ] Synthesis Path-Upstream 1~3

1
[ 19355-69-2 ]
[ 50846-36-1 ]

Reference： [1] Patent: WO2005/21487, 2005, A1, . Location in patent: Page/Page column 64-65

2
[ 67-64-1 ]
[ 50846-36-1 ]

Reference： [1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 6, p. 988 - 991

3
[ 151-50-8 ]
[ 67-64-1 ]
[ 50846-36-1 ]

Reference： [1] Canadian Journal of Chemistry, 1987, vol. 65, p. 282 - 289

[ 50846-36-1 ] Synthesis Path-Downstream 1~37

1
[ 6780-38-7 ]
[ 50846-36-1 ]
[ 109259-02-1 ]

Reference： [1],1958,vol. 3,p. 175,180
Chem.Abstr.,1960,p. 20896

2
[ 590-28-3 ]
[ 50846-36-1 ]
[ 79662-84-3 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1926,vol. <2>113,p. 263 Anm.4

3
[ 50846-36-1 ]
[ 543-20-4 ]
[ 100377-44-4 ]

Reference： [1],1958,vol. 3,p. 175,183
Chem.Abstr.,1960,p. 20896

4
[ 50846-36-1 ]
[ 88-95-9 ]
[ 63081-95-8 ]

Reference： [1],1958,vol. 1,p. 97,103
Chem.Abstr.,1959,p. 14961

5
[ 50846-36-1 ]
[ 16248-71-8 ]

Reference： [1]Journal of general chemistry of the USSR,1967,vol. 37,p. 802 - 804
Zhurnal Obshchei Khimii,1967,vol. 37,p. 852 - 855

6
[ 50846-36-1 ]
[ 30550-11-9 ]

Reference： [1]Journal of Organic Chemistry USSR (English Translation),1970,vol. 6,p. 2438 - 2442
Zhurnal Organicheskoi Khimii,1970,vol. 6,p. 2426 - 2431

7
[ 50846-36-1 ]
[ 16248-81-0 ]

Reference： [1]Journal of general chemistry of the USSR,1967,vol. 37,p. 805 - 808
Zhurnal Obshchei Khimii,1967,vol. 37,p. 856 - 859

8
[ 590-28-3 ]
[ 50846-36-1 ]
[ 79662-84-3 ]
[ 1749-99-1 ]

Reference： [1]Monatshefte fur Chemie,1981,vol. 112,p. 853 - 866

9
[ 50846-36-1 ]
[ 16252-90-7 ]

Reference： [1]Journal of Organic Chemistry USSR (English Translation),1984,vol. 20,p. 1243 - 1247
Zhurnal Organicheskoi Khimii,1984,vol. 20,p. 1367 - 1371

10
[ 151-50-8 ]
[ 67-64-1 ]
[ 50846-36-1 ]

Reference： [1]Canadian Journal of Chemistry,1987,vol. 65,p. 282 - 289

11
[ 50846-36-1 ]
[ 67-64-1 ]
[ 2582-16-3 ]

Reference： [1]Canadian Journal of Chemistry,1987,vol. 65,p. 282 - 289

12
[ 50846-36-1 ]
[ 100-07-2 ]
[ 1026308-88-2 ]

Reference： [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 1810 - 1822

13
[ 590-28-3 ]
[ 7732-18-5 ]
[ 50846-36-1 ]
[ 79662-84-3 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1926,vol. <2>113,p. 263 Anm.4

14
[ 50846-36-1 ]
C₄H₇ClN₂O₂S [ No CAS ]

Reference： [1]Patent: US6337398,2002,B1 .Location in patent: Page column 35

15
[ 215301-34-1 ]
[ 50846-36-1 ]
naphthalene-2-carboxylic acid[1-(1-cyano-1-methyl-ethylcarbamoyl)-3-R-methyl-butyl]-amide [ No CAS ]
[ 225118-52-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; In DMF (N,N-dimethyl-formamide); at -10 - 10℃; for 1.5h;	C. naphthalene-2-carboxylic acid[ 1-(1-cyano-1-methyl-ethylcarbamoyl)-3-methyl-butyl]-amide N-(Naphthalene-2-carbonyl)-leucine (279 mg, 0.98 mmol), 1-cyano-1-methyl-ethylamine hydrochloride (137 mg, 1.14 mmol, 1.2 eq.) and HOBt (297 mg, 2.20 mmol, 2.2 eq.) are dissolved in dimethylformamide (5 ml) and WSCD (0.2 ml, 1.09 mmol, 1.1 eq.) is added at 10.. After stirring for 1.5 hours at -10, 5% sodium bicarbonate solution is added and the mixture is extracted with ethyl acetate.. The organic layer is washed with brine, dried over sodium sulfate and evaporated.. Chromatography on silica gel (n-hexane/ethyl acetate=20/1, 10/1, 5/1, 3/1 and 1/1) gives the product in 8.7% yield (mixture of enantiomers). Rf=0.54 (n-hexane/ethyl acetate=1/1)

Reference： [1]Patent: US6353017,2002,B1 .Location in patent: Page column 30

16
2-tert-Butyloxycarbonylamino-2-methylpropiononitrile [ No CAS ]
[ 50846-36-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	With hydrogenchloride; In 1,4-dioxane; at 0 - 20℃; for 2.5h;	N-tert-Butyloxycarbonyl-1-cyano-1-methyl-ethylamine (3.09 g, 16.8 mmol) is dissolved in dioxane (15 ml) and 4N hydrochloric acid-dioxane (25 ml) is added at 0. The reaction mixture is stirred at 0 for 1.5 hours, then at rt for 1 hour. The mixture is concentrated and diethyl ether is added. The resulting white precipitate is washed with diethyl ether and dried to give the product in 83% yield. The crude product is used for the next coupling without further purification. Rf=0.66(n-PrOH/H2O/ethyl acetate/NH3=5/1/2/1)

Reference： [1]Patent: US6353017,2002,B1 .Location in patent: Page column 30

17
[ 603142-83-2 ]
[ 50846-36-1 ]
N¹-(1-cyano-1-methylethyl)-N²-{(1S)-2,2,2-trifluoro-1-[4'-(methylsulfonyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 72.0h;	Step 2: Preparation of N1-(1-cyano-1-methylethyl)-N2-{(1S)-2,2,2-trifluoro-1-[4'- (METHYLSULFONYL) BIPHENYL-4-YLL ETHYL}-L-LEUCINAMIDE To a DMF (30 mL) solution of the acid from Example 4, Step 6 (1.2 g) was added BENZOTRIAZOL-L-YLOXYTRIS (dimethylamino) phosphoniumhexafluorophosphate (1.55 g), 2-AMINO-2- methylpropanenitrile hydrochloride from Step 1 (720 mg) and the mixture was cooled to 0 C. Triethylamine (1. 3 ML) was added drop wise and the mixture was warmed to room temperature and stirred for 72 hours. It was poured into ice and saturated aqueous sodium bicarbonate and extracted with diethyl ether (3 X 50 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on Si02 using a gradient of ethyl acetate and hexanes (1: 2 to 1 : 1) as eluant, followed by trituration using diethyl ether and hexanes to yield the title compound. 'H NMR (CD3COCD3) 8 8.08 (2H, d), 7.95 (2H, d), 7. 80 (2H, d), 7. 68 (1H, bs), 7.65 (2H, d), 4. 32-4. 42 (1H, m), 3.43-3. 52 (1H, m), 3.20 (3H, s), 2.65-2. 75 (1H, m), 1.90-2. 00 (1H, m), 1.57 (3H, s), 1.52 (3H, s), 1.52- 1.57 (1H, m), 1.40-1. 50 (1H, m), 0.90-0. 98 (6H, m).

Reference： [1]Patent: WO2005/21487,2005,A1 .Location in patent: Page/Page column 65

18
[ 19355-69-2 ]
[ 50846-36-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In diethyl ether; at 0℃; for 0.5h;	EXAMPLE 12 Synthesis OFNL- (L-CYANO-L-METH LEYL)-N2- (LS)-2, 2, 2-TRIFLUORO-1-R4 - (METHYLSULFONYL) BIPHENYL-4- YLLETHYL}-L-LEUCINAMIDE STEP 1 : Preparation of 2-AMINO-2-METHYLPROPANENITRILE hydrochloride; To a 0 C solution of ammonium chloride (15.5 g) in water (50 mL) was added a solution of acetone (17 mL) in diethyl ether (50 mL). Then a solution of the sodium cyanide (11.9 g. ) in water (35 ML) was slowly added at such a rate that the temperature never exceeds 10 C. The reaction mixture was stirred for one hour at 0 C after the addition of the cyanide solution then it was allowed to stand overnight. The ether layer was separated and the aqueous layer was extracted with diethyl ether (2 x 30 ML). The combined organic layers were washed with brine, dried with magnesium sulfate and the solvent were removed in vacuo to yield a residue which was diluted with methyl alcohol (80 mL). The solution was cooled at-78 C and saturated with ammonia gas (An Ace pressure tube with plunger valve and thermo well was used). The reaction mixture was allowed to stand at room temperature for two days. The excess ammonia was expelled by a current of air and the methyl alcohol was removed by evaporation. The residue was dissolved in diethyl ether (50 mL) and cooled to 0 C then a solution of 40 mL of hydrogen chloride (1.0 M in diethyl ether) was added. The mixture was stirred for 30 minutes and filtered to yield the title compound. 1H NMR (CD3SOCD3) 8 9.45 (1H, s), 1.70 (6H, s).

Reference： [1]Patent: WO2005/21487,2005,A1 .Location in patent: Page/Page column 64-65

19
potassium cyanide [ No CAS ]
[ 67-64-1 ]
[ 50846-36-1 ]

Reference： [1]Organic and Biomolecular Chemistry,2008,vol. 6,p. 988 - 991

20
2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid [ No CAS ]
[ 50846-36-1 ]
N-(2-cyanopropan-2-yl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10.7%	With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; for 1.0h;	2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-l,2,4- oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 30 mg, 0.070 mmol), 2-amino-2- methylpropanenitrile-HCl (12.58 mg, 0.104 mmol) [Ingate, S.T. et al, Tetrahedron, 53 : 17795-17814 (1997)], HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were dissolved in DMF (1 mL). After stirring 1 h, the mixture was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5-muiotaeta particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-muiotaeta particles; Mobile Phase A: 5:95 methanol: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanohwater with 10-mM ammonium acetate; Gradient: 40-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to provide single enantiomer N-(2-cyanopropan-2-yl)-2- hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-l,2,4-oxadiazol-3- yl)phenyl)acetamide (3.7 mg, 0.007 mmol, 10.7% yield): LCMS = 498.0 [M+H]+; XH NMR (400 MHz, methanol-cU) delta ppm 8.13-8.19 (2 H, m), 7.49-7.70 (7 H, m), 5.13 (1 H, s), 1.71 (3 H, s), 1.67 (3 H, s); HPLC peak RT = 2.9 min (Method E).

Reference： [1]Patent: WO2011/133734,2011,A1 .Location in patent: Page/Page column 109

21
[ 1258451-18-1 ]
[ 50846-36-1 ]
[ 1258444-79-9 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 9789 - 9801

22
[ 31562-43-3 ]
[ 50846-36-1 ]
N-(2-cyanopropan-2-yl)-2-methylpropane-2-sulfinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1.0h;	2-methylpropane-2-sulfinic chloride (1.28 g, 9.12 mmol) was added to a stirring solution of <strong>[50846-36-1]2-amino-2-methylpropanenitrile hydrochloride</strong> (1.0 g, 8.3 mmol) in DCM (21 ml) and N-ethyl-N-isopropylpropan-2-amine (3.04 ml, 17.4 mmol) at rt. DMAP (10 mg, 0.083 mmol) was added and the reaction was allowed to stir 1 h. The mixture was then diluted with dichloromethane and washed with sat NH4Cl aq, and sat NaCl aq. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product N-(2-cyanopropan-2-yl)-2-methylpropane-2-sulfinamide (1.45 g, 7.71 mmol, 93% yield) consistent by LCMS and NMR. LC-MS retention time: 2.15 min; m/z (MH+): 189. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3 u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, CHLOROFORM-d) delta 1.76 (s, 3H), 1.69 (s, 3H), 1.24 (s, 9H).

Reference： [1]Patent: US2014/275154,2014,A1 .Location in patent: Paragraph 0068
[2]Organic Process Research and Development,2016,vol. 20,p. 1328 - 1335

23
5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)-2-methoxybenzoic acid [ No CAS ]
[ 50846-36-1 ]
C₂₉H₂₅F₄N₅O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 4.0h;	To a solution of Compound 20 (20 mg), <strong>[50846-36-1]2-amino-2-methylpropanenitrile hydrochloride</strong> (9.32 mg, 0.077 mmol) and HATU (22.05 mg) in DMF (2 mL) was added iPr2NEt (0.027 mL). The mixture was stirred at room temperature for 4 hours. The product was isolated by preparative HPLC system

Reference： [1]Patent: US2015/266886,2015,A1 .Location in patent: Paragraph 0146

24
2-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoic acid [ No CAS ]
[ 50846-36-1 ]
C₂₈H₂₂F₅N₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1.0h;	General procedure: iPr2NEt (8 eq.) and HATU (1.5 eq.) were added into a solution of 2-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoic acid (1 eq.) and amine (1 eq.) in DMF. The reaction mixture was stirred at room temperature for 1 hour. The entire reaction mixture was purified via preparative HPLC to obtain the desired product

Reference： [1]Patent: US2015/266886,2015,A1 .Location in patent: Paragraph 0169-0170

25
5-[2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridin-5-yl]-2-methoxypyridine-3-carboxylic acid [ No CAS ]
[ 50846-36-1 ]
C₂₉H₂₅F₄N₅O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1.0h;	General procedure: iPr2NEt (8 eq.) and HATU (1.5 eq.) were added into a solution of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridin-5-yl)-2-methoxynicotinic acid (1 eq.) and amine (1 eq.) in DMF. The reaction mixture was stirred at room temperature for 1 hour. The entire reaction mixture was purified via preparative HPLC to obtain the desired product

Reference： [1]Patent: US2015/266886,2015,A1 .Location in patent: Paragraph 0192-0193

26
5-[2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-[(2,2,2-trifluoroethyl)amino]furo[2,3-b]pyridin-5-yl]-2-methoxypyridine-3-carboxylic acid [ No CAS ]
[ 50846-36-1 ]
C₂₈H₂₄F₄N₆O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1.0h;	General procedure: iPr2NEt (8 eq.) and HATU (1.5 eq.) were added into a solution of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)-2-methoxynicotinic acid (1 eq.) and amine (1 eq.) in DMF. The reaction mixture was stirred at room temperature for 1 hour. The entire reaction mixture was purified via preparative HPLC to obtain the desired product

Reference： [1]Patent: US2015/266886,2015,A1 .Location in patent: Paragraph 0198-0199

27
3-(6-(sec-butyl)-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoic acid [ No CAS ]
[ 50846-36-1 ]
3-(6-(sec-butyl)-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 0.5h;	2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (45 mg, 0.12 mmol) was added to stirring solution of 3-(6-(sec-butyl)-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoic acid (35 mg, 0.078 mmol), N-ethyl-N-isopropylpropan-2-amine (41 mul, 0.24 mmol) and <strong>[50846-36-1]2-amino-2-methylpropanenitrile hydrochloride</strong> (11 mg, 0.094 mmol) in DMF (0.8 mul) at room temperature. The mixture was allowed to stir at room temperature for 30 minutes. The entire reaction mixture was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-mum particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammoniumacetate; Gradient: 40-80% B over 20 minutes, then a 7-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified through chiral separation. First eluting isomer: The yield of the product was 8.9 mg, and its purity was 100%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column: Waters BEH C18, 2.0×50 mm, 1.7-mum particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40 C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm. Retention time: 2.99 min, (M+H)+: 513 Injection 2 conditions: Column: Waters BEH C18, 2.0×50 mm, 1.7-mum particles; Mobile Phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10 mM ammonium acetate; Temperature: 40 C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min; Detection: UV at 220 nm. Retention time: 4.04 min, (M+H)+: 513. 1H NMR (500 MHz, DMSO-d6) delta 8.86 (s, 1H), 8.55-8.47 (m, 1H), 8.10-8.02 (m, 2H), 7.98-7.94 (m, 1H), 7.90 (s, 2H), 7.66-7.61 (m, 1H), 7.59-7.55 (m, 1H), 7.43-7.36 (m, 1H), 2.93-2.86 (m, 1H), 2.81 (d, J=4.3 Hz, 3H), 1.83-1.74 (m, 1H), 1.71 (s, 6H), 1.58-1.47 (m, 1H), 1.19 (d, J=6.7 Hz, 3H), 0.65 (s, 3H). Second eluting isomer: The yield of the product was 9.5 mg, and its purity was 100%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column: Waters BEH C18, 2.0×50 mm, 1.7-mum particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40 C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm. Retention time: 2.99 min, (M+H)+: 513. Injection 2 conditions: Column: Waters BEH C18, 2.0×50 mm, 1.7-mum particles; Mobile Phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10 mM ammonium acetate; Temperature: 40 C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min; Detection: UV at 220 nm. Retention time: 4.04 min, (M+H)+: 513. 1H NMR (500 MHz, DMSO-d6) delta 8.82 (s, 1H), 8.50-8.45 (m, J=4.3 Hz, 1H), 8.06 (dd, J=8.9, 5.5 Hz, 2H), 7.96 (d, J=7.9 Hz, 1H), 7.92-7.85 (m, 2H), 7.67-7.60 (m, 1H), 7.60-7.54 (m, 1H), 7.41 (t, J=8.9 Hz, 2H), 2.93-2.86 (m, 1H), 2.81 (d, J=4.6 Hz, 2H), 1.84-1.75 (m, 1H), 1.71 (s, 6H), 1.58-1.49 (m, 1H), 1.20 (d, J=6.7 Hz, 3H), 0.66 (t, J=7.3 Hz, 3H)

Reference： [1]Patent: US2015/266886,2015,A1 .Location in patent: Paragraph 0206

28
[ 50846-36-1 ]
[ 501-53-1 ]
[ 100134-82-5 ]

Reference： [1]Organic Process Research and Development,2016,vol. 20,p. 1328 - 1335

29
[ 24424-99-5 ]
[ 50846-36-1 ]
2-tert-Butyloxycarbonylamino-2-methylpropiononitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
190 g	With triethylamine; In methanol; at 10℃; for 5.0h;Reflux;	200 g of <strong>[50846-36-1]2-amino-2-methylpropionitrile hydrochloride</strong> was added to a 3. 0 L round bottom flask and 1.5 g of methanol and 167 g of triethylamine were added to the reaction flask again, and the reaction solution was cooled to 10 And then 325 g of di-tert-butyl dicarbonate was added dropwise to the reaction solution at room temperature for 2. 0 h, and the temperature was raised to reflux 3. Oh; TLC detection, the reaction was complete and concentrated under reduced pressure. The remaining solid was dissolved with ethyl acetate, The aqueous layer was washed twice with ethyl acetate and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 190 g.

Reference： [1]Organic Process Research and Development,2016,vol. 20,p. 1328 - 1335
[2]Patent: CN104016885,2016,B .Location in patent: Paragraph 0027; 0028

30
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(2,2,2-trifluoroethoxy)benzofuran-5-yl)benzoic acid [ No CAS ]
[ 50846-36-1 ]
5-(3-((2-cyanopropan-2-yl)carbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(2,2,2-trifluoroethoxy)benzofuran-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26.40%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 16.0h;Inert atmosphere;	To a stirred mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(2,2,2- trifluoroethoxy) benzofuran-5-yl)benzoic acid (40 mg, 0.082 mmol) and 2-amino-2- methylpropanenitrile hydrochloride (9.90 mg, 0.082 mmol) in DMF (2.5 mL) at room temperature under a N2 atmosphere was added DIPEA (0.072 mL, 0.410 mmol). The mixture was cooled to 0C, and HATU (46.8 mg, 0.123 mmol) was added to the mixture, and then stirring was continued at r.t for 16 hr. After completion of the reaction, the mixture was diluted with water and the product extracted with EtOAc (25 ml x 3). The combined organic layers were washed with saturated brine solution, dried over Na2S04, filtered and concentrated under reduced pressure. The crude solid product was purified by Prep HPLC to obtained 5-(3-((2-cyanopropan-2- yl)carbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(2,2,2- trifluoroethoxy )benzofuran-3-carboxamide as a white solid. Yield: 12.00 mg, (26.40 %). PREPARATIVE HPLC: Column: X-BRIDGE C-18(19* 150)mm*5u, Mobile Phase: lOmM Ammonium acetate (A): MeCN (B), Flow: 15 ml/min, Rt: 10.38 min. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm = 7.93 - 7.84 (m, 4 H), 7.82 (s, 1 H), 7.72 - 7.69 (m, 1 H), 7.56 - 7.51 (m, 1 H), 7.20 (t, J= 8.7 Hz, 2 H), 7.14 (s, 1 H), 6.22 (s, 1 H), 5.84 (bs, 1H), 4.36 (q, J= 8.1 Hz, 2 H), 3.01 (d, J= 4.9 Hz, 3 H), 1.84 (s, 6 H). 19F NMR (376.6 MHz, CHLOROFORM-d) delta: -73.38, -109.44. LCMS: (ES+) m/z = 554.2 (M+H)+, Column-Acentis Express C18 (50 x 2.1 mm; 2.7 urn), Buffer : lOmM Ammonium Formate in Water pH 4.5, Mobile phase A: Buffer : MeCN (98 : 2), Mobile phase B: Buffer : MeCN (2 : 98), Flow: l .Oml/min. Rt: 2.18 min, wavelength: 220nm. HPLC Method: SUNFIRE (150 X 4.6mm) 3.5micron, Buffer: 0.05% TFA in water, Mobile Phase A: Buffer: MeCN (95:5), Mobile Phase B: MeCN: Buffer (95:5), Flow: 1.0 ml/min, Wavelength: 254 nm, Rt: 19.37 min, Wavelength: 220 nm, Rt: 19.37 min. HPLC Method: XBridge Phenyl (150 X 4.6mm) 3.5micron SC/749, Buffer: 0.05% TFA in water, Mobile Phase A: Buffer: MeCN (95:5), Mobile Phase B: Buffer: MeCN (5:95), Flow: 1.0 ml/min, Wavelength: 254 nm, Rt: 17.00 min, Wavelength: 220 nm, Rt: 17.00 min.

Reference： [1]Patent: WO2016/137832,2016,A1 .Location in patent: Page/Page column 90-92

31
methyl-5-(6-ethoxy-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-(methoxy-d3)benzoate [ No CAS ]
[ 50846-36-1 ]
N-(2-cyanopropan-2-yl)-5-(6-ethoxy-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-(methoxy-d3)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28.79%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 16.0h;Inert atmosphere;	To a stirred solution of 5-(6-ethoxy-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-5-yl)-2-(methoxy-i)nicotinic acid (35 mg, 0.075 mmol) and <strong>[50846-36-1]2-amino-2-methylpropanenitrile hydrochloride</strong> (9.03 mg, 0.075 mmol) in DMF (5.0 mL) at room temperature under a nitrogen atmosphere was added DIPEA (0.065 mL, 0.374 mmol). The mixture was cooled to 0C, and HATU (42.7 mg, 0.112 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 16 hr. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water, stirred for 5 min and the solid filtered. The crude product was purified by Prep HPLC to obtained the desired compound as a white solid. Yield: 11.50 mg, (28.79 %). PREPARATIVE HPLC: Column: Sunfire C-18(19* 150)mm*5um, Mobile Phase: 20mM Ammonium acetate pH 4.5 with acetic acid (A): MeCN (B), Flow: 18 ml/min, Rt: 10.74 min. NMR (400MHz, DMSO- de) delta ppm = 8.62 (s, 1 H), 8.50 (d, J= 2.4 Hz, 1 H), 8.44 (d, J= 4.6 Hz, 1 H), 8.23 (s, 1 H), 8.00 - 7.96 (m, 2 H), 7.58 (s, 1 H), 7.50 (s, 1 H), 7.41 - 7.36 (m, 2 H), 4.17 (q, J = 7.0 Hz, 2 H), 2.84 (d, J= 4.6 Hz, 3 H), 1.72 (s, 6 H), 1.32 (t, J= 6.9 Hz, 3 H). 19F NMR (376.6 MHz, DMSO-de) delta: -111.37. LCMS: (ES+) m/z = 534.4 (M+H)+, Column- Acentis Express C18 (50 x 2.1 mm; 2.7 um), Buffer : lOmM Ammonium Acetate pH-5 adjusted with HCOOH, Mobile phase A: Buffer : MeCN (95:5), Mobile phase B: Buffer : MeCN (5:95), Flow: 0.8 ml/min. Rt: 1.11 min, wavelength: 220nm. HPLC Method: SUNFIRE (150 X4.6mm) 3.5micron, Buffer: 0.05% TFA in water pH 2.5, Mobile Phase A: Buffer: MeCN (95:5), Mobile Phase B: MeCN: Buffer (95:5), Flow: 1.0 ml/min, Wavelength: 254 nm, Rt: 19.96 min, Wavelength: 220 nm, Rt: 19.96 min. HPLC Method: XBridge Phenyl (150 X4.6mm) 3.5micron SC/749, Buffer: 0.05% TFA in water pH 2.5, Mobile Phase A: Buffer: MeCN (95:5), Mobile Phase B: Buffer: MeCN (5:95), Flow: 1.0 ml/min, Wavelength: 254 nm, Rt: 16.94 min, Wavelength: 220 nm, Rt: 16.94 min.

Reference： [1]Patent: WO2016/137832,2016,A1 .Location in patent: Page/Page column 103; 104

32
methyl-5-(6-ethoxy-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-(methoxy-d3)benzoate [ No CAS ]
[ 50846-36-1 ]
5-(3-((2-cyanopropan-2-yl)carbamoyl)-4-(methoxy-d3)phenyl)-6-ethoxy-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 25℃; for 4.0h;Inert atmosphere;	To a solution of 5-(6-ethoxy-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5- yl)-2-(methoxy-<a)benzoic acid (0.04 g, 0.086 mmol), DIPEA (0.045 mL, 0.257 mmol) and HATU (0.033 g, 0.086 mmol) in DMF (4 mL) at 0C was added 2-amino 2-methylpropanenitrile hydrochloride (0.012 g, 0.103 mmol). The reaction mixture was stirred at 25C for 4 hours. The reaction mixture was diluted with ice-cold water, the solid filtered and dried under suction. The crude product was submitted for reverse phase prep HPLC purification to obtain 5-(3-((2-cyanopropan-2- yl)carbamoyl)-4-(methoxy-i)phenyl)-6-ethoxy-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide. Preparative HPLC Method : Inertsil ODS (250 x 4.6mm,5um). Mobile phase A: lOmM Ammonium Acetate in Water pH 4.6 adjusted with acetic acid. Mobile phase B: MeCN. Flow : 1.0 ml/min. Rt: 15.97 min.wavelength. NMR (400 MHz, METHANOL-^) delta ppm 8.09 (d, J=2.38 Hz, 1 H), 7.96-7.92 (m, 2 H), 7.75 (dd, J= 8.63, 2.42 Hz, 1 H), 7.56 (s, 1 H), 7.31 (s, 1 H), 7.27-7.22 (m, 3 H), 4.15 (q, J=6.96 Hz, 2 H), 2.97 (s, 3 H), 1.82 (s, 6 H) 1.39 (t, J = 6.96 Hz, 3 H). 19F NMR (376.6 MHz, METHANOLS) : delta ppm = -113.40. LCMS: (ES+) m/z = 533.4 (M+H)+. Column- ACQUITY UPLC BEH C8 (50X2. lmm; 1.7mupiiota). Buffer: lOmM AmmoniumAcetate pH-5 adjusted with HCOOH. M phase A : Buffer : MeCN (95:5). M phase B : Buffer: MeCN (5:95). Flow : 0.8ml/min., Method:%B: 0min-5%: l . lmin -95%: 1.7min-95%. Rt min: 1.11, wavelength: 220nm

Reference： [1]Patent: WO2016/137832,2016,A1 .Location in patent: Page/Page column 121-123

33
methyl 6-(2-(6-fluoropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)picolinate [ No CAS ]
[ 50846-36-1 ]
N-(2-cyanopropan-2-yl)-6-(2-(6-fluoropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		2 M Lithium hydroxide (175 mL, 350 mmol, 10 equiv) was added to a solution of compound 27 (17.1 g, 35 mmol, 1 equiv) in THF (350 mL). The reaction mixture was stirred overnight at room temperature, at which point LC/MS indicated all the starting (0509) material was consumed. In addition to the desired product, ~20% of compound 28(b) (loss of benzenesulfonyl group) was also present. The reaction was poured into 1N HCl (0.5 L) and extracted with ethyl acetate (1 L). The organic layer was separated and concentrated under reduced pressure to give a crude mixture of compound 28(b) and compound 28(a), which were used subsequently. [0250] Step 5 - N-(2-Cyanopropan-2-yl)-6-(2-(6-fluoropyridin-3-yl)-1-(phenylsulfonyl)- 1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide (30): N,N'-diisopropylethylamine (14.1 mL, 81 mmol, 4 equiv) was added to a solution of the ~1 to 4 mixture of compound 28(b) and compound 28(a) (9.6 g, 20.23 mmol, 1 equiv) in DMF (135 mL). 2-Amino-2- methylpropanenitrile hydrochloride (3.7 g, 30.4 mmol, 1.5 equiv) was added and the reaction was stirred for ~30 minutes at room temperature. Propylphosphonic anhydride (T3P, 50 wt% in ethyl acetate) (23.8 mL, 40.5 mmol, 2 equiv) was added dropwise, with the internal temperature gradually increasing from 20 to 30 C during the addition. After stirring overnight, LC/MS indicated ~50% conversion of starting material. Stirring an additional 24 hours resulted in no further conversion. The reaction mixture was poured into water (1 L) and extracted with ethyl acetate (500 mL). The organic layer was separated, washed with saturated brine (500 mL) and concentrated under reduced pressure. The crude solid was dissolved in THF, dry-loaded onto silica gel and purified on an AnaLogix column (80 g), eluting with a gradient of 0 to 50% ethyl acetate in dichloromethane. The resulting solid was triturated with MTBE (15 mL) to give N-(2- cyanopropan-2-yl)-6-(2-(6-fluoropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)picolinamide.

Reference： [1]Patent: WO2018/226846,2018,A1 .Location in patent: Paragraph 0249-250

34
[ 21190-87-4 ]
[ 50846-36-1 ]
6-bromo-N-(2-cyanopropan-2-yl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Triethylamine (93 mL, 683 mmol, 3 equiv) was added to a solution of compound 32 (46 g, 228 mmol, 1 equiv) and HBTU (99 g, 262 mmol, 1.15 equiv) in DMF (690 mL). After stirring at room temperature for 30 minutes, <strong>[50846-36-1]2-amino-2-methylpropanenitrile hydrochloride</strong> (35.7 g, 296 mmol, 1.3 equiv) was added and the reaction mixture was stirred overnight. The solution was poured into water (4 L) (0512) and extracted with ethyl acetate (3 L). The organic layer was separated, washed with saturated brine (2 L) and concentrated under reduced pressure. The crude product which was dissolved in dichloromethane and purified over silica gel (0.7 Kg), eluting with a gradient of 10 to 20% ethyl acetate in heptanes to give 6-bromo-N-(2-cyanopropan-2-yl)picolinamide.

Reference： [1]Patent: WO2018/226846,2018,A1 .Location in patent: Paragraph 0253

35
[ 100047-36-7 ]
[ 50846-36-1 ]
4-amino-N-(1-cyano-1-methylethyl)pyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 72.0h;	To a mixture of 4-aminopyridine-2-carboxylic acid (15 g, 108.6 mmol), TBTU (41.84 g,130.32 mmol) and triethylamine (37.84 mL, 271.5 mmol) in DMF (271.52 mL) was added2-amino-2-methyl-propanenitrile hydrochloride (14.4 g, 119.46 mmol) and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtered and the solid washed with DMF (2 x 30 mL). The combined filtrate was concentrated in vacuo and the crude residue dissolved in EtOAc (300 mL) and washed with sat. NaHCO3 solution (2 x300 mL). The aqueous portion was re-extracted with EtOAc (30 mL) and the organic layers were combined, washed with brine (160 mL x 2), dried over anhydrous Na2504 and concentrated in vacuo. Purification of the resulting solid by chromatography on silica eluting with 0-100% EtOAc in heptane yielded a solid which was triturated with ice cold TBME:heptane (3:1 mixture) to afford the titled compound as a colourless crytalline solid.1H NMR (400 MHz, DMSO-d6) O 8.60 (5, 1H), 8.03 (d, J = 5.6 Hz, 1H), 7.21 (d, J = 2.3Hz, 1H), 6.62 (dd, J = 5.6, 2.4 Hz, 1H), 6.40 (5, 2H), 1.70 (5, 6H).LCMS (Method E) Rt 0.35 mins; MS m/z 205.0 = [M+H]+

Reference： [1]Patent: WO2019/145726,2019,A1 .Location in patent: Page/Page column 295; 296

36
4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid [ No CAS ]
[ 50846-36-1 ]
4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-cyano-1-methylethyl)pyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3.0h;	4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1)(4.0 g, 13.04 mmol) and 2-amino-2-methyl-propanenitrile hydrochloride (3.15 g, 26.08 mmol) were suspended in DMF (40 mL) and treated with DIPEA (9.11 mL, 52.17 mmol) and stirred to form a solution. HATU (5.95 g, 15.65 mmol) was added the reactionmixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (60 mL) and 4:1 EtOAc/heptane (100 ml). The biphasic suspension was filtered using minimal EtOAc and the organic portion was separated, washed with water, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by chromatography on silica eluting with 0-100% EtOAc in heptane followed by 0-100% MeOH in EtOAc affordeda yellow glassy solid. TBME (10 mL) was added to the solid and the mixture was heated to reflux (90 00) and further TBME (90 mL) was added gradually. MeCN was added in 0.5 mL aliquots until full dissolution occurred (9 mL).The mixture was cooled to 60 00 then to 0 00 for 3 hours. The resulting mixture was allowed to stand at room temperature for 4 days and then filtered and dried in a vacuum oven to afford the titled compound as a whitecrystalline solid.1H NMR (500 MHz, DMSO-d6) O 10.88 (5, 1H), 9.87 (5, 1H), 8.82 (5, 1H), 8.50 (d, J = 5.5Hz, 1H), 8.21 (d, J = 1.9 Hz, 1H), 7.86 (dd, J = 5.5, 2.2 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H),7.11 (dd, J = 8.6, 2.7 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 3.67 (5, 2H), 1.72 (5, 6H).LC-MS (Method A): Rt 2.81 mins; MS m/z 373.2/375.2 = [M+H]+ (98% 215nm)

Reference： [1]Patent: WO2019/145726,2019,A1 .Location in patent: Page/Page column 211; 212

37
[ 50846-36-1 ]
[ 79-22-1 ]
(cyano-dimethyl-methyl)carbamic acid methyl ester [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,2019,vol. 56,p. 2683 - 2690

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P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
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

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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. 50846-36-1 ] {[proInfo.proName]}

Quality Control of [ 50846-36-1 ]

Related Doc. of [ 50846-36-1 ]

Product Details of [ 50846-36-1 ]

Calculated chemistry of [ 50846-36-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 50846-36-1 ]

Application In Synthesis of [ 50846-36-1 ]

[ 50846-36-1 ] Synthesis Path-Upstream 1~3

[ 50846-36-1 ] Synthesis Path-Downstream 1~37

Similar Product of [ 50846-36-1 ]

Related Functional Groups of [ 50846-36-1 ]

Aliphatic Chain Hydrocarbons

Amines

Nitriles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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[ 50846-36-1 ]

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[ 50846-36-1 ]