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[ CAS No. 33402-75-4 ] {[proInfo.proName]}

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Chemical Structure| 33402-75-4
Chemical Structure| 33402-75-4
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Product Details of [ 33402-75-4 ]

CAS No. :33402-75-4 MDL No. :MFCD09258869
Formula : C8H9NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :XEXPJABJVHEOCX-UHFFFAOYSA-N
M.W : 151.16 Pubchem ID :10877301
Synonyms :

Calculated chemistry of [ 33402-75-4 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.25
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 40.48
TPSA : 39.19 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.46 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.78
Log Po/w (XLOGP3) : 1.07
Log Po/w (WLOGP) : 1.18
Log Po/w (MLOGP) : 0.66
Log Po/w (SILICOS-IT) : 1.64
Consensus Log Po/w : 1.27

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.72
Solubility : 2.86 mg/ml ; 0.0189 mol/l
Class : Very soluble
Log S (Ali) : -1.48
Solubility : 4.95 mg/ml ; 0.0328 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.47
Solubility : 0.512 mg/ml ; 0.00339 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.37

Safety of [ 33402-75-4 ]

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

Application In Synthesis of [ 33402-75-4 ]

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

  • Upstream synthesis route of [ 33402-75-4 ]
  • Downstream synthetic route of [ 33402-75-4 ]

[ 33402-75-4 ] Synthesis Path-Upstream   1~18

  • 1
  • [ 33402-75-4 ]
  • [ 3222-50-2 ]
YieldReaction ConditionsOperation in experiment
58.4%
Stage #1: With water; sodium hydroxide In 1,4-dioxane at 50 - 60℃; for 1 h;
Stage #2: With hydrogenchloride In water
4-Methyl-nicotinic acid
4-Methyl-nicotinic acid methyl ester (15 g, 0.1 mol) was added into the mixture of aqueous NaOH (2 M, 55 mL) and dioxane (100 mL), then the reactant was heated to 50~60° C. for 1 hour.
The solvent was removed in vacuo.
The residue was diluted with water (20 mL) and acidified by 1N HCl to PH≈6, the solid formed was filtered and dried in vacuo to give 8.0 g of 4-methyl-nicotinic acid as a white solid in 58.4percent yield.
58.4%
Stage #1: With water; sodium hydroxide In 1,4-dioxane at 50 - 60℃; for 1 h;
Stage #2: With hydrogenchloride In 1,4-dioxane; water
4-Methyl-nicotinic acid4-Methyl-nicotinic acid methyl ester (15 g, 0.1 mol) was added into the mixture of aqueous NaOH (2 M, 55 mL) and dioxane (100 mL), then the reactant was heated to 50-60 °C for 1 hour. The solvent was removed in vacuo. The residue was diluted with water (20 mL) and acidified by IN HC1 to PH~6, the solid formed was filtered and dried in vacuo to give 8.0 g of 4-methyl-nicotinic acid as a white solid in 58.4 percent yield.
58.4% With sodium hydroxide In 1,4-dioxane; water at 50 - 60℃; for 1 h; 4-Methyl-nicotinic acid methyl ester (15 g, 0.1 mol) was added into the mixture of aqueous NaOH (2 M, 55 mL) and dioxane (100 mL), then the reactant was heated to 50˜60° C. for 1 hour.
The solvent was removed in vacuo.
The residue was diluted with water (20 mL) and acidified by 1N HCl to PH≈6, the solid formed was filtered and dried in vacuo to give 8.0 g of 4-methyl-nicotinic acid as a white solid in 58.4 percent yield.
Reference: [1] Patent: US2011/224247, 2011, A1, . Location in patent: Page/Page column 12
[2] Patent: WO2011/110183, 2011, A1, . Location in patent: Page/Page column 31
[3] Patent: US2013/190499, 2013, A1, . Location in patent: Paragraph 0147
  • 2
  • [ 67-56-1 ]
  • [ 201230-82-2 ]
  • [ 3430-22-6 ]
  • [ 33402-75-4 ]
YieldReaction ConditionsOperation in experiment
66% With triethylamine In N,N-dimethyl-formamide at 70 - 80℃; for 10 h; 4-Methyl-nicotinic acid methyl ester
Triethylamine (45 g, 0.45 mol) was added into the mixture of compound 3-bromo-4-methyl-pyridine (25 g, 0.15 mol), Pd(OAc)2 (3.37 g, 0.015 mol) and dppf (6.19 g, 0.015 mol) in DMF/MeOH (150 mL/150 mL) dropwise.
Then the mixture was heated to 70~80° C. under 50 psi of CO for 10 hours.
The reaction mixture was cooled to room temperature and filtered.
The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate=10:1) to afford 15 g of 4-methyl-nicotinic acid methyl ester as a yellow oil in 66percent yield.
66% With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; triethylamine In N,N-dimethyl-formamide at 70 - 80℃; for 10 h; Trieithylamine (45 g, 0.45 mol) was added into the mixture of compound 3-bromo-4-methyl-pyridine (25 g, 0.15 mol), Pd(OAc)2 (3.37 g, 0.015 mol) and dppf (6.19 g, 0.015 mol) in DMF/MeOH (150 mL/150 mL) dropwise.
Then the mixture was heated to 70˜80° C. under 50 psi of CO for 10 hours.
The reaction mixture was cooled to room temperature and filtered.
The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate=10:1) to afford 15 g of 4-methyl-nicotinic acid methyl ester as a yellow oil in 66 percent yield.
51% With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; triethylamine In N,N-dimethyl-formamide at 140℃; Autoclave A metal reactor was charged with 3-bromo-4-methyl-pyridine (200 g, 0.116 mol) and a mixture of DMF/MeOH (1 L/1L). To this was added Et3N (400 g, 0.395 mol), palladium (II) acetate (8 g, 0.036 mol) and 1,1'- bis(diphenylphosphino)ferrocene (16 g, 0.029 mol). The reactor was closed and pressurized with CO gas (3 MPa) and the reaction mixture was stirred and heated overnight at 140 °C. The RM was cooled, filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (gradient eluent: EtO Ac/Petroleum ether from 1/1 to 1/0). The product fractions were collected and the solvent was evaporated to afford the desired intermediate 1 (90 g, 51percent).
51% With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; triethylamine In N,N-dimethyl-formamide at 140℃; Procedure b: A metal reactor was charged with 3-bromo-4-methyl-pyridine (200 g, 0.116 mol) and a mixture of DMF/MeOH (1 L/1L). To this was added Et3N (400 g, 0.395 mol), palladium (II) acetate (8 g, 0.036 mol) and 1 , l'-bis(diphenylphosphino)- ferrocene (16 g, 0.029 mol). The reactor was closed and pressurized with CO gas (3 MPa) and the reaction mixture was stirred and heated overnight at 140 °C. The RM was cooled, filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (gradient eluent: EtO Ac/Petroleum ether from 1/1 to 1/0). The product fractions were collected and the solvent was evaporated to afford the desired intermediate 1(90 g, 51percent).
51% With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; triethylamine In N,N-dimethyl-formamide at 140℃; Procedure b: A metal reactor was charged with 3-bromo-4-methyl-pyridine (200 g, 0.1 16 mol) and a mixture of DMF/MeOH (1 L/1L). To this was added Et3N (400 g, 0.395 mol), palladium (II) acetate (8 g, 0.036 mol) and 1 , -bis(diphenylphosphino)ferrocene (16 g, 0.029 mol). The reactor was closed and pressurized with CO gas (3 MP a) and the reaction mixture was stirred and heated overnight at 140 °C. The RM was cooled, filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (gradient eluent: EtO Ac/Petroleum ether from 1/1 to 1/0). The product fractions were collected and the solvent was evaporated to afford the desired intermediate 1 (90 g, 51percent).
51% With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; triethylamine In N,N-dimethyl-formamide at 140℃; A metal reactor was charged with 3-bromo-4-methyl-pyridine (200 g,0.116 mol) and a mixture of DMF/MeOH (1 L/1L). To this was added Et3N (400 g,0.395 mol), palladium (II) acetate (8 g, 0.036 mol) and 1,1’-bis(diphenylphosphino)ferrocene (16 g, 0.029 mol). The reactor was closed and pressurized with CO gas (3 MPa) and the reaction mixture was stirred and heated overnight at 140 °C. The RM was cooled, filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (gradient eluent:EtOAc/Petroleum ether from 1/1 to 1/0). The product fractions were collected and the solvent was evaporated to afford the desired intermediate 1 (90 g, 5 1percent).
51% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; palladium diacetate; triethylamine In N,N-dimethyl-formamide at 140℃; Procedure b: A metal reactor was charged with 3-bromo-4-methyl-pyridine (200 g, 0.116 mol) and a mixture of DMF/MeOH (1 L/1L). To this Et3N (400 g, 0.395 mol), palladium (II) acetate (8 g, 0.036 mol) and 1 , -bis(diphenylphosphino)ferrocene (16 g, 0.029 mol) were added. The reactor was closed and pressurized with CO gas (3 MP a) and the reaction mixture was stirred and heated overnight at 140 °C. The RM was cooled, filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (gradient eluent: EtO Ac/Petroleum ether from 1/1 to 1/0). The product fractions were collected and the solvent was evaporated to afford the desired intermediate 21 (90 g, 51percent).

Reference: [1] Patent: US2011/224247, 2011, A1, . Location in patent: Page/Page column 12
[2] Patent: WO2011/110183, 2011, A1, . Location in patent: Page/Page column 30
[3] Patent: US2013/190499, 2013, A1, . Location in patent: Paragraph 0146
[4] Patent: WO2017/76900, 2017, A1, . Location in patent: Page/Page column 19
[5] Patent: WO2018/83103, 2018, A1, . Location in patent: Page/Page column 27
[6] Patent: WO2018/83098, 2018, A1, . Location in patent: Page/Page column 37; 38
[7] Patent: WO2018/83101, 2018, A1, . Location in patent: Page/Page column 29; 30
[8] Patent: WO2018/154133, 2018, A1, . Location in patent: Page/Page column 53; 54
  • 3
  • [ 67-56-1 ]
  • [ 3222-50-2 ]
  • [ 33402-75-4 ]
YieldReaction ConditionsOperation in experiment
94% at 60℃; for 16 h; A solution of 4-methylnicotinic acid (2.00 g, 14.6 mmol) and concentrated H2SO4 (4.66 mL, 87.6 mmol) in MeOH (50 mL) was heated at about 60° C. for about 16 h. The reaction was concentrated under reduced pressure then partitioned with EtOAc (150 mL) and saturated aqueous NaHCO3 (200 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a constant weight to afford methyl 4-methylnicotinate as a clear liquid (2.30 g, 94percent): LC/MS (Table 2, Method a) Rt=1.67 min; MS m/z: 152 (M+H)+.
81% Reflux General procedure: To a solution of carboxylic acid 22 or 29–31 (0.1mol) in dry methanol (150mL), concd H2SO4 (20mL) was added. The mixture was refluxed for 15–20h (LC–MS control). The solvent was removed in vacuo, and the residue was dissolved in H2O. The solution was made alkaline with cold saturated aq K2CO3 and extracted with CH2Cl2 (4×50mL). The combined organic extracts were dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography (EtOAc as eluent) or distilled in vacuo to give 17–20.
Reference: [1] Patent: US2009/312338, 2009, A1, . Location in patent: Page/Page column 121
[2] Tetrahedron, 2013, vol. 69, # 33, p. 6799 - 6803
[3] Journal of the American Chemical Society, 1944, vol. 66, p. 1456,1458
[4] Canadian Journal of Chemistry, 1983, vol. 61, p. 2813 - 2820
[5] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 1913 - 1919
[6] Patent: WO2011/29046, 2011, A1, . Location in patent: Page/Page column 160; 161
  • 4
  • [ 67-56-1 ]
  • [ 94015-05-1 ]
  • [ 33402-75-4 ]
YieldReaction ConditionsOperation in experiment
83% Reflux 4-Methyl-3-pyridinecarboxylic acid hydrochloride (1 : 1) (40 g, 230.4 mmol) was added to a refluxing mixture of sulphuric acid (20 mL) and MeOH (400 mL). The mixture was re fluxed overnight, then it was evaporated and the resulting slurry was added to a cold solution of NaHCOs (64 g) in water (360 mL). The product was extracted with DCM and the organic layer was dried over MgSC^, filtered and evaporated, yielding intermediate 1 (28.70 g, 83percent).
83% Reflux Procedure a: 4-Methyl-3-pyridinecarboxylic acid hydrochloride (1 : 1) (40 g, 230.4 mmol) was added to a refluxing mixture of sulphuric acid (20 mL) and MeOH (400 mL). The mixture was refluxed overnight, then it was evaporated and the resulting slurry was added to a cold solution of NaHC03 (64 g) in water (360 mL). The product was extracted with DCM and the OL was dried over MgS04, filtered and evaporated, yielding intermediate 1 (28.70 g, 83percent).
83% Reflux Procedure a: 4-Methyl-3-pyridinecarboxylic acid hydrochloride (1 : 1) (40 g, 230.4 mmol) was added to a refluxing mixture of sulphuric acid (20 mL) and MeOH (400 mL). The mixture was refluxed overnight, then it was evaporated and the resulting slurry was added to a cold solution of NaHC03 (64 g) in water (360 mL). The product was extracted with DCM and the OL was dried over MgS04, filtered and evaporated, yielding intermediate 1 (28.70 g, 83percent).
83% Reflux 4-Methyl-3-pyridinecarboxylic acid hydrochloride (1:1) (40 g, 230.4mmol) was added to a refluxing mixture of sulphuric acid (20 mL) and MeOH (400mL). The mixture was refluxed overnight, then it was evaporated and the resulting slurry was added to a cold solution of NaHCO3 (64 g) in water (360 mL). The product was extracted with DCM and the OL was dried over MgSO4, filtered and evaporated, yielding intermediate 1 (28.70 g, 83percent).
83% With sulfuric acid In methanolReflux 4-Methyl-3-pyridinecarboxylic acid hydrochloride (1:1) (40 g, 230.4 mmol) was added to a refluxing mixture of sulphuric acid (20 mL) and MeOH (400mL). The mixture was refluxed overnight, then it was evaporated and the resulting slurry was added to a cold solution of NaHCO3 (64 g) in water (360 mL). The product was extracted with DCM and the OL was dried over MgSO4, filtered and evaporated, yielding intermediate 21(28.70 g, 83percent)

Reference: [1] Patent: WO2017/76900, 2017, A1, . Location in patent: Page/Page column 19
[2] Patent: WO2018/83103, 2018, A1, . Location in patent: Page/Page column 26-27
[3] Patent: WO2018/83098, 2018, A1, . Location in patent: Page/Page column 37; 38
[4] Patent: WO2018/83101, 2018, A1, . Location in patent: Page/Page column 29
[5] Patent: WO2018/154133, 2018, A1, . Location in patent: Page/Page column 53; 54
  • 5
  • [ 67-56-1 ]
  • [ 33402-75-4 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogenchloride In water at 20℃; for 21 h; Heating; Reflux Collection A: Preparation of 4-Me-101A 500-mL, three-neck, round-bottomed flask was charged with 4-methylnicotinic acid hydrochloride (7.4 g, 42.8 mmol) and hydrochloric acid in methanol (200 mL; 200 mg/mL). The mixture was heated at a gentle reflux for 5 h, then it was stirred for 16 h, while cooling to ambient temperature. An in-process HPLC was run after stirring for 15 h at ambient temperature [HPLC (Method A): 95.0percent (AUC), tR=1.84 min]. The solution was evaporated under reduced pressure to dryness to give 4-Me-101 (10.9 g, quantitative).
Reference: [1] Patent: US2010/93706, 2010, A1, . Location in patent: Page/Page column 34
  • 6
  • [ 3222-50-2 ]
  • [ 74-88-4 ]
  • [ 33402-75-4 ]
Reference: [1] Patent: EP1726590, 2006, A1, . Location in patent: Page/Page column 33-34
  • 7
  • [ 94015-05-1 ]
  • [ 33402-75-4 ]
Reference: [1] Journal of Pharmaceutical Sciences, 1992, vol. 81, # 10, p. 1015 - 1019
  • 8
  • [ 68981-86-2 ]
  • [ 33402-75-4 ]
Reference: [1] Journal of Pharmaceutical Sciences, 1992, vol. 81, # 10, p. 1015 - 1019
  • 9
  • [ 68981-84-0 ]
  • [ 33402-75-4 ]
Reference: [1] Journal of Pharmaceutical Sciences, 1992, vol. 81, # 10, p. 1015 - 1019
  • 10
  • [ 89808-30-0 ]
  • [ 33402-75-4 ]
Reference: [1] Canadian Journal of Chemistry, 1995, vol. 73, # 4, p. 531 - 538
  • 11
  • [ 67-56-1 ]
  • [ 155136-54-2 ]
  • [ 33402-75-4 ]
Reference: [1] Journal of Pharmaceutical Sciences, 1992, vol. 81, # 10, p. 1015 - 1019
  • 12
  • [ 5444-01-9 ]
  • [ 33402-75-4 ]
Reference: [1] Tetrahedron, 2013, vol. 69, # 33, p. 6799 - 6803
  • 13
  • [ 93-60-7 ]
  • [ 676-58-4 ]
  • [ 1885-14-9 ]
  • [ 33402-75-4 ]
  • [ 5470-70-2 ]
Reference: [1] Heterocycles, 1984, vol. 22, # 1, p. 151 - 157
[2] Heterocycles, 1984, vol. 22, # 1, p. 151 - 157
  • 14
  • [ 67-56-1 ]
  • [ 93-60-7 ]
  • [ 33402-75-4 ]
  • [ 5470-70-2 ]
  • [ 67367-26-4 ]
  • [ 26218-80-4 ]
Reference: [1] Chemistry Letters, 1980, p. 131 - 134
[2] Chemistry Letters, 1980, p. 131 - 134
[3] Bulletin of the Chemical Society of Japan, 1981, vol. 54, # 6, p. 1761 - 1766
  • 15
  • [ 93-60-7 ]
  • [ 676-58-4 ]
  • [ 1885-14-9 ]
  • [ 33402-75-4 ]
  • [ 5470-70-2 ]
Reference: [1] Heterocycles, 1984, vol. 22, # 1, p. 151 - 157
[2] Heterocycles, 1984, vol. 22, # 1, p. 151 - 157
  • 16
  • [ 67-56-1 ]
  • [ 93-60-7 ]
  • [ 33402-75-4 ]
  • [ 5470-70-2 ]
  • [ 67367-26-4 ]
  • [ 26218-80-4 ]
Reference: [1] Chemistry Letters, 1980, p. 131 - 134
[2] Chemistry Letters, 1980, p. 131 - 134
[3] Bulletin of the Chemical Society of Japan, 1981, vol. 54, # 6, p. 1761 - 1766
  • 17
  • [ 67-56-1 ]
  • [ 93-60-7 ]
  • [ 33402-75-4 ]
  • [ 5470-70-2 ]
  • [ 67367-26-4 ]
  • [ 26218-80-4 ]
Reference: [1] Chemistry Letters, 1980, p. 131 - 134
[2] Chemistry Letters, 1980, p. 131 - 134
[3] Bulletin of the Chemical Society of Japan, 1981, vol. 54, # 6, p. 1761 - 1766
  • 18
  • [ 33402-75-4 ]
  • [ 4664-27-1 ]
Reference: [1] Canadian Journal of Chemistry, 1983, vol. 61, p. 2813 - 2820
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