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[ CAS No. 603139-19-1 ] {[proInfo.proName]}

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Cat. No.: {[proInfo.prAm]}
Chemical Structure| 603139-19-1
Chemical Structure| 603139-19-1
Structure of 603139-19-1 * Storage: {[proInfo.prStorage]}
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Quality Control of [ 603139-19-1 ]

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Product Details of [ 603139-19-1 ]

CAS No. :603139-19-1 MDL No. :MFCD11042419
Formula : C25H27F4N3O3S Boiling Point : -
Linear Structure Formula :- InChI Key :FWIVDMJALNEADT-SFTDATJTSA-N
M.W : 525.56 Pubchem ID :10152654
Synonyms :
MK-0822

Calculated chemistry of [ 603139-19-1 ]

Physicochemical Properties

Num. heavy atoms : 36
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.44
Num. rotatable bonds : 11
Num. H-bond acceptors : 9.0
Num. H-bond donors : 2.0
Molar Refractivity : 126.57
TPSA : 107.44 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.57 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.99
Log Po/w (XLOGP3) : 4.13
Log Po/w (WLOGP) : 7.0
Log Po/w (MLOGP) : 2.75
Log Po/w (SILICOS-IT) : 5.18
Consensus Log Po/w : 4.41

Druglikeness

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

Water Solubility

Log S (ESOL) : -5.22
Solubility : 0.00316 mg/ml ; 0.00000601 mol/l
Class : Moderately soluble
Log S (Ali) : -6.09
Solubility : 0.000424 mg/ml ; 0.000000807 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -8.47
Solubility : 0.0000018 mg/ml ; 0.0000000034 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 4.07

Safety of [ 603139-19-1 ]

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

Application In Synthesis of [ 603139-19-1 ]

* 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.

  • Downstream synthetic route of [ 603139-19-1 ]

[ 603139-19-1 ] Synthesis Path-Downstream   1~22

  • 1
  • [ 603142-96-7 ]
  • [ 603139-19-1 ]
YieldReaction ConditionsOperation in experiment
97% With sodium tungstate; dihydrogen peroxide; tetra(n-butyl)ammonium hydrogensulfate In dichloromethane; toluene at 20℃; for 3h;
With dihydrogen peroxide In dichloromethane; water; toluene at 20℃; for 3h; 15.11 Step 11: Preparation of N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4'-(methylsulfonyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide To a 0° solution of the sulfide (0.265 g) from Step 10 in toluene (5 mL) and dichloromethane (5 mL) was added Na2WO4.2H2O (0.002 g) and n-Bu4NHSO4 (0.01 g). 30% Hydrogen peroxide (0.137 mL) was then slowly added and the mixture was stirred at room temperature for 3 hours. The mixture was poured slowly onto a mixture of ice, dilute aqueous sodium thiosulfate and ethyl acetate. The organic layer was separated and the aqueous further extracted with ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo to yield a residue which was purified on SiO2 using ethyl acetate, hexanes and dichloromethane (1:1:0.1) as eluant. The residue was triturated in diethyl ether to yield N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4'-(methylsulfonyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide.
With sodium tungstate; dihydrogen peroxide; tetra(n-butyl)ammonium hydrogensulfate In dichloromethane; toluene at 0 - 20℃; for 3h; 2.12 Step 12: Preparation of N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4'- (METHYLSULFONYL)-L 1 -BIPHENYL4-ELLETHEL}-L-LEUCINAMIDE; To a 0 ° solution of the sulfide (0.265 g) from Step 11 in toluene (5 mL) and dichloromethane (5 mL) was added NA2WO4} 2H20 (0.002 g) and N-BU4NHS04 (0.01 g). Then 30 % hydrogen peroxide (0.137 ML) was slowly added and the mixture was stirred at room temperature for 3 hours. The mixture was poured slowly on a mixture of ice, dilute aqueous sodium thiosulfate and ethyl acetate.. The organic layer was separated and the aqueous further extracted with ethyl acetate. 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 purified on SIO2 using ethyl acetate, hexanes and dichloromethane (1: 1: 0.1) as eluant. The residue was triturated in diethyl ether to yield N1-(1- CYANOCYCLOPROPYL)-4-FLUORO-N2-{ {(1S)-2, 2, 2-TRIFLUORO-L- [4 - (METHYLSULFONYL)-L, L -BIPHENYL-4-YL] ETHYL}-L- leucinamide. 1H NMR (CD3COCD3) 8 8.2 (1H, NH), 8.05-8. 1 (2H, M), 7.95-8. 0 (2H, M), 7.8 (2H, M), 7.65 (2H, M), 4.35- 4.45 (1H, M), 3.5-3. 6 (1H, M), 3.2 (3H, s), 2.8-2. 9 (1H, NH), 1.9-2. 1 (2H, M), 1.3-1. 5 (8H, M), 1.05-1. 15 (1H, M), 0.9-1. 0 (1H, M).
With sodium tungstate; dihydrogen peroxide; tetra(n-butyl)ammonium hydrogensulfate In dichloromethane; water; toluene at 20℃; for 3h; 5.12 Step 12: Preparation of NL- (L-CYANOC PROPYL)-4-FLUORO-N2-F (LS)-2, 2, 2-TRIFLUORO-L-R4 - (methylsulfonyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide To a 0 ° solution of the sulfide (0.265 g) from Step 11 in toluene (5 mL) and dichloromethane (5 ML) was added NA2WO4*2H2O (0.002 g) and N-BU4NHS04 (0.01 g). Then 30 % hydrogen peroxide (0.137 ML) was slowly added and the mixture was stirred at room temperature for 3 hours. The mixture was poured slowly on a mixture of ice, dilute aqueous sodium thiosulfate and ethyl acetate.. The organic layer was separated and the aqueous further extracted with ethyl acetate. 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 purified on SI02 using ethyl acetate, hexanes and dichloromethane (1: 1: 0.1) as eluant. The residue was triturated in diethyl ether to yield NUL-(1- CYANOCYCLOPROPYL)-4-FLUORO-N2-{ (LS)-2, 2, 2-TRIFLUORO-L- [4 - (METHYLSULFONYL)-L, L -BIPHENYL-4-YL] ETHYL}-L- leucinamide. 1H NMR (CD3COCD3) 8 8.2 (1H, NH), 8.05-8. 1 (2H, m), 7.95-8. 0 (2H, m), 7.8 (2H, M), 7.65 (2H, M), 4. 35- 4.45 (1H, M), 3.5-3. 6 (1H, m), 3.2 (3H, s), 2.8-2. 9 (1H, NH), 1.9-2. 1 (2H, M), 1.3-1. 5 (8H, M), 1.05-1. 15 (1H, m), 0.9-1. 0 (1H, m).

YieldReaction ConditionsOperation in experiment
97% Stage #1: In tetrahydrofuran; water at 20℃; for 18.5h; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide for 2.5h; 2 EXAMPLE 2; N-(I -CYANOCYCLOPROPYL)-4-FLUORO-N2- {(1 S)-2,2,2-TRIFLUORO- 1 -[4'- (METHYLSULFOνYL)BIPHEνYL-4- YL]ETHYL}-L-LEUCINAMIDE; Acid (1.9 g) was dissolved in DMAc (10 mL) and cooled to 0°C. 1 -Aminocyclopropane carbonitrile hydrochloride (0.57 g) and HATU (1.85 g) were added. The resulting slurry was stirred for 15 min and DIEA (2.12 mL) was added over 1.5 h. The reaction was aged for 1 h. Water (11.2 mL) was added via dropping funnel over 70 min and the slurry was aged for Ih at 2O0C. The mixture was filtered and the filter cake was washed with a solution of DMAc:water (9.4 mL, 1 : 1.2), water (18.7 mL), 2-propanol (9.3 mL) The batch was dried to yield 1.67 g, 79% yield of the corresponding amide.Amide (2.56 g), was dissolved in THF (30.7 mL) at 30°C. Water (19 mL) was added via dropping funnel. The batch was seeded and aged for Ih at 2O0C. Additional water (40.9 mL) was added over 1.5 h and the batch was aged for 16 h. The batch was filtered and washed with water (15 mL). The solids were dried to a constant weight to yield 2.50 g, 97% yield of pure amide. 1H NMR (CD3OD) δ 8.17 (bs, IH), 8.05 (d, 2H, J= 8.5), 7.96 (d, 2H, J= 8.5), 7.80 (d, 2H, J= 8.0), 7.64 (d, 2H, J= 8.0), 4.43 (m, IH), 3.55 (ddd, IH, J= 5.0, 8.5, 8.0), 3.18 (s, 3H), 2.84 (bm, IH), 2.02 (m, 2H), 1.46 (d, 3H, J= 21.5), 1.43 (d, 3H, J= 22.0), 1.36 (m, 2H), 1.07 (m, IH), 0.94 (m, IH); 13C NMR (CD3OD) δ; 19F NMR (CD3OD) δ -73.2, -136.8; IR (cm"1) 3331, 2244, 1687, 1304, 1152; mp 223-224 0C, [α]D20 + 23.3 (c = 0.53, MeOH).
94.9% Stage #1: In water; acetone at 23 - 40℃; for 12.5h; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide for 2.5h; 3 EXAMPLE 3; N-(l-CYANOCYCLOPROPYL)-4-FLUORO-iV2-{(l1S)-2,2,2-TRrFLUORO-l-[4'- (METHYLSULFONYL)BIPHENYL^-YL]ETHYL) -L-LEUCINAMIDE; A round-bottom flask was charged with biphenyl acid'DCHA salt (76.6 g, 99.2% ee, diastereomeric ratio 342:1) and DMF (590 g). Solid aminocyclopropane carbonitrile-HCl (15.2 g), HOBt-H2O (17.9 g), and EDCηC1 (29.1 g) were all charged forming a white slurry. The batch was then heated to 38-42°C and aged for 5 hours. The batch was then cooled to 20- 250C and held overnight. HPLC analysis showed 99.4% conversion. The batch was heated to 38-42°C and water (375 g) was charged to batch over 2 hours. The batch remained as a slurry throughout the water addition. The batch was then heated to 58-620C and aged for 1 hour. Following age, water (375 g) was charged over 3 hours, at a rate of 2.1 g/min. The batch was then cooled to 15-25°C and aged overnight. The batch was filtered and washed with 39% DMF in water (2 x 300 g) and 2-propanol (180 g). The solids were dried in the filter at 40-600C for 24 hours. The desired crude product was isolated as a white solid (57g, 92% yield, 99.4 wt%). A round-bottom flask was charged with crude solid (57 g) and acetone/water solution (324 g, 88/12). The slurry was then heated to 400C, at which point the batch was in solution, and aged for an hour. Water (46 g) was then charged over 30 minutes. The batch was then seeded (1.7 g, 3.0 wt%), and the batch was aged at 40°C for an hour prior to proceeding with the crystallization. Water (255 g) was charged over 4.5 h. The batch was then cooled to 230C over 1.5 h, aged for 4 h and filtered. The solids were washed with acetone/water (158 g, 45/55) and water (176 g). The filter cake was dried with nitrogen sweep / vacuum at 55°C. The desired product (57.2 g , 99.9wt%, 99.8A% (enantiomer ND), was obtained in 94.9% yield. 1H NMR (CD3OD) δ 8.17 (bs, IH), 8.05 (d, 2H, J= 8.5), 7.96 (d, 2H, J= 8.5), 7.80 (d, 2H, J= 8.0), 7.64 (d, 2H, J= 8.0), 4.43 (m, IH), 3.55 (ddd, IH, J= 5.0, 8.5, 8.0), 3.18 (s, 3H), 2.84 (bm, IH), 2.02 (m, 2H), 1.46 (d, 3H, J= 21.5), 1.43 (d, 3H, J= 22.0), 1.36 (m, 2H), 1.07 (m, IH), 0.94 (m, IH); 13C NMR(CD3OD) δ; 19F NMR (CD3OD) δ -73.2, -136.8; IR (cm"1) 3331, 2244, 1687, 1304, 1152; mp 223-224 0C, [α]D20 + 23.3 (c = 0.53, MeOH).
  • 3
  • [ 1064076-86-3 ]
  • [ 127946-77-4 ]
  • [ 603139-19-1 ]
YieldReaction ConditionsOperation in experiment
92% Stage #1: (2S)-4-fluoro-4-methyl-2-({(1S)-2,2,2-trifluoro-1-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}amino)pentanoic acid dicyclohexylamine salt; 1-amino-1-cyclopropanecarbonitrile hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20 - 42℃; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide for 2.5h; 3 EXAMPLE 3; N-(l-CYANOCYCLOPROPYL)-4-FLUORO-iV2-{(l1S)-2,2,2-TRrFLUORO-l-[4'- (METHYLSULFONYL)BIPHENYL^-YL]ETHYL) -L-LEUCINAMIDE; A round-bottom flask was charged with biphenyl acid'DCHA salt (76.6 g, 99.2% ee, diastereomeric ratio 342:1) and DMF (590 g). Solid aminocyclopropane carbonitrile-HCl (15.2 g), HOBt-H2O (17.9 g), and EDCηC1 (29.1 g) were all charged forming a white slurry. The batch was then heated to 38-42°C and aged for 5 hours. The batch was then cooled to 20- 250C and held overnight. HPLC analysis showed 99.4% conversion. The batch was heated to 38-42°C and water (375 g) was charged to batch over 2 hours. The batch remained as a slurry throughout the water addition. The batch was then heated to 58-620C and aged for 1 hour. Following age, water (375 g) was charged over 3 hours, at a rate of 2.1 g/min. The batch was then cooled to 15-25°C and aged overnight. The batch was filtered and washed with 39% DMF in water (2 x 300 g) and 2-propanol (180 g). The solids were dried in the filter at 40-600C for 24 hours. The desired crude product was isolated as a white solid (57g, 92% yield, 99.4 wt%). A round-bottom flask was charged with crude solid (57 g) and acetone/water solution (324 g, 88/12). The slurry was then heated to 400C, at which point the batch was in solution, and aged for an hour. Water (46 g) was then charged over 30 minutes. The batch was then seeded (1.7 g, 3.0 wt%), and the batch was aged at 40°C for an hour prior to proceeding with the crystallization. Water (255 g) was charged over 4.5 h. The batch was then cooled to 230C over 1.5 h, aged for 4 h and filtered. The solids were washed with acetone/water (158 g, 45/55) and water (176 g). The filter cake was dried with nitrogen sweep / vacuum at 55°C. The desired product (57.2 g , 99.9wt%, 99.8A% (enantiomer ND), was obtained in 94.9% yield. 1H NMR (CD3OD) δ 8.17 (bs, IH), 8.05 (d, 2H, J= 8.5), 7.96 (d, 2H, J= 8.5), 7.80 (d, 2H, J= 8.0), 7.64 (d, 2H, J= 8.0), 4.43 (m, IH), 3.55 (ddd, IH, J= 5.0, 8.5, 8.0), 3.18 (s, 3H), 2.84 (bm, IH), 2.02 (m, 2H), 1.46 (d, 3H, J= 21.5), 1.43 (d, 3H, J= 22.0), 1.36 (m, 2H), 1.07 (m, IH), 0.94 (m, IH); 13C NMR(CD3OD) δ; 19F NMR (CD3OD) δ -73.2, -136.8; IR (cm"1) 3331, 2244, 1687, 1304, 1152; mp 223-224 0C, [α]D20 + 23.3 (c = 0.53, MeOH).
Stage #1: (2S)-4-fluoro-4-methyl-2-({(1S)-2,2,2-trifluoro-1-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}amino)pentanoic acid dicyclohexylamine salt; 1-amino-1-cyclopropanecarbonitrile hydrochloride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide at -10 - 35℃; for 5h; Stage #3: With phosphoric acid In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 35 - 45℃; 2 EXAMPLE 2N-(l-CYANOCYCLOPROPYL)-4-FLUORO-N2-{(l1?)-252,2-TRIFLUORO-l-[4'- (METHYLSULFONYL)BIPHENYL-4-YL]ETHYL}-L-LEUCINAMIDEFA round-bottom flask was charged with biphenyl acid'DCHA salt (10.3 g), aminocyclopropane carbonitrile»HCl (2.21 g), pyridine (2.46 g) and DMF (85 mL). The thick slurry was stirred at ambient temperature for lh. The slurry was cooled to -10°C and EDC*HC1 (4.47 g) added in one portion. The reaction mixture was aged at -10°C for lh and warmed to - 5°C for 3h. The batch was then warmed to 35°C and aged lh. HPLC analysis showed 99.5% conversion. Aqueous phosphoric acid (100 mL) was added at 35-45°C and the resultant slurry cooled to 20°C. The batch was filtered and washed with 55/45 DMF/water (50 mL) and water (50 mL). The solids were dried in the filter at 40-60°C for 24 hours. The desired crade product was isolated as a white solid (7.57g, 94% yield, >99 %ee, 99.0 wt%). NMR (CD3OD) δ 8.17 (bs, 1H), 8.05 (d, 2H, J= 8.5), 7.96 (d, 2H, J- 8.5), 7.80 (d, 2H, J- 8.0), 7.64 (d, 2H, J= 8.0), 4.43 (m, 1H), 3.55 (ddd, 1H, J= 5.0, 8.5, 8.0), 3.18 (s, 3H), 2.84 (bm, 1H), 2.02 (m, 2H), 1.46 (d, 3H, J= 21.5), 1.43 (d, 3H, J- 22.0), 1.36 (m, 2H), 1.07 (m, 1H), 0.94 (m, 1H); 13C NMR (CD3OD) δ; J9F NMR (CD3OD) δ -73.2, -136.8; IR (cm"1) 3331, 2244, 1687, 1304, 1152; mp 223-224 °C, [ ]D20 + 23.3 (c - 0.53, MeOH).
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 acetamide at 0 - 20℃; A.4 Step 4), preparation of odangcate (V) Dicyclohexylamine carboxylate (IB') 34.0g (53.0mmol, 1eq) and 1-aminocyclopropanecarbonitrile hydrochloride 7.5g (63.6mmol, 1.2eq) in 150mL DMAc Stir to dissolve, add HATU 24.2g (63.6mmol, 1.2eq).The system was cooled to 0-5°C, 20.5 g (159 mmol) of DIPEA was added dropwise, and the temperature of the system was maintained at 0-10°C.Slowly warm up to room temperature for 3-4 hours.After the completion of the reaction, the reaction solution was added to 450 mL of water, stirred to precipitate a solid, and filtered.The filter cake is washed with water and dried to obtain odangcate.
  • 4
  • [ 875272-89-2 ]
  • [ 127946-77-4 ]
  • [ 603139-19-1 ]
YieldReaction ConditionsOperation in experiment
79% Stage #1: 1-amino-1-cyclopropanecarbonitrile hydrochloride With HATU In N,N-dimethyl acetamide at 0℃; for 0.25h; Stage #2: (S)-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4’-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)pentanoic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide for 2.5h; 2 EXAMPLE 2; N-(I -CYANOCYCLOPROPYL)-4-FLUORO-N2- {(1 S)-2,2,2-TRIFLUORO- 1 -[4'- (METHYLSULFOνYL)BIPHEνYL-4- YL]ETHYL}-L-LEUCINAMIDE; Acid (1.9 g) was dissolved in DMAc (10 mL) and cooled to 0°C. 1 -Aminocyclopropane carbonitrile hydrochloride (0.57 g) and HATU (1.85 g) were added. The resulting slurry was stirred for 15 min and DIEA (2.12 mL) was added over 1.5 h. The reaction was aged for 1 h. Water (11.2 mL) was added via dropping funnel over 70 min and the slurry was aged for Ih at 2O0C. The mixture was filtered and the filter cake was washed with a solution of DMAc:water (9.4 mL, 1 : 1.2), water (18.7 mL), 2-propanol (9.3 mL) The batch was dried to yield 1.67 g, 79% yield of the corresponding amide.Amide (2.56 g), was dissolved in THF (30.7 mL) at 30°C. Water (19 mL) was added via dropping funnel. The batch was seeded and aged for Ih at 2O0C. Additional water (40.9 mL) was added over 1.5 h and the batch was aged for 16 h. The batch was filtered and washed with water (15 mL). The solids were dried to a constant weight to yield 2.50 g, 97% yield of pure amide. 1H NMR (CD3OD) δ 8.17 (bs, IH), 8.05 (d, 2H, J= 8.5), 7.96 (d, 2H, J= 8.5), 7.80 (d, 2H, J= 8.0), 7.64 (d, 2H, J= 8.0), 4.43 (m, IH), 3.55 (ddd, IH, J= 5.0, 8.5, 8.0), 3.18 (s, 3H), 2.84 (bm, IH), 2.02 (m, 2H), 1.46 (d, 3H, J= 21.5), 1.43 (d, 3H, J= 22.0), 1.36 (m, 2H), 1.07 (m, IH), 0.94 (m, IH); 13C NMR (CD3OD) δ; 19F NMR (CD3OD) δ -73.2, -136.8; IR (cm"1) 3331, 2244, 1687, 1304, 1152; mp 223-224 0C, [α]D20 + 23.3 (c = 0.53, MeOH).
70.1% 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 - 15℃; for 2h; 7 Intermediate III 20.3 g (0.044 mol), amine cyclopropanecarbonitrile hydrochloride 6.52 g dissolved in N,N-dimethylformamide 100 mL, cooled to 0 ° C, added O-(7-azabenzotriene) Zin-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) 19.3 g (0.051 mol), and then added dropwise diisopropylethylamine 25.3 g (0.196 mol) After stirring at 10 to 15 ° C for 2 hours, 200 mL of water was added thereto, and the mixture was stirred at 10 to 15 ° C for 1 hour, and then filtered to obtain a crude product of Oduccito II, which was recrystallized from N,N-dimethylformamide and acetone. Vacuum drying (35 ° C ~ 45 ° C, -0.01 MPa ~ -0.1 MPa) 12 to 16 hours to get Odanacatib II 16.2 g, yield 70.1%, HPLC purity 99.83%, maximum single impurity 0.05%.
60% 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 acetamide at 0 - 20℃; for 5h;
Stage #1: (S)-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4’-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)pentanoic acid; 1-amino-1-cyclopropanecarbonitrile hydrochloride With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl acetamide at 0℃; for 0.25h; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide; water at 20℃; for 5h; 1 General Procedure A General procedure: Odanacatib acid 1 (60 mg) was dissolved in 3 mL DMAc and cooled to 0 °C. Amine (1.2 eq.) and HATU (59 mg) were added. The resulting solution was stirred for 15 min and DIPEA (68 mL) was added. The reaction was stirred for 2.5h. Water was slowly added dropwise and the slurry was stirred 2.5h at room temperature. The mixture was filtered and the solid material was washed with a 1 :1.2 DMF/water solution, water and 2-propanol. The material was removed from the filter by addition of THF. The filtrate was concentrated and purified by FCC (silica, gradient DCM to 2% MeOH in DCM). The products were obtained as a white solid.According to general procedure A, the reaction between Odanacatib acid 1 (59.8 mg) and 1-amino-cyclopropanecarbonitrile hydrogenchloride (18.5 mg) afforded product ODN as a white solid 1 H NMR (300 MHz, CDCI3) d = 8.03 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.42 (s, 1 H), 4.17 (q, J = 7.2 Hz, (0199) 1 H), 3.59 (dd, J = 8.9, 3.3 Hz, 1 H), 3.10 (s, 3H), 2.17 - 1.85 (m, 2H), 1.56 - 1.44 (m, 2H), 1.47 (d, J = 21.7 Hz, 3H), 1.44 (d, J = 22.0 Hz, 3H), 1.1 1 - 0.85 (m, 2H). 13C NMR (75 MHz, CDCI3) d = 174.42, 145.69, 140.57, 139.94, 134.53, 129.40, 128.22, 128.20, 126.02 (0200) (q, J = 279.3 Hz), 119.56, 96.84 (d, J = 163.8 Hz), 63.44 (q, J = 29.3 Hz), 59.03, 44.75, 43.64 (d, J = 19.9 Hz), 28.37 (d, J = 24.4 Hz), 25.83 (d, J = 24.7 Hz), 20.21 , 16.86, 16.48. HRMS (ESI+): calculated for C25H28F4N303S [M+H]+ 526.1788, found: 526.1816.

  • 5
  • [ CAS Unavailable ]
  • [ 127946-77-4 ]
  • [ 603139-19-1 ]
YieldReaction ConditionsOperation in experiment
79% Stage #1: (2S)-4-fluoro-4-methyl-2-((2,2,2-trifluoro-1-(4'-(methylsulfonyl)biphenyl-4-yl))amino)pentanoic acid; 1-amino-1-cyclopropanecarbonitrile hydrochloride With HATU In N,N-dimethyl acetamide at 3℃; for 0.25h; Inert atmosphere; Large scale reaction; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 10℃; for 1.5h; Inert atmosphere; Large scale reaction; optical yield given as %de;
  • 6
  • [ 875272-88-1 ]
  • [ 603139-19-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium carbonate / methanol / 4 h / 50 °C 2.1: zinc(II) tetrahydroborate / acetonitrile; methanol / 1.5 h / -5 - 5 °C 2.2: 0.5 h / 20 °C 2.3: 1.5 h / 20 °C 3.1: pyridine / N,N-dimethyl-formamide / 1 h / 20 °C 3.2: 5 h / -10 - 35 °C 3.3: 35 - 45 °C
  • 7
  • [ 848949-85-9 ]
  • [ 603139-19-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium carbonate / methanol / 4 h / 50 °C 2.1: zinc(II) tetrahydroborate / acetonitrile; methanol / 1.5 h / -5 - 5 °C 2.2: 0.5 h / 20 °C 2.3: 1.5 h / 20 °C 3.1: pyridine / N,N-dimethyl-formamide / 1 h / 20 °C 3.2: 5 h / -10 - 35 °C 3.3: 35 - 45 °C
  • 8
  • [ 603139-19-1 ]
  • [ 2043026-01-1 ]
YieldReaction ConditionsOperation in experiment
25% With potassium <i>tert</i>-butylate; 1-(bromomethyl)-2,4-difluorobenzene In tetrahydrofuran at -75 - -15℃;
  • 9
  • [ 603139-19-1 ]
  • [ 2043026-02-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium <i>tert</i>-butylate; 1-(bromomethyl)-2,4-difluorobenzene / tetrahydrofuran / -75 - -15 °C 2: potassium carbonate / acetonitrile / 2.5 h / 23 °C
  • 10
  • [ 92-86-4 ]
  • [ 603139-19-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: tri-n-butyllithium magnesate complex / tetrahydrofuran; hexane; diethyl ether / 3 h / 0 °C 1.2: 15 h / 20 °C 2.1: n-butyllithium / toluene; tert-butyl methyl ether / 2 h / -10 °C 2.2: 1 h 3.1: sodium tungstate (VI) dihydrate; tetrabutylammonium sulfate; dihydrogen peroxide / tetrahydrofuran; toluene / 2 h / 45 °C 4.1: potassium carbonate / methanol / 16 h / 50 °C 4.2: 4 h / 50 °C 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 15 °C
  • 11
  • [ 16184-89-7 ]
  • [ 603139-19-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / N,N-dimethyl-formamide / 12 h / 90 °C / Inert atmosphere 2.1: sodium phosphate; tris-(dibenzylideneacetone)dipalladium(0) / 5,5-dimethyl-1,3-cyclohexadiene; water / 12 h / 80 °C / Inert atmosphere 3.1: potassium carbonate / methanol / 16 h / 50 °C 3.2: 4 h / 50 °C 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 15 °C
  • 12
  • [ 3393-00-8 ]
  • [ 603139-19-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: n-butyllithium / toluene; tert-butyl methyl ether / 2 h / -10 °C 1.2: 1 h 2.1: sodium tungstate (VI) dihydrate; tetrabutylammonium sulfate; dihydrogen peroxide / tetrahydrofuran; toluene / 2 h / 45 °C 3.1: potassium carbonate / methanol / 16 h / 50 °C 3.2: 4 h / 50 °C 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 15 °C
Multi-step reaction with 4 steps 1.1: n-butyllithium / hexane; tetrahydrofuran 2.1: tetra(n-butyl)ammonium hydrogensulfate; sodium tungstate (VI) dihydrate; dihydrogen peroxide / water; tetrahydrofuran; toluene / 45 °C 2.2: Dean-Stark; Reflux 3.1: potassium carbonate / methanol 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 5 h / 0 - 20 °C
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / -78 °C 2.1: dihydrogen peroxide; tetra(n-butyl)ammonium hydrogensulfate; sodium tungstate (VI) dihydrate / water; tetrahydrofuran; toluene / 45 °C / Dean-Stark 3.1: potassium carbonate / methanol 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl acetamide / 0.25 h / 0 °C 4.2: 5 h / 20 °C
  • 13
  • [ 893407-15-3 ]
  • [ 603139-19-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: sodium tungstate (VI) dihydrate; tetrabutylammonium sulfate; dihydrogen peroxide / tetrahydrofuran; toluene / 2 h / 45 °C 2.1: potassium carbonate / methanol / 16 h / 50 °C 2.2: 4 h / 50 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 15 °C
Multi-step reaction with 3 steps 1.1: tetra(n-butyl)ammonium hydrogensulfate; sodium tungstate (VI) dihydrate; dihydrogen peroxide / water; tetrahydrofuran; toluene / 45 °C 1.2: Dean-Stark; Reflux 2.1: potassium carbonate / methanol 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 5 h / 0 - 20 °C
Multi-step reaction with 3 steps 1.1: dihydrogen peroxide; tetra(n-butyl)ammonium hydrogensulfate; sodium tungstate (VI) dihydrate / water; tetrahydrofuran; toluene / 45 °C / Dean-Stark 2.1: potassium carbonate / methanol 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl acetamide / 0.25 h / 0 °C 3.2: 5 h / 20 °C
  • 14
  • [ 1004294-77-2 ]
  • [ 603139-19-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: sodium phosphate; tris-(dibenzylideneacetone)dipalladium(0) / 5,5-dimethyl-1,3-cyclohexadiene; water / 12 h / 80 °C / Inert atmosphere 2.1: potassium carbonate / methanol / 16 h / 50 °C 2.2: 4 h / 50 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 15 °C
  • 15
  • [ 893407-18-6 ]
  • ethyl (2S)-2-amino-4-fluoro-4-methylpentanoate sulfate salt [ No CAS ]
  • odanacatib [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate / methanol / 16 h / 50 °C 1.2: 4 h / 50 °C 2.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 15 °C
  • 16
  • [ 98546-51-1 ]
  • [ 603139-19-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: sodium carbonate; bis-triphenylphosphine-palladium(II) chloride / 1,2-dimethoxyethane; water / 5 h / 100 °C 2.1: n-butyllithium / hexane; tetrahydrofuran 3.1: tetra(n-butyl)ammonium hydrogensulfate; sodium tungstate (VI) dihydrate; dihydrogen peroxide / water; tetrahydrofuran; toluene / 45 °C 3.2: Dean-Stark; Reflux 4.1: potassium carbonate / methanol 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 5 h / 0 - 20 °C
Multi-step reaction with 5 steps 1.1: sodium carbonate; bis-triphenylphosphine-palladium(II) chloride / 1,2-dimethoxyethane; water / 5 h / 100 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran / -78 °C 3.1: dihydrogen peroxide; tetra(n-butyl)ammonium hydrogensulfate; sodium tungstate (VI) dihydrate / water; tetrahydrofuran; toluene / 45 °C / Dean-Stark 4.1: potassium carbonate / methanol 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl acetamide / 0.25 h / 0 °C 5.2: 5 h / 20 °C
  • 17
  • [ 589-87-7 ]
  • [ 603139-19-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: sodium carbonate; bis-triphenylphosphine-palladium(II) chloride / 1,2-dimethoxyethane; water / 5 h / 100 °C 2.1: n-butyllithium / hexane; tetrahydrofuran 3.1: tetra(n-butyl)ammonium hydrogensulfate; sodium tungstate (VI) dihydrate; dihydrogen peroxide / water; tetrahydrofuran; toluene / 45 °C 3.2: Dean-Stark; Reflux 4.1: potassium carbonate / methanol 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 5 h / 0 - 20 °C
Multi-step reaction with 5 steps 1.1: sodium carbonate; bis-triphenylphosphine-palladium(II) chloride / 1,2-dimethoxyethane; water / 5 h / 100 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran / -78 °C 3.1: dihydrogen peroxide; tetra(n-butyl)ammonium hydrogensulfate; sodium tungstate (VI) dihydrate / water; tetrahydrofuran; toluene / 45 °C / Dean-Stark 4.1: potassium carbonate / methanol 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl acetamide / 0.25 h / 0 °C 5.2: 5 h / 20 °C
  • 18
  • [ 893407-18-6 ]
  • (S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)pentanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / methanol 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 5 h / 0 - 20 °C
Multi-step reaction with 2 steps 1.1: potassium carbonate / methanol 2.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl acetamide / 0.25 h / 0 °C 2.2: 5 h / 20 °C
Multi-step reaction with 3 steps 1.1: potassium carbonate / methanol / 50 °C 2.1: anhydrous zinc chloride / methanol; lithium hydroxide monohydrate / 0.5 h / 25 - 30 °C 2.2: -5 - 5 °C 2.3: 2 h / 25 - 30 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 0 - 20 °C
  • 19
  • [ 603139-19-1 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
98% With hydrogenchloride In 1,4-dioxane at 40℃; for 1h; 1-2 The preparation of embodiment 1 Odankati hydrochloride Dissolve 526 mg of odancate in 2 ml of 1,4-dioxane solution, then add about 210 mg of 17% 1,4-dioxane hydrochloric acid solution, stir for 1 hour, and concentrate at 40°C to obtain odancate The solid hydrochloride was dried under vacuum at 35°C for 1 d, and the weight yield was 98%.
  • 20
  • [ 603139-19-1 ]
  • [ 104-15-4 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
In propan-2-one for 1h; 3-4 The preparation of embodiment 4 Odancart p-toluenesulfonate Dissolve 526 mg of Odantocate and 190 mg of p-toluenesulfonic acid monohydrate in 2 ml of acetone solution, stir for 1 hour, add 4 ml of isopropyl ether or n-hexane or methyl tert-butyl ether, and stir for 4 hours to obtain Odantocate The solid p-toluenesulfonate was dried under vacuum at 35°C for 1 d, and the weight yield was 126%.
  • 21
  • [ 156047-39-1 ]
  • [ 603139-19-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium carbonate / methanol / 50 °C 2.1: anhydrous zinc chloride / methanol; lithium hydroxide monohydrate / 0.5 h / 25 - 30 °C 2.2: -5 - 5 °C 2.3: 2 h / 25 - 30 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 0 - 20 °C
  • 22
  • [ CAS Unavailable ]
  • [ 603139-19-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: anhydrous zinc chloride / methanol; lithium hydroxide monohydrate / 0.5 h / 25 - 30 °C 1.2: -5 - 5 °C 1.3: 2 h / 25 - 30 °C 2.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 0 - 20 °C
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