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[ CAS No. 64119-42-2 ] {[proInfo.proName]}

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Cat. No.: {[proInfo.prAm]}
Chemical Structure| 64119-42-2
Chemical Structure| 64119-42-2
Structure of 64119-42-2 * Storage: {[proInfo.prStorage]}
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Quality Control of [ 64119-42-2 ]

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Product Details of [ 64119-42-2 ]

CAS No. :64119-42-2 MDL No. :MFCD00179894
Formula : C10H9ClN2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :QXZBVLFURRXJLB-UHFFFAOYSA-N
M.W : 224.64 Pubchem ID :2786689
Synonyms :

Calculated chemistry of [ 64119-42-2 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.3
Num. rotatable bonds : 3
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 55.01
TPSA : 62.98 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.14 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.26
Log Po/w (XLOGP3) : 2.15
Log Po/w (WLOGP) : 2.09
Log Po/w (MLOGP) : 0.9
Log Po/w (SILICOS-IT) : 2.67
Consensus Log Po/w : 2.01

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.69
Solubility : 0.464 mg/ml ; 0.00206 mol/l
Class : Soluble
Log S (Ali) : -3.1
Solubility : 0.176 mg/ml ; 0.000786 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.6
Solubility : 0.056 mg/ml ; 0.000249 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.26

Safety of [ 64119-42-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 64119-42-2 ]

* 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 [ 64119-42-2 ]

[ 64119-42-2 ] Synthesis Path-Downstream   1~85

  • 1
  • [ 64119-42-2 ]
  • [ 103038-00-2 ]
  • 2
  • [ 52600-52-9 ]
  • [ 64119-42-2 ]
  • 9
  • [ 64119-42-2 ]
  • [ 625-30-9 ]
  • 5-Cyano-2-methyl-6-(1-methyl-butylamino)-nicotinic acid ethyl ester [ No CAS ]
  • 18
  • [ 110-91-8 ]
  • [ 64119-42-2 ]
  • 2-methyl-6-morpholino-5-cyano-3-ethoxycarbonylpyridine [ No CAS ]
  • 19
  • [ 64119-42-2 ]
  • [ 4822-44-0 ]
  • [ 204765-68-4 ]
  • 20
  • [ 64119-42-2 ]
  • [ 623-51-8 ]
  • 3-amino-6-methyl-2,5-diethoxycarbonylthieno[2,3-b]pyridine [ No CAS ]
  • 21
  • [ 52600-52-9 ]
  • [ 64119-42-2 ]
YieldReaction ConditionsOperation in experiment
98% With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; for 18h;Reflux; Ethyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (2.00 g, 9.70 mmol) [18(b)] was suspended in DCM(40 mL). Oxalyl chloride (6.16 g, 4.25 mL, 48.5 mmol) was added. DMF (0.071 g, 0.080 mL, 0.97 mmol) was added slowly and the reaction mixture was heated to reflux for 18 h. The mixture was cooled to rt, diluted with DCM (250 mL) and poured onto ice-water (250 mL). The organic phase was separated, washed with brine (250 mL), NaHCO3 (2 250 mL, saturated, aq solution), and brine (250 mL), dried (Na2SO4) and concentrated. Yield: 2.18 g (98%).
95% With trichlorophosphate; In 1,4-dioxane; at 80℃; for 1h; General procedure: To a solution of 9a-9h (10 mmol) in 10 mL of 1,4-dioxane, POCl3(2.3 mL, 25 mmol) was added dropwise. The reaction mixture wasstirred at 80 C for 1 h. After cooled to room temperature, themixture was poured to 50 mL of ice water. 20 N NaOH aqueoussolutionwas added to adjust pH = 7. Solid was precipitated, filteredand purified by column chromatography (eluent: petroleum ether/ethyl acetate = 10:1) to provide the title compound. 1H NMR and13C NMR data of selected products are shown as follows.
80% With trichlorophosphate; at 100℃; (c) Ethyl 6-chloro -5-cyano-2-methylnicotinate; Ethyl 5-cyano-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (70.33 g, 341.1 mmol) was suspended in POCi (124.5 ml, 1364 mmol) and the system heated at 100 C overnight. The reaction mixture was cooled to r.t and concentrated under reduced pressure. The residue was diluted with DCM and poured onto ice. The bi-phasic mixture was stirred at r.t and slowly quenched with solid K2CO3 until all the POCt had hydrolysed. The aqueous was extracted into DCM and the organics, dried (Mg5O4) and passed through a silica plug. The organics were concentrated under reduced pressure to afford ethyl 6-chloro-5-cyano-2- methylnicotinate as a solid, which was used without further purification. Yield: 61 g (80 %). 1H NMR (4,00 MHz, CDCi): 6 1.42 (3H, t, J = 7.1 Hz), 2.91 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 8.49 (1H, s).
80% (c) Ethyl 6-chloro-5-cyano-2-methylnicotinate Ethyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (70.33 g, 341 mmol) was suspended in phosphoryl trichloride (124.5 mL, 1364 mmol) and the system heated at 100 C. overnight. The reaction mixture was cooled to r.t and concentrated under reduced pressure. The residue was diluted with DCM and poured onto ice. The bi-phasic mixture was stirred at r.t and slowly quenched with solid K2CO3 until all the POCl3 had hydrolysed. The aqueous phase was extracted into DCM and the organics, dried (MgSO4) and passed through a silica plug. The organics were concentrated under reduced pressure to afford ethyl 6-chloro-5-cyano-2-methylnicotinate as a solid, which was used without further purification. Yield: 61 g (80%). 1H NMR (400 MHz, CDCl3): delta 1.42 (3H, t, J=7.1 Hz), 2.91 (3H, s), 4.40 (2H, q, J=7.1 Hz), 8.49 (1H, s).
80% With trichlorophosphate; at 100℃; (c) Ethyl 6-chloro-5-cyano-2-methylnicotinate Ethyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (70.33 g, 341 mmol) was suspended in phosphoryl trichloride (124.5 mL, 1364 mmol) and the system heated at 100 C. overnight. The reaction mixture was cooled to r.t and concentrated under reduced pressure. The residue was diluted with DCM and poured onto ice. The bi-phasic mixture was stirred at r.t and slowly quenched with solid K2CO3 until all the POCl3 had hydrolyzed. The aqueous phase was extracted into DCM and the organics, dried (MgSO4) and passed through a silica plug. The organics were concentrated under reduced pressure to afford ethyl 6-chloro-5-cyano-2-methylnicotinate as a solid, which was used without further purification. Yield: 61 g (80%). 1H NMR (400 MHz, CDCl3): delta1.42 (3H, t, J=7.1 Hz), 2.91 (3H, s), 4.40 (2H, q, J=7.1 Hz), 8.49 (1H, s).
80% With trichlorophosphate; at 100℃; (c) Ethyl beta-chloro-S-cyano^-methylnicotinateEthyl 5-cyano-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (70.33 g, 341 mmol) was suspended in phosphoryl trichloride (124.5 mL, 1364 mmol) and the system heated at 100 0C overnight. The reaction mixture was cooled to r.t and concentrated under reduced pressure. The residue was diluted with DCM and poured onto ice. The bi-phasic mixture was stirred at r.t and slowly quenched with solid K2CO3 until all the POC^ had hydro lysed. The aqueous phase was extracted into DCM and the organics. dried (MgSO4) and passed through a silica plug. The organics were concentrated under reduced pressure to afford ethyl 6-chloro-5-cyano-2-methylnicotinate as a solid, which was used without further purification. Yield: 61 g (80 %). 1H NMR (400 MHz, CDQ): delta 1.42 (3H, t, J = 7.1 Hz), 2.91 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 8.49 (IH, s). MS m/z: 225 (M+l).
80% With trichlorophosphate; at 100℃; (c) Ethyl beta-chloro-S-cyano-Z-methylnicotinateEthyl 5-cyano-2-methyl-6-oxo-l,6-diliydropyridine-3-carboxylate (70.33 g, 341 mmol) was suspended in phosphoryl trichloride (124.5 mL, 1364 mmol) and heated at 100 0C overnight. The reaction mixture was cooled to r.t and concentrated under reduced pressure. The residue was diluted withdichloromethane and poured onto ice. The bi-phasic mixture was stirred at r.t and slowly quenched with solid K2CO3 until all the POGb had hydrolysed. The aqueous phase was extracted withdichloromethane. The organic phase was dried (MgSO4) and passed through a silica plug. The organic phase was concentrated 0 under reduced pressure to afford ethyl 6-chloro-5-cyano-2-methylnicotinate as a solid, which was used without further purification. Yield: 61 g (80 %). 1HNMR (400 MHz, CDQ): delta 1.42 (3H, t, J = 7.1 Hz), 2.91 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 8.49 (IH, s).
75% Toluene (4000 mL) and thionylchloride (507 g, 4262 mmol) were added to ethyl 5-cyano-2- methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (293 g, 1421 mmol) under an atmosphere of nitrogen and the mixture was heated to 50 0C (oil bath temperature) and DMF (100 g, 1368 ?mmol) was added during 2 minutes. The temperature was raised to 80 0C (oil bath temperature) and the stirring was continued for 2 hours. The mixture was concentrated in vaccuo (about 3500 ml was evaporated off) leaving a red oil. EtOH (1000 mL, 99%) was added and then evaporated off. Dichloromethane (4000 mL) was added followed by 4 % NaHCO3 solution (4000 mL) and the mixture was stirred for 15 minutes. The organic phase was separated and evaporated to give ethyl 6-chloro-5-cyano-2-methyhiicotinate as a dark red crude solid which was used without further purification. Yield: 301 g (75 %).1H NMR (400 MHz, CDCl5): delta 1.42 (3H, t, J = 7.1 Hz), 2.91 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 8.49 (IH, s).
75% Toluene (4000 mL) and thionylchloride (507 g, 4262 mmol) were added to ethyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (293 g, 1421 mmol) under an atmosphere of nitrogen and the mixture was heated to 50 C. (oil bath temperature) and DMF (100 g, 1368 mmol) was added during 2 minutes. The temperature was raised to 80 C. (oil bath temperature) and the stirring was continued for 2 hours. The mixture was concentrated in vaccuo (about 3500 ml was evaporated off) leaving a red oil. EtOH (1000 mL, 99%) was added and then evaporated off. Dichloromethane (4000 mL) was added followed by 4% NaHCO3 solution (4000 mL) and the mixture was stirred for 15 minutes. The organic phase was separated and evaporated to give ethyl 6-chloro-5-cyano-2-methylnicotinate as a dark red crude solid which was used without further purification. Yield: 301 g (75%).1H NMR (400 MHz, CDCl3): delta 1.42 (3H, t, J=7.1 Hz), 2.91 (3H, s), 4.40 (2H, q, J=7.1 Hz), 8.49 (1H, s).
75% With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 50 - 80℃; for 2.03333h; (c) Ethyl beta-chloro-S-cyano^-methylnicotinateToluene (4000 mL) and thionylchloride (507 g, 4262 mmol) were added to ethyl 5-cyano- 2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (293 g, 1421 mmol) under an atmosphere of nitrogen and the mixture was heated to 50 0C (oil bath temperature) and DMF (100 g, 1368 mmol) was added during 2 minutes. The temperature was raised to 80 0C (oil bath temperature) and the stirring was continued for 2 hours. The mixture was concentrated in vaccuo (about 3500 ml was evaporated off) leaving a red oil. EtOH (1000 mL, 99%) was added and then evaporated off. Dichloromethane (4000 mL) was added followed by 4 % NaHCO3 solution (4000 mL) and the mixture was stirred for 15 minutes. The organic phase was separated and evaporated to give ethyl 6-chloro-5-cyano-2- methylnicotinate as a dark red crude solid which was used without further purification. Yield: 301 g (75 %). 1H NMR (400 MHz, CDCl3): delta 1.42 (3H, t, J = 7.1 Hz), 2.91 (3H, s), 4.40 (2H, q, J = 7.1 Hz)3 8.49 (IH, s).
75% With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 50 - 80℃; for 2.03333h;Inert atmosphere; (c) Ethyl -chloro-S-cyano-l-methylnicotinateToluene (4000 niL) and thionylchloride (507 g, 4262 mmol) were added to ethyl 5-cyano- 2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (293 g, 1421 mmol) under an atmosphere of nitrogen and the mixture was heated to 50 0C (oil bath temperature) and DMF (100 g, 1368 mmol) was added during 2 minutes. The temperature was raised to 80 0C (oil bath temperature) and the stirring was continued for 2 hours. The mixture was concentrated in vaccuo (about 3500 ml was evaporated off) leaving a red oil. EtOH (1000 mL, 99%) was added and then evaporated off. Dichloromethane (4000 mL) was added followed by 4 % NaHCO3 solution (4000 mL) and the mixture was stirred for 15 minutes. The organic phase was separated and evaporated to give ethyl 6-chloro-5-cyano-2- methylnicotinate as a dark red crude solid which was used without further purification. Yield: 301 g (75 %).1H NMR (400 MHz, CDCl3): delta 1.42 (3H, t, J = 7.1 Hz), 2.91 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 8.49 (IH, s).

  • 23
  • [ 302-84-1 ]
  • [ 64119-42-2 ]
  • 8-cyano-3-hydroxy-2-hydroxymethyl-5-methyl-imidazo[1,2-<i>a</i>]pyridine-6-carboxylic acid ethyl ester [ No CAS ]
  • 24
  • [ 617-65-2 ]
  • [ 64119-42-2 ]
  • 2-(2-carboxy-ethyl)-8-cyano-3-hydroxy-5-methyl-imidazo[1,2-<i>a</i>]pyridine-6-carboxylic acid ethyl ester [ No CAS ]
  • 25
  • [ 64119-42-2 ]
  • [ 18595-16-9 ]
  • 5-cyano-6-(2-methoxycarbonyl-4-methyl-phenylamino)-2-methyl-nicotinic acid ethyl ester [ No CAS ]
  • 26
  • [ 64119-42-2 ]
  • [ 118-92-3 ]
  • [ 837412-26-7 ]
  • 27
  • [ 64119-42-2 ]
  • [ 56-40-6 ]
  • 8-cyano-6-ethoxycarbonyl-3-hydroxy-5-methylimidazo[1,2-a]pyridine [ No CAS ]
  • 28
  • [ 64119-42-2 ]
  • [ 617-45-8 ]
  • 2-carboxymethyl-8-cyano-3-hydroxy-5-methyl-imidazo[1,2-<i>a</i>]pyridine-6-carboxylic acid ethyl ester [ No CAS ]
  • 29
  • [ 64119-42-2 ]
  • [ 87-25-2 ]
  • 5-cyano-6-(2-ethoxycarbonyl-phenylamino)-2-methyl-nicotinic acid ethyl ester [ No CAS ]
  • 30
  • [ 878388-34-2 ]
  • [ 64119-42-2 ]
  • [ 1001022-72-5 ]
YieldReaction ConditionsOperation in experiment
73% With N-ethyl-N,N-diisopropylamine; In ethanol; water; at 100℃; for 0.0833333h;Microwave irradiation; (f) Ethyl 6-[4-(aminosulfonyl)piperidin-1-yl]-5-cyano-2-methylnicotinate Ethyl 6-chloro-5-cyano-2-methylnicotinate (674 mg, 3 mmol), the crude piperidine-4-sulfonamide (493 mg, 3 mmol), DIPEA (0.6 ml) were mixed in EtOH/H2O (7/3 ml) and the reaction mixture was heated to 100 C. for 5 min using microwave single node heating. LCMS showed full conversion to product. NaHCO3(aq) was added and the mixture was extracted with DCM (*3). The combined organic layer was run through a phase separator and evaporated. The crude product was purified by prepHPLC prepHPLC [Kromasil C8, Gradient: 25 to 50% (CH3CN/0.1M NH4AcO(aq), pH=7)] to afford ethyl 6-[4-(aminosulfonyl)piperidin-1-yl]-5-cyano-2-methylnicotinate. Yield: 777 mg (73%). MS m/z: 353 (M+1), 351 (M-1).
  • 31
  • [ 1001022-75-8 ]
  • [ 64119-42-2 ]
  • ethyl 6-(4-[(benzylsulfonyl)amino]sulfonyl}piperidin-1-yl)-5-cyano-2-methylnicotinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
25% With N-ethyl-N,N-diisopropylamine; In ethanol; water; at 100℃; for 0.0833333h;Microwave irradiation; (d) ethyl 6-(4-[(benzylsulfonyl)amino]sulfonyl}piperidin-1-yl)-5-cyano-2-methylnicotinate Ethyl 6-chloro-5-cyano-2-methylnicotinate (209 mg, 0.93 mmol), the crude N-(benzylsulfonyl)piperidine-4-sulfonamide (318 mg, 1.0 mmol), DIPEA (0.8 ml, 4.6 mmol) were mixed in EtOH/H2O (6/6 ml) and the reaction mixture was heated to 100 C. for 5 min using microwave single node heating. LCMS showed full conversion. NaHCO3(aq) was added and the mixture was extracted with DCM (*3). The combined organic layer was run through a phase separator and evaporated. The crude product was purified by prepHPLC [Kromasil C8, Gradient: 20 to 40% (CH3CN/0.1 M % NH4AcO(aq), pH=7)] yielding ethyl 6-(4-[(benzylsulfonyl)amino]sulfonyl}piperidin-1-yl)-5-cyano-2-methylnicotinate the product. Yield: 119 mg (25%). 1H NMR (500 MHz, DMSO-d6): delta1.31 (3H, t, J=7.2 Hz), 1.64 (2H, m), 2.11 (2H, m), 2.65 (3H, s), 3.12 (2H, m), 3.40 (1H, m), 4.21 (2H, s), 4.25 (2H, q, J=7.0 Hz), 4.62 (2H, m) 7.29 (3H, m), 7.36 (2H, m), 8.33 (1H, s). MS m/z: 507 (M+1), 505 (M-1).
  • 32
  • [ 933707-13-2 ]
  • [ 64119-42-2 ]
  • ethyl 5-cyano-2-methyl-6-[4-(5-phenyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]nicotinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In ethanol; at 120℃; for 0.0833333h;Microwave irradiation; (c) ethyl 5-cyano-2-methyl-6- [4-(5-phenyl-4H-l,2,4-triazol-3-yl)piperidin-l- yl]nicotinateThe crude 4-(5-phenyl-4H- 1 ,2,4-triazolr3-yl)piperidine and ethyl 6-chloro-5-cyano-2- methylnicotinate (178 mg) were dissolved in EtOH (9 ml) and DIPEA was added. The reaction mixture was heated to 120 0C for 5 min using microwave single node heating. <n="61"/>LCMS showed complete conversion of starting material and one by product (1,3,4- oxadiazole). NaHCO3 (aq) was added and the mixture was extracted with dichloromethane (x3). The combined organic layer was run through a phase separator and evaporated. The crude product was purified by prepHPLC [Kromasil C8, Gradient: 40 to 80 % (CH3CN/0. IM NH-iAcCXaq), pH = 7)] to afford ethyl 5-cyano-2-methyl-6-[4-(5-phenyl- 4H-l,2,4-triazot3-yl)rhoiperidin-l-yl]nicotinate. Yield 49 mg (14.8% over 3 steps). (The 1,3,4-oxadiazole was not isolated).1HNMR (500MHz, DMSOd6): 1.31 (3H, t, J=7.1Hz), 1.82-1.90 (2H, m), 2.10-2.15 (2H, m), 2.65 (3H, s), 3.15-3.26 (IH, m), 3.35-3.40 (2H, m), 4.25 (2H, q, J=7.1), 4.59-4.65 (2H, m), 7.39-7.48 (3H, m), 7.96-7.99 (2H, m), 8.34 (IH, s), 13.85 (IH, br s), MS m/z: 417 (MH-I), 415 (M-I).
  • 33
  • [ 280111-48-0 ]
  • [ 64119-42-2 ]
  • ethyl 6-[4-(5-benzyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-5-cyano-2-methyl-nicotinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In ethanol; at 120℃; for 0.0833333h; (c) Ethyl 6-[4-(5-benzyI-4eta-l,2,4-triazol-3-yl)piperidin-l-yl]-5-cyano-2- methylnicotinateEthyl 6-chloro-5-cyano-2-methyhiicotinate (225 mg, 1.0 mmol)) and the crude 4-(5- benzyl-4H-l,2,4-triazol-3-yl)piperidine (267 mg, 1.1 mmol) were dissolved in EtOH (10 ml) and DIPEA (1 ml) was added. The reaction mixture was heated to 120 0C for 5 min.LCMS showed product and the 1,3, 4- oxadiazole byproduct. NaHCO3 (aq) was added and the mixture was extracted with dichloromethane (x3). The combined organic layer was run through a phase separator and evaporated. The crude product was purified by prepHPLC [Kromasil C8, Gradient: 30 to 60 % (CH3CN/0.1M NH4AcO(aq), pH = 7)] giving ethyl 6-[4-(5-benzyl-4H-l,2,4-triazoltau3-yl)piperidin-l-yl]-5-cyano-2-methyhiicotinate. Yield:38mg (9 % over 3 steps). The 1,3, 4- oxadiazole was not isolated.1HNMR (500MHz, DMSOd6): 1.32 (3H, t, J=7.1Hz), 1.72-1.81 (2H, m), 2.03-2.08 (2H, m), 2.66 (3H, s), 3.05-3.15 (IH, m), 3.29-3.32 (2H, m), 3.99 (2H, s), 4.27 (2H, q, J=7.1), 4.55-4.61 (2H, m), 7.20-7.24 (IH, m), 7.26-7.33 (4H, m), 8.35 (IH, s), 13.45 (IH, br s).MS m/z: 431 (M+l), 429 (M-I).
  • 34
  • [ 64119-42-2 ]
  • [ 89614-96-0 ]
  • [ 1000979-54-3 ]
YieldReaction ConditionsOperation in experiment
29% With triethylamine; In ethanol; at 120℃; for 0.166667h;Microwave irradiation; (d) 3-[3-Cyano -5-(ethoxycarbonyl>6-(methyl)pyridin-2- yl] amino} cyclopentanecarboxylic acid <n="62"/>DIPEA (1.0 mL, 5.7 mmol) was added to a solution of ethyl 6-chloro-5-cyano-2- methylnicotinate (748 mg, 3.3 mmol) and 3-aminocyclopentanecarboxylic acid (438 mg, 3.4 mmol) in EtOH (10 mL). The mixture was heated in a microwave reactor at 120 C for 5 min. As statring material was still left more 3-aminocyclopentanecarboxylic acid (1195 mg, 0.9 mmol) was added and the mixture was heated in a microwave reactor at 120 0C for another 5 min. Saturated NELjClf°q) was added and the mixture was extracted with DCM (3 times). The combined organic phase was filtered through a phase separator and evaporated. The crude product was purified by prepHPLC [Kromasil C8, Gradient 10 to 40% (0.1M NH4OAc (aq) in 5 % CH3CN/ CH3CN)] to afford a white solid, 3-[3-Cyano- io 5-(ethoxycarbonyl)-6-(methyl)pyridin-2-yl]amino}cyclopentanecarboxylic acid. Yield: 302 mg (29 %) MS m4: 318 (M+l).
  • 35
  • [ 64119-42-2 ]
  • 4-cyanopyrido-2-ethoxycarbonyl-1-methyl[2,1-b]quinazolin-10-one [ No CAS ]
  • 36
  • [ 64119-42-2 ]
  • 9-carboxy-3-ethoxycarbonyl-2-methyl-10H-benzo[b]-1,8-naphthyridin-5-one [ No CAS ]
  • 37
  • [ 64119-42-2 ]
  • 2,7-dimethyl-5-oxo-5,10-dihydro-benzo[<i>b</i>][1,8]naphthyridine-3,9-dicarboxylic acid 3-ethyl ester 9-methyl ester [ No CAS ]
  • 38
  • [ 64119-42-2 ]
  • 3,9-di(ethoxycarbonyl)-2-methyl-10H-benzo[b]-1,8-naphthyridin-5-one [ No CAS ]
  • 39
  • [ 64119-42-2 ]
  • N-(3-aminocarbonyl-6-methyl-5-ethoxycarbonyl-2-pyridyl)iminocyclohexane [ No CAS ]
  • 40
  • [ 64119-42-2 ]
  • 7-methyl-3-phenyl-8-ethoxycarbonylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]
  • 42
  • [ 64119-42-2 ]
  • 5-Carbamoyl-2-methyl-6-phenylamino-nicotinic acid [ No CAS ]
  • 43
  • [ 64119-42-2 ]
  • 5-Carbamoyl-2-methyl-6-p-tolylamino-nicotinic acid [ No CAS ]
  • 44
  • [ 64119-42-2 ]
  • 5-Carbamoyl-6-(2,4-dimethyl-phenylamino)-2-methyl-nicotinic acid [ No CAS ]
  • 61
  • [ 64119-42-2 ]
  • [ 100060-48-8 ]
  • 62
  • [ 64119-42-2 ]
  • [ 100795-79-7 ]
  • 63
  • [ 64119-42-2 ]
  • [ 103646-22-6 ]
  • 64
  • [ 64119-42-2 ]
  • [ 109038-21-3 ]
  • 65
  • [ 64119-42-2 ]
  • [ 101351-46-6 ]
  • 66
  • [ 64119-42-2 ]
  • [ 485-35-8 ]
  • 67
  • tert-butyl N-(azetidin-3-ylmethyl)carbamate [ No CAS ]
  • [ 64119-42-2 ]
  • ethyl 6-(3-((tert-butoxycarbonylamino)methyl)azetidin-1-yl)-5-cyano-2-methylnicotinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h; (a) Ethyl 6-(3-((tert-butoxycarbonylamino)methyI)azetidin-1-yl)-5-cyano-2- methylnicotinate; Ethyl 6-chloro-5-cyano-2-methylnicotinate (1.00 g, 4.5 mmol), tert-bvtiyl azetidin-3- ylmethylcarbamate (0.99 g, 5.30 mmol), and DIPEA (3.90 mL, 22.0 mmol) were dissolved in DCM (20 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (40 mL). The combined organics were washed with saturated NH4Cl (2 x 30 mL), H2O (1 x 20 mL), brine (1 x 30 mL), dried (Mg5O4) and concentrated under reduced pressure to afford the crude product Flash chromatography (25 to 35 % EtOAc in hexanes) gave ethyl 6~(3-((tert- butoxycarbonylamino)methyl)azetidin-1-yl)-5-cyano-2-methylnicotinate as a solid. Yield: 1.49 g (90 %)1H NMR (400 MHz, CDCl3): 6 1.37 (3H, t, J= 7.2 Hz), 1.45 (9H, s), 2.70 (3H, s), 2.88-2.99 (1H, m), 3.35-3.46 (2H, m), 4.02-4.14 (2H, m), 4.30 (2H, q, J= 7.2 Hz), 4.39-4.50 (2H, m), 4.64-4.76 (1H, m), 8.26 (1H, s). M5 m/z: 375 (M+l).
  • 68
  • [ 64119-42-2 ]
  • [ 91188-13-5 ]
  • [ 898227-69-5 ]
YieldReaction ConditionsOperation in experiment
66% With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20℃; for 1h; (a) Ethyl 6-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}-5-cyano-2-methylnicotinate; Ethyl 6-chloro-5-cyano-2-methylnicotinate (6.20 g, 29.4 mmol), tert -butyl azetidin-3- ylcarbamate (5.07 g, 29.4 mmol), and DIPEA (5.13 mL, 29.4 mmol) were dissolved in DCE (40 mL) and stirred at r.t for 1 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (40 mL). The combined organics were washed with saturated NaHCO3 (2 x 30 mL), dried (Mg5O4) and concentrated under reduced pressure to afford the crude product. Flash chromatography (1:6 EtOAc/hexanes) gave ethyl 6-{3-[(tert- butoxycarbonyl)amino]azetidin-1-yl}-5-cyano-2-methyhiicotinate as a solid. Yield: 7.00 g (66.0 %) 1H NMR (400 MHz, CDCi): 6 1.37 (3H, t, J= 7.2 Hz), 1.46 (9H, s), 2.70 (1H, s), 4.18-4.22 (2H, m), 4.30 (2H, q, J= 7.2 Hz), 4.59 (1H, s), 4.67-4.72 (2H, m), 5.00 (1H, s), 8.26 (1H, s). M5 "V2: 361 (M+l).
66.0% With N-ethyl-N,N-diisopropylamine; In DCE; at 20℃; for 1h; Ethyl 6-chloro-5-cyano-2-methylnicotinate (6.20 g, 29.4 mmol), tert-butyl azetidin-3- ylcarbamate (5.07 g, 29.4 mmol), and DIPEA (5.13 mL, 29.4 mmol) were dissolved in DCE (40 mL) and stirred at r.t for 1 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (40 mL). The combined organics were washed with saturated NaHCtheta3 (2 x 30 mL), dried (MgSO4) and concentrated under reduced pressure to afford the crude product. Flash chromatography (1:6 EtOAc/hexanes) gave ethyl 6-{3-[(tert- butoxycarbonyl)amino]azetidin-l-yl}-5-cyano-2-methylnicotinate as a solid. Yield: 7.00 g (66.0 %)1H NMR (400 MHz, CDCi): delta 1.37 (3H, t, J= 7.2 Hz), 1.46 (9H, s), 2.70 (IH, s), 4.18-4.22 (2H, m), 4.30 (2H, q, J= 7.2 Hz), 4.59 (IH, s), 4.67-4.72 (2H, m), 5.00 (IH, s), 8.26 (IH, s). MS m/z: 361 (M+l).
66% With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20℃; for 1h; (a) Ethyl 6-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}-5-cyano-2-methylnicotinate Ethyl 6-chloro-5-cyano-2-methylnicotinate (6.20 g, 29.4 mmol), tert-butyl azetidin-3-ylcarbamate (5.07 g, 29.4 mmol), and DIPEA (5.13 mL, 29.4 mmol) were dissolved in DCE (40 mL) and stirred at r.t for 1 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (40 mL). The combined organics were washed with saturated NaHCO3 (2×30 mL), dried (MgSO4) and concentrated under reduced pressure to afford the crude product. Flash chromatography (1:6 EtOAc/hexanes) gave ethyl 6-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}-5-cyano-2-methylnicotinate as a solid. Yield: 7.00 g (66%) 1H NMR (400 MHz, CDCl3): delta 1.37 (3H, t, J=7.2 Hz), 1.46 (9H, s), 2.70 (1H, s), 4.18-4.22 (2H, m), 4.30 (2H, q, J=7.2 Hz), 4.59 (1H, s), 4.67-4.72 (2H, m), 5.00 (1H, s), 8.26 (1H, s). MS m/z: 361 (M+1).
66% With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20℃; for 1h; 7 (6.20 g, 29.4 mmol), tert-butyl azetidin-3-ylcarbamate (5.07 g,29.4 mmol), and DIPEA (5.13 mL, 29.4 mmol) were dissolved in DCE (40 mL) and the reaction mixture was stirred at rt for 1 h. The mixture was concentrated and then diluted with EtOAc (40 mL). The organic phase was washed with NaHCO3 (2 30 mL, saturated,aq solution), dried (MgSO4) and concentrated. The crude was purifiedby flash chromatography (EtOAc/hexanes 1:6). Yield: 7.00 g (66%) as a solid.

  • 69
  • [ 64119-42-2 ]
  • [ 74494-52-3 ]
  • [ 898229-67-9 ]
YieldReaction ConditionsOperation in experiment
54% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h; (b) { 1-[3-Cyano-5-(ethoxycarbonyl)-6-inethylpyridin-2-yI]piperdin-3-yl}acetic acid; Ethyl 6-chloro-5-cyano-2-methylnicotinate (1.00 g, 4.45 mmol), piperidin-3-ylacetic acid (0.701 g, 4.90 mmol) and DIPEA (2.33 mL, 13.4 mmol) were dissolved in DMF (30 mL) and stirred at r.t for 3 days. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated NH4Cl (2 x 25 mL), saturated NaHCO3 (2 x25 mL), brine (25 m), dried (Mg5O4) and concentrated under reduced pressure to afford crude material. Flash chromatography (9:1 EPO <DP n="235"/>EtOAc/hexanes with 1% AcOH) gave {1-[3-cyano-5-(ethoxycarbonyl)-6-methylpyridin-2- yl]piperdin-3-yl}acetic acid as a solid. Yield: 0.791 g (54 %).1HNMR (400 MHz, CDCl3): 6 1.37 (3H, t, J= 7.1 Hz), 1.39-1.44 (1H, m), 1.63-1.73 (1H, m), 1.78-1.85 (1H, m), 1.98-2.03 (1H, m), 2.16-2.24 (1H, m), 2.29-2.34 (1H, m), 2.40-2.46 (1H, m), 2.71 (3H, s), 3.08-3.13 (1H, m), 3.26-3.32 (1H, m), 4.31 (2H, q, J= 7.1 Hz), 4.44- 4.50 (1H, m), 4.52-4.56 (1H, m), 8.33 (1H, s). M5 m/z: 330 (M-I).
  • 70
  • [ 141449-85-6 ]
  • [ 64119-42-2 ]
  • [ 898229-91-9 ]
YieldReaction ConditionsOperation in experiment
55% With triethylamine; In dichloromethane; at 120℃; for 0.333333h;Microwave irradiation; (a) tert-butyl 5-[3-cyano-5-(ethoxycarbonyl)-6-methylpyridin-2- yl]hexahydropyrrolo[3,4-c]pyrrole-2(Lff)-carboxylate; Ethyl 6-chloro-5-cyano-2-methylnicotinate (0.090 g, 0.4 mmol) was dissolved in ethanol (2 iriL, 98 %) in a 5mith process vial, tert -Butyl hexahydropyrrolo[3,4-c]pyrrble-2(lH)- carboxylate (0.093 g, 0.44 mmol) and triethylamine (0.202 g, 2.0 mmol) were added. The sealed vial was heated in a microwave oven, single node heating, at 120C for 20 minutes.The solvent was evaporated. Flash chromatography on 5i- gel with heptane/ethyl acetate 3:1 as eluent gave the wanted product. Yield: 0.088 g (55 %).1H NMR (400 MHz, CDCfe): 6 1.35 (3H, t, J= 7.1 Hz), 1.44 (9H, s), 2.68 (3H, s), 2.92-3.02 (2H, m), 3.24-3.35 (2H, m), 3.56-3.69 (2H, m), 3.72-3.79 (2H, m), 4.03-4.13 (2H, m), 4.28(2H, q, J= 7.1 Hz), 8.30 (1H, s).13C NMR (100 MHz, CDCl3): 5 14.1, 25.5, 28.3, 40.6, 41.7, 49.2, 49.5, 52.15, 52.25, 60.6,79.5, 86.9, 113.4, 118.7, 147.4, 154.2, 155.4, 164.6, 164.7M5 m/z: 401 (M+l)
55% With triethylamine; In ethanol; at 120℃; for 0.333333h;Microwave irradiation; A solution of 7 (0.090 g, 0.4 mmol), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.093 g, 0.44 mmol) and TEA (0.202 g, 2.0 mmol) in EtOH (2 mL) was heated in a microwave oven at 120 C for 20 minutes. The mixture was concentrated and the crude was purified by flash chromatography (heptane/EtOAc 3:1). Yield: 0.088 g (55%). 1H NMR (400MHz, CDCl3): 1.35 (3H, t, J = 7.1 Hz), 1.44 (9H, s), 2.68 (3H, s), 2.92-3.02 (2H, m), 3.24-3.35 (2H,m), 3.56-3.69 (2H, m), 3.72-3.79 (2H, m), 4.03-4.13 (2H, m), 4.28 (2H, q, J = 7.1 Hz), 8.30 (1H, s). MS m/z: 401 (M+1). tert-Butyl 5-[3-cyano-5-(ethoxycarbonyl)-6-methylpyridin-2-yl]hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.085 g, 0.21 mmol) was dissolved in TFA/DCM 1:1 (2 mL) and the reaction mixture was stirred at rt for 30 minutes and then concentrated. The crude material was dissolved in DCM (1 mL). TEA (0.106 g, 1.05 mmol) and benzenesulfonyl isocyanate (0.042 g, 0.23 mmol) were added at 0 C. The reaction mixture was stirred at 0 C for 10 minutes and then at rt for 1.5 h. The mixture was concentrated and the crude was purifed by reverse phase HPLC. Yield: 0.075 g (74%).
  • 71
  • [ 64119-42-2 ]
  • [ 36476-78-5 ]
  • [ 898227-90-2 ]
YieldReaction ConditionsOperation in experiment
100% (d) l-[3 -Cyano-5-(ethoxycarbonyl) -6-methylpyridine -2-yI] azetidinc -3-carboxylic acid; Ethyl 6-chloro-5-cyano-2-methylnicotinate (50.98 g, 227 mmol), azetidine-3-carboxylic acid (24.09 g, 238 mmol) and DIPEA (118.9 mL, 681 mmol) were suspended in EtOH (250 mL) and heated at reflux for 1 h. The reaction mixture was cooled to r.t and added drop- wise to KH5O4 (154.5 g, 1135 mmol) in water (3000 mL). The solids were collected by filtration and dried under vacuum to afford 1-[3-Cyano-5-(ethoxycarbonyl)-6-methylpyridine-2- yl]azetidine-3-carboxylic acid as a solid, which was used without further purification. Yield: 65.33 g (100%). 1H NMR (400 MHz, CDCl3): 6 1.37 (3H, t, J= 7.1 Hz), 2.72 (3H, s), 3.59-3.68 (1H, m), 4.31 (2H, q, J= 7.1 Hz), 4.55-4.68 (4H, m), 8.28 (1H, s). M5 m/z: 290 (M+l).
100% Ethyl 6-chloro-5-cyano-2-methylnicotinate (50.98 g, 227 mmol), azetidine-3-carboxylic acid(24.09 g, 238 mmol) and DIPEA (118.9 mL, 681 mmol) were suspended in EtOH (250 mL) . and heated at reflux for 1 h. The reaction mixture was cooled to r.t and added drop- wise toKHSO4 (154.5 g, 1135 mmol) in water (3000 mL). The solids were collected by filtration and dried under vacuum to afford l-[3-Cyano-5-(ethoxycarbonyl)-6-methylpyridine-2- yl] azetidine-3-carboxylic acid as a solid, which was used without further purification. Yield:65.33 g (100%).1H NMR (400 MHz, CDQs): delta 1.37 (3H, t, J = 7.1 Hz), 2.72 (3H, s), 3.59-3.68 (IH, m), 4.31(2H, q, J= 7.1 Hz), 4.55-4.68 (4H, m), 8.28 (IH, s). MS m/z: 290 (M+l).
100% With N-ethyl-N,N-diisopropylamine; In ethanol; for 1h;Heating / reflux; (a) 1-[3-Cyano-5-(ethoxycarbonyl)-6-methylpyridine-2-yl]azetidine-3-carboxylic acid Ethyl 6-chloro-5-cyano-2-methylnicotinate (50.98 g, 227 mmol), azetidine-3-carboxylic acid (24.09 g, 238 mmol) and DIPEA (118.9 mL, 681 mmol) were suspended in EtOH (250 mL) and heated at reflux for 1 h. The reaction mixture was cooled to r.t and added drop-wise to KHSO4 (154.5 g, 1135 mmol) in water (3000 mL). The solids were collected by filtration and dried under vacuum to afford 1-[3-Cyano-5-(ethoxycarbonyl)-6-methylpyridine-2-yl]azetidine-3-carboxylic acid as a solid, which was used without further purification. Yield: 65.33 g (100%). 1H NMR (400 MHz, CDCl3): delta 1.37 (3H, t, J=7.1 Hz), 2.72 (3H, s), 3.59-3.68 (1H, m), 4.31 (2H, q, J=7.1 Hz), 4.55-4.68 (4H, m), 8.28 (1H, s). MS m/z: 290 (M+1).
100% With N-ethyl-N,N-diisopropylamine; In ethanol; for 1h;Heating / reflux; Ethyl 6-chloro-5-cyano-2-methylnicotinate (50.98 g, 227 mmol), azetidine-3-carboxylic acid (24.09 g, 238 mmol) and DIPEA (118.9 mL, 681 mmol) were suspended in EtOH (250 mL) and heated at reflux for 1 h. The reaction mixture was cooled to r.t and added drop-wise to KHSO4 (154.5 g, 1135 mmol) in water (3000 mL). The solids were collected by filtration and dried under vacuum to afford 1-[3-Cyano-5-(ethoxycarbonyl)-6-methylpyridine-2-yl]azetidine-3-carboxylic acid as a solid, which was used without further purification. Yield: 65.33 g (100%).1H NMR (400 MHz, CDCl3): delta 1.37 (3H, t, J=7.1 Hz), 2.72 (3H, s), 3.59-3.68 (1H, m), 4.31 (2H, q, J=7.1 Hz), 4.55-4.68 (4H, m), 8.28 (1H, s).MS m/Z: 290 (M+1).
With N-ethyl-N,N-diisopropylamine; In ethanol; for 1h;Reflux; (a) 1- [3-Cyano-5-(ethoxycarbonyl)-6-methylpyridine-2-yl] azetidine-3-carboxylic acid Ethyl -chloro-S-cyano^-methylnicotinate (See Example l(c))(50.98 g, 227 mmol), azetidine-3-carboxylic acid (24.09 g, 238 mmol) and DIPEA (118.9 mL, 681 mmol) were suspended in EtOH (250 mL) and heated at reflux for 1 h. The reaction mixture was cooled to r.t. and added drop-wise to KHSO4 (154.5 g, 1135 mmol) in water (3000 mL). The solids were collected by filtration and dried under vacuum to afford l-[3-cyano-5- (ethoxy carbonyl)-6-methylpyridine -2 -yl] azetidine-3-carboxylic acid as a solid, which was used without further purification. Yield: 65.33 g (100%).1H NMR (400 MHz, CDCl3): delta 1.37 (3H, t, J= 7.1 Hz), 2.72 (3H, s), 3.59-3.68 (IH, m), 4.31 (2H, q, J= 7.1 Hz), 4.55-4.68 (4H, m), 8.28 (IH, s). MS m/z: 290 (M+ 1).

  • 72
  • [ 64119-42-2 ]
  • [ 113451-59-5 ]
  • [ 898229-94-2 ]
YieldReaction ConditionsOperation in experiment
99% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; (a) (lS,4S)-tert -Butyl 5-(3-cyano -5-(ethoxycarbonyl>6-methylpyridin-2-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate; A solution of ethyl 6-chloro-5-cyano-2-methylnicotinate (1.00 g, 4.45 mmol), (l5,45)-tert- butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.06 g, 5.34 mmol), and DIPEA (2.33 mL, 13.4 mmol) in DMF (10 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated NH4Cl (4 x 50 mL), brine (3 x 50 mL), dried (Mg5O4), passed through silica gel and concentrated to produce (15,45)- EPO <DP n="247"/>tert-butyl 5-(3-cyano-5-(ethoxycarbonyl)-6-methylpyridin-2-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate as an oil. Yield: 1.71 g (99 %). M5 "7Z: 387 (M+l).
99% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; 7 (1.00 g, 4.45 mmol) and (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.06 g, 5.34 mmol) were dissolved in DMF (10 mL). DIPEA (2.33 mL, 13.4 mmol) was added and the reaction mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc (100 mL), washed with NH4Cl (4 x 50 mL, saturated, aq solution), brine (3 x 50 mL), dried (MgSO4), passed through silica gel and concentrated. Yield: 1.71 g (99%) asan oil. MS m/Z: 387 (M+1). (1S,4S)-tert-Butyl 5-(3-cyano-5-(ethoxycarbonyl)-6-methylpyridin-2-yl)-2,5-diazabicyclo-[2.2.1]heptane-2-carboxylate (1.71 g, 4.42 mmol) was dissolved in EtOH (40 mL) and HCl (4 M in1,4-dioxane, 40 mL) was added. The reaction mixture was stirred at rt for 18 h. The mixture was concentrated, diluted with EtOAc (300 mL), washed with NaHCO3 (100 mL, saturated, aq solution)and brine (100 mL), dried (MgSO4), and concentrated. Yield: 1.13 g (89%). A solution of ethyl 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-cyano-2-methylnicotinate (0.128g, 0.447 mmol), 9 (0.145 g, 0.447 mmol), DMAP (0.0027 g, 0.022 mmol), and DIPEA (0.39 mL, 2.23mmol) in DMA (3 mL) was heated to 120 C for 3 h. The reaction mixture was diluted with EtOAc (100 mL), washed with NHCl4 (3 x 50 mL, saturated, aq solution) and brine (50 mL), dried (MgSO4)and concentrated. The crude was purified by flash chromatography (EtOAc/hexanes 1:3 with 1%AcOH) followed by reverse phase preparative HPLC. Yield: 0.070 g (30%).
  • 73
  • [ 110-85-0 ]
  • [ 64119-42-2 ]
  • [ 898226-99-8 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine; In ethanol; at 160℃; for 0.416667h;Microwave irradiation; 7 (2.00 g, 8.90 mmol) and piperazine (2.30 g, 26.7 mmol) were suspended in EtOH (30 mL). TEA (1.35 g, 13.4 mmol) was added and the reaction mixture was heated in a microwave oven at 160 C for25 min. The mixture was concentrated, diluted with DCM (30 mL),washed with NaHCO3 (30 mL, saturated, aq solution) and brine(30 mL), dried (Na2SO4) and concentrated. Yield: 2.44 g (100%).
With triethylamine; In ethanol; at 160℃; for 0.416667h;Microwave irradiation; (a) Ethyl 5-cyano -Z-methy 1-beta-piperazin-1-ylnicotinate; Ethyl 6-chloro-5-cyano-2-methylnicotinate (2.00 g, 8.90 mmol) and piperazine (2.30 g, 26.7 mmoi) was taken in ethanol (30 ml). Triethylamine (1.35 g, 13.4 mmol) was added. The mixture was heated in a microwave reactor at 160 0C for 25 min. The mixture was diluted with dichloromethane (300 ml) and washed in succession with saturated sodium hydrogen carbonate solution and brine respectively. The organics were dried over sodium sulphate, filtered' and the solvents were removed under reduced pressure to give Ethyl 5-cyano-2- methyl-6-piperazm-1-ylnicotinate which was used crude in the consecutive step. 1H NMR (CDCl3): 6 1.37 (3H, t, J= 7.2 Hz), 2.71 (3H, s), 2.96-3.02 (4H, m), 3.88-3.95 (4H, m), 4.31 (2H, q, J= 7.2 Hz), 8.28 (1H, s). M5 m/z: 275 (M+l).
With triethylamine; In ethanol; at 160℃; for 0.416667h;Microwave irradiation; (d) Ethyl 5-cyano -l-methyl--piperazin-l-ylnicotinateEthyl 6-chloro-5-cyano-2-methyhiicotinate (2.00 g, 8.90 mmol) and piperazine (2.30 g, 26.7 mmol) was taken in ethanol (30 ml). Triethylamine (1.35 g, 13.4 mmol) was added. The mixture was heated in a microwave reactor at 160 0C for 25 min. The mixture was 0 diluted with dichloromethane (300 ml) and washed in succession with saturated sodium hydrogen carbonate solution and brine respectively. The organics were dried over sodium sulphate, filtered and the solvents were removed under reduced pressure to give ethyl S cyano-2-methyl-6-piperazin-l-yhiicotinate which was used crude in the consecutive step. 1H NMR (400 MHz, CDQ): delta 1.37 (3H, t, J= 7.2 Hz), 2.71 (3H, s), 2.96-3.02 (4H, m), S 3.88-3.95 (4H, m), 4.31 (2H, q, J= 7.2 Hz), 8.28 (IH, s). MS m/z: 275 (M+l).
  • 74
  • [ 919354-20-4 ]
  • [ 64119-42-2 ]
  • [ 898228-16-5 ]
YieldReaction ConditionsOperation in experiment
43% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20.0℃; (e) 1-[3-Cyano -5-(ethoxycarbonyl) -6-methylpyridin-2 -yl] -4-methylpiperidine -4- carboxylic acid; Ethyl 6-chloro-5-cyano-2-methylnicotinate (0.28 g, 1.3 mmol) and 4-methylpiperidine-4- carboxylic acid hydrochloride (0.34 g, 1.9 mmol) were suspended in DMF (20 mL) and DIPEA (1.1 mL, 6.3 mmol) was added. The reaction mixture was stirred at r.t until complete consumption of the starting materieal was observed by HPLC analysis. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated NH4Cl (70 mL), water (2 X 70 mL) and brine (50 mL). The organics were dried (Mg5O4) and concentrated under reduced pressure to afford the crude material. Flash column chromatography (1:3 EtOAc/hexanes, 0.5 % AcOH to 1:2 EtOAc/hexanes, 0.5 % AcOH) gave 1-[3-cyano-5-(ethoxycarbonyl)-6- methylpy?din-2-yl]-4-methylpiperidine-4-carboxylic acid as a solid. Yield: 0.179 g (43%). 1H NMR (400 MHz, DM5O- d6): 6 1.20 (3H, s), 1.30 (3H, t, J= 7.1Hz), 1.44-1.54 (2H, m), 2.02-2.11 (2H, m), 2.63 (3H, s), 3.39-3.48 (2H, m), 4.15-4.29 (4H, m), 8.32 (1H, s), 12.52 (1H, br s). M5 m/z: 332 (M+l).
  • 75
  • [ 1114876-08-2 ]
  • [ 64119-42-2 ]
  • [ 898228-38-1 ]
YieldReaction ConditionsOperation in experiment
96% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; (d) Ethyl 5-cyano -6-(3-(methoxycarbonyl)-3-methylazetidin-1-yl)-2-methylnicotinate; Methyl 3-methylazetidine-3-carboxylate hydrochloride (0.49 g, 2.97 mmol) and ethyl 6- chloro-5-cyano-2-methylnicotinate (0.56 g, 2.5 mmol) were suspended in DMF (10 mL) and DIPEA (2.2 ml, 12 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure to afford the crude material. The crude material was partitioned between EtOAc (100 mL) and sat. aqueoues NH4Cl (70 mL). The organics were washed with water (2 x 50 mL), brine (1 x 50 mL), dried (Mg5O4) and concentrated under reduced pressure to afford the crude material, Flash chromatography (15 - 25 % EtOAc / Hexanes) gave ethyl 5-cyano-6-(3-(methoxycarbonyl)-3-methylazetidin-1-yl)- 2-methylnicotinate as a solid. Yield: 0.752 g (96 %). 1H NMR (400 MHz, CDCl3): 6 1.37 (3H, t, J= 7.1 Hz), 1.64 (3H, s), 2.71 (3H, s), 3.78 (3H, s), 4.16-4.18 (2H, m), 4.31 (2H, q, J= 7.1 Hz), 4.67-4.69 (2H, m), 8.27 (1H, s). M5 m/z: 318 (M+l).
  • 76
  • [ 898227-73-1 ]
  • [ 64119-42-2 ]
  • ethyl 6-[4-([(5-chloro-2-thienyl)sulfonyl]amino}carbonyl)piperidin-1-yl]-5-cyano-2-methylnicotinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 160℃; for 0.5h; Example 117; Ethyl 6-[4-({ [(5-chloro-2-thienyl)sulfonyl] amino}carbonyl)piperidin-1-yl]-5-cyano -2- methylnicotinate; Ethyl 6-chloro-5-cyano-2-methylnicotinate (0.20 g, 0.89 ?raiol), N-(5-chlorothiophen-2- ylsulfonyl)piperidine-4-carboxamide hydrochloride (0.41 g. 1.3 mmol), see example 158, and DEPEA (0.62 ml, 3.6 mmol) were combined in DMA (2.0 ml). The reaction was heated at 160 C for 30 minutes. The reaction was then cooled and dissolved in EtOAc (75 ml) and washed with aqueous NH4Cl (2 x 40 ml) followed by brine (40 ml). The organic phase was dried (Mg5O4) and concentrated in vacuo to provide a crude solid. This solid was purified by washing with MeOH followed by EtOAc to provide the desired product, ethyl 6-[4-([(5- chloro-2-thienyl)sutfonyl]aniino}carbonyl)piperidin-1-yl]-5-cyano-2-methylnicotinate, as a white solid. Yield: 198 mg (45%).1H NMR (400 MHz, d6-DM5O): 6 1.30 (3H, t, J= 7.1 Hz), 1.50-1.59 (4H, m), 1.80 (2H, d, J = 11.0 Hz), 2.42-2.56 (1H, obs), 2.63 (3H, s), 3.15 (2H, d, J= 11.9 Hz)1 4.24 (2H, q, J= 7.1 Hz), 4.49 (2H, d, J = 13.5 Hz), 7.28 (1H, d, J= 4.1 Hz), 7.67 (1H, d, J= 4.1 Hz), 8.32 (1H, s). M5 m/z: 497 (M+l).
  • 77
  • [ 892493-65-1 ]
  • [ 64119-42-2 ]
  • [ 898227-84-4 ]
YieldReaction ConditionsOperation in experiment
89% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 80℃; for 2h; (a) Ethyl 6-(4-(^rT-butoxycarbonyl)piperidin-1-yl)-5-cyano-2-methyInicotinate; A solution of ethyl 6-chloro-5-cyano-2-methylnicotinate (6.00 g, 26.7 mmol), tert -butyl piperidine-4-carboxylate hydrochloride (6.51, 29.4 mmol) and DIPEA (23.3 mL, 134 mmol) in DMA (50 mL) were heated to 8O°C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (300 mL), washed with saturated NH4Cl (4 x 50 mL), brine (50 mL), dried (Mg5O4), passed through silica gel and concentrated. Flash chromatography produced Ethyl 6-(4-(tert-butoxycarbonyl)piperidin-1-yl)-5-cyano-2-methylnicotinate as a solid. Yield 8.85 g (89 percent). EPO <DP n="146"/>1HNMR (400 MHz, CDCl3): 6 1.37 (3H, t, J= 7.1 Hz), 1.45 (9H, s), 1.75-1.84 (2H3 m), 1.99- 2.03 (2H, m), 2.49-2.57 (1H, m), 2.72 (3H, s), 3.24-3.31 (2H, m), 4.31 (2H, q, J= 7.1 Hz), 4.55-4.60 (2H, m), 8.34 (1H, s). M5 "Vz: 374 (M+l).
89% With N-ethyl-N,N-diisopropylamine; In DMA; at 80℃; for 2h; A solution of ethyl 6-chloro-5-cyano-2-methyhiicotinate (6.00 g, 26.7 mmol), <strong>[892493-65-1]tert-butyl piperidine-4-carboxylate hydrochloride</strong> (6.51, 29.4 mmol) and DBPEA (23.3 mL, 134 mmol) in DMA (50 mL) were heated to 80 °C for 2 h. After cooling to r.t, the reaction mixture was diluted with EtOAc (300 mL), washed with saturated NH4Cl (4 x 50 mL), brine (50 mL), dried (MgSO4), passed through silica gel and concentrated. Flash chromatography produced ethyl 6-(4-(tert-butoxycarbonyl)piperidm-l-yl)-5-cyano-2-memylnicotinate as a solid. Yield: 8.85 g (89 percent). EPO <DP n="138"/>1H NMR (400 MHz, CDCl): delta 1HNMR (400 MHz, CDCl5): delta 1.37 (3H, t, J= 7.1 Hz), 1.45 (9H, s), 1.75-1.84 (2H, m), 1.99-2.03 (2H, m), 2.49-2.57 (IH, m), 2.72 (3H, s), 3.24-3.31 (2H, m), 4.31 (2H, q, J= 7.1 Hz), 4.55-4.60 (2H, m), 8.34 (IH, s). MS m/z: 374 (M+l).
  • 78
  • [ 498-94-2 ]
  • [ 64119-42-2 ]
  • [ 919354-24-8 ]
YieldReaction ConditionsOperation in experiment
45% With triethylamine; for 0.166667h;Heating / reflux; Ethyl 6-chloro-5-cyano-2-methylnicotinate (3.00g, 13.35 mmol), Piperidine-4-carboxylic acid (1.897g, 14.69 mmol), and TEA (2.703 g, 26.71 mmol) were mixed and the mixture was refluxed for 10 minutes. LC/MS showed full conversion. The reaction mixture was evaporated, water/EtOAc 1:1 (100 mL) was added and the water phase was acidified to pH3. The EtOAc phase was separated and the water phase was extracted with an additional EtOAc (40 mL). The combined organic phases were dried (Na2SO4), filtered and evaporated to give 3.8 g of a crude material. Purification with preperative BPLC at pH=7 (0.1 M NH4OAC/CH3CN) with subsequent switch to pH=3 gave the pure product. Yield: 1.9 g (45 %). EPO <DP n="128"/>1H NMR ^OO MHZ, CDCi): 5 1.38 (t,J= 7.1 Hz, 3H), 1.94-1.82 (m, 2H), 2.13-2.05 (m, 2H)3 2.75-2.66 (m, 5H), 3.37-3.27 (m, 2H), 4.33 (q, J= 7.1 Hz, 2H), 4.63-4.55 (m, 2H), 8.36 (s, IH)MS m/z: 318 (M+l).
With triethylamine; for 0.166667h;Heating / reflux; Ethyl 6-chloro-5-cyano-2-methylnicotinate (3.00 g, 13.35 mmol), piperidine-4-carboxylic acid (1.897 g, 14.69 mmol), and TEA (2.703 g, 26.71 mmol) were mixed and the mixture was refluxed for 10 minutes. LC/MS showed full conversion. The reaction mixture was evaporated, water/EtOAc 1:1 (100 mL) was added and the water phase was acidified to pH3. The EtOAc phase was separated and the water phase was extracted with an additional EtOAc (40 mL). The combined organic phases were dried (Na2SO4), filtered and evaporated to give 3.8 g of a crude material.Purification with preparative HPLC (Kromasil C8, 10 mum at pH=7 (0.1 M NH4OAc/CH3CN) with subsequent switch to pH=3) gave the pure product. Yield: 1.9 g (451H NMR (400 MHz, CDCl3): delta 1.38 (t, J=7.1 Hz, 3H), 1.94-1.82 (m, 2H), 2.13-2.05 (m, 2H), 2.75-2.66 (m, 5H), 3.37-3.27 (m, 2H), 4.33 (q, J=7.1 Hz, 2H), 4.63-4.55 (m, 2H), 8.36 (s, 1H)MS m/Z: 318 (M+1).
  • 79
  • [ 64119-42-2 ]
  • [ 73874-95-0 ]
  • [ 898229-84-0 ]
YieldReaction ConditionsOperation in experiment
95.4% With N-ethyl-N,N-diisopropylamine; In ethanol; at 20 - 94℃; for 4h; Ethyl delta-chloro-S-cyanonicotinate (2.00 g, 8.90 mmol) and tert-butyl piperidin-4-ylcarbamate(1.78 g, 8.90 mmol) were dissolved in EtOH (50 mL) at room temperature. DIPEA (4.65 mL,26.7 mmol) was added and the system heated at 94 0C for 4 h. The reaction mixture was cooled to room temperature and the solvent concentrated under reduced pressure. The material was partitioned between EtOAc (50 mL) and saturated aqueous NH4Cl (2 x 30 mL). The organics were washed with brine (30 mL), dried (MgSO4) and concentrated under . reduced pressure to afford the crude product. No purification was done. Yield: 3.30 g (95.4%).1H NMR (400 MHz, CDCi): 5 1.37 (3H, t, J= 7.1 Hz), 1.46 (HH, s), 2.05-2.14 (2H, m),2.72 (3H, s), 3.15-3.26 (2H, m), 3.71-3.83 (IH, m), 4.32 (2H, q, J= 7.1 Hz), 4.42-4.51 (IH, m), 4.58-4.67 (2H, m), 8.34 (IH, s).MS m/z: 389 (M+l).
  • 80
  • [ 64119-42-2 ]
  • [ 919354-75-9 ]
YieldReaction ConditionsOperation in experiment
33% Ethyl 6-ct°oro-5-cyano-2-me&ylnicotinate (1.00 g, 4.45 mmol) was dissolved in DCM (25mL) and cooled on an ice-bath. Urea hydrogen peroxide (2.09 g, 22.3 mmol) was charged and triftuoroaceticacid anhydride (3.11 mL, 22.3 mmol) was added droppwise during 2-3 minutes. The cooling bath was removed after 15min and the reaction mixture was stirred over night. Sodium Pyrosulphite 4.2g in 15 mL water was added and the reaction mixture was stirred for 3 min, followed by addition of DCM (5ml) and IM KHSO4 (2ml) and stirring continued for 5 min. The aqueous layer was extracted three times with DCM and the combined organics were dried over sodium sulphate. Concentration yielded 900mg of a light yellow sticky solid. The crude material was purified by preparative HPLC, 50x300mm, C8, lOum'to give <strong>[64119-42-2]ethyl 6-chloro-5-cyano-2-methylnicotinate</strong> 1-oxide. Yield=356mg (33%) 1H-NMR (400 MHz, DMSO-d6) 5 1.34(3H, t, J= Z 1 Hz), 2.68(3H, s), 4.36(2H, q, J=Zi Hz), 8.25(1H, s)
  • 81
  • [ 898229-66-8 ]
  • [ 64119-42-2 ]
  • [ 898229-67-9 ]
YieldReaction ConditionsOperation in experiment
54% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 72h; Ethyl 6-chloro-5-cyano-2-methyhiicotinate (1.00 g, 4.45 mmol), piperidin-3-ylacetic acid (0.701 g, 4.90 mmol) and DIPEA (2.33 mL, 13:4 mmol) were dissolved in DMF (30 mL) and stirred at r.t for 3 days. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated NH4Cl (2 x 25 mL), saturated NaHCO3 (2 x 25 mL), brine (25 m), dried (MgSO4) and concentrated under reduced pressure to afford crude material. Flash chromatography (9:1 EtOAc/hexanes with 1% HOAc) gave {l-[3-cyano-5-(ethoxycarbonyl)-6-methylpyridin-2- yl]rhoiperdm-3-yl}acetic acid as a solid. Yield: 0.791 g (54 %).1H NMR (400 MHz, CDCl;): delta 1.37 (3H, t, J= 7.1 Hz), 1.39-1.44 (IH, m), 1.63-1.73 (IH, m), 1.78-1.85 (IH, m), 1.98-2.03 (IH, m), 2.16-2.24 (IH, m), 2.29-2.34 (IH, m), 2.40-2.46 (IH, m), 2.71 (3H, s), 3.08-3.13 (IH3 m), 3.26-3.32 (IH, m), 4.31 (2H, q, J= 7.1 Hz), 4.44- 4.50 (IH, m), 4.52-4.56 (IH, m), 8.33 (IH, s). MS m/z: 330 (M-I).
  • 82
  • [ 64119-42-2 ]
  • [ 162648-32-0 ]
  • [ 898228-16-5 ]
YieldReaction ConditionsOperation in experiment
43% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; Ethyl 6-chloro-5-cyano-2-methylnicotinate (0.28 g, 1.3' mmol) and 4-methylpiperidine-4- carboxylic acid hydrochloride (0.34 g, 1.9 mmol) were suspended in DMF (20 mL) and DIPEA (Ll mL, 6.3 mmol) was added. The reaction mixture was stirred at r.t until complete consumption of the starting materieal was observed by HPLC analysis. The reaction mixture . was diluted with EtOAc (100 mL) and washed with saturated NH4Cl (70 mL), water (2 x 70 mL) and brine (50 mL). The organics were dried (MgSO4) and concentrated under reduced pressure to afford the crude material. Flash column chromatography (1 :3 EtOAc/hexanes, 0.5 % AcOH to 1:2 EtOAc/hexanes, 0.5 % AcOH) gave l-[3-cyano-5-(ethoxycarbonyl)-6- methylpyridin-2-yl]-4-methylpiperidine-4-carhoxylic acid as a solid. Yield: 0.179 g (43%). 1HNMR (400 MHz, DMSO- d6): delta 1.20 (3H3 s), 1.30 (3H, t, J= 7.1Hz), 1.44-1.54 (2H, m), 2.02-2.11 (2H, m), 2.63 (3H, s), 3.39-3.48 (2H, m), 4.15-4.29 (4H, m), 8.32 (IH, s), 12.52 (IH, br s). MS m/z: 332 (M+l).
  • 83
  • [ 64119-42-2 ]
  • [ 57260-71-6 ]
  • [ 898229-38-4 ]
YieldReaction ConditionsOperation in experiment
89.2% With N-ethyl-N,N-diisopropylamine; In ethanol; at 20 - 55℃; for 6h; Ethyl -chloro-S-cyanonicotinate (0.500 g, 2.23 mmol) and tert-butyl rhoiperazine-1- carboxylate (0.623 g, 3.35 mmol) were dissolved in EtOH (50 mL) at r.t. DIPEA (1.16 mL, 6.68 mmol) was added and the system heated at 55 0C for 6 h. The reaction mixture was cooled to r.t and the solvent concentrated under reduced pressure. The material was partitioned between EtOAc (50 mL) and saturated aqueous NH4Cl (2 x 30 mL). The organics were washed with brine (30 mL), dried (MgSO4) and concentrated under reduced pressure to afford the crude product. Flash Chromatography (20 % EtOAc in Hexanes) gave tert-Bntyl 4- (3-cyano-5-(ethoxycarbonyl)-6-methylpyridin-2-yl)piperazine- 1 -carboxylate. Yield: 0.743 g (89.2 %). EPO <DP n="182"/>1H NMR (400 MHz, COCl): 8 1.38 (3H, q, J= 7.1 Hz), 1.49 (9H, s), 2.73 (3H, s), 3.53-3.61 (4H, m), 3.86-3.95 (4H, m), 4.32 (2H, q, J= 7.1 Hz), 8.36 (IH, s). MS m/z: 375 (M+l).
  • 84
  • [ 919354-21-5 ]
  • [ 64119-42-2 ]
  • ethyl 6-{4-[(benzylsulfonyl)carbamoyl]-piperidin-1-yl}-5-cyano-2-methylpyridine-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% With triethylamine; In ethanol; at 20 - 100℃; for 0.916667h; A solution of ethyl 6-chloro-5-cyano-2-methykiicotinate (47.5 g, 211 mmol) and triethyl amine (58.36 g, 577 mmol) in EtOH (314 ml) was added to a stirred mixture of N-(benzylsulfonyl)piperidine-4-carboxamide (53.55 g, 189.7 mmol, See Example 31(b)) and EtOH (100 ml) at r.t. and the mixture was heated to 100 oC (bath temperature, 20-100 oC during 40 minutes, 100 0C 15 minutes then cool to r.t.) for 15 minutes. A solution of KHSO4 (142.93 g in 900 mL water) was added to make the product precipitate out. The precipitate was filtered off and washed with water (2 x 250 mL) to give 87 g of a crude product (84 % pure ). The crude product was slurried in 50 % EtOH (1200 mL) and heated to 50 oC (bath temperature) for 2 houra and 45 minutes followed by stirring over night at r.t. Filtration gave a crude product which was further washed by stirring with 25 % EtOH (1600 mL) at 50 0C for 2 hours followed by 20 % EtOH (1000 mL) at 50 0C for 2 hours. (An attempt to purify the material by using a 50% EtOH/water solution was not successful because it dissolved to much of the product). The solid obtained after the washings above (89 % pure) was dissolved in 700 mL EtOAc at 70 0C and the solution was left to crystallise at r.t. over night. The crystals was filtered off and washed with EtOAc (200 mL) to give pure 6-(4- EPO <DP n="130"/>[(ben2ylsulfonyl)amino]carbonyl}pirhoeridin-l-yl)-5-cyano-2-methylnicotinic acid ethyl ester as an orange solid (fine needles) after drying. Yield: 54.94 g of . Recrystallization of the solids from the motherliquor using EtOAc gave another 10.50 g. Yield 65.44 g (73%). The product can also be crystallized from CHC^. 1HNMR (400 MHz, CDCl5): delta 1.38 (3H, t, J= 7.0 Hz), 1.77-1.91 (4H, m), 2.37-2.44 (IH, m), 2.73 (3H, s), 3.10-3.17 (2H, m), 4.33 (2H, q, J= 7.0 Hz), 4.64-4.68 (4H, m), 7.36-7.41 (5H, m), 8.36 (IH, s). MS m/z: 471(M+1).The product obtained from crystallization in EtOAc (TOrm I) was characterised by the presence, in X-ray powder diffraction (XRPD) measurements, of peaks at about the 2-Theta and relative intensity values detailed in Table 3 below and the product obtained from crystallization in CHC| (Form IT) in Table 4 below.Table 3 : XRPD Peaks for Form I of 6- (4- { [phienzylsulfonyl)a:rrio]caxbonyl}piperidin- 1 -yl)-5-cyano-2-methyhtauicotinic acid ethyl ester EPO <DP n="131"/>Table 4: XRPD Peaks for Form II of 6-(4-[(ben2ylsulfonyl)amino]carbonyl}piperidin-l-yl)-5-cyano-2-methylnictinic acid ethyl esterThe crystalline forms may be further characterised by the presence of one or more of the additional properties listed below:(i) for Form I(I) when characterised by thermogravimetric analysis, a weight loss of approx. 0.8% occurs in the range from 25C up to 205C, and/or (Tf) when characterised by differential scanning calorimetry, at a heating rate of1O0C per minute in a closed cup with a pinhole under flowing nitrogen, a melting temperature (Tm) having an onset at about 194 C and/or an associated endotherm of melting of about 96 J/g; and/or (III) when stored at 80% RH (ambient) less than 0.2 % moisture is adsorbed.(i) for Form II(T) when characterised by thermogravimetric analysis, a weight loss of approx. 0.2 % occurs in the range from 25C up to 2050C, and/or EPO <DP n="132"/>(U) when characterised by differential scanning calorimetry, at a heating rate of 10 C per minute in a closed cup with a pinhole under flowing nitrogen, a melting temperature (Tm) having an onset at about 1930C and/or an associated endotherm of melting of about 105 J/g.
73% With triethylamine; In ethanol; at 20 - 100℃; for 0.916667h; Example 1; 6-(4-[(Benzylsulfonyl)amino]carbonyl}piperidin-l-yl)-5-cyano-2-methylnicotinic acid ethyl ester; A solution of ethyl delta-chloro-S-cyano^-methylriicotinate (47.5 g, 211 mmol) and triethyl amine (58.36 g, 577 mmol) in EtOH (314 ml) was added to a stirred mixture of N- (benzylsulfonyl)piperidine-4-carboxamide (53.55 g, 189.7 mmol, see Comparative Example 2(b)) and EtOH (100 ml) at r.t. and the mixture was heated to 100 0C (bath temperature, 20-100 C during 40 minutes, 100 0C 15 minutes then cool to r.t.) for 15 minutes. A solution OfKHSO4 (142.93 g in 900 mL water) was added to make the product precipitate out. The precipitate was filtered off and washed with water (2 x 250 mL) to give 87 g of a crude product (84 % pure ). The crude product was slurried in 50 % EtOH (1200 mL) and heated to 500C (bath temperature) for 2 hours and 45 minutes followed by stirring over night at r.t. Filtration gave a crude product which was further washed by stirring with 25 % EtOH (1600 mL) at 50 0C for 2 hours followed by 20 % EtOH (1000 mL) at 50 0C for 2 hours. (An attempt to purify the material by using a 50% EtOH/water solution was not successful because it dissolved to much of the product). The solid obtained after the washings above (89 % pure) was dissolved in 700 mL EtOAc at 70 0C and the solution was left to crystallise at r.t. over night. The crystals was filtered off and washed with EtOAc (200 mL) to give pure 6-(4- [(benzylsulfonyl)amrno]carbonyl} - piperidin-l-yl)-5-cyano-2-methylnicotinic acid ethyl ester as an orange solid (fine needles) after drying. Yield: 54.94 g. Recrystallization of the solids from the mother liquor using EtOAc gave another 10.50 g. Yield 65.44 g (73%). The product can also be crystallized from CHCi. 1H NMR (400 MHz, CDCfe): delta 1.38 (3H, t, J= 7.0 Hz), 1.77-1.91 (4H, m), 2.37-2.44 (IH, m), 2.73 (3H, s), 3.10-3.17 (2H, m), 4.33 (2H, q, J= 7.0 Hz), 4.64-4.68 (4H, m), 7.36-7.41 (5H, m), 8.36 (IH, s). MS m/z: 471(M+1).
73% With triethylamine; In ethanol; at 20 - 100℃; for 0.25h; (f) 6-(4-{ [(Benzylsulfonyl)amino] carbonyI}piperidin-l-yl)-5-cyano-2-methylnicotinic 0 acid ethyl ester <n="107"/>A solution of <strong>[64119-42-2]ethyl 6-chloro-5-cyano-2-methylnicotinate</strong> (47.5 g, 211 mmol) and triethyl amine (58.36 g, 577 mmol) in EtOH (314 ml) was added to a stirred mixture of N- (benzylsulfonyl)piperidine-4-carboxamide (53.55 g, 189.7 mmol, See Example 31(b)) and EtOH (100 ml) at r.t. and the mixture was heated to 100 oC (bath temperature, 20-100 0C during 40 minutes, 100 0C 15 minutes then cool to r.t.) for 15 minutes. A solution of KHSO4. (142.93 g in 900 mL water) was added to make the product precipitate out. The precipitate was filtered off and washed with water (2 x 250 mL) to give 87 g of a crude product (84 % pure ). The crude product was slurried in 50 % EtOH (1200 mL) and heated to 50 0C (bath temperature) for 2 houra and 45 minutes followed by stirring over night at r.t. Filtration gave a crude product which was further washed by stirring with 25 % EtOH (1600 mL) at 50 0C for 2 hours followed by 20 % EtOH (1000 mL) at 50 0C for 2 hours. (An attempt to purify the material by using a 50% EtOH/water solution was not successful because it dissolved to much of the product). The solid obtained after the washings above (89 % pure) was dissolved in 700 mL EtOAc at 70 0C and the solution was left to crystallise at r.t. over night. The crystals was filtered off and washed with EtOAc (200 mL) to give pure 6-(4-[(benzylsulfonyl)amino]carbonyl}piperidin-l-yl)-5-cyano-2- methylnicotinic acid ethyl ester as an orange solid (fine needles) after drying. Yield: 54.94 g of . Recrystallization of the solids from the motherliquor using EtOAc gave another 10.50 g. Yield 65.44 g (73%). The product can also be crystallized from CHCl3. 1H NMR (400 MHz, CDCl3): delta 1.38 (3H, t, J= 7.0 Hz), 1.77-1.91 (4H, m), 2.37-2.44 (IH, m), 2.73 (3H, s), 3.10-3.17 (2H, m), 4.33 (2H, q, J= 7.0 Hz), 4.64-4.68 (4H, m), 7.36-7.41 (5H, m), 8.36 (IH, s). MS m/z: 471(M+l).
73% With triethylamine; In ethanol; at 20 - 100℃; for 0.75h; (f) 6-(4-[(Benzylsulfonyl)amino]carbonyl}piperidin-l-yl)-5-cyano-2-methylnicotinic acid ethyl esterA solution of <strong>[64119-42-2]ethyl 6-chloro-5-cyano-2-methylnicotinate</strong> (47.5 g, 211 mmol) and triethyl amine (58.36 g, 577 mmol) in EtOH (314 ml) was added to a stirred mixture of N- (benzylsulfonyl)piperidine-4-carboxamide (53.55 g, 189.7 mmol, and EtOH (100 ml) at r.t. and the mixture was heated to 100 0C (bath temperature, 20-100 oC during 40 minutes, 100 0C 15 minutes then cool to r.t.) for 15 minutes. A solution of KHSO4 (142.93 g in 900 mL water) was added to make the product precipitate out. The precipitate was filtered off and washed with water (2 x 250 mL) to give 87 g of a crude product (84 % pure ). The crude product was slurried in 50 % EtOH (1200 mL) and heated to 50 0C (bath temperature) for 2 hours and 45 minutes followed by stirring over night at r.t.. Filtration gave a crude product which was further washed by stirring with 25 % EtOH (1600 mL) at 50 0C for 2 hours followed by 20 % EtOH (1000 mL) at 50 0C for 2 hours. (An attempt to purify the material by using a 50% EtOH/water solution was not successful because it dissolved to much of the product). The solid obtained after the washings above (89 % pure) was dissolved in 700 mL EtOAc at 70 0C and the solution was left to crystallise at r.t. over night. The crystals was filtered off and washed with EtOAc (200 mL) to give pure 6-(4- [(benzylsulfonyl)amino]carbonyl}piperidin-l-yl)-5-cyano-2-methylnicotinic acid ethyl ester as an orange solid (fine needles) after drying. Yield: 54.94 g of . Recrystallization of the solids from the motherliquor using EtOAc gave another 10.50 g. Yield 65.44 g (73%). 1H NMR (400 MHz, CDCl3): delta 1.38 (3H, t, J= 7.0 Hz), 1.77-1.91 (4H, m), 2.37-2.44 (IH, m), 2.73 (3H, s), 3.10-3.17 (2H, m), 4.33 (2H, q, J= 7.0 Hz), 4.64-4.68 (4H, m), 7.36-7.41 (5H, m), 8.36 (IH, s). MS m/z: 471(M+1).

  • 85
  • [ 64119-42-2 ]
  • [ 183062-92-2 ]
  • [ 919354-67-9 ]
YieldReaction ConditionsOperation in experiment
43.3% With N-ethyl-N,N-diisopropylamine; In ethanol; at 100℃; for 0.0833333h;Microwave irradiation; Azetidin-3-ylacetic acid (460.5 mg , 5.00 mmol) from previous step was dissolved inEtOH(8mL) and <strong>[64119-42-2]ethyl 6-chloro-5-cyano-2-methylnicotinate</strong> (1.02 g, ), DIPEA(2mL) were added. The reaction mixture was heated at 100C for 5min using microwave single node heating. NBLiClf°q) was added and the mixture was extracted with DCM three times. The combined organic layers were run through a phase separator and the solvents were removed in vacuo. The crude product was purified by prepHPLC.Column: Kromasil C8 lOmum, 50.8x300mm, Mobilephase A: 100% AcN, Mobilephase B 5%, AcN, 95% NH4AcO(aq) (pH7), Gradient: 20=>60% A over 60min, Flow: 50ml/min andUV: 280nm.This gave {l-[3-cyano-5-(ethoxycarbonyl)-6-methylpyridin-2-yl]azetidin-3-yl}acetic acid yield=526mg.(43.3%)1H-NMR (500MHz, DMSO-d6) delta?1.29 (3H, t,J=7.J), 2.60 (3H, s), 2.63-2.66 (2H, m). 2.93- 3.02 (IH, m), 3.95-4.05(2H, m), 4.34 (2H, q ,j=7.1), 4.37-4.47(2H, m)
Same Skeleton Products
Historical Records

Related Functional Groups of
[ 64119-42-2 ]

Chlorides

Chemical Structure| 303146-25-0

[ 303146-25-0 ]

Methyl 6-chloro-5-cyano-2-methylnicotinate

Similarity: 0.97

Chemical Structure| 75894-43-8

[ 75894-43-8 ]

Ethyl 2-chloro-5-cyano-6-methylnicotinate

Similarity: 0.93

Chemical Structure| 40108-12-1

[ 40108-12-1 ]

Ethyl-2-chloro-3-cyano-6-methylisonicotinate

Similarity: 0.93

Chemical Structure| 1239731-83-9

[ 1239731-83-9 ]

3-Ethyl 5-methyl 2-chloro-6-methylpyridine-3,5-dicarboxylate

Similarity: 0.91

Chemical Structure| 898227-78-6

[ 898227-78-6 ]

6-Chloro-5-cyano-2-methylnicotinic acid

Similarity: 0.90

Esters

Chemical Structure| 303146-25-0

[ 303146-25-0 ]

Methyl 6-chloro-5-cyano-2-methylnicotinate

Similarity: 0.97

Chemical Structure| 75894-43-8

[ 75894-43-8 ]

Ethyl 2-chloro-5-cyano-6-methylnicotinate

Similarity: 0.93

Chemical Structure| 40108-12-1

[ 40108-12-1 ]

Ethyl-2-chloro-3-cyano-6-methylisonicotinate

Similarity: 0.93

Chemical Structure| 1239731-83-9

[ 1239731-83-9 ]

3-Ethyl 5-methyl 2-chloro-6-methylpyridine-3,5-dicarboxylate

Similarity: 0.91

Chemical Structure| 54453-94-0

[ 54453-94-0 ]

Ethyl 6-chloro-2,4-dimethylnicotinate

Similarity: 0.88

Nitriles

Chemical Structure| 303146-25-0

[ 303146-25-0 ]

Methyl 6-chloro-5-cyano-2-methylnicotinate

Similarity: 0.97

Chemical Structure| 75894-43-8

[ 75894-43-8 ]

Ethyl 2-chloro-5-cyano-6-methylnicotinate

Similarity: 0.93

Chemical Structure| 40108-12-1

[ 40108-12-1 ]

Ethyl-2-chloro-3-cyano-6-methylisonicotinate

Similarity: 0.93

Chemical Structure| 898227-78-6

[ 898227-78-6 ]

6-Chloro-5-cyano-2-methylnicotinic acid

Similarity: 0.90

Chemical Structure| 106718-96-1

[ 106718-96-1 ]

Ethyl 6-chloro-2-cyanonicotinate

Similarity: 0.87

Related Parent Nucleus of
[ 64119-42-2 ]

Pyridines

Chemical Structure| 303146-25-0

[ 303146-25-0 ]

Methyl 6-chloro-5-cyano-2-methylnicotinate

Similarity: 0.97

Chemical Structure| 75894-43-8

[ 75894-43-8 ]

Ethyl 2-chloro-5-cyano-6-methylnicotinate

Similarity: 0.93

Chemical Structure| 40108-12-1

[ 40108-12-1 ]

Ethyl-2-chloro-3-cyano-6-methylisonicotinate

Similarity: 0.93

Chemical Structure| 1239731-83-9

[ 1239731-83-9 ]

3-Ethyl 5-methyl 2-chloro-6-methylpyridine-3,5-dicarboxylate

Similarity: 0.91

Chemical Structure| 898227-78-6

[ 898227-78-6 ]

6-Chloro-5-cyano-2-methylnicotinic acid

Similarity: 0.90