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Product Details of [ 6975-44-6 ]

CAS No. :6975-44-6 MDL No. :MFCD00834976
Formula : C8H9NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :QDHHLXABEXNRJX-UHFFFAOYSA-N
M.W :183.16 Pubchem ID :54676837
Synonyms :

Calculated chemistry of [ 6975-44-6 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.25
Num. rotatable bonds : 3
Num. H-bond acceptors : 5.0
Num. H-bond donors : 2.0
Molar Refractivity : 44.37
TPSA : 79.65 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.53 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.68
Log Po/w (XLOGP3) : 1.25
Log Po/w (WLOGP) : 0.67
Log Po/w (MLOGP) : -0.08
Log Po/w (SILICOS-IT) : 0.58
Consensus Log Po/w : 0.82

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.91
Solubility : 2.27 mg/ml ; 0.0124 mol/l
Class : Very soluble
Log S (Ali) : -2.52
Solubility : 0.552 mg/ml ; 0.00301 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.36
Solubility : 8.07 mg/ml ; 0.0441 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.93

Safety of [ 6975-44-6 ]

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 [ 6975-44-6 ]

* 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 [ 6975-44-6 ]
  • Downstream synthetic route of [ 6975-44-6 ]

[ 6975-44-6 ] Synthesis Path-Upstream   1~28

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Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
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Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
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  • [ 405230-82-2 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
  • 4
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  • [ 52559-11-2 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1948, vol. 67, p. 29,37
  • 5
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  • [ 166526-03-0 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
  • 6
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  • [ 73027-79-9 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
[2] Tetrahedron Letters, 2011, vol. 52, # 4, p. 512 - 514
[3] Patent: WO2014/52365, 2014, A1,
[4] Antimicrobial Agents and Chemotherapy, 2016, vol. 60, # 8, p. 4442 - 4452
  • 7
  • [ 6975-44-6 ]
  • [ 5466-62-6 ]
Reference: [1] Gazzetta Chimica Italiana, 1898, vol. 28 I, p. 489[2] Chemische Berichte, 1898, vol. 31, p. 1686
  • 8
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  • [ 40296-46-6 ]
YieldReaction ConditionsOperation in experiment
90% for 2 h; Reflux Ethyl 4,6-dihydroxynicotinate (60 g, 0.328 mol) was added slowly to POCl3 (500 mL), then heated to reflux for 2 h.
The resulting mixture was distilled under reduced pressure to remove excess POCl3.
The residue was poured into ice water and stirred for 30 minutes before extracting with EtOAc (3*).
The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give ethyl 4,6-dichloronicotinate (65 g, 90percent, yield).
1H NMR (300 MHz, DMSO-d6): δ 8.80 (s, 1H), 7.95 (s, 1H), 4.34 (q, J=6.9 Hz, 2H), 1.31 (t, J=6.9 Hz, 3H); MS (ESI) m/z: 220.1 [M+H]+.
90% for 2 h; Reflux Ethyl 4,6-dihydroxynicotinate (60 g, 0.328 mol) was added slowly to POCb (500mL ), then heated to reflux for 2 h. The resulting mixture was distilled under reduced pressureto remove excess POCb. The residue was poured into ice water and stirred for 30 minutesbefore extracting with EtOAc (3x). The combined extracts were washed with brine, dried(MgS04) and concentrated in vacuo to give ethyl 4,6-dichloronicotinate (65 g, 90percent, yield).1H NMR (300 MHz, DMSO-d6): 8 8.80 (s, 1 H), 7.95 (s, 1 H), 4.34 (q, J = 6.9 Hz, 2 H), 1.31(t, J = 6.9 Hz, 3 H); MS (ESI) m/z: 220.1 [M+Ht.
79% at 110℃; for 2.5 h; (Wallace, E., et.al, ibid.)'. A stirred suspension of compound ii (1.40 g, 7.67 mmol) in phosphorus (V) oxychloride (15 mL) was heated to 110°C for 2.5 h with a guard tube (CaCl2) fitted. The reaction mixture was cooled to room temperature, reduced in vacuo and the resulting dark brown residue taken up in a small volume of DCM (~ 5 mL) and transferred dropwise onto a slurry of ice in water (250 mL) whilst stirring vigorously. The aqueous mixture was extracted with EtOAc (3 x 100 mL), the organic extracts combined, dried (MgS04) and evaporated to dryness to afford the crude product as an orange gum. Column chromatography (S1O2), eluting with 15: 1 Hexanes-EtOAc, afforded compound iii. (1.33 g, 6.14 mmol, 79percent) as a colourless oil; [M+H]+ m/z = 220.0.
79% at 110℃; for 2.5 h; A stirred suspension of compound 35 (1.40 g, 7.67 mmol) in phosphorus (V) oxychloride (15 mL) was heated to 110 °C for 2.5 h with a guard tube (CaCl2) fitted. The reaction mixture was cooled to room temperature, reduced in vacuo and the resulting dark brown residue taken up in a small volume of DCM (ca. 5 mL) and transferred dropwise onto vigourously stirred ice / water (250 mL). The aqueous mixture was extracted with EtOAc (3 × 100 mL). Combined extracts were dried (MgSO4) and reduced in vacuo to give the crude product as an orange gum. Column chromatography (SiO2), eluting with 15:1 Petrol–EtOAc, afforded the title compound17 (1.33 g, 6.14 mmol, 79percent) as a colourless oil; Rf 0.63 (8:1 Petrol–EtOAc); (Found: C, 43.9; H, 3.15; N, 6.2; C8H7Cl2NO2 requires C, 43.7; H, 3.20; N, 6.4percent); δH (300 MHz, DMSO-d6); 8.82 (1H, s, 2-H), 7.99 (1H, s, 5-H), 4.37 (2H, q, J 6.9, 3-CO2CH2CH3), 1.33 (3H, t, J 6.9, 3-CO2CH2CH3); δC (75 MHz, DMSO-d6); 163.0 (3-CO2CH2CH3), 153.9 (6-C), 152.0 (2-C), 144.9 (4-C), 126.2 (3-C), 125.6 (5-C), 62.4 (3-CO2CH2CH3), 14.3 (3-CO2CH2CH3); νmax/cm-1 (solid); 3091, 2984, 1736 and 1567; m/z (ES) 220.0 (100percent, MH+); (Found MH+, 219.9924. C8H7Cl2NO2 requires MH 219.9927); LC-MS; RT= 1.87min, m/z (ES+) found MH+, 220.0
78% at 0 - 80℃; for 20 h; POCl3 (100 mL, 1092 mmol) was added to 4,6-dihydroxynicotinic acid ethyl ester (J. Heterocyclic Chem. 1983, 20, 1363) (20.0 g, 109 mmol).
The resulting suspension was cooled to 0° C. and triethylamine (15.2 mL, 109 mmol) was added dropwise at such a rate as to maintain the internal reaction mixture temperature below 25° C.
Upon completion of addition, the reaction mixture was warmed to room temperature and then to 80° C.
After 4 hours, the reaction mixture was cooled to room temperature and stirred for 16 hours.
The reaction mixture was carefully poured onto 2 L crushed ice.
The mixture was extracted with EtOAc and diethyl ether.
The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated.
The dark brown liquid was purified by passing through a plug of silica gel (CH2Cl2) to give the desired product (22) as a low melting yellow solid (18.7 g, 78percent).
57% at 0 - 110℃; for 4 h; To ethyl 4,6-dihydroxynicotinate (75 g, 1.0 eq) in a round bottomed flask at 0°C, phosphorus oxychloride (500 mL) was added drop wise with stirring and the contents heated at 110°C for 4 h while monitoring by TLC. After TLC showed completion of starting material, the excess phosphorus oxychloride was removed under vacuum and the residue quenched with ice cold water (50 mL) at 0°C. The mixture was extracted with EtOAc (3 x 500 mL) and combined organic extract was washed with saturated NaHC03 solution (100 mL), brine (100 mL), dried over anhydrous sodium sulphate, filtered and concentrated. The resulting crude material was purified by column chromatography (silica gel 60-120) using EtOAc in hexane as eluent. The desired product was eluted using 5percent EtOAc in hexane and the fractions with pure product were concentrated to obtain ethyl 4,6-dichloronicotinate as off-white solid (41.9 g, 57percent). 1H NMR (400 MHz, CDC13): δ 8.845 (s, 1H), 7.475 (s, 1H), 4.466 (q, 2H), 1.424 (t, 3H).
8.7 g at 110℃; for 2 h; A mixture of scheme 1 compound 2 (8.01 g, 43.7 mmol) and POCl3 (70 mL, 751.1 mmol) was stirred at 110 °C for 2h. TLC showed the starting material was consumed completely. After cooling down, most of POCl3 was removed under vacuum. The residue was mixed with ice-water, and neutralized with sodium carbonate solution. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous Na2S04 , concentrated to give scheme 1 compound 3 (8.7 g) as a brown solid which was used in the next step immediately without further purification.

Reference: [1] European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1487 - 1495
[2] European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1487 - 1495
[3] European Journal of Medicinal Chemistry, 2016, vol. 119, p. 17 - 33
[4] Patent: US8461179, 2013, B1, . Location in patent: Page/Page column 66
[5] Patent: WO2013/184119, 2013, A1, . Location in patent: Paragraph 0204
[6] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 3, p. 403 - 427
[7] Patent: WO2013/91011, 2013, A1, . Location in patent: Page/Page column 66; 67
[8] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 31 - 38
[9] Patent: US2005/49419, 2005, A1, . Location in patent: Page/Page column 24
[10] Tetrahedron Letters, 2011, vol. 52, # 4, p. 512 - 514
[11] Antimicrobial Agents and Chemotherapy, 2016, vol. 60, # 8, p. 4442 - 4452
[12] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 7, p. 2355 - 2361
[13] Patent: WO2015/38417, 2015, A1, . Location in patent: Page/Page column 76
[14] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
[15] Journal of Medicinal Chemistry, 2007, vol. 50, # 21, p. 5090 - 5102
[16] Patent: US2004/142930, 2004, A1,
[17] Patent: US2005/54701, 2005, A1,
[18] Patent: WO2008/51757, 2008, A1, . Location in patent: Page/Page column 31-32
[19] Patent: WO2005/34869, 2005, A2, . Location in patent: Page/Page column 39-40
[20] Patent: US2007/60577, 2007, A1, . Location in patent: Page/Page column 30; 43
[21] Patent: EP1847535, 2007, A1, . Location in patent: Page/Page column 122
[22] Patent: WO2011/97526, 2011, A1, . Location in patent: Page/Page column 30
[23] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 21, p. 6348 - 6352
[24] Patent: WO2014/52365, 2014, A1, . Location in patent: Page/Page column 165-166
[25] European Journal of Medicinal Chemistry, 2014, vol. 87, p. 52 - 62
[26] Patent: WO2007/136465, 2007, A2, . Location in patent: Page/Page column 33
[27] Patent: WO2009/105712, 2009, A1, . Location in patent: Page/Page column 35-36
[28] Patent: WO2005/34869, 2005, A2, . Location in patent: Page/Page column 39-40
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Reference: [1] Patent: EP1364950, 2003, A1, . Location in patent: Page/Page column 39
  • 10
  • [ 122-51-0 ]
  • [ 105-50-0 ]
  • [ 6975-44-6 ]
YieldReaction ConditionsOperation in experiment
81.6%
Stage #1: at 120℃; for 2 h;
Stage #2: With ammonia In water at 0℃; for 1 h;
Diethyl 3-oxopentanedioate (1, 10.00 g, 49.45 mmol), triethyl orthoformate (7.33 g, 49.45 mmol) and acetic anhydride (10.10 g, 98.93 mmol) were combined and stirred at 120 °C for 2 h then allowed to cool to ambient temperature. The volatiles were removed under vacuum. The residue was then cooled in an ice bathand aqueous ammonia (25 mL) was added in portions with stirring. The reaction mixture was stirred at 0 C for 1 h and was then acidified with 2N hydrochloric acid to pH < 5. The precipitate was collected by filtration and allowed to dry to provide 2 as yellowsolid. Yield: 81.6percent. Mp: 207-210 °C. 1H NMR (400 MHz, DMSO-d6,ppm) d: 11.78 (s, br, 1H), 10.74 (s, br, 1H), 8.02 (s, 1H), 5.61 (s, 1H), 4.27 (q, 2H, J 7.1), 1.29 (t, 3H, J 7.1). 13C NMR (100 MHz, DMSOd6,ppm) d: 166.57, 166.40, 164.00, 142.97, 100.44, 98.96, 61.35, 14.46.
55.7%
Stage #1: at 130℃; for 3 h;
Stage #2: With ammonium hydroxide In water at 20℃; for 0.5 h;
Step 1:
Preparation of ethyl 4,6-dihydroxy-5-nitronicotinate (14)
A mixture of diethyl 1,3-acetonedicarboxylate (80.0 g, 0.40 mol), acetic anhydride (80.8 g, 0.79 mol) and ethyl orthoformate (59.2 g, 0.40 mol) was heated to 130 °C for 3 h.
Volatile components were removed under reduced pressure and the remaining mixture was treated with aqueous ammonia 160 ml.
The resulting mixture was stirred for another 30 min at ambient temperature.
Subsequently the pH of the mixture was adjusted to 2 with 6 mol/L hydrochloric acid aqueous.
The solid was filtered off, washed with cold water and dried in vacuum overnight.
Toluene (120 ml) was then added to the crude product before the mixture was stirred at 0 °C for 30 min, filtered and dried to give 14 40.4 g as red solid, yield 55.7percent.
Mp 214-216 °C. 1H NMR (300 MHz, CDCl3), δ (ppm): 8.21 (s, 1H), 5.95 (s, 1H), 4.37 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). MS (ESI+) m/z: 184 [M+H]+.
50%
Stage #1: at 120℃; for 2 h;
Stage #2: With ammonia In water at 20℃; for 0.5 h;
A mixture of 5.0 g (24.73 mmol) diethyl 1,3-acetonedicarboxylate, 5.05 g (49.45 mmol) acetic anhydride and 3.7 g (24.73 mmol) ethyl orthoformate was heated to 12O0C for 2 hours. Volatile components were removed under reduced pressure and the remaining mixture was treated with 10 ml of aqueous ammonia (25percent). The mixture was stirred for 30 minutes at room temperature. Subsequently the pH of the mixture was adjust to pH 2 with aqueous HCl (2N). The solid was filtered off, washed with cold water and dried. 8 ml of toluene were added to the crude product, the mixture was stirred at O0C for 30 minutes and then filtered and dried to give 2.26 g (50percent) of a red solid. 1H-NMR (DMSOd6): 11.77 (s, br, IH); 10.74 (s, br, IH); 8.01 (s, IH); 5.60 (s, IH); 4.26 (q, 2H); 1.28 (t, 3H).
50%
Stage #1: at 120℃; for 2 h;
Stage #2: at 20℃; for 0.5 h;
G] Preparation of compound 5 -G A mixture of 5.0 g (24.73 mmol) diethyl 1,3-acetonedicarboxylate, 5.05 g (49.45 mmol) acetic anhydride and 3.7 g (24.73 mmol) ethyl orthoformate is heated to 1200C for 2 hours. Volatile components are removed under reduced pressure and the remaining mixture is treated with 10 ml of aqueous ammonia (25percent). The mixture is stirred for 30 minutes at room temperature. Subsequently the pH of the mixture is adjust to pH 2 with aqueous HCl (2N). The solid is filtered off, washed with cold water and dried. 8 ml of toluene are added to the crude product, the mixture is stirred at 00C for 30 minutes and then filtered and dried to give 2.26 g (50percent) of a red solid.1H-NMR (DMSO-de): 11.77 (s, br, IH); 10.74 (s, br, IH); 8.01 (s, IH); 5.60 (s, IH); 4.26 (q, 2H); 1.28 (t, 3H).
50%
Stage #1: at 120℃; for 2 h;
Stage #2: With ammonia In water at 20℃; for 0.5 h;
A mixture of 5.0 g (24.73 mmol) diethyl 1,3-acetonedicarboxylate, 5.05 g (49.45 mmol) acetic anhydride and 3.7 g (24.73 mmol) ethyl orthoformate was heated to 12O0C for 2 hours. Volatile components were removed under reduced pressure and the remaining mixture was treated with 10 ml of aqueous ammonia (25percent). The mixture was stirred for 30 minutes at room temperature. Subsequently the pH of the mixture was adjust to pH 2 with aqueous HCl (2N). The solid was filtered off, washed with cold water and dried. 8 ml of toluene were added to the crude product, the mixture was stirred at O0C for 30 minutes and then filtered and dried to give 2.26 g (50percent) of a red solid. 1H-NMR (DMSOd6): 11.77 (s, br, IH); 10.74 (s, br, IH); 8.01 (s, IH); 5.60 (s, IH); 4.26 (q, 2H); 1.28 (t, 3H).
22%
Stage #1: at 120℃; for 1.5 h;
Stage #2: With ammonium hydroxide In water at 0℃; for 1 h;
Stage #3: With hydrogenchloride In water
A mixture of scheme 1 compound 1 (50.0 g, 247.5 mmol), triethyl orthofomate (40.3 g, 272.3 mmol) and acetic anhydride (50.5 g, 495.0 mmol) was heated at 120 °C for 1.5h with vigorous stirring. The dark yellow solution was cooled in an ice bath, and mixed with ammonia (20 mL, 30percent water solution). The resulting mixture was stirred at 0 °C for lh. A yellow solid formed in the mixture. After the mixture was acidified with 2N HC1 to pH = 5, a white solid formed. The mixture was filtered, washed with water and air dried to give scheme 1 compound 2 (10.0 g, yield: 22.0percent) as a white solid. 1H NMR (400 MHz, MeOD): δ 8.16 (s, 1H, ArH), 5.79 (s, 1H, ArH), 4.38 (q, J= 7.2 Hz, 2H, CH2), 1.37 (t, J= 7.2 Hz, 3H, CH3).

Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 87, p. 52 - 62
[2] Antimicrobial Agents and Chemotherapy, 2016, vol. 60, # 8, p. 4442 - 4452
[3] European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1487 - 1495
[4] European Journal of Medicinal Chemistry, 2016, vol. 119, p. 17 - 33
[5] Tetrahedron Letters, 2011, vol. 52, # 4, p. 512 - 514
[6] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 20, p. 6551 - 6559
[7] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 3, p. 403 - 427
[8] Patent: WO2008/17696, 2008, A1, . Location in patent: Page/Page column 50-51
[9] Patent: WO2009/106419, 2009, A1, . Location in patent: Page/Page column 78
[10] Patent: WO2008/17696, 2008, A1, . Location in patent: Page/Page column 50-51
[11] Patent: WO2014/52365, 2014, A1, . Location in patent: Page/Page column 165-166
[12] Patent: WO2008/51757, 2008, A1, . Location in patent: Page/Page column 31
[13] Patent: WO2005/34869, 2005, A2, . Location in patent: Page/Page column 39
[14] Patent: WO2011/97526, 2011, A1, . Location in patent: Page/Page column 30
[15] Patent: WO2007/136465, 2007, A2, . Location in patent: Page/Page column 33
[16] Patent: WO2009/105712, 2009, A1, . Location in patent: Page/Page column 35-36
[17] Patent: WO2005/34869, 2005, A2, . Location in patent: Page/Page column 39
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YieldReaction ConditionsOperation in experiment
55% With ammonia; acetic anhydride In water at 0 - 120℃; for 20 h; Inert atmosphere (E. Wallace, B. Hurley, H. W. Yang, J. Lyssikatos and J. Blake, Int. Pat. App. WO200523759, 2005): Trimethylorthoformate (5.95 mL, 54.4 mmol) was added to a solution of diethyl 1,3-acetonedicarboxylate (i) (8.98 mL, 49.5 mmol) in acetic anhydride (9.34 mL, 99.0 mmol). The reaction mixture was heated under N2(g) to 120°C for 2 h, cooled to room temperature and the excess solvent removed in vacuo. The resulting dark orange residue was cooled to 0°C and treated with an aqueous solution of ammonia (33percent, 4 mL) followed by water (15 mL). The mixture was stirred at room temperature for 18 h and the resulting heavy tan precipitate filtered, washed with water (20 mL) and air dried to give compound ii. (5.00 g, 27.3 mmol, 55percent) as a light tan solid, [M+H]+ m/z = 184.1.
55%
Stage #1: at 120℃; for 2 h; Inert atmosphere
Stage #2: With ammonia In water; acetic anhydride at 0 - 20℃; for 18 h; Inert atmosphere
Trimethylorthoformate (5.95 mL, 54.4 mmol) was added to a solution of diethyl 1,3-acetonedicarboxylate 34 (8.98 mL, 49.5 mmol) in acetic anhydride (9.34 mL, 99.0 mmol). The reaction mixture was heated under N2(g) to 120 °C for 2 h, cooled to room temperature and the excess solvent removed in vacuo. The resulting dark orange residue was cooled to 0 °C and treated with an aqueous solution of ammonia (33percent, 4 mL) followed by water (15 mL). The mixture was stirred at room temperature for 18 h and the resulting heavy tan precipitate filtered, washed with water (20 mL) and air dried to give the title compound17 (5.00 g, 27.3 mmol, 55percent) as a light tan solid, m.p. 200-204 °C (from EtOH–water, lit.18 m.p. 213 °C); Rf 0.27 (EtOAc); δH (300 MHz, DMSO-d6); 8.02 (1H, s, 2-H), 5.60 (1H, s, 5-H), 4.27 (2H, q, J 7.2, 3-CO2CH2CH3), 1.28 (3H, t, J 7.2, 3-CO2CH2CH3); δC (75 MHz, DMSO-d6); 166.4 (3-CO2CH2CH3), 166.3 (6-C), 163.9 (4-C), 143.0 (2-C), 100.4 (5-C), 98.8 (3-C), 61.2 (3-CO2CH2CH3), 14.4 (3-CO2CH2CH3); νmax/cm-1 (solid); 3053, 2689, and 1658; m/z (ES) 184.1 (100percent, MH+); (Found MH+, 184.0606. C8H9NO4 requires MH 184.0610); LC-MS; RT= 1.23min, m/z (ES+) found MH+, 184.1.
Reference: [1] Patent: WO2013/91011, 2013, A1, . Location in patent: Page/Page column 66; 67
[2] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 31 - 38
[3] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 7, p. 2355 - 2361
[4] Patent: US2007/60577, 2007, A1, . Location in patent: Page/Page column 30; 43
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  • [ 6975-44-6 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: at 120℃; for 2 h;
Stage #2: With ammonia In dichloromethane at 0 - 20℃;
3-Oxo-pentanedioic acid diethyl ester (101 g, 0.5 mmol), triethyl orthoformate (81.4 g, 0.55 mol) and acetic anhydride (102 g, 1 mol) were combined and heated to 120° C. for 2 h.
The resulting mixture was cooled to RT and dissolved in DCM (1 L).
After further cooling to 0° C., ammonia (30percent, 80 mL) was added and the reaction mixture was allowed to warm to RT overnight.
The product was extracted with water (2*) and the aqueous layer was acidified to pH 5 with conc. HCl.
The precipitate was collected by filtration to afford ethyl 4,6-dihydroxynicotinate (60.0 g, 60percent yield).
1H NMR (400 MHz, DMSO-d6): δ 7.99 (s, 1H), 5.58 (s, 1H), 4.23 (q, J=6.8, 14.0 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 184.1 [M+H]+.
Reference: [1] Patent: US8461179, 2013, B1, . Location in patent: Page/Page column 66
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YieldReaction ConditionsOperation in experiment
82.8%
Stage #1: at 120℃; for 3 h;
Stage #2: at 0℃; for 1 h;
Diethyl 1,3-acetonedicarboxylate (2 x 50 g, 1.0 eq, Aldrich) was added in portions to acetic anhydride (2 x 58.6 g, 2.0 eq) in a round bottomed flask. To this solution, triethyl orthoformate (2 x 51 g, 1.2 eq) was added slowly and the contents heated under a reflux condenser at 120°C for 3 h. The contents were cooled to 0°C and 25percent aqueous ammonia was added slowly while stirring. The mixture continued stirring for 1 h at 0°C and the mixture acidified with 3N HC1 solution. The solid that separated out was filtered and dried under vacuum to obtain product as white solid ethyl 4,6-dihydroxynicotinate (75.1 g, 82.8percent). LCMS: Purity: 99.84percent, MS: 184.18 (M+H).
Reference: [1] Patent: WO2015/38417, 2015, A1, . Location in patent: Page/Page column 75; 76
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  • [ 108-24-7 ]
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YieldReaction ConditionsOperation in experiment
60% at 120℃; for 2 h; Example C3: 3-0xo-pentanedioic acid diethyl ester (101 g, 0.5 mmol), triethylorthoformate (81.4 g, 0.55mol) and acetic anhydride (102 g, 1 mol) were combined andheated to 120°C for 2 h. The resulting mixture was cooled toRT and dissolved in DCM (1L). After further cooling to 0°C, ammonia (30percent, 80 mL) was added and the reaction mixturewas allowed to warm to RT overnight. The product was extracted with water (2x) and theaqueous layer was acidified to pH 5 with cone. HCl. The precipitate was collected byfiltration to afford ethyl 4,6-dihydroxynicotinate (60.0 g, 60percent yield). 1H NMR (400 MHz,DMSO-d6): 8 7.99 (s, 1 H), 5.58 (s, 1 H), 4.23 (q, J = 6.8, 14.0 Hz, 2 H), 1.25 (t, J = 7.2 Hz, 3H); MS (ESI) mlz: 184.1 [M+Ht.
Reference: [1] Patent: WO2013/184119, 2013, A1, . Location in patent: Paragraph 0203
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Reference: [1] European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1487 - 1495
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  • [ 570-08-1 ]
  • [ 64-19-7 ]
  • [ 122-51-0 ]
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Reference: [1] Gazzetta Chimica Italiana, 1898, vol. 28 I, p. 482,484, 487[2] Chemische Berichte, 1898, vol. 31, p. 1683,1684, 1685
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  • [ 89282-12-2 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1948, vol. 67, p. 29,37
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  • [ 5975-12-2 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1948, vol. 67, p. 29,37
  • 19
  • [ 6975-44-6 ]
  • [ 6317-97-1 ]
YieldReaction ConditionsOperation in experiment
77.6% at 0 - 20℃; Step 2:
Preparation of ethyl 4,6-dichloro-5-nitronicotinate (15)
To a cooled solution of ethyl 4,6-dihydroxynicotinate 14 (40.0 g, 0.22 mol) in concentrated sulfuric acid (330 ml), fuming nitric acid (12.7 ml) was added by dropwise under 0 °C.
The mixture was stirred for 1 h and then allowed to stir at room temperature.
After stirring for another 1 h the mixture was poured into ice-water.
The mixture was stirred vigorously for 10 min and the precipitate was collected by filtration, washed with water and dried in vacuum to give 15 38.7 g as light yellow solid, yield 77.6percent.
Mp 238-240 °C. 1H NMR (300 MHz, DMSO-d6), δ (ppm): 8.22 (s, 1H), 4.31 (q, J = 7.0 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H). MS (ESI(+) 70 V) m/z: 227 [M-H]-.
75% With nitric acid; acetic anhydride In water at 60 - 90℃; for 20 h; To a solution of 2.34 g (12.78 mmol) of the product of example 8 step A in 9 ml of acetic acid was added dropwise at 6O0C 1.24 g nitric acid (65percent; 12.78 mmol). The mixture was stirred at 9O0C for 20 hours. The reaction mixture was cooled to O0C, filtered and the filter cake was washed with cold water. The solid was dried to give 2.2 g (75percent) of the desired product as light yellow crystals. MS (ESI): 229.0 ([MH]+).
75% at 60 - 90℃; H] Preparation of compound 5 -H To a solution of 2.34 g (12.78 mmol) of compound 5-G in 9 ml of acetic acid is added dropwise at 600C 1.24 g nitric acid (65percent; 12.78 mmol). The mixture is stirred at 900C for 20 hours. The reaction mixture is cooled to 00C, filtered and the filter cake is washed with cold water. The solid is dried to give 2.2 g (75percent) of the desired product as light yellow crystals.MS (ESI): 229.0 ([MH]+).
75% With nitric acid; acetic anhydride In water at 60 - 90℃; for 20 h; To a solution of 2.34 g (12.78 mmol) of the product of example 8 step A in 9 ml of acetic acid was added dropwise at 6O0C 1.24 g nitric acid (65percent; 12.78 mmol). The mixture was stirred at 9O0C for 20 hours. The reaction mixture was cooled to O0C, filtered and the filter cake was washed with cold water. The solid was dried to give 2.2 g (75percent) of the desired product as light yellow crystals. MS (ESI): 229.0 ([MH]+).

Reference: [1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 20, p. 6551 - 6559
[2] Patent: WO2008/17696, 2008, A1, . Location in patent: Page/Page column 51
[3] Patent: WO2009/106419, 2009, A1, . Location in patent: Page/Page column 79
[4] Patent: WO2008/17696, 2008, A1, . Location in patent: Page/Page column 51
[5] Recueil des Travaux Chimiques des Pays-Bas, 1948, vol. 67, p. 29,37
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Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
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Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1948, vol. 67, p. 29,37
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  • [ 154012-15-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 20, p. 6551 - 6559
[2] Patent: WO2009/106419, 2009, A1,
[3] Patent: WO2008/17696, 2008, A1,
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Reference: [1] Patent: WO2015/38417, 2015, A1,
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  • [ 846036-96-2 ]
Reference: [1] Patent: WO2014/52365, 2014, A1,
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  • [ 380626-81-3 ]
Reference: [1] Patent: WO2014/52365, 2014, A1,
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  • [ 1206979-33-0 ]
Reference: [1] Patent: WO2015/38417, 2015, A1,
[2] Patent: WO2015/38417, 2015, A1,
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Reference: [1] Patent: WO2015/38417, 2015, A1,
[2] Patent: WO2015/38417, 2015, A1,
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Reference: [1] Patent: WO2014/52365, 2014, A1,
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