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[ CAS No. 55-22-1 ] {[proInfo.proName]}

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Chemical Structure| 55-22-1
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Product Citations      Expand+

Anushree Mondal ; Pronay Roy ; Jaclyn Carrannatto , et al. DOI: PubMed ID:

Abstract: The prenylated-flavin mononucleotide-dependent decarboxylases (also known as UbiD-like enzymes) are the most recently discovered family of decarboxylases. The modified flavin facilitates the decarboxylation of unsaturated carboxylic acids through a novel mechanism involving 1,3-dipolar cyclo-addition chemistry. UbiD-like enzymes have attracted considerable interest for biocatalysis applications due to their ability to catalyse (de)carboxylation reactions on a broad range of aromatic substrates at otherwise unreactive carbon centres. There are now ∼35[thin space (1/6-em)]000 protein sequences annotated as hypothetical UbiD-like enzymes. Sequence similarity network analyses of the UbiD protein family suggests that there are likely dozens of distinct decarboxylase enzymes represented within this family. Furthermore, many of the enzymes so far characterized can decarboxylate a broad range of substrates. Here we describe a strategy to identify potential substrates of UbiD-like enzymes based on detecting enzyme-catalysed solvent deuterium exchange into potential substrates. Using ferulic acid decarboxylase (FDC) as a model system, we tested a diverse range of aromatic and heterocyclic molecules for their ability to undergo enzyme-catalysed H/D exchange in deuterated buffer. We found that FDC catalyses H/D exchange, albeit at generally very low levels, into a wide range of small, aromatic molecules that have little resemblance to its physiological substrate. In contrast, the sub-set of aromatic carboxylic acids that are substrates for FDC-catalysed decarboxylation is much smaller. We discuss the implications of these findings for screening uncharacterized UbiD-like enzymes for novel (de)carboxylase activity.

Purchased from AmBeed: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;

Hegde, Pooja ; Boshoff, Helena I. M. ; Rusman, Yudi , et al. DOI: PubMed ID:

Abstract: Isoniazid (INH) remains a cornerstone for treatment of drug susceptible tuberculosis (TB), yet the quant. structure-activity relationships for INH are not well documented in the literature. In this paper, we have evaluated a systematic series of INH analogs against contemporary Mycobacterium tuberculosis strains from different lineages and a few non-tuberculous mycobacteria (NTM). Deletion of the pyridyl nitrogen atom, isomerization of the pyridine nitrogen to other positions, replacement of the pyridine ring with isosteric heterocycles, and modification of the hydrazide moiety of INH abolishes antitubercular activity. Similarly, substitution of the pyridine ring at the 3-position is not tolerated while substitution at the 2-position is permitted with 2-methyl-INH 9 displaying antimycobacterial activity comparable to INH. To assess the specific activity of this series of INH analogs against mycobacteria, we assayed them against a panel of gram-pos. and gram-neg. bacteria, as well as a few fungi. As expected INH and its analogs display a narrow spectrum of activity and are inactive against all non-mycobacterial strains evaluated, except for 4, which has modest inhibitory activity against Cryptococcus neoformans. Our findings provide an updated anal. of the structure-activity relationship of INH that we hope will serve as useful resource for the community.

Keywords: Isoniazid ; SAR

Purchased from AmBeed: ; ; ; ; 54-92-2 ; ; ;

Product Details of [ 55-22-1 ]

CAS No. :55-22-1 MDL No. :MFCD00006429
Formula : C6H5NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :TWBYWOBDOCUKOW-UHFFFAOYSA-N
M.W : 123.11 Pubchem ID :5922
Synonyms :
Chemical Name :4-Pyridinecarboxylic acid

Calculated chemistry of [ 55-22-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 31.2
TPSA : 50.19 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) : -6.82 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.76
Log Po/w (XLOGP3) : 0.32
Log Po/w (WLOGP) : 0.78
Log Po/w (MLOGP) : -1.13
Log Po/w (SILICOS-IT) : 0.75
Consensus Log Po/w : 0.3

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -1.23
Solubility : 7.21 mg/ml ; 0.0586 mol/l
Class : Very soluble
Log S (Ali) : -0.94
Solubility : 14.2 mg/ml ; 0.116 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.35
Solubility : 5.46 mg/ml ; 0.0444 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 55-22-1 ]

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 [ 55-22-1 ]

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

  • Upstream synthesis route of [ 55-22-1 ]
  • Downstream synthetic route of [ 55-22-1 ]

[ 55-22-1 ] Synthesis Path-Upstream   1~38

  • 1
  • [ 55-22-1 ]
  • [ 498-94-2 ]
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[2] Chemische Berichte, 1918, vol. 51, p. 1675
[3] Chemische Berichte, 1917, vol. 50, p. 386[4] Chemische Berichte, 1919, vol. 52, p. 210
[5] Recueil des Travaux Chimiques des Pays-Bas, 1944, vol. 63, p. 136
[6] Patent: US2833775, 1955, ,
[7] Zhurnal Obshchei Khimii, 1958, vol. 28, p. 3115,3118; engl. Ausg. S. 3146, 3148
[8] Helvetica Chimica Acta, 1954, vol. 37, p. 1672,1676
[9] Russian Journal of Applied Chemistry, 2006, vol. 79, # 3, p. 499 - 500
[10] Patent: US2833775, 1955, ,
  • 2
  • [ 55-22-1 ]
  • [ 67-56-1 ]
  • [ 2459-09-8 ]
YieldReaction ConditionsOperation in experiment
80% Reflux Isonicotinic acid (0.1 mol), sulfuric acid (0.12 mol) and anhydrous methanol (0.12 mol), was added to a 150 ml single-necked flask, the reaction was heated to reflux, after the end of the reaction, spin off the solvent, washed with water to prepare 12.08 g of isonicotinate as shown in formula (II), Yield 80percent.
75% for 6 h; Reflux General procedure: A catalytic amount of concentrated H2SO4 wasadded to a solution of carboxylic acids 16(a–j) (1.0 mmol)in 50 mL of methanol, and the mixture was refluxed for 6 h. It was allowed to cool. The saturated solution ofNaHCO3 was added to the reaction mixture, and it wasextracted with EtOAc (2 X 50 mL). The combined organiclayer was dried Na2SO4 and concentrated to obtain puremethyl esters 17(a–j).
2.82 g at 0 - 5℃; for 3 h; Inert atmosphere; Reflux Thionyl chloride (0.7 mL, 0.009 mole) was added drop wise to a stirred suspension of isonicotinic acid (5 g, 0.04 mole) in methanol (50 mL) under N2 at 0 - 5 °C. The reaction mixture was then refluxed for 3 hours to obtain a clear solution. The reaction mass was cooled to RT and concentrated to obtain a residue that was diluted with water (20 mL) and extracted with ethyl acetate (100 mL x 3). The organic extracts were combined, washed with aqueous sodium bicarbonate (10 mL), brine (20 mL) dried over anhydrous Na2SC>4 and concentrated under vacuum to obtain the crude compound that was further purified by flash chromatography using ethyl acetate: hexane (40:60) to obtain methyl isonicotinate. Yield: 2.82 g; lH - NMR (CDC13, 400 MHz) δ ppm: 3.96 (s, 3H); 7.83 - 7.85 (d, J = 5.3 Hz, 2H), 8.77 - 8.78 (d, J = 5.2 Hz, 2H); Mass (m/z): 138.0 (M+H)+.
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[3] Patent: CN106699776, 2017, A, . Location in patent: Paragraph 0024-0025; 0027-0029
[4] Medicinal Chemistry Research, 2016, vol. 25, # 4, p. 627 - 643
[5] Synthetic Communications, 2002, vol. 32, # 11, p. 1703 - 1707
[6] Inorganica Chimica Acta, 2012, vol. 388, p. 78 - 83
[7] Journal of the Chemical Society, 1953, p. 1358,1361
[8] Journal of the American Chemical Society, 1951, vol. 73, p. 5614
[9] Archiwum Chemji i Farmacji, 1936, vol. 3, p. 109,113[10] Chem. Zentralbl., 1937, vol. 108, # II, p. 74
[11] Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999), 1990, # 1, p. 307 - 310
[12] Phytochemistry (Elsevier), 1984, vol. 23, # 6, p. 1225 - 1228
[13] Patent: WO2010/104933, 2010, A1, . Location in patent: Page/Page column 262
[14] Chemistry - A European Journal, 2011, vol. 17, # 15, p. 4273 - 4282
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[16] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 11, p. 3615 - 3621
[17] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 16, p. 5185 - 5189
[18] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4407 - 4424
[19] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2013, vol. 115, p. 683 - 689
[20] RSC Advances, 2014, vol. 4, # 61, p. 32276 - 32282
[21] New Journal of Chemistry, 2015, vol. 39, # 1, p. 453 - 460
[22] ChemMedChem, 2014, vol. 9, # 11, p. 2445 - 2448
[23] Journal of Inorganic Biochemistry, 2015, vol. 150, p. 100 - 107
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[25] Patent: WO2018/42362, 2018, A1, . Location in patent: Page/Page column 42
  • 3
  • [ 55-22-1 ]
  • [ 2459-09-8 ]
Reference: [1] Patent: US4560692, 1985, A,
[2] Patent: WO2011/138250, 2011, A1,
  • 4
  • [ 55-22-1 ]
  • [ 74-88-4 ]
  • [ 2459-09-8 ]
Reference: [1] Synthetic Communications, 2001, vol. 31, # 14, p. 2177 - 2183
  • 5
  • [ 55-22-1 ]
  • [ 74-88-4 ]
  • [ 2459-09-8 ]
  • [ 38117-49-6 ]
Reference: [1] Synthetic Communications, 2008, vol. 38, # 22, p. 3937 - 3946
  • 6
  • [ 67-56-1 ]
  • [ 54-85-3 ]
  • [ 55-22-1 ]
  • [ 2459-09-8 ]
Reference: [1] Journal of Chemical Research - Part S, 1996, # 2, p. 100 - 101
  • 7
  • [ 55-22-1 ]
  • [ 616-38-6 ]
  • [ 2459-09-8 ]
Reference: [1] Organic Process Research and Development, 2009, vol. 13, # 4, p. 769 - 773
  • 8
  • [ 186581-53-3 ]
  • [ 55-22-1 ]
  • [ 2459-09-8 ]
Reference: [1] Magnetic Resonance in Chemistry, 1989, vol. 27, # 6, p. 585 - 591
  • 9
  • [ 55-22-1 ]
  • [ 1445-45-0 ]
  • [ 2459-09-8 ]
Reference: [1] Journal of Chemical and Engineering Data, 2007, vol. 52, # 2, p. 580 - 585
  • 10
  • [ 55-22-1 ]
  • [ 2971-79-1 ]
Reference: [1] Helvetica Chimica Acta, 1954, vol. 37, p. 1672,1676
  • 11
  • [ 55-22-1 ]
  • [ 68947-43-3 ]
Reference: [1] Journal of the American Chemical Society, 1959, vol. 81, p. 1201
[2] Patent: US2833775, 1955, ,
  • 12
  • [ 55-22-1 ]
  • [ 22282-72-0 ]
Reference: [1] Tetrahedron Letters, 1988, vol. 29, # 35, p. 4389 - 4392
[2] Organic and Biomolecular Chemistry, 2004, vol. 2, # 15, p. 2253 - 2261
[3] Patent: EP1801102, 2007, A1, . Location in patent: Page/Page column 9-10
  • 13
  • [ 55-22-1 ]
  • [ 22282-72-0 ]
  • [ 99-11-6 ]
Reference: [1] Patent: EP1801102, 2007, A1, . Location in patent: Page/Page column 9-10
[2] Patent: EP1801102, 2007, A1, . Location in patent: Page/Page column 9-10
[3] Patent: EP1801102, 2007, A1, . Location in patent: Page/Page column 9-10
  • 14
  • [ 55-22-1 ]
  • [ 1690-75-1 ]
Reference: [1] Archiwum Chemji i Farmacji, 1936, vol. 3, p. 109,113[2] Chem. Zentralbl., 1937, vol. 108, # II, p. 74
  • 15
  • [ 1453-82-3 ]
  • [ 55-22-1 ]
  • [ 54-85-3 ]
YieldReaction ConditionsOperation in experiment
90.4% With hydrazine dihydrochloride In aq. phosphate buffer at 30℃; for 1 h; Enzymatic reaction Fed-batch biotransformation was carried out in 250ml Erlenmeyer flask containing 50ml of reaction mixture with initial isonicotinamide and hydrazine–2HCl concentration of 100 and 1000mM respectively in phosphate buffer (100mM, pH 7) at 30°C and 2.0mgdcw/ml resting cells of B. smithii strain IITR6b2. Powdered isonicotinamide (0.61g) and highly concentrated solution (1ml, 5M, pH 7) of hydrazine–2HCl were fed in subsequent seven feeds at an interval of 60min to restrict the residual isonicotinamide and hydrazine–2HCl concentration above 100 and 1000mM respectively. 500μl of sample was withdrawn at every 30min during the reaction and monitored for isoniazid, isonicotinic acid and isonicotinamide concentration. Effort was made to maintain the reaction volume constant around 50ml. A control experiment was also conducted with same parameters without enzyme for any spontaneous chemical reaction
Reference: [1] Journal of Molecular Catalysis B: Enzymatic, 2013, vol. 97, p. 67 - 73
  • 16
  • [ 55-22-1 ]
  • [ 54-85-3 ]
Reference: [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2010, vol. 49, # 4, p. 526 - 531
[2] Asian Journal of Chemistry, 2011, vol. 23, # 6, p. 2648 - 2652
[3] Meditsinskaya Promyshlennost SSSR, 1957, vol. 11, # 4, p. 19,20[4] Chem.Abstr., 1958, p. 7315
[5] Acta Chemica Scandinavica (1947-1973), 1957, vol. 11, p. 1787
[6] Patent: US2891067, 1957, ,
[7] Helvetica Chimica Acta, 1959, vol. 42, p. 1324,1326
[8] Journal of Pharmacy and Pharmacology, 2001, vol. 53, # 2, p. 267 - 272
[9] Phosphorus, Sulfur and Silicon and the Related Elements, 2006, vol. 181, # 9, p. 2079 - 2087
[10] European Journal of Medicinal Chemistry, 2006, vol. 41, # 7, p. 841 - 846
[11] Acta Chimica Academiae Scientiarum Hungaricae, 1958, vol. 14, p. 197,199
[12] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 1, p. 184 - 187
[13] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 21, p. 6225 - 6229
[14] Journal of Heterocyclic Chemistry, 2010, vol. 47, # 5, p. 1225 - 1229
[15] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 24, p. 7246 - 7250
[16] Arzneimittel-Forschung/Drug Research, 2011, vol. 61, # 8, p. 452 - 457
[17] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 11, p. 3615 - 3621
[18] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4407 - 4424
[19] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 16, p. 5185 - 5189
[20] Medicinal Chemistry Research, 2012, vol. 21, # 7, p. 1451 - 1470
[21] Medicinal Chemistry Research, 2012, vol. 21, # 8, p. 1935 - 1952,18
[22] Medicinal Chemistry Research, 2012, vol. 21, # 8, p. 1935 - 1952
[23] Medicinal Chemistry Research, 2012, vol. 21, # 11, p. 3646 - 3655
[24] Medicinal Chemistry, 2013, vol. 9, # 1, p. 53 - 76
[25] Journal of the Brazilian Chemical Society, 2013, vol. 24, # 1, p. 115 - 120
[26] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 8, p. 2286 - 2297
[27] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 11, p. 1097 - 1101
[28] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 199 - 218
[29] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2013, vol. 115, p. 683 - 689
[30] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2013, vol. 52, # 10, p. 1318 - 1324
[31] Dyes and Pigments, 2014, vol. 108, p. 32 - 40
[32] Archives of Pharmacal Research, 2014, vol. 37, # 7, p. 852 - 861
[33] New Journal of Chemistry, 2015, vol. 39, # 1, p. 453 - 460
[34] Letters in Drug Design and Discovery, 2014, vol. 11, # 9, p. 1107 - 1111
[35] Letters in Drug Design and Discovery, 2014, vol. 11, # 9, p. 1119 - 1123
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[37] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 13, p. 3397 - 3407
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[39] Medicinal Chemistry Research, 2015, vol. 24, # 12, p. 4166 - 4180
[40] Journal of Inorganic Biochemistry, 2015, vol. 150, p. 100 - 107
[41] Transition Metal Chemistry, 2015, vol. 40, # 6, p. 665 - 671
[42] RSC Advances, 2015, vol. 5, # 118, p. 97089 - 97101
[43] Medicinal Chemistry Research, 2016, vol. 25, # 4, p. 627 - 643
[44] Journal of the Chemical Society of Pakistan, 2016, vol. 38, # 5, p. 990 - 995
[45] Inorganica Chimica Acta, 2017, vol. 461, p. 301 - 315
[46] ChemMedChem, 2017, vol. 12, # 12, p. 972 - 985
[47] Patent: CN106699776, 2017, A,
[48] Patent: CN107011255, 2017, A,
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[51] Chemistry and Biodiversity, 2018, vol. 15, # 9,
[52] Patent: DE1116667, 1956, ,
  • 17
  • [ 55-22-1 ]
  • [ 302-01-2 ]
  • [ 54-85-3 ]
  • [ 4329-75-3 ]
  • [ 38634-05-8 ]
Reference: [1] Meditsinskaya Promyshlennost SSSR, 1957, vol. 11, # 12, p. 38[2] Chem.Abstr., 1958, p. 20151
  • 18
  • [ 55-22-1 ]
  • [ 33972-97-3 ]
Reference: [1] Journal of Organic Chemistry, 1959, vol. 24, p. 196
  • 19
  • [ 55-22-1 ]
  • [ 13958-93-5 ]
  • [ 88912-27-0 ]
Reference: [1] Chemische Berichte, 1928, vol. 61, p. 2214
  • 20
  • [ 55-22-1 ]
  • [ 7719-09-7 ]
  • [ 13958-93-5 ]
  • [ 88912-27-0 ]
Reference: [1] Chemische Berichte, 1928, vol. 61, p. 2214
  • 21
  • [ 55-22-1 ]
  • [ 62-53-3 ]
  • [ 3034-31-9 ]
YieldReaction ConditionsOperation in experiment
99%
Stage #1: for 2 h; Reflux
Stage #2: With potassium carbonate In tetrahydrofuran at 20℃; for 24 h;
A solution of isonicotinic acid (14, 5.0 g, 40.6 mmol) in thionyl chloride (40 mL) was heated at reflux for 2 h. After completion of the reaction, thionyl chloride was removed under reduced pressure. THF (50 mL), K2CO3 (16.8 g, 121.9 mmol) and aniline (3.78 g, 40.6 mmol) were added to the residue and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was concentrated and the residue was recrystallized from EtOAc-hexanes (60:40) to afford the product 15 (8.0 g, 99percent) as a light yellow solid: mp 166-168 °C. IR (KBr) 1344, 1653, 1465, 665 cm 1; *H NMR (DMSO-ifc, 300 MHz) δ 10.49 (s, 1 H), 8.78 (m, 2 H), 7.86 (m, 2 H), 7.78 (m, 2 H), 7.39 (t, = 8.0 Hz, 2 H), 7.15 (t, = 6.5 Hz, 1 H).
Reference: [1] Patent: WO2017/160898, 2017, A1, . Location in patent: Paragraph 00105; 00125
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1370 - 1387
[3] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 11, p. 6027 - 6033
[4] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1981, vol. 20, # 11, p. 1007 - 1008
  • 22
  • [ 55-22-1 ]
  • [ 62-53-3 ]
  • [ 3034-31-9 ]
  • [ 1126-46-1 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 40℃; for 2.5 h;
Stage #2: for 20 h;
A solution of 1,10-carbonyldiimidazole (130 g,0.81 mol), isonicotinic acid (100 g, 0.81 mol) and DMF (300 mL) was heated at 40 C for 2.5 h before aniline (100 g, 0.81 mol) was added in a single portion. After 20 h, water (1.2 L) was added. The resulting suspension was filtered andthe solids dried under vacuum to afford isonicotinanilide (39) (142.6 g, 89percent).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 4, p. 976 - 981
  • 23
  • [ 55-22-1 ]
  • [ 3034-31-9 ]
Reference: [1] Organic Letters, 2016, vol. 18, # 18, p. 4602 - 4605
  • 24
  • [ 55-22-1 ]
  • [ 3034-31-9 ]
Reference: [1] Journal of Organic Chemistry, 1999, vol. 64, # 23, p. 8546 - 8556
[2] Pharmaceutical Chemistry Journal, 1998, vol. 32, # 11, p. 597 - 599
[3] Tetrahedron, 1989, vol. 45, # 23, p. 7469 - 7476
[4] Organic Letters, 2014, vol. 16, # 11, p. 3142 - 3145
[5] Journal of Medicinal Chemistry, 2016, vol. 59, # 8, p. 3840 - 3853
  • 25
  • [ 55-22-1 ]
  • [ 26377-17-3 ]
YieldReaction ConditionsOperation in experiment
42%
Stage #1: With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 2 h;
Stage #2: With toluene-4-sulfonic acid In ethanolHeating / reflux
25 g (203 mmol) Isonicotinsaeure, 35.12 g (243.7 mmol) 2, 2-Dimethyl-1, 3-dioxolan- 4,6-dion und 49.6 g (406 mmol) 4-Dimethylaminopyridin werden in 300 [ML] Dichlor- methan vorgelegt und auf [0°C] gekuehlt. Es wird eine 1N Loesung von 46.1 g (223.4 mmol) 1, 3-Dicyclohexylcarbodiimid in Dichlormethan zugetropft. Es wird 2 Stunden bei Raumtemperatur nachgeruehrt. Der entstandene Niederschlag wird abfiltriert und mit Dichlormethan nachgewaschen. Das Filtrat wird im Vakuum eingeengt. Der Rueckstand wird in 1200 ml Ethanol geloest und mit einer Loesung aus 96.6 g (507.7 mmol) p-Toluolsulfonsaeure-monohydrat in 300 ml Ethanol versetzt und eine Stunde unter Rueckfluss geruehrt. Nach dem Abkuehlen wird das Ethanol im Vakuum abgezogen. Der Rueckstand wird in 1000 ml Ethylacetat und 900 ml Wasser aufgenommen und in der Hitze geloest. Die organische Phase wird abgetrennt, mit 600 ml gesaettigter Natriumhydrogencarbonatloesung und gesaettigter Natriumchlorid- loesung gewaschen und ueber Natriumsulfat getrocknet. Es wird im Vakuum eingeengt. Das Rohprodukt wird ueber eine Kieselgel-Fritte mit Dichlormethan-Methanol 10 : 1 filtriert. Da die waessrige Phase noch Produkt enthaelt, wird diese mit Dichlormethan extrahiert, ueber Natriumsulfat getrocknet und im Vakuum eingeengt. Das Roh- produkt wird ueber eine Kieselgel-Fritte mit Dichlormethan-Methanol 10 : 1 filtriert. Insgesamt erhaelt man 25.9 g (42 percent d. Th. ) Produkt. [1H-NMR] (300 MHz, DMSO-d6) : [5] = 1.17 (t, 3H), 4.12 (q, 2H), 4.25 (s, 2H), 7.82 (dd, 2H), 8.83 (dd, 2H) LC-MS (Methode 3) : [RT =] 2.40 min MS (ESIpos) : [M/Z =] 194 [(M+H) +]
Reference: [1] Patent: WO2003/106450, 2003, A1, . Location in patent: Page column 39,40
[2] Patent: WO2012/67664, 2012, A1,
  • 26
  • [ 55-22-1 ]
  • [ 6148-64-7 ]
  • [ 26377-17-3 ]
YieldReaction ConditionsOperation in experiment
25%
Stage #1: With magnesium chloride In tetrahydrofuran at 50℃;
Stage #2: With 1,1'-carbonyldiimidazole In tetrahydrofuran for 18 h;
To ethyl potassium malonate (6.25 g, 36.7 mmol) in THF (30 mL) was added MgCl2 (2.71 g, 28.4 mmol) and the mixture heated to 50° C.
In another flask, CDI (6 g, 36.6 mmol) was added to a solution of isonicotinic acid (3 g, 24.4 mmol) in THF (30 mL) at 10° C.
This mixture was stirred at 25° C. for 1 h, after which it was added to the ethyl potassium malonate/MgCl2 suspension and stirred for 18 h.
Upon completion, water was added, and the aqueous mixture extracted with EtOAc (3*50 mL).
The organic phase was washed with brine, dried over Na2SO4, concentrated, and the crude material purified by column chromatography (30percent EtOAc-Hexane) to give 3-Oxo-3-pyridin-4-yl-propionic acid ethyl ester (1.2 g, 25percent).
Reference: [1] Patent: US2011/71150, 2011, A1, . Location in patent: Page/Page column 27
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6933 - 6937
  • 27
  • [ 55-22-1 ]
  • [ 530-62-1 ]
  • [ 26377-17-3 ]
YieldReaction ConditionsOperation in experiment
74% With magnesium chloride In tetrahydrofuran 1.1.
Preparation of Ethyl 3-(4-pyridyl)-3-oxopropionate
Isonicotinic acid (35.56 g, 289 mmol) was added to a solution of 1,1'-carbonylbis-1H-imidazole (46.98 g, 290 mmol) in tetrahydrofuran (700 ml), and the resulting solution was stirred for 1.5 hr at 50° C.
After cooling to room temperature, malonic acid monoester potassium salt (51.7 g, 304 mmol) and magnesium chloride (34.33 g, 361 mmol) were added, and the mixture was refluxed for 1 hr and then heated at 50° C. for 6 hr.
The solvent was removed under reduced pressure and the residue was quenched by the addition of dilute acetic acid.
The organic layer was extracted with ethyl acetate (3 times) and the combined extracts were washed with dilute aqueous sodium bicarbonate and brine, and were concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=2/1 to 1/1) and recrystallization from hexane-ethyl acetate gave 41.52 g (74percent) of the title compound.
74% With magnesium chloride In tetrahydrofuran 1.1.
Preparation of Ethyl 3-(4-pyridyl)-3-oxopropionate
Isonicotinic acid (35.56 g, 289 mmol) was added to a solution of 1,1'-carbonylbis-1H-imidazole (46.98 g, 290 mmol) in tetrahydrofuran (700ml), and the resulting solution was stirred for 1.5 hr at 50°C.
After cooling to room temperature, malonic acid monoester potassium salt (51.7 g, 304 mmol) and magnesium chloride (34.33 g, 361 mmol) were added, and the mixture was refluxed for 1 hr and then heated at 50°C for 6 hr.
The solvent was removed under reduced pressure and the residue was quenched by the addition of dilute acetic acid.
The organic layer was extracted with ethyl acetate (3 times) and the combined extracts were washed with dilute aqueous sodium bicarbonate and brine, and were concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate = 2/1 to 1/1) and recrystallization from hexane - ethyl acetate gave 41.52 g (74percent) of the title compound.
74% With magnesium chloride In tetrahydrofuran 1.1.
Preparation of Ethyl 3-(4-pyridyl)-3-oxopropionate
Isonicotinic acid (35.56 g, 289 mmol) was added to a solution of 1,1'-carbonylbis-1H-imidazole (46.98 g, 290 mmol) in tetrahydrofuran (700ml), and the resulting solution was stirred for 1.5 hr at 50°C.
After cooling to room temperature, malonic acid monoester potassium salt (51.7 g, 304 mmol) and magnesium chloride (34.33 g, 361 mmol) were added, and the mixture was refluxed for 1 hr and then heated at 50°C for 6 hr.
The solvent was removed under reduced pressure and theresidue was quenched by the addition of dilute acetic acid.
The organic layer was extracted with ethyl acetate (3 times) and the combined extracts were washed with dilute aqueous sodium bicarbonate and brine, and were concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate = 2/1 to 1/1) and recrystallization from hexane - ethyl acetate gave 41.52 g (74percent) of the title compound.
Reference: [1] Patent: US2003/187004, 2003, A1,
[2] Patent: EP1136099, 2001, A1,
[3] Patent: EP1136483, 2001, A1,
  • 28
  • [ 55-22-1 ]
  • [ 117326-21-3 ]
  • [ 64-17-5 ]
  • [ 26377-17-3 ]
Reference: [1] Patent: WO2004/39796, 2004, A1, . Location in patent: Page/Page column 73-74
  • 29
  • [ 55-22-1 ]
  • [ 59290-82-3 ]
Reference: [1] Acta Chemica Scandinavica, 1999, vol. 53, # 2, p. 141 - 144
  • 30
  • [ 55-22-1 ]
  • [ 10128-71-9 ]
Reference: [1] Heterocyclic Communications, 2003, vol. 9, # 5, p. 489 - 492
[2] Polish Journal of Chemistry, 2005, vol. 79, # 11, p. 1813 - 1819
[3] Chemische Berichte, 1928, vol. 61, p. 2214
[4] Croatica Chemica Acta, 2010, vol. 83, # 3, p. 291 - 298
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  • [ 55-22-1 ]
  • [ 88912-27-0 ]
Reference: [1] Tetrahedron, 2002, vol. 58, # 33, p. 6723 - 6728
  • 32
  • [ 55-22-1 ]
  • [ 13958-93-5 ]
  • [ 88912-27-0 ]
Reference: [1] Chemische Berichte, 1928, vol. 61, p. 2214
  • 33
  • [ 55-22-1 ]
  • [ 7719-09-7 ]
  • [ 13958-93-5 ]
  • [ 88912-27-0 ]
Reference: [1] Chemische Berichte, 1928, vol. 61, p. 2214
  • 34
  • [ 55-22-1 ]
  • [ 22282-72-0 ]
  • [ 99-11-6 ]
Reference: [1] Patent: EP1801102, 2007, A1, . Location in patent: Page/Page column 9-10
[2] Patent: EP1801102, 2007, A1, . Location in patent: Page/Page column 9-10
[3] Patent: EP1801102, 2007, A1, . Location in patent: Page/Page column 9-10
  • 35
  • [ 55-22-1 ]
  • [ 75-65-0 ]
  • [ 81660-73-3 ]
Reference: [1] Chemistry - A European Journal, 2015, vol. 21, # 40, p. 14030 - 14035
[2] Journal of the American Chemical Society, 2015, vol. 137, # 45, p. 14465 - 14472
[3] Journal of Chemical Research, Miniprint, 1987, # 3, p. 642 - 679
  • 36
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  • [ 39178-35-3 ]
Reference: [1] Journal of Materials Chemistry, 2011, vol. 21, # 24, p. 8574 - 8582
[2] Russian Journal of General Chemistry, 1994, vol. 64, # 12.2, p. 1809 - 1815[3] Zhurnal Obshchei Khimii, 1994, vol. 64, # 12, p. 2040 - 2047
[4] Molecules, 2001, vol. 6, # 1, p. 47 - 51
[5] RSC Advances, 2015, vol. 5, # 105, p. 86191 - 86198
[6] Journal of Medicinal Chemistry, 1995, vol. 38, # 1, p. 28 - 33
[7] Chemistry - A European Journal, 2010, vol. 16, # 20, p. 5961 - 5968
[8] Chemistry - A European Journal, 2006, vol. 12, # 4, p. 1097 - 1113
[9] Organometallics, 2015, vol. 34, # 11, p. 2543 - 2549
[10] Chemische Berichte, 1926, vol. 59, p. 1479,1482
[11] Journal of Organic Chemistry, 1982, vol. 47, # 13, p. 2633 - 2637
[12] Phosphorus and Sulfur and the Related Elements, 1981, vol. 11, p. 33 - 46
[13] Journal of Heterocyclic Chemistry, 1992, vol. 29, # 5, p. 1245 - 1273
[14] Acta Poloniae Pharmaceutica, 1993, vol. 50, # 2.3, p. 243 - 248
[15] Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 7, p. 1020 - 1023
[16] Russian Chemical Bulletin, 2001, vol. 50, # 3, p. 520 - 524
[17] Patent: WO2004/76450, 2004, A1, . Location in patent: Page 135
[18] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 2, p. 890 - 901
[19] Chemistry - A European Journal, 2010, vol. 16, # 7, p. 2258 - 2271
[20] Phosphorus, Sulfur and Silicon and the Related Elements, 2011, vol. 186, # 3, p. 552 - 557
[21] Synthetic Communications, 2012, vol. 42, # 17, p. 2555 - 2563
[22] MedChemComm, 2017, vol. 8, # 1, p. 152 - 157
[23] European Journal of Medicinal Chemistry, 2017, vol. 141, p. 362 - 372
  • 37
  • [ 55-22-1 ]
  • [ 80194-83-8 ]
Reference: [1] Tetrahedron, 1989, vol. 45, # 23, p. 7469 - 7476
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