796600-15-2|2-Chloro-4-fluoro-3-methylbenzonitrile| Ambeed

Structure of 796600-15-2

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Quality Control of [ 796600-15-2 ] Purity: 98% SDS Specification

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Product Details of [ 796600-15-2 ]

CAS No. :	796600-15-2
Formula :	C₈H₅ClFN
M.W :	169.58
SMILES Code :	ClC1=C(C#N)C=CC(=C1C)F
MDL No. :	MFCD13193544
InChI Key :	IOKBJSAKTZEMBR-UHFFFAOYSA-N
Pubchem ID :	44550971

Safety of [ 796600-15-2 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 796600-15-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	41.09
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	23.79 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.99
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	2.73
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.08
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.	2.79
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	3.31
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.78

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.01
Solubility	0.164 mg/ml ; 0.000966 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.	-2.88
Solubility	0.222 mg/ml ; 0.00131 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-3.76
Solubility	0.0295 mg/ml ; 0.000174 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	Yes
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.	-5.4 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	2.0
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	0.0 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<1.0
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)	1.85

Application In Synthesis of [ 796600-15-2 ]

* 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 [ 796600-15-2 ]

[ 796600-15-2 ] Synthesis Path-Downstream 1~35

1
[ 796600-15-2 ]
[ 870889-89-7 ]
[ 899821-23-9 ]

Yield	Reaction Conditions	Operation in experiment
40%	With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 18h;	Example 26 2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-methylbenzonitrile (198RL93) <strong>[796600-15-2]2-Chloro-4-fluoro-3-methylbenzonitrile</strong> (<strong>[796600-15-2]198RL18</strong>, 2.48 g, 14.6 mmol), endo-3-exo-methyl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (197FBA20a, 3.37 g, 19.0 mmol), and potassium carbonate (6.67 g, 48.2 mmol) were dissolved in dimethyl sulphoxide (40 mL), and the mixture stirred under argon at 80 C. for 18 hours. The reaction mixture was poured into water (200 mL) and stirred for 30 min. The off-white solid was filtered off and recrystallised twice from toluene, giving a white powder (1.53 g). The mother liquor was evaporated and the residue recrystallised to yield a second batch of compound (210 mg), giving an overall yield of 40%. Mp=145-147 C. Rf=0.68 (ethyl acetate/dichloromethane 1:1) LC/MS m/z 291 [M+H]+. 1H-NMR (CDCl3) delta 7.39 (d, 1H, J=8.6, Ar-H), 6.84 (d, 1H, J=8.6, Ar-H), 3.82 (m, 2H, Tr-H), 2.36 (s, 3H, Ar-CH3), 2.32-2.22 (m, 2H, Tr-H), 2.17-1.98 (m, 2H, Tr-H), 1.92-1.77 (m, 4H, Tr-H), 1.26 (s, 3H, Tr-CH3).

References: [1]Patent: US2006/160845,2006,A1 .Location in patent: Page/Page column 22.

2
[ 796600-15-2 ]
[ 538-09-0 ]
2-chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbenzonitrile, hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%		Example 4 2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbenzonitrile, hydrochloride (165RL90) <strong>[796600-15-2]2-Chloro-4-fluoro-3-methylbenzonitrile</strong> (165RL87a, 55 mg, 0.32 mmol) and nortropine (165 mg, 1.29 mmol) was dissolved in pyridine (2 mL) and the mixture irradiated at 220 C. for 2 hours in a microwave oven. Dichloromethane (50 mL) was added and the mixture washed with hydrochloric acid (0.4 M, 2×30 mL) followed by sat. sodium hydrogen carbonate (20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The product was further purified by column chromatography using dichloromethane to give the title compound (16.2 mg, 18%). Rf=0.45 (CH2Cl2). LC/MS m/z 277 [M+H]+. 1H-NMR (CDCl3, 300 MHz) delta 7.37 (d, 1H, J=8.6, Ar-H), 6.78 (d, 1H, J=8.6, Ar-H), 4.20 (m, 1H, Tr-H), 3.80 (m, 2H, Tr-H), 2.37 (s, 3H, Ar-CH3), 2.32-2.22 (m, 4H, Tr-H), 1.98-1,81 (m, 4H, Tr-H).

References: [1]Patent: US2006/160845,2006,A1 .Location in patent: Page/Page column 18.

3
[ 203302-92-5 ]
[ 557-21-1 ]
[ 796600-15-2 ]

Yield	Reaction Conditions	Operation in experiment
71%	tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃; for 2h;Product distribution / selectivity;	Example 8 2-Chloro-4-fluoro-3-methylbenzonitrile (198RL18) 3-Bromo-2-chloro-6-fluorotoluene (7.0 g, 31 mmol), zinc cyanide (3.7 g, 31 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.81 g, 1.56 mmol) was added to a flask under argon atmosphere. Dry DMF (35 mL) was added and the reaction mixture was stirred under argon at 120 C. The reaction was monitored by GC-MS and full conversion was observed after 2 hours. The mixture was diluted with dichloromethane (300 mL), washed with water (100 mL) and 4% magnesium sulfate solution (100 mL), dried over magnesium sulphate, filtered, and evaporated to give a clear oil. The product was further purified by column chromatography on silica gel using n-heptane/ethyl acetate (9:1) giving a white solid (3.79 g, 71%). 1H-NMR (CDCl3) delta 7.43 (dd, 1H, J=5.6, 8.8, Ar-H), 6.87 (t, 1H, J=8.8, Ar-H), 2.36 (d, 3H, J=2.4, CH3).
42%	tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 200℃; for 0.0416667h;Microwave;Product distribution / selectivity;	Example 3 2-Chloro-4-fluoro-3-methylbenzonitrile (165RL87a) 3-Bromo-2-chloro-6-fluorotoluene 165RL91 (173 mg, 0.78 mmol), zinc cyanide (91 mg, 0.78 mmol) and tetrakis(triphenylphosphine)palladium(0) (27 mg, 23 mumol) was charged in a vial, DMF (1 mL) added, and the mixture irradiated for 150 sec at 200 C. in a microwave oven. Diethyl ether (30 ml) was added and the reaction mixture washed with magnesium sulphate (4% solution, 3*20 mL) followed by brine (20 mL). The organic layer was dried and evaporated. The product was further purified by column chromatography on silica gel using n-heptane/ethyl acetate (9:1) giving a white solid (55 mg, 42%). GC/MS m/z 169 [M+H]+. 1H-NMR (CDCl3, 300 MHz) delta 7.43 (dd, 1H, J=5.6, 8.8, Ar-H), 6.87 (t, 1H, J=8.8, Ar-H), 2.36 (d, 3H, J=2.4, CH3).

References: [1]Patent: US2006/160845,2006,A1 .Location in patent: Page/Page column 19.
[2]Patent: US2006/160845,2006,A1 .Location in patent: Page/Page column 18.

4
[ 796600-15-2 ]
[ 609-36-9 ]
1-(3-chloro-4-cyano-2-methylphenyl)proline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%		Heat a slurry of <strong>[796600-15-2]2-chloro-4-fluoro-3-methyl-benzonitrile</strong> (0.4 g, 2.36 mmol) and L-proline (2.11 g, 18.8 mmol) in N-methylmorpholine (1.6 mL) at 200 0C in a microwave for 30 min. Partition the reaction between 2N aqueous hydrochloric acid and ethyl acetate. Separate and extract the organic portion with 2N aqueous sodium hydroxide. Acidify the aqueous extract to pH 1 by adding concentrated EPO <DP n="71"/>hydrochloric acid and back extract into ethyl acetate. Extract the combined organic portions with brine, dry over magnesium sulphate, filter, and concentrate under reduced pressure to give the title compound. (0.395 g, 63%) mass spectrum (m/e): 263(M-I); 1H NMR (300 MHz, CDCl3): delta 8.66(bs,lH0, 7.31(d, IH), 6.75(d, IH), 4.38(t,lH), 3.67(m, IH), 3.10(m,lH), 2.43(m,lH), 2.29(s,3H), 2.20-1.90(m.3H).

References: [1]Patent: WO2006/124447,2006,A2 .Location in patent: Page/Page column 68-69.

5
[ 796600-15-2 ]
[ 914954-55-5 ]
2-chloro-3-methyl-4-(4-hydroxy-2-phenyl-pyrrolidin-1-yl)-benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.6%		Heat a mixture of 2,4-dihydroxy-4-phenyl-l -butylamine (1.8 g, 10 mmol) and 2-chloro-4- fluoro-3-methyl-benzonitrile (1.0 g 6 mmol), cesium carbonate (4.Og, 12 mmol) and anhydrous dimethyl sulphoxide (10 ml) at 100 0C for 5 h. Allow the reaction cool and partition between ethyl acetate (100 ml) and water (3 x 50 ml). Wash the organic layer with 1.0M hydrochloric acid, dry over magnesium sulphate and concentrate to give a yellow oil (1.0 g). Dissolve this material in dichloromethane (20 ml) and treat with trifluoroacetic acid (5 ml). Allow the reaction mixture to stand at room temperature overnight and then wash with water (20 ml) and 2.0M sodium hydroxide (20 ml). Dry the organic layer over EPO <DP n="79"/>magnesium sulphate and concentrate to dryness. Purify the residue by silica gel chromatography (eluting with 5 to 10% methanol / dichloromethane) to give 50 mg (1.6% yield as a single diastereoisomer) of the title compound as a white solid. MS: 313 [M C135+H]+ and 335 [M Cl35+Na]+; 1H NMR (300 MHz, CDCl3): delta 7.28 (m, 5H), 7.20 (d, IH), 6.72 (d, IH), 5.09 (m, IH), 4.60 (br m, IH), 4.29 (m, IH), 3.10 (m, IH), 2.44 (m, IH), 2.43 (s, 3H), 2.00 (m, IH).

References: [1]Patent: WO2006/124447,2006,A2 .Location in patent: Page/Page column 76-77.

6
[ 796600-15-2 ]
[ 914954-59-9 ]
[ 914954-60-2 ]

Yield	Reaction Conditions	Operation in experiment
51%	With 1-methyl-pyrrolidin-2-one; at 120℃; for 2h;microwave reactor;	Heat a solution of 5-amino-4-methyl-2-pyridin-3-yl-pentan-2-ol (630 mg,3.24 mmol) and <strong>[796600-15-2]2-chloro-4-fluoro-3-methyl-benzonitrile</strong> (493 mg, 2.92 mmol) in NMP (2 mL) at 120 0C for 2 h in a microwave reactor. Purify the crude product by SCX to obtain 570 mg (51%) of the title compound.

References: [1]Patent: WO2006/124447,2006,A2 .Location in patent: Page/Page column 79.

7
[ 796600-15-2 ]
[ 1006-64-0 ]
2-chloro-3-methyl-4-(2-phenyl-pyrrolidin-1-yl)-benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With 4-methyl-morpholine; at 150℃;	Heat <strong>[796600-15-2]2-chloro-4-fluoro-3-methyl-benzonitrile</strong> (144 mg, 0.85 mmol) and 2- . phenyl-pyrrolidine (0.15 g, 1.02 mmol, 1.20 equivalents) in N-methylmorpholine (0.11 ml, 1.02 mmol, 1.20 equivalents) at 150 0C overnight. Allow the reaction mixture to cool to room temperature, dilute with dichloromethane (1 ml), load on silica, and purify by chromatography (12 g silica gel, 0 to 100% ethyl acetate/hexanes over 20 minutes) to obtain 150 mg of an oily residue. Recrystallize from ethyl acetate/hexanes to obtain the title compound (92 mg, 37%). LCMS(APCI+): 297.0 (M+l)+; 1H NMR (400 MHz, CDCl3): delta 7.25 (s, 2H), 7.19 (m, 2H), EPO <DP n="58"/>6.65 (d, IH), 4.70 (m, IH), 4.06 (m, IH), 3.18 (m, IH), 2.44 (m, IH), 2.43 (s, 3H), 2.12 (m, IH), 1.94 (m, 2H).

References: [1]Patent: WO2006/124447,2006,A2 .Location in patent: Page/Page column 55-56.

8
[ 796600-15-2 ]
[ 664364-48-1 ]
2-chloro-4-[(2S,3S)-3-hydroxy-2-methylpyrrolidin-1-yl]-3-methylbenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
114 mg	With lithium carbonate; In dimethyl sulfoxide; at 100℃; for 2h;	Toan ice-cold solution of (4S,5S)-4-hydroxy-5-methylpyrrolidin-2-one 6 (0.95g, 8.25 mmol) in THF (38 ml) was added dropwise 65-80% Red-Al intoluene (9.21 g), and the mixture was refluxed for 3 h. Aftercooling to 0 C,NaHCO3?10 H2O(3.78g)was added to the reaction mixture at 0 C.After stirring at room temperature for 18 h,the mixture was filteredthroughCeliteand the insoluble material was washed with THF. The filtrate wasconcentrated undervacuum to give pyrrolidine 7(crude, 3.73 g). Amixture of the obtained pyrrolidine 7(1.24 g, <strong>[796600-15-2]2-chloro-4-fluoro-3-methylbenzonitrile</strong>(424 mg, 2.50 mmol) and lithium carbonate (370 mg, 5.00 mmol) inDMSO (12.5 ml) was stirred at 100 C for 2 h. The resultingmixture was cooled to room temperature, and partitioned betweenethyl acetate and water. The organic layer was washed with satd aq.NaCl, dried over Na2SO4, and concentrated invacuo. The residue was purified by silica gel column chromatography(1:0 to 1:1 hexane/EtOAc), and recrystallized with ethylacetate andhexane to give B (114 mg, 18%) as a colorless solid. mp151-153 C; 1H-NMR (300MHz, CDCl3) 1.13(d, J = 6.3Hz, 3H), 1.77 (d, J = 5.1Hz, 1H), 1.98-2.09(m, 2H), 2.34 (s, 3H), 2.86-2.93(m, 1H), 3.72-3.79(m, 1H), 3.88-3.97(m, 1H), 4.35-4.42(m, 1H), 6.80 (d, J = 8.4Hz, 1H), 7.41 (d, J = 8.4Hz,1H); IR (KBr) 2975, 2224, 1586, 1472, 1319cm-1; Anal.Calcd for C13H15ClN2O: C, 62.28; H,6.03; N, 11.17. Found:C, 62.40; H, 6.15; N, 11.14; [alpha]25D -266.8 (c 0.4970, CHCl3).

References: [1]Patent: WO2007/15567,2007,A1 .Location in patent: Page/Page column 91-92.
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1897 - 1901.

9
[ 796600-15-2 ]
(2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalic acid salt [ No CAS ]
2-chloro-4-[(2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine-1-yl]-3-methylbenzonitrile [ No CAS ]

References: [1]Patent: WO2007/15567,2007,A1 .Location in patent: Page/Page column 89.

10
[ 924626-56-2 ]
[ 796600-15-2 ]

References: [1]Patent: WO2007/15567,2007,A1 .Location in patent: Page/Page column 87-88.

11
[ 796600-15-2 ]
[ 312-84-5 ]
[ 1182367-37-8 ]

Yield	Reaction Conditions	Operation in experiment
29%		Example 58; (R)-2-Chloro-4-(1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxyethylamino)-3-methylbenzonitrile; Intermediate 58a; (R)-2-(3-Chloro-4-cyano-2-methylphenylamino)-3-hydroxypropanoic acid K2CO3 (5.71 g, 41.28 mol) was added to a solution of <strong>[796600-15-2]2-chloro-4-fluoro-3-methylbenzonitrile</strong> (3.5 g, 20.64 mmol) and D-Serine (2.17 g, 20.096 mol) in DMSO (100 mL) at room temperature. The reaction mixture was heated to 75 C. and stirred for 19 h, then was allowed to cool to room temperature whereupon water (30 mL) was added followed by citric acid monohydrate (5g). After stirring for 10 min the mixture was partitioned between EtOAc (50 mL) and water. The organic phase was then washed with water (20 mL), brine (20 mL), dried (Na2SO4), filtered and concentrated to furnish a pale yellow solid (4.2 g). This crude product was then passed through a silica-plug [hexanes-EtOAc (95:5) as eluent] to furnish the title compound as a white solid (1.5 g, 29%) 1H NMR (500 MHz, acetone-d6, delta in ppm) 7.49 (d, J=9 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 5.56 (d, J=8 Hz, 1H), 4.43-4.40 (m, 1H), 4.06 (dd, J=11, 18 Hz, 1H), 4.05 (dd, J=11, 18 Hz, 1H) and 2.31 (s, 3H).
		Examples 11 and 12Example 11 Example 12 11a to l ib(R)-2-(3 -chloro-4-cyano-2-methylphenylamino)-3 -hydroxypropanoic acidTo a stirred solution of <strong>[796600-15-2]2-chloro-4-fluoro-3-methylbenzonitrile</strong> (1 la) (1.0 gm, 5.8 mmol) in DMSO (10 mL), D-Serine (1.4 gm, 13.3 mmol) was added followed by K2C03 (1.7 gm, 12.3 mmol) at room temperature. The resulting reaction mixture was heated to 90C for 12 h. After completion of reaction (by TLC), the reaction mixture was poured into ice-cold water (300 mL) and extracted with EtOAc (100 mL). The aqueous layer was acidified with citric acid (pH ~3) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over Na2S04, and concentrated under reduced pressure to afford the acid 1 lb (0.3 gm, crude) as off- white solid. The crude material was taken for the next step without purification.TLC: 10% MeOH/DCM (Rf: 0.2)1H NMR (500MHz, DMSO-c¾, delta in ppm): 8.2-10.2 (br s, 1H), 7.54 (d, J= 8.5 Hz, 1H), 6.57 (d, J= 9.0 Hz, 1H), 5.79 (d, J= 7.5 Hz, 1H), 4.20 (t, J= 3.0 Hz, 1H), 3.86-3.79 (m, 2H), 3.22 (br s, 1H), 2.25 (s, 3H).

References: [1]Patent: US2009/253758,2009,A1 .Location in patent: Page/Page column 109.
[2]Patent: WO2012/47617,2012,A1 .Location in patent: Page/Page column 59-60.

12
[ 796600-15-2 ]
[ 2280-48-0 ]
[ 1182367-29-8 ]

Yield	Reaction Conditions	Operation in experiment
		Example 14; (R)-2-chloro-4-(2-hydroxy-2-methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile; Intermediate 14a; (R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoic acid; <strong>[796600-15-2]2-chloro-4-fluoro-3-methylbenzonitrile</strong> (1.06 g, 6.26 mmol) was mixed together with (R)-2-amino-3-hydroxy-3-methylbutanoic acid (1.00 g, 7.51 mmol) in DMSO (25 mL). K2CO3 (1.73 g, 12.52 mmol) was added to the reaction mixture and stirred at 75 C. for 24 h. Then the reaction mixture was cool down to room temperature and poured slowly in to a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexane/EtOAc (4:6) and then with EtOAc, 100% to get the title compound (1.40 g). 1H NMR (500 MHz, acetone-d6, delta in ppm) 7.51 (d, J=9 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 5.48 (d, J=9 Hz, 1H), 4.16 (d, J=9 Hz, 1H), 2.34 (s, 3H), 1.43 (s, 3H), 1.41 (s, 3H).

References: [1]Patent: US2009/253758,2009,A1 .Location in patent: Page/Page column 46-47.

13
[ 796600-15-2 ]
[ 24830-94-2 ]
[ 1182366-72-8 ]

Yield	Reaction Conditions	Operation in experiment
63%		Example 3; 2-chloro-4-((1R,2R)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile; Intermediate 3a; (2R,3R)-2-(3-Chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid; <strong>[796600-15-2]2-Chloro-4-fluoro-3-methylbenzonitrile</strong> (1.19 g, 7.00 mmol) was mixed together with H-D-allo-Thr-OH (1.0 g, 8.40 mmol) in DMSO (15 mL). K2CO3 (1.93 g, 13.99 mmol) was added to the reaction mixture and stirred at 75 C. for 24 h. Then the reaction mixture was cooled down to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed on silica gel with a gradient of hexanes/EtOAc and then with EtOAc, 100% to get the purified final product (1.20 g, 63%). 1H NMR (500 MHz, Acetone-d6, delta in ppm) 7.47 (d, J=9 Hz, 1H), 6.73 (d, J=9 Hz, 1H), 5.48 (d, J=9 Hz, 1H), 4.26 (m, 2H), 2.28 (s, 3H), 1.32 (d, J=6 Hz, 3H).

References: [1]Patent: US2009/253758,2009,A1 .Location in patent: Page/Page column 31.

14
[ 796600-15-2 ]
[ 6027-21-0 ]
[ 1182369-21-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium carbonate; In dimethyl sulfoxide; at 20 - 80℃;	Example 79; (R)-2-chloro-4-(1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-3-hydroxypropylamino)-3-methylbenzonitrile; Intermediate 79a; (R)-2-(3-chloro-4-cyano-2-methylphenylamino)-4-hydroxybutanoic acid; To a suspension of D-Homoserine (2.5 g, 20.99 mmol) and K2CO3 (5.8 g, 41.98 mmol) in DMSO (30 mL) was added 2-chloro-3-methyl-4-fluorobenzonitrile (3.56 g, 20.99 mmol) at room temperature. The reaction mixture was heated to 80 C. and stirred for 17 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (200 mL) and extracted with EtOAc (3×200 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×100 mL). The organic extracts were combined, washed with H2O (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a beige solid (3.39 g, 60%): 1H NMR (400 MHz, delta in ppm) 7.49 (d, J=9 Hz, 1H), 6.62 (d, J=9 Hz, 1H), 6.06 (br d, J=9 Hz, 1H), 4.49-4.41 (m, 1H), 3.83-3.80 (m, 2H), 2.29 (s, 3H), 2.27-2.20 (m, 1H) and 2.18-2.09 (m, 1H).

References: [1]Patent: US2009/253758,2009,A1 .Location in patent: Page/Page column 136.

15
[ 796600-15-2 ]
[ 632-20-2 ]
[ 1182366-63-7 ]

Yield	Reaction Conditions	Operation in experiment
54%		Example 1; 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile; Intermediate 1a; (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid; <strong>[796600-15-2]2-chloro-4-fluoro-3-methylbenzonitrile</strong> (CAS 796600-15-2, 45g, 265.4 mmol) was mixed together with H-D-Thr-OH (37.92 g, 318.4 mmol) in DMSO (250 mL). K2CO3 (73.35 g, 530.7 mmol) was added to the reaction mixture and the reaction mixture stirred at 75 C. for 24 h. The reaction mixture was cooled to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed on silica gel with a gradient of hexanes/EtOAc and then with EtOAc, 100% to get the purified final product (39.0 g, 54%) 1H NMR (500 MHz, Acetone-d6, delta in ppm) 7.49 (d, J=9 Hz, 1H), 6.70 (d, J=9 Hz, 1H), 5.38 (d, J=10 Hz, 1H), 4.47 (d, J=6 Hz, 1H), 4.25 (m, 1H), 2.34 (s, 3H), 1.33 (d, J=6 Hz, 3H).
42%		Examples 17 and 18Example 17 Example 18 17aTo a stirred solution of D-Threonine (4.63 g, 38.8 mmol) in DMSO (50 mL), cooled to 0 C K2C03 (4.7 g, 34.8 mmol) was added. After being stirred for 15 min, <strong>[796600-15-2]2-chloro-4-fluoro-3-methylbenzonitrile</strong> (3.0 g, 17.7 mmol) was added to the reaction mixture. The resulting reaction mixture was heated to 80C for 36 h. After completion of reaction (by TLC), the reaction mixture was brought to room temperature, diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The aqueous layer was acidified by citric acid (pH 2-3) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with ice-cold water (5 * 30 mL), dried over Na2S04 and concentrated under reduced pressure to give the crude product. The crude material was triturated with 10% EtOAc/Hexane to afford the acid 17a (2.0 g, 42%) as an off-white solid.TLC: 30% MeOH/DCM (Rf: 0.2)1H NMR (500MHz, DMSO-<¾, delta in ppm): 7.54 (d, J= 8.5 Hz, 1H), 6.58 (d, J= 9.0 Hz, 1H), 5.46 (d, J= 9.0 Hz, 1H), 4.25-4.23 (dd, J= 6.5, 3.5Hz, 1H), 4.13-4.11 (dd, J= 8.5, 3.0 Hz, 1H), 2.26 (s, 3H), 1.19 (d, J= 6.5 Hz, 3H).

References: [1]Patent: US2009/253758,2009,A1 .Location in patent: Page/Page column 28-29.
[2]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 124 - 129.
[3]Patent: WO2012/47617,2012,A1 .Location in patent: Page/Page column 74-75.

16
[ 796600-15-2 ]
[ 69-96-5 ]
DL-threo-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-phenylpropanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 38; DL-Threo-2-chloro-4-(2-hydroxy-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethylamino)-3-methylbenzonitrile; Intermediate 38a; DL-Threo-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-phenylpropanoic acid; <strong>[796600-15-2]2-chloro-4-fluoro-3-methylbenzonitrile</strong> (2.0 g, 11.79 mmol) was mixed together with DL-Threo-3-phenylserine hydrate (2.82 g, 14.15 mmol) in DMSO (15 mL). K2CO3 (3.26 g) was added to the reaction mixture and stirred at 75 C. for 24 h. The reaction mixture was cooled to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexanes/EtOAc and then with EtOAc, 100% to get the pure final product (800 mg). 1H NMR (500 MHz, acetone-d6, delta in ppm) 7.52 (m, 3H), 7.37 (d, J=9 Hz, 1H), 7.2-7.30 (m, 2H), 6.81 (d, J=9 Hz, 1H), 6.44 (d, J=6 Hz, 1H), 5.42 (m, 1H), 4.5 (br s, 1H), 4.17 (m, 1H) 2.24 (s, 3H)

References: [1]Patent: US2009/253758,2009,A1 .Location in patent: Page/Page column 76.

17
[ 60702-69-4 ]
[ 74-88-4 ]
[ 796600-15-2 ]

Yield	Reaction Conditions	Operation in experiment
76%		Cool a solution of diisopropylamine (80.6 niL, 0.575 mol) in THF (1 L) to about -5 0C using an ice water/MeOH bath. Add /z-butyllithium (2.5 M in hexanes, 212 mL, 0.530 mol) dropwise over 1 h via a syringe pump (4 mL/min) while maintaining the reaction temperature between -5 to 0 0C during the addition. Stir the lithium diisopropylamide (LDA) solution for 1 h at 0 C and then transfer it via canula, over 1 h, to a -78 0C solution of 2-chloro-4-fluoro-benzonitrile (68.7 g, 0.442 mol) in THF (1 L). Allow the temperature of the reaction mixture to warm to about -65 0C during the initial addition of the LDA solution; however, keep the internal temperature below -70 0C during the remainder of the LDA addition. Keep the temperature of the resulting dark red-orange reaction mixture below -70 0C for 5 h and add iodomethane (251.2 g, 1.77 mol, ~3 mL/min) at such a rate that the reaction temperature is maintained below -65 0C during the addition. Allow the reaction mixture to slowly warm overnight. After stirring for 14 h, the temperature of the reaction mixture is -5 0C. Quench the reaction with saturated aqueous ammonium chloride (500 mL) and water (750 mL) and dilute with diethyl ether (about 2 L). Separate the layers and extract the aqueous layer with diethyl ether (about 1 L). Dry the combined organic layer (about 5.5 L) over MgSO4, filter, and concentrate to afford the crude title compound as a red-brown oily solid (about 86.7 g). Subject the crude residue (dry loaded on silica gel using methylene chloride) to flash chromatography (silica gel (10 x 30 cm), gradient of 99: 1 to 93:7 hexane/EtOAc) to obtain the title compound (56.7 g, 76%) as a white solid, m.p. 63 - 65 0C; 1H NMR (300 MHz, CDCl3): delta 7.54 (dd, J= 8.6, 5.6 Hz, IH), 7.08 (dd, J = 8.6, 8.6 Hz , IH), 2.36 (d, / = 2.4 Hz, 3H).
74%		Preparation 12-Chloro-4-fluoro-3-methyl-benzonitrileTo a solution of diisopropylamine (474 mL, 3.35 mol) in anhydrous THF (5.8 L) at-5 C under a nitrogen atmosphere is added dropwise 2.5 M n-butyllithium in hexanes (1.24 L, 3.10 mol) over 3 h and the resulting mixture is stirred at -5 C for one additional hour. The LDA solution is added dropwise to a solution of 2-chloro-4-fluoro-benzonitrile (400 g, 2.58 mol) in anhydrous THF (5.8 L) at -70 C over 6 h and then stirred at -70 C overnight. lodomethane (643 mL, 10.32 mol) is added dropwise over 2.5 h and the temperature is raised to -5 C for 17 h. Saturated aqueous ammonium chloride (3 L) is added. The solution is diluted with water (3.5 L) and extracted with diethyl ether (2 x 2 L). The organic phases are separated, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a black solid. The solid is purified through a silica gel pad eluting withEtOAc/hexanes (1/40) to obtain the title compound (323 g, 74%). 1H NMR (300 MHz, CDCls) delta 7.08 (dd, J= 8.6, 8.6 Hz, 1H), 7.54 (dd, J= 8.6, 5.6 Hz, 1H), 2.36 (d, J= 2.4 Hz, 3H).
		2-chloro-4-fluorobenzonitrile (1g) and TMEDA (1.13 mL) in THF (10 mL) were cooled to-78 C, under nitrogen. Sec-butyllithium (1. 3M in cyclohexane, 8.54 ML) was added over 20min, keeping the temperature BELOW-70 C. The mixture was then stirred at -78 C FOR 2. 5H. Methyl iodode (0. 5ML) was added and the mixture allowed to warm to 15 C, over 35MIN. The reaction was quenched with a saturated aqueous solution of ammonium chloride and the product was extracted with ethyl acetate. The ethyl acetate was washed with brine, dried (MgS04), filtered and concentrated under reduced pressure to give crude product (1.28g). Retention time 2.12 min (standard)

References: [1]Patent: WO2006/124447,2006,A2 .Location in patent: Page/Page column 45-46.
[2]Patent: WO2013/55577,2013,A1 .Location in patent: Page/Page column 24-25.
[3]Journal of Medicinal Chemistry,2016,vol. 59,p. 750 - 755.
[4]Patent: WO2004/99144,2004,A1 .Location in patent: Page 25.

18
[ 796600-15-2 ]
[ 870889-89-7 ]
2-chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]-oct-8-yl)-3-methylbenzonitrile hydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7186 - 7191.

19
[ 203302-92-5 ]
zinc cyanide [ No CAS ]
[ 796600-15-2 ]

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7186 - 7191.

20
[ 796600-15-2 ]
[ 538-09-0 ]
2-chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbenzonitrile [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7186 - 7191.

21
[ 796600-15-2 ]
[ 1252051-57-2 ]
[ 1252051-62-9 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 7f(2R,3S)-3-(benzyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)-4,4,4-trifluorobutanoic acid Cs2CO3 (3.5 g, 10.7 mmol) was added to a mixture of <strong>[796600-15-2]2-chloro-4-fluoro-3-methylbenzonitrile</strong> (0.79 g, 4.65 mmol) and (2R,3S)-2-amino-3-(benzyloxy)-4,4,4-trifluorobutanoic acid hydrochloride salt (0.93 g, 3.1 mmol) in DMSO (18 mL) at room temperature. The resulting mixture was heated to 80 C. and stirred for 2 days. After cooling to room temperature, the reaction mixture was poured into ice-water (150 mL) and extracted with 10% EtOAc in hexanes (2×50 mL). The aqueous phase was acidified to pH=23 with 2N HCl and extracted with EtOAc (2×100 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by flash chromatography to afford the crude (2R,3S)-3-(benzyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)-4,4,4-trifluorobutanoic acid (280 mg) as a mixture.

References: [1]Tetrahedron Letters,2010,vol. 51,p. 5361 - 5363.
[2]Patent: US2012/4270,2012,A1 .Location in patent: Page/Page column 18-19.

22
[ 796600-15-2 ]
[ 1182367-49-2 ]

References: [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 124 - 129.

23
[ 796600-15-2 ]
[ 1182367-50-5 ]

References: [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 124 - 129.

24
[ 796600-15-2 ]
[ 1182367-48-1 ]

References: [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 124 - 129.

25
[ 796600-15-2 ]
[ 1371609-13-0 ]