[ CAS No. 1080-79-1 ] {[proInfo.proName]}

Name: 1080-79-1|Diethyl 1H-imidazole-4,5-dicarboxylate|97%
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SKU: A147481
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Quality Control of [ 1080-79-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1080-79-1 ]

SDS Specification

Alternatived Products of [ 1080-79-1 ]

Product Details of [ 1080-79-1 ]

CAS No. :	1080-79-1	MDL No. :	MFCD00723829
Formula :	C₉H₁₂N₂O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NQKKUSLBNWTXQI-UHFFFAOYSA-N
M.W :	212.20	Pubchem ID :	350670
Synonyms :

Calculated chemistry of [ 1080-79-1 ] Expand+

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.44
Num. rotatable bonds :	6
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	50.76
TPSA :	81.28 Å²

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) :	-6.76 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.71
Log Po/w (XLOGP3) :	1.17
Log Po/w (WLOGP) :	0.76
Log Po/w (MLOGP) :	-0.07
Log Po/w (SILICOS-IT) :	1.37
Consensus Log Po/w :	0.99

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.74
Solubility :	3.83 mg/ml ; 0.0181 mol/l
Class :	Very soluble
Log S (Ali) :	-2.47
Solubility :	0.715 mg/ml ; 0.00337 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.21
Solubility :	1.32 mg/ml ; 0.00624 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.27

Safety of [ 1080-79-1 ]

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

Application In Synthesis of [ 1080-79-1 ]

* 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 [ 1080-79-1 ]
Downstream synthetic route of [ 1080-79-1 ]

[ 1080-79-1 ] Synthesis Path-Upstream 1~8

1
[ 570-22-9 ]
[ 1080-79-1 ]

Yield	Reaction Conditions	Operation in experiment
46%	With sulfuric acid In ethanol; water	REFERENCE EXAMPLE 13 4,5-Bis(ethoxycarbonyl)imidazole A mixture of 4.0 g (25.6 mmols) of imidazole-4,5-dicarboxylic acid, 600 ml of ethanol and 16 ml of conc. sulfuric acid was heated under reflux for 7 hours. After cooling to 0° C., the mixture was neutralized with a 2 normal aqueous sodium hydroxide solution. The solvent was evaporated under reduced pressure, and then water was added to the residue followed by extraction of the solution with chloroform. The chloroform layer was washed with an aqueous saturated sodium bicarbonate solution and then with an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dried to afford 2.5 g (yield: 46percent) of the title compound. NMR (CDCl₃) δ (ppm): 7.83(1H, s), 7.26(1H, s), 4.41 (4H, q, J=7.2 Hz), 1.38(6H, t, J=7.2 Hz)

Reference： [1] Patent: US5053408, 1991, A,
[2] Patent: US6130326, 2000, A,
[3] Patent: US5420271, 1995, A,

2
[ 570-22-9 ]
[ 64-17-5 ]
[ 1080-79-1 ]

Reference： [1] Journal of Labelled Compounds and Radiopharmaceuticals, 2013, vol. 56, # 8, p. 376 - 381
[2] Journal of Organic Chemistry, 1999, vol. 64, # 18, p. 6575 - 6582
[3] Tetrahedron, 2000, vol. 56, # 4, p. 645 - 657
[4] Patent: EP1254911, 2002, A1, . Location in patent: Example 29
[5] Anales de la Real Sociedad Espanola de Fisica y Quimica, Serie B: Quimica, 1953, vol. 49, p. 599,601, 602
[6] Tetrahedron Letters, 1997, vol. 38, # 48, p. 8425 - 8428

3
[ 50-00-0 ]
[ 59743-08-7 ]
[ 1080-79-1 ]

Reference： [1] Patent: EP2298763, 2011, A1, . Location in patent: Page/Page column 27-28

4
[ 50-00-0 ]
[ 87-91-2 ]
[ 1080-79-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In ethyl acetate at 20℃; for 3 h; Stage #2: With ammonium acetate In water; acetic acid; ethyl acetate at 10 - 50℃; for 3.5 h; Cooling with ice	(Reference Example 3) Diethyl 1H-imidazole-4,5-dicarboxylate Reference Example 3 was carried out under non-light-shielding conditions. To a solution of L-tartaric acid diethyl ester (2.0 g) in ethyl acetate (34.2 ml), 1,3-dibromo-5,5-dimethylhydantoin (3.3 g) was added, and the reaction solution was stirred at room temperature for 3 hours. To the reaction solution, acetic acid (17 ml) was added, and subsequently 36percent aqueous formaldehyde solution (3.45 ml) was added under ice cooling at an internal temperature of 10°C or below, followed by addition of ammonium acetate (17.2 g) at an internal temperature of 10°C or below. The reaction solution was stirred at room temperature for 30 minutes, followed by stirring at 50°C for 3 hours. To the reaction solution, 5N sodium hydroxide was added, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, and dried over magnesium sulfate. Quantitative analysis of the resulting ethyl acetate solution by HPLC showed that the title compound (1.24 g, yield: 60percent) was obtained. Condition for HPLC analysis is identical with that for Example 5. From the results of Reference Example 3 and Example 5, it was shown that the production method of the present invention [the method for producing compound (5) from compound (1)] was superior to the reaction indicated in the known Method X in terms of yield even under non-light-shielding conditions.

Reference： [1] Patent: EP2298763, 2011, A1, . Location in patent: Page/Page column 31

5
[ 64-17-5 ]
[ 78595-41-2 ]
[ 1080-79-1 ]

Reference： [1] Doklady Chemistry, 1980, vol. 255, p. 516 - 518[2] Dokl. Akad. Nauk SSSR Ser. Khim., 1980, vol. 255, # 2, p. 359 - 361
[3] Organic Letters, 2005, vol. 7, # 1, p. 135 - 138

6
[ 69039-88-9 ]
[ 1080-79-1 ]

Reference： [1] Journal of the American Chemical Society, 1952, vol. 74, p. 1084

7
[ 87-91-2 ]
[ 1080-79-1 ]

Reference： [1] Patent: EP2298763, 2011, A1,

8
[ 59743-08-7 ]
[ 100-97-0 ]
[ 1080-79-1 ]

Reference： [1] Anales de la Real Sociedad Espanola de Fisica y Quimica, Serie B: Quimica, 1953, vol. 49, p. 599,601, 602

[ 1080-79-1 ] Synthesis Path-Downstream 1~63

1
[ 570-22-9 ]
[ 64-17-5 ]
[ 1080-79-1 ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2013,vol. 56,p. 376 - 381
[2]Journal of Organic Chemistry,1999,vol. 64,p. 6575 - 6582
[3]Tetrahedron,2000,vol. 56,p. 645 - 657
[4]Patent: EP1254911,2002,A1 .Location in patent: Example 29
[5]Anales de la Real Sociedad Espanola de Fisica y Quimica, Serie B: Quimica,1953,vol. 49,p. 599,601, 602
[6]Tetrahedron Letters,1997,vol. 38,p. 8425 - 8428

2
[ 1080-79-1 ]
[ 33457-48-6 ]

Reference： [1]Anales de la Real Sociedad Espanola de Fisica y Quimica,1953,vol. 49,p. 599,601

3
[ 1080-79-1 ]
[ 5423-20-1 ]

Reference： [1]Journal of the American Chemical Society,1956,vol. 78,p. 159,161, 162

4
[ 59743-08-7 ]
[ 100-97-0 ]
[ 1080-79-1 ]

Reference： [1]Anales de la Real Sociedad Espanola de Fisica y Quimica, Serie B: Quimica,1953,vol. 49,p. 599,601, 602

5
[ 69039-88-9 ]
[ 1080-79-1 ]

Reference： [1]Journal of the American Chemical Society,1952,vol. 74,p. 1084

6
[ 698-63-5 ]
[ 1080-79-1 ]
[ 124928-24-1 ]

Reference： [1]Pharmaceutical Chemistry Journal,1990,vol. 23,p. 408 - 412

7
[ 64-17-5 ]
[ 78595-41-2 ]
[ 1080-79-1 ]

Reference： [1]Doklady Chemistry,1980,vol. 255,p. 516 - 518
Dokl. Akad. Nauk SSSR Ser. Khim.,1980,vol. 255,p. 359 - 361
[2]Organic Letters,2005,vol. 7,p. 135 - 138

8
[ 1080-79-1 ]
[ 100-44-7 ]
[ 1232-51-5 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1992,vol. 28,p. 1006 - 1008
Khimiya Geterotsiklicheskikh Soedinenii,1992,p. 1193 - 1195

9
[ 1080-79-1 ]
[ 106-93-4 ]
[ 131727-40-7 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 827 - 841

10
[ 1080-79-1 ]
[ 74-88-4 ]
[ 1210-92-0 ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657
[2]Tetrahedron Letters,1997,vol. 38,p. 8425 - 8428

11
[ 1080-79-1 ]
[ 129756-78-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With N-Bromosuccinimide; In acetonitrile; at 20℃; for 24h;In the dark;	Under an argon atmosphere 3.30 g (18.54 mmol) N-bromosuccinimide were added to a solution of 2.60 g (12.25 mmol) <strong>[1080-79-1]diethyl imidazole-4,5-dicarboxylate</strong> in 30 ml acetonitrile. The solution was stirred for 24 hours in the dark at ambient temperature and then evaporated down. The residue was taken up in 150 ml of ethyl acetate and washed twice each with saturated aqueous sodium chloride solution and saturated aqueous sodium thiosulphate and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and the solvent was removed. Yield: 3.50 g (98% of theory) C9H11BrN2O4 (291.10) Rf value: 0.6 (silica gel; dichloromethane/ethanol 9:1) Mass spectrum: (M+H)+=291/293 (bromine)

Reference： [1]Patent: US2005/261352,2005,A1 .Location in patent: Page/Page column 9
[2]Patent: WO2005/110999,2005,A1 .Location in patent: Page/Page column 24-25
[3]Journal of Organic Chemistry,1999,vol. 64,p. 6575 - 6582
[4]Journal of labelled compounds and radiopharmaceuticals,2013,vol. 56,p. 376 - 381

Yield	Reaction Conditions	Operation in experiment
10%		Then, Compound 13 was obtained (yield: 10%) in the same manner as in Example 9. Melting point: 205.5-206.0 C. Elemental analysis: as C17 H25 N5 O5 S*3HCl. Calcd. (%); C, 39.20 H, 5.42 N, 13.45. Found (%); C, 39.69 H, 5.67 N, 13.41. IR (KBr) cm-1: 2976, 2340(br), 1650, 1276 NMR (DMSO-d6 delta ppm): 8.65(2H, d, J=4.9 Hz), 7.24(1H, t, J=4.9 Hz), 5.43(1H, m), 5.11(1H, m), 4.83(1H, m), 4.1-4.25(1H, m), 4.07(2H, m), 3.90-4.05(1H, m), 3.3-5.0(9H, m), 3.28(2H, t, J=7.7 Hz), 3.20 (2H, t, J=7.1 Hz), 2.15(2H, m)
		Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-oxoethyl-L-serine, methyl ester (13.6 g) in methylene chloride/trifluoroacetic acid (10:1/330 mL). Stir at room temperature for 2.5 hours and evaporate the solvent in vacuo. Purify by silica gel chromatography (35% ethyl acetate/hexane) and recrystallize (ethyl acetate/hexane) to give the title compound (8.52 g, 68%); mp 70-72 C. Scheme D, step d: [4S-[4alpha, 7alpha(R), 12bbeta]]-7-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)]-3,4,6,7,8,12b-hexahydro-6-oxo-1H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid, diphenylmethyl ester Dissolve [S-(R, R)]-N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-3,4-dihydro-2H-1,4-oxazine-3-carboxylic acid, methyl ester (2.5 g, 5.9 mmol) in methylene chloride (5 mL) and add, by dropwise addition, to a previously prepared solution of trifluoromethanesulfonic acid (4.0 mL, 45 mmol) and trifluoroacetic anhydride (1.0 mL, 7.1 mmol). Place under a nitrogen atmosphere and stir at room temperature for 123 hours. Pour into a separatory funnel containing ice (200 g) and ethyl acetate (200 mL). Separate the organic phase, wash with water (3200 mL) and saturated aqueous sodium chloride (100 mL). Extract the organic phase with 10% wt. potassium hydrogen carbonate (440 mL) and water (40 mL). Layer the combined basic aqueous phases with ethyl acetate (100 mL) and cool in an ice bath. Add, by dropwise addition, 6N hydrochloric acid to adjust the pH to 1 while maintaining the temperature at 5 -10 C. Separate the organic phase and extract the aqueous phase with ethyl acetate (3200 mL), wash with saturated sodium chloride and dry (MgSO4). Evaporate the solvent in vacuo and dry the residue under high vacuum at 56 C. for 24 hours to give the intermediate [4S-[4alpha, 7alpha(R), 12bbeta]]-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-3,4,6,7,8,12b-hexahydro-6-oxo-1H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid (1.75 g, 73%). Dissolve [4S-[4alpha, 7alpha(R), 12bbeta]]-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-3,4,6,7,8,12b-hexahydro-6-oxo-1H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid (500 mg, 1.23 mmol) in methylene chloride (12 mL) and treat with diphenyldiazomethane (360 mg, 1.86 mmol). Stir for 5.5 hours and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound (563 mg, 80%); mp 178-181 C. (isopropanol). Scheme D, step e: [4S-[4alpha, 7alpha(R), 12bbeta]]-7-(Amino)-3,4,6,7,8,12b-hexahydro-6-oxo-1H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid, diphenylmethyl ester Dissolve [4S-[4alpha, 7alpha(R), 12bbeta]]-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-3,4,6,7,8,12b-hexahydro-6-oxo-1H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid, diphenylmethyl ester (296 mg, 0.517 mmol) in methanol (5 mL) and treat with hydrazine monohydrate (1.1 mL of a 1M solution in methanol, 1.1 mmol). Stir at room temperature for 44 hours, evaporate the solvent in vacuo and slurry the residue in methylene chloride (10 mL). Filter and evaporate the solvent in vacuo to give the title compound (218 mg, 95%). Scheme A: [4S-[4alpha, 7alpha(R*), 12bbeta]]-7-[(5-Thio-5-oxo-4,5-dihydro-cyclopentimidazole)methylamino]-3,4,6,7,8,12b-hexahydro-6-oxo-1H-[1,4]-oxazino[3,4,a][2]benzazepine-4-carboxylic acid Dissolve 4,5-imidazoledicarboxylic acid (31.2 g, 0.2 mol) in ethanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60 C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give 4,5-(dicarboethoxy)imidazole.
		Dissolve N-[2-(1,3-dihydro1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-oxoethyl-L-serine, methyl ester (13.6 g) in methylene chloride/trifluoroacetic acid (10:1/330 mL). Stir at room temperature for 2.5 hours and evaporate the solvent in vacuo. Purify by silica gel chromatography (35% ethyl acetate/hexane) and recrystallize (ethyl acetate/hexane) to give the title compound (8.52 g, 68%); mp 70-72 C. Scheme D, step d: [4S,[4alpha, 7alpha(R), 12bbeta]]-7-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)]-3,4,6,7,8,12b-hexahydro-6-oxo-1H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid, diphenylmethyl ester Dissolve [S-(R, R)]-N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-3,4-dihydro-2H-1,4-oxazine-3-carboxylic acid, methyl ester (2.5 g, 5.9 mmol) in methylene chloride (5 mL) and add, by dropwise addition, to a previously prepared solution of trifluoromethanesulfonic acid (4.0 mL, 45 mmol) and trifluoroacetic anhydride (1.0 mL, 7.1 mmol). Place under a nitrogen atmosphere and stir at room temperature for 123 hours. Pour into a separatory funnel containing ice (200 g) and ethyl acetate (200 mL). Separate the organic phase, wash with water (3200 mL) and saturated aqueous sodium chloride (100 mL). Extract the organic phase with 10% wt. potassium hydrogen carbonate (440 mL) and water (40 mL). Layer the combined basic aqueous phases with ethyl acetate (100 mL) and cool in an ice bath. Add, by dropwise addition, 6N hydrochloric acid to adjust the pH to 1 while maintaining the temperature at 5 -10 C. Separate the organic phase and extract the aqueous phase with ethyl acetate (3200 mL), wash with saturated sodium chloride and dry (MgSO4). Evaporate the solvent in vacuo and dry the residue under high vacuum at 56 C. for 24 hours to give the intermediate [4S-[4alpha, 7alpha(R), 12bbeta]]-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-3,4,6,7,8,12b-hexahydro-6-oxo-1H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid (1.75 g, 73%). Dissolve [4S-[4alpha, 7alpha(R), 12bbeta]]-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-3,4, 6,7,8,12b-hexahydro-6-oxo-1H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid (500 mg, 1.23 mmol) in methylene chloride (12 mL) and treat with diphenyldiazomethane (3 60 mg, 1.86 mmol). Stir for 5.5 hours and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound (563 mg, 80%); mp 178-181 C. (isopropanol). Scheme D, step e: [4S-[4alpha, 7alpha(R), 12bbeta]]-7-(Amino)-3,4,6,7,8,12b-hexahydro-6-oxo-1H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid, diphenylmethyl ester Dissolve [4S-[4alpha, 7alpha(R), 12bbeta]]-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-3,4,6,7,8,12b-hexahydro-6-oxo-1H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid, diphenylmethyl ester (296 mg, 0.517 mmol) in methanol (5 mL) and treat with hydrazine monohydrate (1.1 mL of a 1M solution in methanol, 1.1 mmol). Stir at room temperature for 44 hours, evaporate the solvent in vacuo and slurry the residue in methylene chloride (10 mL). Filter and evaporate the solvent in vacuo to give the title compound (218 mg, 95%). Scheme A: [4S-[4alpha, 7alpha(R*), 12bbeta]]-7-[(5-Carboxymethyl-5-oxo-cyclopentimidazole)methylamino]-3,4,6,7,8,12b-hexahydro-6oxo-1H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid Dissolve 4,5-imidazoledicarboxylic acid (31.2 g, 0.2 mol) in ethanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60 C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give 4,5-(dicarboethoxy)imidazole.

13
[ 1080-79-1 ]
[ 33457-49-7 ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657
[2]Tetrahedron Letters,1997,vol. 38,p. 8425 - 8428

14
[ 1080-79-1 ]
[ 263159-45-1 ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657
[2]Tetrahedron Letters,1997,vol. 38,p. 8425 - 8428

15
[ 1080-79-1 ]
[ 200552-04-1 ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657
[2]Tetrahedron Letters,1997,vol. 38,p. 8425 - 8428

16
[ 1080-79-1 ]
[ 263159-46-2 ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657
[2]Tetrahedron Letters,1997,vol. 38,p. 8425 - 8428

17
[ 1080-79-1 ]
[ 263159-54-2 ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657
[2]Tetrahedron,2000,vol. 56,p. 645 - 657
[3]Tetrahedron Letters,1997,vol. 38,p. 8425 - 8428

18
[ 1080-79-1 ]
[2-azido-1-methyl-4-([(methylamino)carbonyl]oxy}methyl)-1H-imidazol-5-yl]methyl methyl-carbamate [ No CAS ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657
[2]Tetrahedron Letters,1997,vol. 38,p. 8425 - 8428

19
[ 1080-79-1 ]
[ 263159-44-0 ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657
[2]Tetrahedron Letters,1997,vol. 38,p. 8425 - 8428

20
[ 1080-79-1 ]
di(tert-butyl) 1-methyl-bis([(methylamino)carbonyl]oxy}methyl)-1H-imidazol-2-ylimidodicarbonate [ No CAS ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657
[2]Tetrahedron,2000,vol. 56,p. 645 - 657
[3]Tetrahedron Letters,1997,vol. 38,p. 8425 - 8428

21
[ 1080-79-1 ]
[ 263159-53-1 ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657
[2]Tetrahedron,2000,vol. 56,p. 645 - 657
[3]Tetrahedron Letters,1997,vol. 38,p. 8425 - 8428

22
[ 1080-79-1 ]
tert-butyl 4,5-bis(hydroxymethyl)-1-methyl-1H-imidazol-2-ylcarbamate [ No CAS ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657

23
[ 1080-79-1 ]
[ 263159-48-4 ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657

24
[ 1080-79-1 ]
N-[4,5-bis(hydroxymethyl)-1-methyl-1H-imidazol-2-yl]-N'-methyl-N-tritylurea [ No CAS ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657

25
[ 1080-79-1 ]
[ 263159-51-9 ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657

26
[ 1080-79-1 ]
{4-(hydroxymethyl)-1-methyl-2-[[(methylamino)carbonyl]-(trityl)amino]-1H-imidazol-5-yl}methyl methyl-carbamate [ No CAS ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657

27
[ 1080-79-1 ]
[ 263159-47-3 ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 645 - 657

28
[ 1080-79-1 ]
[ 773099-17-5 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 6575 - 6582

29
[ 1080-79-1 ]
[ 117121-05-8 ]

Reference： [1]Tetrahedron Letters,1997,vol. 38,p. 8425 - 8428

30
[ 1080-79-1 ]
[ 133778-39-9 ]

Reference： [1]Tetrahedron Letters,1997,vol. 38,p. 8425 - 8428

31
[ 1080-79-1 ]
[ 117120-88-4 ]

Reference： [1]Tetrahedron Letters,1997,vol. 38,p. 8425 - 8428

32
[ 1080-79-1 ]
[ 148320-44-9 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1992,vol. 28,p. 1006 - 1008
Khimiya Geterotsiklicheskikh Soedinenii,1992,p. 1193 - 1195

33
[ 1080-79-1 ]
1-benzyl-5,7-diphenyl-4,5,7,8-tetrahydroimidazo<4,5-e><1,3>diazepin-6-one [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,1992,vol. 28,p. 1006 - 1008
Khimiya Geterotsiklicheskikh Soedinenii,1992,p. 1193 - 1195

34
[ 1080-79-1 ]
[ 33457-07-7 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1992,vol. 28,p. 1006 - 1008
Khimiya Geterotsiklicheskikh Soedinenii,1992,p. 1193 - 1195

35
[ 1080-79-1 ]
[ 131727-38-3 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 827 - 841

36
[ 1080-79-1 ]
[ 6293-09-0 ]

Reference： [1]Journal of the American Chemical Society,1956,vol. 78,p. 159,161, 162

37
[ 1080-79-1 ]
1H-imidazole-4,5-dicarboxylic acid bis-(N'-benzenesulfonyl-hydrazide) [ No CAS ]

Reference： [1]Anales de la Real Sociedad Espanola de Fisica y Quimica, Serie B: Quimica,1953,vol. 49,p. 599,601, 602

38
[ 570-22-9 ]
[ 1080-79-1 ]

Yield	Reaction Conditions	Operation in experiment
46%	With sulfuric acid; In ethanol; water;	REFERENCE EXAMPLE 13 4,5-Bis(ethoxycarbonyl)imidazole A mixture of 4.0 g (25.6 mmols) of imidazole-4,5-dicarboxylic acid, 600 ml of ethanol and 16 ml of conc. sulfuric acid was heated under reflux for 7 hours. After cooling to 0 C., the mixture was neutralized with a 2 normal aqueous sodium hydroxide solution. The solvent was evaporated under reduced pressure, and then water was added to the residue followed by extraction of the solution with chloroform. The chloroform layer was washed with an aqueous saturated sodium bicarbonate solution and then with an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dried to afford 2.5 g (yield: 46%) of the title compound. NMR (CDCl3) delta (ppm): 7.83(1H, s), 7.26(1H, s), 4.41 (4H, q, J=7.2 Hz), 1.38(6H, t, J=7.2 Hz)
5.50 g (52%)	In hydrogenchloride; ethanol; dichloromethane;	Example 29 Diethyl imidazole-4,5-dicarboxylate (46) Imidazole-4,5-dicarboxylic acid (7.55 g, 50.0 mmol) is dissolved in absolute ethyl alcohol (120 mL). The solution was cooled in an ice bath to 0 C. and bubbled dry HCl gas for 1 h. Later, the reaction mixture was refluxed at 80 C. for 7 h during which time all the starting material was consumed. The solvent was removed and the residue that obtained was dissolved in dichloromethane (200 mL) and the organic layer was neutralized with triethylamine. The organic layer was washed with cold water (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give 5.50 g (52%) of white solid: mp 175-177 C.; 1 H NMR (CDCl3) delta 1.40 (t, 3H), 4.41 (m, 2H), 7.84 (1H, C2 H) and 11.55 (br s, 1H, NH).
	With sulfuric acid; In ethanol;	Scheme A, step a [4S-[4alpha, 7alpha(R*), 12bbeta]]-7-[(5-(4-methoxybenzylthio)-5-oxo-1-(carbo-t-butyloxy)-4,5-dihydrocyclopentimidazole)methylamino]-3,4,6,7,8,12b-hexahydro-6-oxo-1H-[1,4]-oxazino[3,4-a][2]benzazepine Dissolve 4,5-imidazoledicarboxylic acid (31.2 g, 0.2 mol) in ethanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60 C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give 4,5-(dicarboethoxy)imidazole.

Reference： [1]Patent: US5053408,1991,A
[2]Patent: US6130326,2000,A
[3]Patent: US5420271,1995,A

39
hexamethyldisilazine [ No CAS ]
[ 1080-79-1 ]
1-O-acetyl-2,3,4-tri-O-benzoyl-L-ribofuranose [ No CAS ]
diethyl 1-(2',3',5'-tri-O-benzoyl-β-L-ribofuranosyl)imidazole-4,5-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium sulfate; tin(IV) chloride; In hexane; ethyl acetate; 1,2-dichloro-ethane; toluene;	Example 30 Diethyl 1-(2',3',5'-tri-O-benzoyl-beta-L-ribofuranosyl)imidazole-4,5-dicarboxylate (47) A mixture of <strong>[1080-79-1]diethyl imidazole-4,5-dicarboxylate</strong> (2.65 g, 12.50 mmol) and ammonium sulfate (50 mg) was heated at reflux at 135 C. for 6 h with hexamethyldisilazine (50 mL). The reaction mixture was evaporated to dryness and the residue was co-evaporated twice with dry toluene (2*50 mL) to remove last traces of hexamethyldisilazine. The solid that obtained was dried in vacuo for 6 h and used for the next step without further characterization. To a solution of the above residue (12.5 mmol) in 1,2-dichlorethane (60 mL) was added 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose (5.06 g, 10 mmol) and tin tetrachloride (1.68 mL, 14.16 mmol) at 10 C. The reaction mixture was stirred under the atmosphere of argon at room temperature for 6 h. The reaction was checked by TLC using hexane and ethyl acetate (7:3). TLC indicated no starting material remained. The reaction mixture was diluted with dichloromethane (200 mL). The organic layer was washed with cold sat. sodium bicarbonate (200 mL) and brine (100 mL), dried over sodium sulfate and concentrated to yield a white foam. The residue was dissolved in dichloromethane (100 mL) and filtered through celite to remove tin salts. After evaporation in vacuo the residue (4.70 g) was dissolved in ethanol and filtered again through celite.

Reference： [1]Patent: US6130326,2000,A

40
[ 1080-79-1 ]
[ 58632-95-4 ]
[ 160501-82-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In bis-tetrahydropyran ether; water; ethyl acetate;	Dissolve 4,5-(dicarboethoxy)imidazole (1.06 g, 5 mmol) and triethylamine (1.5 mL, 7.5 mmol) in 50/50 dioxane water (25 mL). Add [2-(tert-butyloxycarbonyloxyimino)-2-phenylacetonitrile](1.36 g, 5.5 mmol) and stir at room temperature for 2 hours. Add water (7.5 mL) and ethyl acetate (10 mL), separate the aqueous phase and wash with ethyl acetate (10 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify the residue by silica gel chromatography to give N-(carbo-t-butyloxy)-4,5-(dicarboethoxy)imidazole.
	With triethylamine; In bis-tetrahydropyran ether; water; ethyl acetate;	Dissolve 4,5-(dicarboethoxy)imidazole (1.06 g, 5 mmol) and triethylamine (1.5 mL, 7.5 mmol) in 50/50 dioxane water (25 mL). Add [2-(tert-butyloxycarbonyloxyimino)-2-phenylacetonitrile](1.36 g, 5.5 mmol) and stir at room temperature for 2 hours. Add water (7.5 mL) and ethyl acetate (10 mL), separate the aqueous phase and wash with ethyl acetate (10 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify the residue by silica gel chromatography to give N-(carbo-t-butyloxy)-4,5-(dicarboethoxy)imidazole.
	With triethylamine; In bis-tetrahydropyran ether; water; ethyl acetate;	Dissolve 4,5-(dicarboethoxy)imidazole (1.06 g, 5 mmol) and triethylamine (1.5 mL, 7.5 mmol) in 50/50 dioxane water (25 mL). Add [2-(tert-butyloxycarbonyloxyimino)-2-phenylacetonitrile](1.36 g, 5.5 mmol) and stir at room temperature for 2 hours. Add water (7.5 mL) and ethyl acetate (10 mL), separate the aqueous phase and wash with ethyl acetate (10 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify the residue by silica gel chromatography to give N-(carbo-t-butyloxy)-4,5-(dicarboethoxy)imidazole.

Reference： [1]Patent: US5420271,1995,A
[2]Patent: US5428158,1995,A
[3]Patent: US5457196,1995,A

41
[ 1080-79-1 ]
[ 58632-95-4 ]
[ 160501-82-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In bis-tetrahydropyran ether; water; ethyl acetate;	Dissolve 4,5-(dicarboethoxy)imidazole (1.06 g, 5 mmol) and triethylamine (1.5 mL, 7.5 mmol) in 50/50 dioxane water (25 mL). Add [2-(tert-butyloxycarbonyloxyimino)-2phenylacetonitrile](1.36 g, 5.5 mmol) and stir at room temperature for 2 hours. Add water (7.5 mL) and ethyl acetate (10 mL), separate the aqueous phase and wash with ethyl acetate (10 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify the residue by silica gel chromatography to give N-(carbo-t-butyloxy)-4,5-(dicarboethoxy)imidazole.

Reference： [1]Patent: US5604221,1997,A

42
[ 1080-79-1 ]
[ 1493-27-2 ]
N-(o-nitrophenyl)imidazole 4,5-dicarboxylic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate; In water; N,N-dimethyl-formamide;	A. N-o-Nitrophenyl<strong>[1080-79-1]imidazole 4,5-dicarboxylic acid diethyl ester</strong> To a solution of o-fluoronitrobenzene (106 g) and <strong>[1080-79-1]imidazole 4,5-dicarboxylic acid diethyl ester</strong> (106 g) in one liter of N,N-dimethyl formamide (DMF) was added anhydrous potassium carbonate (200 g). The reaction mixture was stirred vigorously for at least four hours. After removal of solvent under oil pump vacuum, the residue was treated with water, then extracted with chloroform (300 ml*3). The combined chloroform extracts were washed with water, dried by magnesium sulfate, then concentrated under vacuum to an oil. Upon treatment with ether, the oil was solidified and the product was obtained as a white solid (136 g, 81% yield). Recrystallized from chloroform-hexane, m.p. 93-95 C.

Reference： [1]Patent: US4440929,1984,A

43
monosodium salt of imidazole-4,5-dicarboxylic acid diethyl ester [ No CAS ]
[ 1080-79-1 ]
[ 19064-18-7 ]
[ 124-63-0 ]
1-(2,6-difluorobenzyl)-imidazole-4,5-dicarboxylic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium; triethylamine; In ice-water; ethanol; dichloromethane; ethyl acetate; toluene;	(b) 13.0 g of 2,6-difluorobenzyl alcohol and 8.4 g of methanesulphonyl chloride are dissolved in 90 ml of methylene chloride, and 17.6 ml of triethylamine in 18 ml of methylene chloride are added dropwise while stirring in an ice bath. The rate at which the triethylamine is added is so regulated that the internal temperature does not exceed 10. The whole is stirred for a further 40 minutes in the ice bath and then 90 ml of ice-water are added and the whole is stirred for a further 60 minutes. The organic phase is separated off and dried over magnesium sulphate, and 21 g of the monosodium salt of <strong>[1080-79-1]imidazole-4,5-dicarboxylic acid diethyl ester</strong> (obtainable, for example, by reacting <strong>[1080-79-1]imidazole-4,5-dicarboxylic acid diethyl ester</strong> with 2.53 g of sodium dissolved in 60 ml of ethanol) are added. The whole is stirred for 3 hours at room temperature, washed three times with water, dried over magnesium sulphate, concentrated to dryness by evaporation, dissolved in toluene/ethyl acetate (1:1), filtered over silica gel, again concentrated to dryness by evaporation and recrystallized from ether/petroleum ether. 1-(2,6-difluorobenzyl)-<strong>[1080-79-1]imidazole-4,5-dicarboxylic acid diethyl ester</strong> having a melting point of 68-70 is obtained.

Reference： [1]Patent: US4851424,1989,A

44
1-(2,6-difluorobenzyl)-imidazole-4,5-dicarboxylic acid diethyl ester [ No CAS ]
[ 1080-79-1 ]
1-(o-chlorobenzyl)-imidazole-4,5-dicarboxylic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In Petroleum ether;	and also, starting from 4-methylimidazole-5-carboxylic acid ethyl ester, 1-(2,6-difluorobenzyl)-4-methylimidazole-5-carboxylic acid ethyl ester, m.p. 59-61 (from hexane) and 1-(2,6-difluorobenzyl)-5-methylimidazole-4-carboxylic acid ethyl ester, m.p. 107-108 (from toluene/ether), 1-(o-chlorobenzyl)-4-methylimidazole-5-carboxylic acid ethyl ester, m.p. 74-76, and 1-(o-chlorobenzyl)-5-methylimidazole-4-carboxylic acid ethyl ester, m.p. 100-104; and also, starting from <strong>[1080-79-1]imidazole-4,5-dicarboxylic acid diethyl ester</strong>, 1-(2,6-difluorobenzyl)-<strong>[1080-79-1]imidazole-4,5-dicarboxylic acid diethyl ester</strong>, m.p. 71-73 (from petroleum ether), 1-(o-chlorobenzyl)-<strong>[1080-79-1]imidazole-4,5-dicarboxylic acid diethyl ester</strong>, m.p. 69-70 (from ether/hexane) and 1-(o-methylbenzyl)-<strong>[1080-79-1]imidazole-4,5-dicarboxylic acid diethyl ester</strong> (oil); and also, starting from 2-methyl<strong>[1080-79-1]imidazole-4,5-dicarboxylic acid diethyl ester</strong>, 1-(2,6-difluorobenzyl)-2-methyl<strong>[1080-79-1]imidazole-4,5-dicarboxylic acid diethyl ester</strong>, m.p. 63-64 (from ether/hexane).

Reference： [1]Patent: US4851424,1989,A

45
[ 1080-79-1 ]
[ 102-47-6 ]
[ 68120-00-3 ]

Yield	Reaction Conditions	Operation in experiment
	In N-methyl-acetamide;	Potassium t-butoxide (10.9 g) was added with stirring to a solution of <strong>[1080-79-1]diethyl imidazole-4,5-dicarboxylate</strong> (20 g, described by Jones, J.A.C.S. 74, 1085 (1952)) in dry dimethylformamide (300 ml) at room temperature and the mixture was stirred for 40 minutes. 3,4-Dichlorobenzyl chloride (20.4 g) was added and the mixture was heated at reflux for 11 hours. The cooled reaction mixture was poured into ice-water (500 ml) and extracted with chloroform (2200 ml). The combined extracts were washed with water (3300 ml), dried over magnesium sulphate, filtered and evaporated to dryness. The solid residue was crystallized from methanol (100 ml) to give diethyl 1-(3,4-dichlorobenzyl)imidazole-4,5-dicarboxylate, m.p. 105-107 C., (13 g) as a colourless solid.

Reference： [1]Patent: US4185992,1980,A

46
[ 3080-30-6 ]
[ 1080-79-1 ]
diethyl 1-(2',3',5'-tri-O-benzoyl-β-L-ribofuranosyl)imidazole-4,5-dicarboxylate [ No CAS ]

Reference： [1]Patent: EP1254911,2002,A1 .Location in patent: Example 30

47
[ 87-91-2 ]
[ 1080-79-1 ]

Reference： [1]Patent: EP2298763,2011,A1

48
[ 50-00-0 ]
[ 87-91-2 ]
[ 1080-79-1 ]

Yield	Reaction Conditions	Operation in experiment
60%		(Reference Example 3) Diethyl 1H-imidazole-4,5-dicarboxylate Reference Example 3 was carried out under non-light-shielding conditions. To a solution of L-tartaric acid diethyl ester (2.0 g) in ethyl acetate (34.2 ml), 1,3-dibromo-5,5-dimethylhydantoin (3.3 g) was added, and the reaction solution was stirred at room temperature for 3 hours. To the reaction solution, acetic acid (17 ml) was added, and subsequently 36% aqueous formaldehyde solution (3.45 ml) was added under ice cooling at an internal temperature of 10C or below, followed by addition of ammonium acetate (17.2 g) at an internal temperature of 10C or below. The reaction solution was stirred at room temperature for 30 minutes, followed by stirring at 50C for 3 hours. To the reaction solution, 5N sodium hydroxide was added, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, and dried over magnesium sulfate. Quantitative analysis of the resulting ethyl acetate solution by HPLC showed that the title compound (1.24 g, yield: 60%) was obtained. Condition for HPLC analysis is identical with that for Example 5. From the results of Reference Example 3 and Example 5, it was shown that the production method of the present invention [the method for producing compound (5) from compound (1)] was superior to the reaction indicated in the known Method X in terms of yield even under non-light-shielding conditions.

Reference： [1]Patent: EP2298763,2011,A1 .Location in patent: Page/Page column 31

49
[ 50-00-0 ]
[ 59743-08-7 ]
[ 1080-79-1 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium acetate; In water; acetic acid; ethyl acetate; at 10 - 50℃; for 3.5h;light-shielding conditions;	(Example 5) Diethyl 1H-imidazole-4,5-dicarboxylate (Steps A-1 and A-2) Example 5 was carried out under light-shielding conditions. L-Tartaric acid diethyl ester (2.0 g), acetic acid (20 ml), 1,3-dibromo-5,5-dimethylhydantoin (6.0 g) and 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (30 mg) were mixed, and the reaction solution was stirred at 55C for 3 hours. The reaction solution was concentrated under reduced pressure until its volume became 10 ml to afford a solution of diethyl dioxobutanedioate in acetic acid as a yellow liquid. To the obtained solution of diethyl dioxobutanedioate in acetic acid, ethyl acetate (17 ml) and acetic acid (7 ml) were added. To the reaction solution, 36% aqueous formaldehyde solution (3.45 ml) was added under ice cooling at an internal temperature of 10C or below, followed by addition of ammonium acetate (17.2 g) at an internal temperature of 10C or below. The reaction solution was stirred at room temperature for 30 minutes, followed by stirring at 50C for 3 hours. To the reaction solution, 5N sodium hydroxide was added, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, and dried over magnesium sulfate. Quantitative analysis of the resulting ethyl acetate solution by HPLC showed that the title compound (1.50 g, yield: 73%) was obtained.

Reference： [1]Patent: EP2298763,2011,A1 .Location in patent: Page/Page column 27-28

50
[ 1080-79-1 ]
[ 1398113-03-5 ]
diethyl (R)-1-(2-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)propyl)-1H-imidazole-4,5-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 90℃; for 5h;	DBU (11.3 mL, 76 mmol) was added to a stirred sol. of (4R)-4-(5-bromo-2-fluorophenyl)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid 2,2-dioxide 1,1-dimethylethyl ester [CAS 1398113-03-5] (18.7 g, 45.6 mmol) and diethyl 1H- imidazole-4,5-dicarboxylate (8.06 g, 38.0 mmol) in acetonitrile (190 mL) at rt. The mixture was stirred at 90 C for 5 h. The mixture was diluted with DCM and washed with HCl IN. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in hexane 0/100 to 40/60). The desired fractions were collected and the solvents evaporated in vacuo to yield intermediate 1-1 (21.7 g, 88%).

Reference： [1]Patent: WO2014/198851,2014,A1 .Location in patent: Page/Page column 35; 36
[2]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1159 - 1165

51
[ 1080-79-1 ]
diethyl (R)-1-[2-amino-2-(5-bromo-2-fluorophenyl)propyl]-1H-imidazole-4,5-dicarboxylate hydrochloride [ No CAS ]

Reference： [1]Patent: WO2014/198851,2014,A1

52
[ 1080-79-1 ]
(R)-6-(5-bromo-2-fluorophenyl)-6-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2014/198851,2014,A1

53
[ 1080-79-1 ]
C₁₄H₁₇F₂NO₅S [ No CAS ]
C₂₃H₂₉F₂N₃O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With caesium carbonate; In acetonitrile; at 20 - 60℃; for 24h;	Cesium carbonate (18.65 g, 57.25 mmol) was added to a stirred sol. of intermediate I-26 (10 g, 28.62 mmol) and diethyl 4,5-imidazole-1H-4,5-dicarboxylate (g, 31.49 mmol) in acetonitrile (186 mL) at rt. The mixture was stirred at 60 C for 24 h. The mixture was diluted with DCM and washed with iN HC1 sol. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude product waspurified by flash column chromatography (silica; MeOH in DCM 0/100 to 2/98). The desired fractions were collected and the solvents evaporated in vacuo to yield intermediate 1-27 (10 g, 73%).

Reference： [1]Patent: WO2014/198853,2014,A1 .Location in patent: Page/Page column 58

54
[ 1080-79-1 ]
[ 1398113-03-5 ]
(R)-1-[2-(5-bromo-2-fluorophenyl)-2-tert-butoxycarbonylaminopropyl]-1H-imidazole-4,5-dicarboxylic acid 4-ethyl ester 5-methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20 - 90℃; for 5h;	DBU (11.3 mL, 76 mmol) was added to a stirred sol. of (4R)-4-(5-bromo-2- fluorophenyl)-4-methyl- 1,2,3 -oxathiazolidine-3 -carboxylic acid 2,2-dioxide 1,1 - dimethylethyl ester [CAS 1398113-03-5] (18.7 g, 45.6 mmol) and <strong>[1080-79-1]diethyl 1H-imidazole-4,5-dicarboxylate</strong> (8.06 g, 38.0 mmol) in acetonitrile (190 mL) at rt. The mixture was stirred at 90 C for 5 h. The mixture was diluted with DCM and washed with a iN HC1 sol. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc/hexane 0/100 to 40/60). The desired fractions werecollected and the solvents evaporated in vacuo to yield intermediate 1-1 (21.7 g, 88%).

Reference： [1]Patent: WO2014/198853,2014,A1 .Location in patent: Page/Page column 46; 47

55
[ 1080-79-1 ]
C₁₁H₆N₂O₃ [ No CAS ]

Reference： [1]Patent: WO2016/51181,A1
Patent: ,2016,

56
[ 1080-79-1 ]
[ 88284-48-4 ]
C₁₃H₁₀N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With tetramethylammonium fluoride; In tetrahydrofuran; at 20℃; for 18h;Inert atmosphere; Sealed tube;	Diethyl 1 H-imidazole-4,5-dicarboxylate (1 .00 g, 4.71 mmol) and tetramethylammonium fluoride (1 .10 g, 1 1 .8 mmol) were added to a flask which was sealed and purged with nitrogen. Anhydrous THF (52 ml) was added to the solid mixture followed by 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1 .26 ml_, 5.18 mmol). The reaction was stirred at room temperature for 18 hours. It was subsequently concentred in vacuo and the resulting residue was partitioned with a mixture of DCM (100 ml) and water (100 ml). Organic and aqueous layers were separated and the aqueous layer was further extracted with DCM (100 ml). The combined organic layers were dried through a phase separator and concentrated in vacuo. Crude product was purified by flash column chromatography (80 g, eluted with a 12-100% ethyl acetate in petroleum ether eluent). Fractions containing desired product were concentrated to afford an orange solid characterised as ethyl 4- oxoimidazo[1 ,5-a]indole-3-carboxylate (953 mg, 3.93 mmol, 83% yield). NMR (CDCI3, 400 MHz) delta: 7.91 (s, 1 H), 7.80 (dq, J 7.5, 0.6 Hz, 1 H), 7.62 (td, J 7.8, 1 .3 Hz, 1 H), 7.42-7.35 (m, 2H), 4.48 (q, J 7.2 Hz, 2H), 1 .47 (t, J 7.2 Hz, 3H). LCMS purity >95%, [M+H]+ = 243.0, 1 .32 min (analytical short).

Reference： [1]Patent: WO2016/51181,A1 .Location in patent: Paragraph 00171
Patent: ,2016, .Location in patent: Paragraph 00171

57
[ 1080-79-1 ]
C₉H₁₃N₃O₄ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 68 - 72

58
[ 1080-79-1 ]
C₉H₁₀N₄O₃ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 68 - 72

59
[ 1080-79-1 ]
ethyl 7-bromo-2-methyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-5-carboxylate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 68 - 72

60
[ 1080-79-1 ]
ethyl 7-bromo-2-methyl-4-(pyrrolidin-1-yl)imidazo[5,1-f][1,2,4]triazine-5-carboxylate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 68 - 72

61
[ 1080-79-1 ]
ethyl 7-(1,3-dimethyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-2-methyl-4-(pyrrolidin-1-yl)imidazo[5,1-f][1,2,4]triazine-5-carboxylate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 68 - 72

62
[ 1080-79-1 ]
(7-(1,3-dimethyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-2-methyl-4-(pyrrolidin-1-yl)imidazo[5,1-f][1,2,4]triazin-5-yl)methanol [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 68 - 72

63
[ 1080-79-1 ]
7-(1,3-dimethyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-5-(hydroxymethyl)-2-methylimidazo[5,1-f][1,2,4]triazin-4-(3H)-one [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 68 - 72

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Technical Information

• Acyl Group Substitution • Alcohols Convert Acyl Chlorides into Esters • Alcoholysis of Anhydrides • Amines Convert Esters into Amides • Bouveault-Blanc Reduction • Catalytic Hydrogenation • Claisen Condensations Produce β-Dicarbonyl Compounds • Claisen Condensations Produce β-Dicarbonyl Compounds • Complex Metal Hydride Reductions • Convert Esters into Aldehydes Using a Milder Reducing Agent • Decarboxylation of 3-Ketoacids Yields Ketones • Deprotection of Cbz-Amino Acids • Ester Cleavage • Ester Hydrolysis • Grignard Reagents Transform Esters into Alcohols • Hantzsch Pyridine Synthesis • Ketones Undergo Mixed Claisen Reactions to Form β-Dicarbonyl Compounds • Reactions with Organometallic Reagents • Reduction of an Ester to an Alcohol • Reduction of an Ester to an Aldehyde • Specialized Acylation Reagents-Carbodiimides and Related Reagents • The Cycloaddition of Dienes to Alkenes Gives Cyclohexenes • Transesterification

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Ethyl 5-methyl-1H-imidazole-4-carboxylate

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[ 3304-70-9 ]

Dimethyl 4,5-imidazoledicarboxylate

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[ 35445-32-0 ]

Ethyl 1,4-dimethyl-1H-imidazole-5-carboxylate

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[ 17325-26-7 ]

Methyl 1H-imidazole-5-carboxylate

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Related Parent Nucleus of
[ 1080-79-1 ]

Imidazoles

[ 137159-36-5 ]

Ethyl 5-formyl-1H-imidazole-4-carboxylate

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[ 51605-32-4 ]

Ethyl 5-methyl-1H-imidazole-4-carboxylate

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[ 3304-70-9 ]

Dimethyl 4,5-imidazoledicarboxylate

Similarity: 0.97

[ 35445-32-0 ]

Ethyl 1,4-dimethyl-1H-imidazole-5-carboxylate

Similarity: 0.91

[ 17325-26-7 ]

Methyl 1H-imidazole-5-carboxylate

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 1080-79-1 ] {[proInfo.proName]}

Quality Control of [ 1080-79-1 ]

Related Doc. of [ 1080-79-1 ]

Product Details of [ 1080-79-1 ]

Calculated chemistry of [ 1080-79-1 ] Expand+

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1080-79-1 ]

Application In Synthesis of [ 1080-79-1 ]

[ 1080-79-1 ] Synthesis Path-Upstream 1~8

[ 1080-79-1 ] Synthesis Path-Downstream 1~63

Technical Information

Related Functional Groups of [ 1080-79-1 ]

Esters

Related Parent Nucleus of [ 1080-79-1 ]

Imidazoles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 1080-79-1 ]

Related Parent Nucleus of
[ 1080-79-1 ]